The University of Western Australia

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1 THE INTRODUCTION AND EVALUATION OF UNIVERSAL UMBILICAL CORD BLOOD GAS OR LACTATE ANALYSIS INTO METROPOLITAN AND REGIONAL PRIMARY AND SECONDARY LEVEL MATERNITY UNITS IN WESTERN AUSTRALIA Christopher Ross Harvey White B Med Sci (Hons) A thesis submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy School of Women s and Infants Health Faculty of Medicine and Dentistry The University of Western Australia 21 st December 2012

2 My darling wife Thank you so very much Without your limitless love, support and encouragement none of this would have been at all possible.

3 In memorium James Arnold White You taught me so much, especially that with quiet determination, hard work and persistence anything is possible and truly amazing things can result.

4 ABSTRACT Perinatal hypoxic-ischaemic injuries have significant medical, legal, financial, and social implications for the healthcare sector extending to families and the wider community. Consequences of in-utero exposure to hypoxic-ischaemic insults exist along a continuum ranging from no sequelae to extensive and debilitating long-term conditions including cerebral palsy and perinatal death. Biochemical data provided by umbilical cord blood-gas analysis (UCBGA) is integral to the diagnosis of perinatal hypoxic-ischaemic insults; the absence of umbilical artery metabolic acidaemia effectively excludes the diagnosis of intrapartum asphyxial injury. There is increasing support to perform UCBGA at delivery. In addition to the medicolegal benefits, recent data have demonstrated that the introduction of universal UCBGA into a tertiary maternity unit resulted in reduced rates of metabolic acidaemia and nursery admissions. Despite these potential benefits, there are a number of technical, financial and institutional challenges associated with introduction of this technique into clinical care. This thesis has two components: 1) the evaluation of the methodological challenges of UCBGA in a clinical environment, and 2) a detailed appraisal of the impact of introducing UCBGA into clinical care. The first experimental chapter of this thesis presents a randomised controlled trial evaluating four approaches to minimise the effect of delay on sampling accuracy. If analyses cannot be performed within minutes of delivery, cord blood samples should be stored in syringes at room temperature. This enables analyses to be delayed up to sixty-minutes without any significant changes in ph and base-excess levels. If lactate levels are measured, irrespective of the approach taken to maintain sample accuracy, processing is required within 15 minutes to prevent significant changes. The collection of paired arterial and venous samples from the umbilical cord is challenging; inaccurate sampling has been reported in 5-50% of samples. The second experimental chapter of this thesis evaluated a number of approaches to confirm that valid paired samples were collected. A new simple algorithm was developed that can be universally applied to identify non-physiological UCBGA values. This approach increased the number of valid

5 UCBGA values, provided more data to clinicians for fetuses born in poor condition and did not increase false positive diagnosis of fetal acidosis. The third experimental chapter evaluated clinical and biochemical predictors of hypoxicischaemic encephalopathy (HIE) in 21,182 term neonates. Univariate analyses suggested that clinical markers were superior to biochemical markers as predictors of HIE and multivariable analyses demonstrated that the combination of the level of neonatal resuscitation and cord arterial lactate values were the most effective predictors of moderate-severe HIE. This simple risk assessment tool allows the rapid identification of neonates who might benefit from tertiary care and neuroprotection. The second half of the thesis evaluated the implementation of cord blood-gas or lactate analysis into clinical practice, by investigating: 1) the impact of introducing universal cord blood-gas or lactate measurement into primary and secondary maternity units; 2) the costs and benefits of universal UCBGA; and, 3) the attitudes of medical and midwifery staff to umbilical cord blood-gas and lactate analyses. After education, UCBGA or lactate analysis was introduced into one primary and two secondary level obstetric units. There were no significant changes in mean blood-gas and lactate values; however, there were significant reductions in the proportion of neonates with metabolic acidaemia. These data suggest the benefits of introducing UCBGA into a tertiary centre can be replicated in non-tertiary obstetric centres. This thesis presents the first cost-benefit analysis study of UCBGA and found that universal sampling was more cost efficient than selective UCBGA, with the potential averted costs exceeding the incurred costs when modelled under a wide range of conditions. The final experimental chapter in this thesis evaluated medical and midwifery staff attitudes to the introduction of universal UCBGA. Whilst a small proportion of individuals regard UCBGA as having no place in perinatal care, most considered UCBGA favourably, and supported its use in perinatal care. Most respondents considered benefits of UCBGA included establishing neonatal status at birth, medicolegal situations, and as an audit and teaching tool. Those surveyed indicated that increased workload, insufficient time and medicalisation of birth are potential impediments to universal UCBGA. If a maternity unit is to introduce universal UCBGA, these concerns need to be considered, and addressed in the education and implementation packages.

6 The data in this thesis provide objective evidence that the introduction of universal UCBGA is a cost-effective proposition. Further, the benefits previously described in a tertiary centre extend to non-tertiary level maternity units. The data generated by universal UCBGA, when combined with data measuring the level of neonatal resuscitation, provide an effective predictor of moderate-severe HIE. Together with other published literature, these data support the introduction of umbilical cord blood-gas or lactate analysis to all obstetric units.

7 DECLARATION I, Christopher Ross Harvey White, declare that this thesis is less than 100,000 words in length, exclusive of appendices, tables, references and illustrative matters. Except where due acknowledgement has been made, this thesis comprises original work that I have undertaken. To the best of my knowledge and belief, this thesis contains no material that has been previously written or published by any other person, except where due reference is given in the text. For the work which has been prepared for publication/published permission from all the co-authors has been sought and obtained for inclusion of the work in this thesis. This thesis was completed during the course of enrolment in this degree at The University of Western Australia, Perth, Western Australia, Australia. No part of this thesis has been submitted to any institution for the award of any other degree or diploma. Christopher Ross Harvey White Associate Professor Craig Pennell

8 ACKNOWLEDGEMENTS Throughout the writing of this thesis, and the research and analysis that formed the component papers, so many people have contributed and assisted me in a myriad ways, and to all of them I must extend my sincere appreciation. Whenever you hear stories of people s PhD, they describe gruelling struggles with multitudes of trials and tribulations; devoid of all enjoyment. While there might have been the odd trial and tribulation in this thesis history, thanks to everyone s support and assistance, it has been a wonderful experience that I feel privileged to have undertaken. My darling wife, the fact that you wanted to marry me in the midst of PhD is a mysterious wonder in itself. Thank you so much for putting up with me and my idiosyncrasies over the last couple of years. Without your love, patience, support, and encouragement this PhD would have never happened. You have provided an emotional and intellectual base that has been indispensible throughout various trials and tribulations and the many long nights. Professor Craig Pennell my tireless (quite literally) supervisor, your unfailing good humour and support has proven instrumental in this thesis, particularly in enduring the medicolegalese Churchillian tomes that I managed to produce at times. Thank you too for the opportunity to spend time with you in the clinical setting it has proved invaluable in placing things in context, improving my clinical skills as well as providing a welcome insight into the non-database world. Finally, thank you for all those astute and intellectual Canadian conversations they will forever be a source of inspiration and wonder. I would also like to acknowledge the staff members at King Edward Memorial Hospital and all the other study sites who collected the cord gas and lactate samples, and entered the obstetric and neonatal data into the databases/birth registers for without them this study would not have been possible. Particular thanks to Dr Paul McGurgan, Reyer Knopper, Dr Tom Cottee, Lyndy Giddy, Dr Peter Kell, Dr Peter Reid, Jenny Wrightson, Hazel Inglis and Kate Reynolds you provided an incalculable amount of support and assistance. Thank you to Linda Hemson, and Dr Seonaid Mulroy; you welcomed me into your workplace and families lives with open arms and made me feel at home. A big thank you to all the staff members at The University of Western Australia s School of Women s and Infants Health, it has been a wonderful place to spend the last few years. To

9 all the administration staff at SWIH, thank you so very much for all your support and patience with the real world issues associated with a PhD. Professor John Newnham, thank you for all your encouragement and support as one of my supervisors, and for the ever insightful tea room discussions on all and sundry. Thank you also to Dr Jennifer Henderson who was a supervisor in the early stages of this thesis. To all the staff in the Biostatistics and Research Design Unit at the Women and Infants Research Foundation, a very big thank you for all the assistance, particularly James Humphreys, Dr Dorota Doherty and Jeff Cannon. Dr Doherty, thank you for all your help as a PhD supervisor and your patient explanations of the statistical side of things. Jeff Cannon, without your cost effectiveness expertise and skills the cost benefit analysis would never have happened and your time and effort is greatly appreciated. Dr Simon Towler, thank you very much for your logistic support and the financial support from the West Australian Health Department. Without this support, the introduction of cord blood gas analysis into the metropolitian and regional centres would not have been possible. Thank you to Dr Rolland Kohan for the access and assistance with the KEMH neonatal database, as well as advising me on all things neonatal. Tabitha Mok, thank you for all your help in the recruitment and pilot project stages of the cord stability study. Maureen Hutchinson provided a multitude of advice on all things obstetric database, as well as continuing in her ability to conjure up data extractions seemingly in a manner of minutes. Paul Antoine developed the software that allowed the merger of the obstetric and neonatal databases and formed the framework from which all analysis could be undertaken. Throughout this he retained the patience of a saint despite having to deal with my technological ignorance on a regular basis and a multitude of technical issues. Finally, there is my family who somewhat ironically I have left to last. Ironic given that they often seemed to come out second best, with many late arrivals or non-appearances met with good humour and forgiveness. Katie and Stephie thank you so much for reminding me that there is a world outside umbilical cords and humouring me when I am get overly excited about something no normal person should. Mum and Dad, Janice and Peter what I can say other than thank you so very much for all your love and support, and I promise I will hurry up and get a real job soon (although a Masters might be nice!). Grandma Sheila, Grandpa Tim, Gran, and Grandad thank you for providing that patient interest and motivation to succeed as well as continuing to demonstrate to me that no problem is ever insurmountable.

10 PRESENTATIONS, ARTICLES AND AWARDS ARISING FROM THIS THESIS Presentations WHITE, C.R.H., HENDERSON, J.J., KOHAN, R., DOHERTY, D.A., NEWNHAM, J.P., PENNELL, C.E. Universal umbilical cord sampling is associated with improved perinatal outcome. Published in the Proceedings of the 18 th Annual Western Perinatal Research Meeting, Banff, British Columbia, Canada, February WHITE, C.R.H., MOK, T., HENDERSON, J.J., DOHERTY, D.A., NEWNHAM, J.P., PENNELL, C.E. Stability of umbilical cord blood gas and lactate results over time. Published in the Proceedings of the 18 th Annual Western Perinatal Research Meeting, Banff, British Columbia, Canada, February WHITE, C.R.H. Umbilical cord blood gas and lactate monitoring during labour and delivery and its role in perinatal care. Women & Infants Research Foundation Rising Stars Symposium, Perth, Western Australia, September WHITE, C.R.H., HENDERSON, J.J., KOHAN, R., DOHERTY, D.A., NEWNHAM, J.P., PENNELL, C.E. Use of umbilical cord blood gas values to predict hypoxic-ischaemic encephalopathy. Published in the Proceedings of the 19 th Annual Western Perinatal Research Meeting, Banff, British Columbia, Canada, February WHITE, C.R.H. Early prediction of hypoxic-ischaemic encephalopathy. Royal Australian and New Zealand College of Obstetricians and Gynaecologists Western Australian Regional Scientific Meeting 2011, Busselton, Western Australia, February WHITE, C.R.H. The prediction of hypoxic-ischaemic encephalopathy at delivery. King Edward Memorial Hospital/Princess Margaret Hospital Neonatal Summer Symposium, Perth, Western Australia, March 2011.

11 WHITE, C.R.H. The role of umbilical cord blood gases in predicting hypoxic-ischaemic encephalopathy. National E Health Transition Authority Research Competition, 53 rd Australian Medical Students Association Convention, Perth Western Australia, July, 2012 Published Articles White, C.R.H., D.A. Doherty, et al. (2013). The impact of introducing universal umbilical cord blood gas analysis and lactate measurement at delivery. Aust NZ J Obstet Gynecol In Press (Chapter Six) White, C.R.H., R. Kohan, et al. (2013). Attitudes and barriers to the introduction of umbilical cord blood gas and lactate analysis at birth Aust NZ J Obstet Gynecol 53(3): (Chapter Eight) White, C. R. H., D. A. Doherty, et al. (2012). "Evaluation of selection criteria for validating paired umbilical cord-blood gas samples: an observational study." BJOG 119(7): (Chapter Five) White, C. R. H., D. A. Doherty, et al. (2012). "Accurate prediction of hypoxic-ischaemic encephalopathy at delivery: a cohort study." J Matern Fetal Neonatal Med 25(9): (Chapter Four) White, C.R.H., T. Mok, et al. (2012) "The effect of time, temperature and storage device on umbilical cord blood gas and lactate measurement: a randomized controlled trial." J Matern Fetal Neonatal Med 25(6): (Chapter Three) Published Chapters WHITE, C. R. H. and C. E. PENNELL (2010). Umbilical cord blood gas analysis. The Thirteenth Report of the Perinatal and Infant Mortality Committee of Western Australia for Deaths in the Triennium Perth, Western Australia, Government of Western Australia Department of Health. (Introduction)

12 Awards Western Perinatal Research Meeting Best Applied Science Oral Presentation, 18 th Annual Western Perinatal Research Meeting, Banff, British Columbia, Canada, February Western Perinatal Research Meeting Best Applied Science Poster Presentation, 18 th Annual Western Perinatal Research Meeting, Banff, British Columbia, Canada, February Western Perinatal Research Meeting Best Applied Science Oral Presentation, 19 th Annual Western Perinatal Research Meeting, Banff, British Columbia, Canada, February National E Health Transition Authority Research Competition Third Place, 53 rd Australian Medical Students Association Convention, Perth Western Australia, July, 2012

13 ABBREVIATIONS AAP ABE ACOG ACTH ADH AF AHA ATP AUC BB BD BE BP CBF CCOPMM cgmp CI cm CNS CO 2 CP CPR CSF CV CVS EFM EPI FBS FHR FSE GIT gm H + H 2 O H 2 O 2 - HCO 3 HIE HIV HPA hr IA ICD ICER ICPTF ILCOR IQ IQR IUGR American Academy of Pediatrics Actual base excess American Congress of Obstetricians and Gynecologists Adrenocorticotropic hormone Anti-diuretic hormone Amniotic fluid American Heart Association Adenosine triphosphate Area under the curve Buffer base Base deficit Base excess Blood pressure Cerebral blood flow Consultative Council on Obstetric and Paediatric Mortality and Morbidity Cyclic guanosine-3 :5 -monophosphate Confidence intervals Centimetre Central nervous system Carbon dioxide Cerebral palsy Cardiopulmonary resuscitation Cerebrospinal fluid Coefficient of variation Cardiovascular system Electronic fetal monitoring Estimated predictive interval Fetal blood sampling Fetal heart rate Fetal scalp electrode Gastrointestinal tract Grams Hydrogen ion Water Hydrogen peroxide Bicarbonate ion Hypoxic-ischaemic encephalopathy Human immunodeficiency virus Hypothalamus-pituitary-adrenal Hour Intermittent auscultation International Classification of Disease Incremental Cost-Effectiveness Ratio International Cerebral Palsy Task Force International Liaison Committee on Resuscitation Intelligence quotient Interquartile range Intrauterine growth restriction

14 IV IVH KEMH kpa LGA MAS MCHRC meq min ml mmhg mmol MRI MRS MSAF mths n NAD + NCPP NE NEC NICE NICU NLR nm NO NS O 2 OR pco 2 PMH po 2 PSA QALY RANZCOG RCOG RCT RDS ROC ROM RR SBE SCN SD SGA UCBG UCBGA UI UK USA WTP yrs Intravenous Intraventricular haemorrhage King Edward Memorial Hospital Kilopascal Large for gestational age Meconium aspiration syndrome Maternal and Child Health Research Consortium Milliequivalent Minute Millilitre Millimetres of mercury Millimole Magnetic resonance imaging Magnetic resonance spectroscopy Meconium stained amniotic fluid Months Number Nicotinamide adenine dinucleotide National Collaborative Perinatal Project Neonatal encephalopathy Necrotising enterocolitis National Institute for Clinical Excellence Neonatal intensive care unit Negative likelihood ratio Nanometres Nitric oxide Not significant Oxygen Odds ratio Partial pressure of carbon dioxide Princess Margaret Hospital Partial pressure of oxygen Probabilistic sensitivity analysis Quality Adjusted Life Year Royal Australian and New Zealand College of Obstetricians and Gynaecologists Royal College of Obstetricians and Gynaecologists Randomised control trial Respiratory distress syndrome Receiver Operator Characteristic Curve Rupture of membranes Relative risk Standard base excess Special Care Nursery Standard deviation Small for gestational age Umbilical cord blood gas Umbilical cord blood gas analysis Unit increase United Kingdom United States of America Willingness to Pay Threshold Years

15 TABLE OF CONTENTS ABSTRACT... IV DECLARATION... VII ACKNOWLEDGEMENTS... VIII PRESENTATIONS, ARTICLES AND AWARDS ARISING FROM THIS THESIS... X PRESENTATIONS... X PUBLISHED ARTICLES... XI PUBLISHED CHAPTERS... XI AWARDS... XII ABBREVIATIONS... XIII TABLE OF CONTENTS... XV TABLE OF FIGURES... XIX TABLE OF TABLES... XX LITERATURE REVIEW AND THESIS OUTLINE INTRODUCTION The clinical problem of adverse perinatal outcomes Aims of research Chapter overview ADVERSE OUTCOMES ASSOCIATED WITH LABOUR Adverse outcomes resulting from intrapartum asphyxial insults Fetal acid-base balance Fetal maintenance of acid-base balance... 6 Interpretation of fetal/neonatal acid-base balance values Normal umbilical cord blood gas values Influence of labour on fetal/neonatal blood gas values Influence of gestational age on fetal/neonatal blood gas values Influence of maternal anaesthesia and analgesia on fetal/neonatal blood gas values Other factors influencing fetal/neonatal blood gas values Umbilical cord acidaemia Pathologic fetal acidaemia Respiratory and metabolic acidaemia Mixed respiratory and metabolic acidaemia Birth asphyxia Definition of birth asphyxia Neurological outcomes of perinatal asphyxia Neuropsychological, intellectual, and cognitive outcomes of perinatal asphyxia Multiorgan dysfunction Neonatal encephalopathy Hypoxic-ischaemic encephalopathy Neonatal seizures Cerebral palsy Summary of adverse outcomes resulting from intrapartum asphyxial insults PREDICTORS OF ADVERSE OUTCOMES ASSOCIATED WITH LABOUR Current predictors of adverse outcomes Risk factor assessment Predictive value of risk factor assessment Role of risk factor assessment today Intermittent auscultation Electronic fetal monitoring Limitations and issues associated with electronic fetal monitoring Electronic fetal monitoring versus intermittent auscultation... 61

16 Electronic fetal monitoring today Meconium passage Limitations of meconium passage Predictive value of meconium passage Role of meconium passage today Fetal scalp ph analysis Limitations and issues associated with fetal scalp blood sampling Fetal and neonatal haemorrhage following fetal scalp blood sampling Fetal and neonatal infection following fetal scalp blood sampling Potential conflict between fetal scalp blood sampling and vacuum delivery Delay in delivery for compromised fetuses Additional limitations of fetal scalp blood sampling Correlation of fetal scalp and central blood gas values Role of fetal scalp blood gas sampling Fetal scalp blood gas sampling today Apgar scores Limitations of the Apgar score Predictive value of the Apgar score Short-term neonatal outcome Long-term neonatal outcomes Overall predictive value of the Apgar score Use of the Apgar score today Umbilical cord blood gas analysis Limitations and issues associated with umbilical cord blood gas analysis Sample contamination Remote asphyxial insults Hidden acidosis Vigorous acidaemia Umbilical cord blood banking Delayed umbilical cord clamping Umbilical cord acidaemia and adverse neonatal outcomes Predictive value of umbilical cord blood gas analysis Role of umbilical cord blood gas analysis Universal versus selective umbilical cord blood gas sampling Role of umbilical cord blood gas measurement in early neonatal management Educational role of universal umbilical cord blood gas analysis Other benefits of universal umbilical cord blood gas analysis Umbilical cord blood gas analysis today Assessment of fetal and neonatal lactate levels Lactate physiology Hypoxic lactate production Non-hypoxic lactate production Effect of lactate on tissue Effect on neural tissue Effect on vascular tissue Fetal lactate levels during pregnancy and labour The relationship of lactate with fetal hypoxic-ischaemic brain injury Lactate measurement Traditional lactate measurement Handheld lactate meters Amperometric lactate measurement Reflectometric lactate measurement Amperometric versus reflectometric lactate analysis Factors influencing lactate measurement Sample contamination Haematocrit Temperature Lactate in fetal scalp blood Relationship between scalp and central lactate concentrations Scalp lactate reference ranges Predictive ability of fetal scalp lactate Lactate in neonatal cord blood Predictive ability of umbilical artery lactate values Limitations of umbilical cord lactate analysis Use of lactate today

17 Summary of the current predictors of adverse outcomes THESIS AIM AND OUTLINE AIM STUDIES PERFORMED Umbilical cord blood gas and lactate analysis at delivery: Stability of results over time Prediction of adverse neonatal outcome using umbilical artery blood gas and lactate values Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study The impact of introducing universal umbilical cord blood gas analysis and lactate measurement at delivery Universal umbilical cord blood analysis: Is it worth the hassle? Attitudes and barriers to universal umbilical cord blood gas and lactate analysis THE EFFECT OF TIME, TEMPERATURE AND STORAGE DEVICE ON UMBILICAL CORD BLOOD GAS AND LACTATE MEASUREMENT: A RANDOMIZED CONTROLLED TRIAL INTRODUCTION MATERIALS AND METHODS Cord collection technique Serial clamping technique Statistical analysis RESULTS DISCUSSION Effect of storage device Effect of temperature Umbilical lactate values Combined effect of temperature and storage device CONCLUSION ACCURATE PREDICTION OF HYPOXIC-ISCHAEMIC ENCEPHALOPATHY AT DELIVERY: A COHORT STUDY INTRODUCTION Chapter aim MATERIALS AND METHODS Statistical methods RESULTS Univariate ROC analysis Multivariable ROC analysis Multivariable prediction of the probability of moderate-severe HIE DISCUSSION CONCLUSION EVALUATION OF SELECTION CRITERIA FOR VALIDATING PAIRED UMBILICAL CORD BLOOD GAS SAMPLES: AN OBSERVATIONAL STUDY INTRODUCTION Study aims METHODS RESULTS DISCUSSION CONCLUSIONS THE IMPACT OF INTRODUCING UNIVERSAL UMBILICAL CORD BLOOD GAS ANALYSIS AND LACTATE MEASUREMENT AT DELIVERY INTRODUCTION METHODS Statistical analysis RESULTS Umbilical cord blood lactate analysis Umbilical cord blood gas analysis

18 6.3.3 One, five and ten minute Apgar scores DISCUSSION CONCLUSION UNIVERSAL UMBILICAL CORD BLOOD ANALYSIS: IS IT WORTH THE HASSLE? BACKGROUND METHODS Study Design Study Population Model structure Probabilities Costs and utilities Health outcomes Cost-effectiveness analysis Sensitivity Analysis RESULTS DISCUSSION CONCLUSION ATTITUDES AND BARRIERS TO UNIVERSAL UMBILICAL CORD BLOOD GAS AND LACTATE ANALYSIS INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS WHERE TO FROM HERE? THE FUTURE OF UNIVERSAL UMBILICAL CORD BLOOD GAS AND LACTATE ANALYSIS ON NEONATES AT DELIVERY: THESIS DISCUSSION AND CONCLUSION REASONS TO INTRODUCE UNIVERSAL UMBILICAL CORD BLOOD GAS ANALYSIS OBSTACLES TO INTRODUCING UNIVERSAL UMBILICAL CORD BLOOD GAS ANALYSIS UMBILICAL CORD BLOOD GAS ANALYSIS VERSUS UMBILICAL CORD BLOOD LACTATE ANALYSIS OTHER BIOCHEMICAL AND BIOLOGICAL MARKERS OF PERINATAL ASPHYXIAL INJURY Molecular predictors of hypoxia FUTURE RESEARCH CONCLUSION APPENDICES APPENDIX A: OUTCOME OF NEONATES EXPOSED TO PERINATAL ASPHYXIAL INJURY APPENDIX B: INCIDENCE/PREVALENCE OF PERINATAL ASPHYXIA APPENDIX C: INCIDENCE/PREVALENCE OF PERINATAL ASPHYXIA RELATED MORTALITY APPENDIX D: INCIDENCE/PREVALENCE OF NEONATAL ENCEPHALOPATHY, AND HYPOXIC-ISCHAEMIC ENCEPHALOPATHY APPENDIX E: INCIDENCE/PREVALENCE OF CEREBRAL PALSY APPENDIX F: ELECTRONIC FETAL MONITORING VERSUS INTERMITTENT AUSCULTATION Rotunda Hospital Randomised Controlled Trial Electronic fetal monitoring versus intermittent auscultation summary APPENDIX G: PROGNOSIS AND AETIOLOGICAL BACKGROUND OF VIGOROUS NEONATES WITH ACIDAEMIA Prognosis of vigorous neonates with acidaemia Aetiological background of vigorous neonates with acidaemia BIBLIOGRAPHY

19 TABLE OF FIGURES Figure 1.1. Aerobic cellular metabolism with carbonic acid formation and dissociation... 5 Figure 1.2. Effect of duration of second stage aspects on umbilical artery ph values... 9 Figure 1.3. Distribution of the various directions of the ph change following delivery Figure 1.4. Application of 2003 ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy acute intrapartum asphyxial hypoxic event criteria Figure 1.5. Relationship between perinatal asphyxia and cerebral palsy in a cohort of singleton live births Figure 1.6. Relationship between neonatal encephalopathy and cerebral palsy Figure 1.7. Swedish 1985 birth cohort and neonatal encephalopathy outcome at years old Figure 1.8. Appropriate utilisation of fetal scalp blood sampling in a tertiary centre Figure 1.9. Relationship between ten-minute Apgar scores and neonatal morbidity and mortality Figure Neonatal biochemical and other outcomes in neonates delivered at Northwestern Memorial Hospital, WI, USA Figure Action of positive and negative biochemical reinforcement on clinical behaviour117 Figure Aerobic and anaerobic metabolism Figure Potential mechanism of action of lactate in causing relaxation of placental vessels131 Figure Lactate Pro amperometric method of blood lactate analysis Figure Reflectometric method of blood lactate analysis Figure Accusport TM reflectometric method of blood lactate analysis Figure 3.1. Change in arterial and venous ph, base excess and lactate values by experimental group Figure 3.2. Change in arterial and venous po 2, pco 2 and bicarbonate values by experimental group Figure 5.1. Application of the Westgate et al., Modified Westgate et al.., Kro et al., and King Edward Memorial Hospital criteria Figure 6.1. Change in proportion of neonates with umbilical artery ph, base excess and lactate values outside the normal range Figure 7.1. Decision tree model for neonatal nursery admissions with and without universal umbilical cord blood gas analysis Figure 7.2. Modelled proportions of SCN admissions under selective and universal CBGA strategies (with 99% confidence interval) Figure 7.3. Threshold rate of averted SCN admissions where universal UCBGA strategy becomes dominant (incremental cost <0 when averted admissions is 0.653%) compared to any rate of SCN admissions under selective UCBGA strategy Figure 7.4. Scatter plots of incremental universal UCBGA costs against effects Figure 7.5. Cost-effectiveness acceptability curves Figure 8.1. Potential benefits of umbilical cord blood gas/lactate analysis Figure 8.2. Potential barriers to umbilical cord blood gas/lactate analysis

20 TABLE OF TABLES Table 1.1. Adverse neonatal outcomes... 4 Table 1.2. Daily acid production in the adult human... 4 Table 1.3. Normal umbilical artery and vein blood gas values... 8 Table 1.4. Correlation between umbilical cord blood gas values and the duration of various aspects of the second stage of labour... 9 Table 1.5. Change in umbilical arterial and venous blood gas values with increasing gestation 10 Table 1.6. Additional factors noted to potential influence fetal/neonatal acid base status Table 1.7. Relationship of umbilical artery acidaemia and acidaemia type with early neurological, renal, cardiac and pulmonary impairments Table 1.8. International Cerebral Palsy Task Force criteria for an acute intrapartum hypoxic event Table 1.9. Factors potentially associated with neurological injury originating outside the intrapartum period Table Application of International Cerebral Palsy Task Force definition of an acute intrapartum hypoxic event Table ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy acute intrapartum asphyxial hypoxic event criteria Table Application of ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy acute intrapartum asphyxial hypoxic event criteria Table Perlman definition of intrapartum asphyxial event Table Effects of intrapartum asphyxia on various organ systems Table Neonates with perinatal asphyxia and evidence of organ system dysfunction Table Grading of hypoxic-ischaemic encephalopathy Table Relationship between neonatal encephalopathy grade and neonatal outcome at months of age Table Types of neurodevelopmental disorders experienced by the handicapped survivors Table Influence of the grade of hypoxic-ischaemic encephalopathy on neurodevelopmental status at three and a half years old Table Comparison of psychoeducation scores at eight years of age between encephalopathy grade and peers Table Selection of aetiological factors implicated in neonatal seizures Table Differences in intrapartum and neonatal outcomes between intermittent intrapartum fetal monitoring methods Table Comparison of perinatal outcomes between those exposed and not exposed to meconium Table Change in mean fetal scalp blood and tissue ph values over the peripartum Table Fetal blood sampling s impact on maternal and neonatal outcome Table Correlation between fetal scalp ph values and one and five minute Apgar scores. 74 Table The Apgar score Table One-minute Apgar score as a predictor of neonatal encephalopathy Table Correlation between Apgar scores and umbilical artery ph values Table Relationship between one-minute Apgar scores and neonatal mortality Table Prevalence and relative risk of neonatal death for five minute Apgar scores in term and preterm neonates Table Predictive value of one and five minute Apgar scores for neonatal mortality Table Meta-analysis of the association between Apgar scores and neonatal mortality Table Predictive value of one and five minute Apgar scores for cerebral palsy... 85

21 Table Neurological condition at two to five years of severe perinatal asphyxia survivors 86 Table Sensitivity and specificity of Apgar scores in predicting adverse outcomes at one to five years of age Table Relative risk of mortality and morbidity according to the five minute Apgar score87 Table Odds of cerebral palsy diagnosis by five years of age based on five minute Apgar score Table Meta-analysis of the association between Apgar scores and cerebral palsy and neonatal mortality Table Relationship between one and five minute Apgar scores and cerebral palsy in a Turkish population Table Predictive ability of low one and five minute Apgar scores of poor IQ scores at 17 years of age Table Distribution of neurological disability and IQ by five minute Apgar score Table Relationship between five minute Apgar score and education at a specialised institution Table Estimates of the proportion of neonates with low five minute Apgar scores without neurodevelopmental abnormalities Table Relationship between umbilical arterial, venous and mixed cord blood gas values 95 Table Impact of delayed umbilical cord clamping on umbilical cord blood gas values Table Meta-analysis of the relationship between umbilical artery ph values and cerebral palsy and neonatal mortality Table Relationship between early neonatal complications and umbilical artery ph value101 Table Relationship between umbilical artery ph values and encephalopathy, seizures and nursery admissions Table Umbilical artery blood gas values in neonates developing complications Table Incidence of neurosensory impairments in surviving 500 to 1000 gm infants by umbilical ph Table Umbilical artery ph and base excess values amongst neonates exposed to acute asphyxia like insults Table Relationship between adverse neonatal neurological condition and arterial ph and base excess values Table Ability of umbilical artery ph values to predict low one-minute Apgar scores Table Ability of umbilical artery blood gas and lactate values to predict five minute Apgar scores less than seven and less than five Table Ability of umbilical artery ph, umbilical artery lactate, and five minute Apgar scores to predict adverse outcome at one year of age Table Predictive ability of umbilical artery ph values Table Predictive ability of umbilical artery base excess values Table Factors affecting the utilisation of umbilical cord blood gas analysis in a selective model Table Normal ranges for scalp lactate in first stage of labour Table Area under ROC curves for scalp blood lactate concentration and ph value in patient samples obtained at the same sampling event Table Correlation between scalp ph and scalp lactate values and umbilical cord blood gas values Table Normal reference ranges for umbilical artery lactate values after labour Table 3.1. Baseline mean (standard deviation) umbilical arterial and venous blood gas and lactate values Table 3.2. Generalised estimating equation change over time for umbilical artery and venous values by experimental group Table 3.3. Prediction of baseline umbilical blood gas and lactate values following thirty or sixty minute delays Table 4.1. Definitions of the various levels of neonatal resuscitation

22 Table 4.2. Criteria for the diagnosis of mild, moderate, and severe hypoxic-ischaemic encephalopathy Table 4.3. Maternal, obstetric, intrapartum and neonatal characteristics, n (%) Table 4.4. Sensitivity, specificity, and AUC of univariate predictors of neonatal outcome Table 4.5. Sensitivity, specificity, and AUC of multivariate predictors of neonatal outcome Table 4.6. Probability equations for multivariate models Table 4.7. Percentage risk of moderate-severe hypoxic-ischaemic encephalopathy based on level of neonatal resuscitation and umbilical artery lactate values Table 5.1. Definitions of various cord blood gas validation criteria Table 5.2. Maternal, obstetric, intrapartum and neonatal characteristics for King Edward Memorial Hospital cohort Table 5.3. Cord blood gas values for clinical outcomes stratified by selection criteria Table 5.4. Proportion of neonates with adverse outcomes stratified by selection criteria Table 5.5. Neonates with normal and abnormal blood gas values stratified by selection criteria and clinical outcome Table 6.1. Demographic and intrapartum characteristics at cord blood gas analysis sites Table 6.2. Unadjusted and adjusted mean umbilical artery blood gas and lactate values Table 6.3. Unadjusted and adjusted logistic regression of umbilical artery biochemical outcomes following introduction of universal umbilical cord blood gas or lactate analysis Table 7.1. Change in demographic, intrapartum, and neonatal characteristics over the study period Table 7.2. Change in neonatal nursery and intensive care unit admissions over the study period stratified by gestation and birth weight Table 7.3. Observed and modelled (first four years) number and proportion of all neonates admitted to the NICU and term neonates with birth weight greater 2499 grams admitted to the SCN under the universal UCBGA strategy Table 7.4. Base case assumptions of fixed and variable costs Table 7.5. Parameter distributions used during probabilistic sensitivity analysis in the costeffectiveness SCN admission of term neonates with BW >2499 grams Table 7.6. Cumulative cost and effects under base case selective and universal cord blood gas screening strategies Table 7.7. Percent of simulations expected to be cost-effective during PSA with 50,000 sets of probability distribution samples drawn for each year Table 8.1. Population demographics Table 8.2. Attitudes towards the benefits of umbilical cord blood gas/lactate analysis Table 8.3. Perceived barriers and impediments to the introduction of universal umbilical cord blood gas/lactate analysis Table 9.1. Potential biochemical markers of intrapartum fetal hypoxia Table F.1. Comparison of mortality and neonatal morbidity by gestational ages between those monitored with and without EFM Table F.2. Comparison of intermittent auscultation and continuous electronic fetal monitoring associated outcomes Table F.3. Comparison of intermittent auscultation and continuous electronic fetal monitoring associated outcomes in high and low risk populations Table G.1 Umbilical cord blood gas values amongst vigorous and non-vigorous acidaemic neonates

23 Chapter One LITERATURE REVIEW AND THESIS OUTLINE 1.1 Introduction The clinical problem of adverse perinatal outcomes Throughout the world the primary causes of neonatal mortality are premature birth, infection, congenital malformations, and birth asphyxia. 1 Each year, it has been estimated there are four to nine million fetuses exposed to intrapartum asphyxial injuries, which are responsible for 24-61% of all perinatal mortality. Annually, approximately one million neonates die as a result of intrapartum asphyxial injury and an additional one million fetuses are stillborn. 2-8 Furthermore, intrapartum asphyxial injury can produce major neurodevelopmental disorders in the survivors that have widespread medical, legal, financial and social ramifications to both the medical and wider communities. While congenital malformations and preterm birth are be considered by the public at large as unavoidable consequences of pregnancy, birth asphyxia tends to be instinctively associated with an implied lack of medical and/or midwifery competence and skill. That being so, the majority of asphyxial deaths occur in developing countries, usually at home with neonates dying unnamed and unrecorded suggesting a perceived inevitability of these deaths. 2,4-5,9 In contrast, the small proportion of asphyxia related deaths that occur in developed nations are subject to multiple inquiries and public censure if there is any suspicion of substandard medical facilities and services. 10 Intrapartum asphyxial injury generates intense media and public interest; however, it receives considerably less attention in health policy and research funding; despite it being responsible for more childhood morbidity and mortality than malaria and measles combined. 3,11 Litigation as a result of adverse perinatal outcomes impacts upon the provision and practice of medical care, and is becoming increasingly expensive. 10,12-17 Obstetricians account for only 2% of all Australian physicians; but are associated with a significant proportion of all medical indemnity claims, 18 with a similar situation in the United Kingdom (UK) In line with other countries, the proportion of all Australian indemnity claims that relate to obstetric practice is rising; the median award is AU$2.3 million with some awards reaching AU$15 1 P a g e

24 million. 10,21-22 Due to the size of awards, medical defence organisations and insurance companies are becoming less able to insure obstetricians at realistic premiums, with premiums in some parts of Australia being as high as AU$200,000 annually. 10 In addition to medico-legal costs, there are financial implications for the provision of medical and allied health as well as other support services. Much harder to quantify are the non-economic costs of birth asphyxia to children and families as well as demands on diagnostic, therapeutic, technical and social facilities in the community. 23 A greater understanding of adverse outcomes associated with labour is important, not only due to the number of deaths and long-term neurodevelopmental disabilities that arise but also the widespread medical, legal, financial, and social implications. The need therefore exists for a simple, inexpensive technique for predicting (and possibly preventing) adverse intrapartum outcomes associated with asphyxial injury Aims of research Traditional measures of neonatal condition at birth, five-minute Apgar scores and meconium stained amniotic fluid (MSAF) are poor predictors of important adverse outcomes of intrapartum asphyxia. It is widely accepted that umbilical cord blood acid-base status at delivery is a sensitive reflection of birth asphyxia, with the absence of acidaemia effectively excluding birth asphyxia as a potential diagnosis Further, there is a growing body of evidence that umbilical lactate analysis may be a valid, cheaper and more practical alternative to umbilical cord blood gas analysis (UCBGA) Despite this body of evidence, there have been no studies to date evaluating the introduction of umbilical cord lactate analysis into a maternity unit, and no studies outside a tertiary unit of universal UCBGA s introduction. The aim of the research presented in this thesis is to evaluate the impact of introducing a universal umbilical cord blood gas and/or lactate sampling program into a number of metropolitan and regional maternity units over a two-year period. Further, a variety of additional factors associated with the introduction of universal UCBGA into a maternity unit have been evaluated, including the predictive ability of umbilical cord blood gas and lactate values, methods to minimise pre-analytical errors in cord blood gas and lactate analysis, and the attitudes of medical and midwifery staff members towards cord blood gas and lactate analysis. Finally, the first extensive economic evaluation of costs and benefits of universal UCBGA has been conducted. 2 P a g e

25 1.1.3 Chapter overview This chapter provides an overview of adverse outcomes resulting from intrapartum asphyxial insults including metabolic acidaemia, hypoxic-ischaemic encephalopathy (HIE), and cerebral palsy (CP). Additionally, current predictors of neonatal outcome will be discussed, with particular emphasis on the strengths and limitations of current predictors of intrapartum asphyxial injury. 1.2 Adverse outcomes associated with labour Adverse outcomes resulting from intrapartum asphyxial insults A number of adverse outcomes apart from perinatal mortality result from intrapartum asphyxial insults (Table 1.1) (Appendix A). Some are apparent at the time of birth, whilst others become evident during the early neonatal period, or may take years to manifest. Adverse outcomes related to labour can be divided into three categories based on timing; poor condition at birth, early neonatal issues, and long-term issues. Poor neonatal condition at birth is clinically recognised by the need for resuscitation, nursery admission, and neonatal intensive care unit (NICU) admission. Apgar scores traditionally assess neonatal condition at birth; however, it can also be assessed biochemically by measuring acid-base balance in umbilical cord or early neonatal blood samples. Early neonatal consequences of intrapartum adverse events include respiratory and cardiovascular issues, coagulopathies, neonatal encephalopathy (NE), HIE and seizures. Long-term consequences include CP, educational delay and other neurodevelopmental disabilities Fetal acid-base balance Normal fetal metabolism results in constant production of acid; however, buffering maintains extracellular and thus intracellular ph within a narrow range. Endogenous hydrogen ion (H + ) production due to metabolic processes has three major sources: 1) carbohydrate and lipid oxidation producing organic acids; 2) oxidation of amino-acids that contain sulphur; and 3) hydrolysis and oxidation of phosphoprotein residues. The acidic metabolites can be divided into two major categories: 1) volatile acids, namely carbonic acid; and 2) non-volatile acids, which include weak and strong inorganic acids. Volatile acids constitute most of the daily acid production (Table 1.2.). 3 P a g e

26 Table 1.1. Adverse neonatal outcomes Adverse Outcome Prevalence Reference Perinatal mortality Nguyen et al. 2008; 30 Douglas Intrapartum hypoxic-ischaemic associated perinatal mortality Cerebral palsy Cerebral palsy due to intrapartum hypoxic-ischaemic insult Wu et al., 2004; 32 Douglas Hypoxic-ischaemic encephalopathy Neonatal encephalopathy Neonatal seizures Badwai et al., 2005; 33 Reid et al., 2006; 34 Rankin et al Yudkin et al. 1995; 36 Nelson et al., Smith et al., 2000; 38 Milsom et al., 2002; 39 Allwood et al., 2003; 40 Pierrat et al., Badwai et al. 1997; 42 Badwai et al., 1998; 43 Badwai et al., 1998; 44 Pierrat et al Cowan et al. 2002; 45 Cowan et al., Severe metabolic acidosis * 5.3 White et al., Note: per 1,000 live births; stillbirths, and neonatal deaths (within 28 days) per 1000 total births excluding pregnancy terminations; and, * umbilical artery ph<7.00 and base excess>-12 mmol/l. Table 1.2. Daily acid production in the adult human Category Volatile Acids Non- Volatile Acids Daily Production (mmol/day) Total Production Percentage Acid Source 15-30, Carbonic acid Carbohydrate, lipid & protein metabolism Strong inorganic acids Sulphuric acid Phosphoric acid Weak organic acids Lactic acid Ketoacids Adapted from Siggaard-Andersen, Uric acid Protein Phosphoprotein Phospholipid Incomplete carbohydrate & lipid oxidation. Protein Nucleic acid During normal cellular metabolism, in the presence of oxygen (O 2 ), glucose is broken down into carbon dioxide (CO 2 ) and water (H 2 O). Carbonic acid is generated by CO 2 hydration 4 P a g e

27 catalysed by carbonic anhydrase. Carbonic acid then dissociates into its conjugate base bicarbonate (HCO 3- ) and hydrogen ions (H + ) (Figure 1.1.). The reverse process allows H + removal from metabolic sites to the placenta where CO 2 as the anhydride of carbonic acid is transferred into maternal circulation. This is an efficient and rapid process as carbonic acid is only found in very low concentrations in the blood, hence the term volatile acid due to its prompt removal from fetal circulation. In the fetus, CO 2 elimination is directly proportional to maternal and fetal placental perfusion. 49 Figure 1.1. Aerobic cellular metabolism with carbonic acid formation and dissociation C 6 H 12 O 6 + 6O 2 6CO 2 + 6H 2 O 6H 2 CO 3 6H + + 6HCO 3 - Carbohydrates (C 6 H 12 O 6 ) are broken down in the presence of oxygen (O 2 ) to form carbon dioxide (CO 2 ) and water (H 2 O). Hydration of CO 2 catalysed by carbonic anhydrase produces carbonic acid (H 2 CO 3 ). Carbonic acid dissociates to produce free hydrogen ions (H + ) and the conjugate base bicarbonate (HCO - 3 ). Non-carbonic (non-volatile) acids are produced by incomplete carbohydrate and fatty acid breakdown resulting in lactic and ketoacids. Non-sulphur containing amino acids can be utilised with resulting uric acid formation. Strong inorganic acids, such as sulphuric acid and phosphoric acid, can also be produced by protein, phosphoprotein and phospholipid breakdown; however, they only exist in small amounts with weak organic acids forming the majority of non-volatile acids. Of the non-carbonic acids, the majority either diffuse slowly across the placenta or require transport via membrane bound transporters, which considerably slows transplacental movement Different placental transport mechanisms are important, as an acidaemia composed predominantly of non-volatile acids will take longer to equilibrate over the placenta. 49 Normally, fetal metabolism is an aerobic process with glucose converted to CO 2 and H 2 O via the glycolytic pathway and citric acid cycle. The healthy fetus is able, to an extent, compensate for hypoxaemia (decreased oxygen partial pressure [po 2 ] or O 2 content); however, when fetal defence mechanisms are no longer functioning, tissue hypoxia occurs. In hypoxic circumstances, anaerobic metabolism transpires to maintain energy production and cellular and organ function. Anaerobic metabolism is less effective in adenosine 5 P a g e

28 triphosphate (ATP) production and produces potentially harmful metabolites, such as lactate and H Fetal maintenance of acid-base balance Fetal acid-base regulation differs from the adult process. In adults, gas exchange occurs via the lungs, which are in series with tissues. In the fetus, the placenta is in a parallel circulation loop with the tissues. Consequently, only half of fetal blood passes through the placenta every fetal circulation. 54 Fetal blood ph maintenance is limited depending on functional development and maternal conditions, with the primary regulation organ being the placenta; acting as the respiratory organ to regulate CO 2. Diffusion takes place down the concentration gradient from fetal to maternal circulation, with CO 2 partial pressure (pco 2 ) in maternal circulation decreasing during pregnancy due to maternal respiration changes. Placental O 2 and CO 2 diffusion over the placenta is rapid allowing respiratory compensation to occur quickly and effectively; however, the process works in both directions, which can result in maternal acid-base abnormalities affecting the fetus. The adult model of acid-base physiology assumes renal function with fixed acid elimination; however, fetal renal function is not sufficiently developed to handle excretion of non-carbonic acids. Further, while fetal kidneys have the capability to excrete H +, this ability may be compromised during acidosis. 55 Consequently, non-carbonic acids either diffuse slowly across the placenta (e.g. beta-hydroxybutyric acid and uric acid) or are actively transported (e.g. lactate), after which they are excreted by the maternal kidney in exchange for reabsorbing HCO Consequently, various factors can influence fetal acid-base balance with fetal O 2 supply dependent on adequate maternal oxygenation, placental blood flow, placental transfer, fetal circulation, and fetal tissue delivery. Carbon dioxide removal is dependent upon fetal blood flow to the placenta, placental transport, uptake by maternal haemoglobin and removal from maternal circulation. Disruption of any step in this pathway can produce fetal asphyxial injury. Respiratory factors affecting fetal acid-base balance can be grouped into two main categories; those causing decreased placental and/or umbilical cord perfusion and those impairing maternal alveolar function. Perfusion related factors include umbilical cord compression, uterine hyperstimulation and placental abruption, while alveolar function related factors include analgesia, anaesthesia, hypokalaemia, myasthenia gravis, magnesium sulphate, chronic obstructive pulmonary disease, asthma and infections. 6 P a g e

29 Metabolic factors potentially affecting fetal acid-base balance can be maternal or fetal in origin, and usually imply chronic metabolic derangement. Most metabolic factors can be grouped into several categories, namely: 1) chronic uteroplacental hypoperfusion leading to - anaerobic metabolism; 2) reduction in acid excretion; 3) increased HCO 3 loss; and 4) prolonged respiratory acidaemia. Chronic uteroplacental hypoperfusion, such as that seen clinically in intrauterine growth restriction (IUGR), can result in fetal metabolic acidaemia, through decreased O 2 delivery causing a shift to anaerobic metabolism. Reduction in - maternal acid excretion may be due to ketoacidosis or renal failure, while increased HCO 3 loss might follow renal tubular acidosis, hyperparathyroidism or diarrhoea Interpretation of fetal/neonatal acid-base balance values Acid-base values in various tissues, such as fetal brain, need to be established to obtain an accurate understanding of fetal status. Conditions in fetal tissues are best approximated by measurements obtained from blood draining from the tissues. Mixed venous return from capillaries draining fetal organs collects in the umbilical artery; therefore, umbilical artery blood provides the best insight into fetal tissue oxygenation and acid-base balance. Furthermore, blood is readily able to be collected from the umbilical cord soon after delivery without adverse neonatal effects. Umbilical artery blood gas analysis displays biochemical data from fetal metabolism, conversely umbilical venous blood gas analysis shows the equivalent for uteroplacental metabolism Normal umbilical cord blood gas values There is a variety of normal reference ranges for neonatal acid-base balance values based on samples of 100 to over 17,000 neonates (Table 1.3.). The variation in these reference ranges is partially due to diverse inclusion and exclusion criteria in these studies. Before labour the fetus typically has an umbilical artery ph of 7.37 and an umbilical venous ph of 7.41, 56 which decreases to 7.24 and 7.30 after delivery Influence of labour on fetal/neonatal blood gas values Labour itself is associated with development of a mild maternal mixed respiratory and metabolic acidaemia Correlations have been demonstrated between length of aspects of the second stage of labour and umbilical ph and BE values (Table 1.4.), as well as umbilical venous pco 2 values. 62 Change in ph and BE values have been found to be directly proportional to the length of each aspect of the second stage, with the gradient increasing as the second stage progressed (Figure 1.2.) P a g e

30 Table 1.3. Normal umbilical artery and vein blood gas values Reference Umbilical Artery Umbilical Vein ph po 2 pco 2 Base Excess ph po 2 pco 2 Base Excess Yeomans et al., ( ) 7.28 (0.05) 18.0 (6.0) 49.2 (8.4) 7.35 (0.05) 29.0 (7.0) 38.2 (5.6) Ramin et al., ( ) 7.28 (0.07) 49.9 (14.2) -3.6 (2.8) Riley & Johnson, ( ) 7.27 (0.07) 50.3 (11.1) -2.7 (2.8) 7.34 (0.06) 40.7 (7.9) -2.4 (2.0) Thorp et al., (*) 7.24 (0.07) 17.9 (6.9) 56.3 (8.6) -3.6 (2.7) 7.32 (0.06) 28.7 (7.3) 43.8 (6.7) -2.9 (2.4) Sykes et al., (α) 7.20 (0.08) -8.3 (4) Eskes et al., (α) 7.23 (0.07) (4.0) 7.23 (0.07) -6.0 (3.0) Ruth & Raivio, (α) 7.29 (0.07) -4.7 (4) Low et al., (α) 7.26 (0.07) 15.1 (4.9) 54.9 (9.9) Huisjes et al., (β) 7.20 (0.09) 7.29 (0.08) Arikan et al., (β) 7.24 (0.08) -4.8 (2.9) 7.33 (0.07) -3.9 (2.3) Gjerris et al., (β) 7.27 (0.10) (3.15) Westgren et al., (γ) 7.27 (0.09) 25 (14) 46 (13) (3.92) Victory et al., (γ) 7.24 (0.07) -5.6 (3.3) 7.33 (0.06) -4.5 (2.4) Ramanah et al (γ) 7.25 (0.08) (3.22) Miller et al., (δ) 7.27 (0.06) 15.6 (5.7) 56.0 (7.6) -3.3 (2.8) 7.35 (0.05) 27.9 (7.7) 42.5 (5.9) -2.5 (2.2) Helwig et al., (δ) 7.26 (0.07) 17.0 (6.0) 53.0 (10.0) -4.0 (3.0) 7.34 (0.06) 29.0 (7.0) 41.0 (7.0) -3.0 (3.0) Note: 1) Mean (SD); 2) po 2 and pco 2 in mmhg and base excess in mmol/l; 3) Blank spaces signify data not available; 4) Cohorts included: selected vaginal deliveries; universal vaginal deliveries; * unselected nulliparous patients; α all deliveries; β unselected singletons; γ selected singletons; and, δ selected vigorous neonates.

31 Table 1.4. Correlation between umbilical cord blood gas values and the duration of various aspects of the second stage of labour Correlation Coefficient Umbilical Artery Umbilical Vein ph Base Deficit ph Base Deficit Second stage Head on view to start of delivery Head on view to delivery Perineum distension to delivery Delivery of head Delivery of trunk & limbs Delivery of neonate Adapted from Wood et al., 1973 and Wood et al., Note: Significant (p<0.05) Figure 1.2. Effect of duration of second stage aspects on umbilical artery ph values Adapted from Wood et al., on average for study cohort Note: Gradient based on regression lines and time based Although many correlations are statistically significant, most are unlikely to be clinically profound as the magnitude of change is units in the artery and units in the vein. 62 In complicated deliveries or already compromised fetuses the clinical significance of such biochemical changes are likely to be greater. Larger changes in po 2 and pco 2 values over labour have been noted in premature fetuses. 77 A similar situation is likely to exist for shoulder dystocia, with the head and body delivery interval inversely correlated with umbilical artery ph (r=-0.210; p=0.003) and BE (r=-0.144; p=0.045) values. 78 Multivariate analysis found that during the head to body interval arterial ph decreased by units per minute 9 P a g e

32 (95% Confidence Interval [CI] 0.017, 0.004; p=0.002), while arterial BE declined by meq/l per minute (95%CI 0.544, 0.008; p=0.044). The authors noted that significantly more neonates had arterial ph values less than 7.00 when the head to body delivery interval was greater than five minutes (5.9% vs. 0.5%; p=0.034) Influence of gestational age on fetal/neonatal blood gas values As fetal gestational age advances, blood gas changes occur; at 30 weeks gestation the placental and umbilical venous blood ph, po 2 and pco 2 values are almost identical, indicating near complete placental diffusion equilibrium. 54 As gestation advances beyond 30 weeks, progressive placental efficiency develops, which by term develops to the extent that up to 30% umbilical arteriovenous shunting occurs. The fetal po 2 decrease with increasing gestational age is probably due to arteriovenous shunting, with term umbilical venous po 2 lower than maternal arterial and placental venous po 2. A number of studies of the effect of gestational age have used cordocentesis obtained fetal blood samples (Table 1.5.). 56,79-80 The effect of gestational age on umbilical cord blood samples obtained after delivery has also been evaluated. The timing of sample collection after delivery enables the collection of larger cohorts It can thus be seen that most literature suggests that there are significant cord blood gas changes as gestation progresses. Table 1.5. Change in umbilical arterial and venous blood gas values with increasing gestation Study n ph po 2 pco 2 - HCO 3 BE Umbilical Artery Soothill et al., Nicolaides et al., Kitlinski et al., ,390 Wiberg et al., ,336 Wiberg et al., ,213 Umbilical Vein Soothill et al., Nicolaides et al., Hseih et al., Wiberg et al., ,336 Note: indicates significant (p<0.05) decrease with increasing gestation and indicates significant increase with increasing gestation. Blank indicates no significant change or information available 10 P a g e

33 Influence of maternal anaesthesia and analgesia on fetal/neonatal blood gas values Blood gas values of fetuses from uncomplicated pregnancies that were delivered before labours, by an elective caesarean delivery, are altered by maternal anaesthesia. 56,84-87 Maternal anaesthesia and analgesia has also been implicated in altering fetal acid-base balance in labouring mothers Other factors influencing fetal/neonatal blood gas values Other factors implicated as potential influences on fetal acid-base status are detailed in Table 1.6. Table 1.6. Additional factors noted to potential influence fetal/neonatal acid base status Maternal/Antenatal Intrapartum/Postpartum Multiplicity. 94 Intrapartum procedures. 112 Umbilical cord anomalies/pathologies Tocolytics. 113 Intravenous hypertonic sugar, glucose Recreational drugs. 99 and dextrose Placental anomalies/pathologies Labour augmentation. 98, Fetal anomalies/pathologies. 80, Fetal/in utero infections. 105 Altitude. 106 Maternal medical conditions. 98, Blood sampling site Maternal position during labour and delivery Supplementary O Maternal hyperventilation Umbilical cord acidaemia Hydrogen ions accumulate within tissues following a shift from aerobic to anaerobic metabolism after hypoxic episodes in which insufficient tissue oxygenation occurs. Fetal acidaemia (independent of maternal acidaemia) is typically due to reduced placental perfusion, or umbilical cord compression with each typically having different neonatal outcome. Uteroplacental problems result in a fetal acidaemia biochemically apparent in the umbilical artery and vein. Umbilical cord compression produces respiratory acidaemia in fetal tissues, which will be biochemically apparent in the umbilical artery but not initially in the umbilical vein, which reflects placental perfusion and function. This irregularity is due to slowing of placental circulation, which leads to increased placental exchange time allowing equilibration of fetal and maternal intervillous blood, thereby increasing O 2 uptake and CO 2 excretion. Consequently, normal umbilical venous blood will be unable to circulate to the fetus, maintaining the acidotic milieu within the fetus and umbilical artery. In cases of 11 P a g e

34 reduced placental perfusion, umbilical arterial and venous ph values decrease; the umbilical venous ph value is 0.05 units higher than the arterial value By contrast, in umbilical cord compression the average arteriovenous ph difference is 0.12 units. Some authors have suggested that mild to moderate acidaemia is actually beneficial Various mechanisms have been postulated for the beneficial effects; acidaemia is typically associated with CO 2 accumulation and hypercarbia, and CO 2 has been found to be a strong cerebral vasodilator. 139 Consequently, the hypercarbia associated cerebral blood flow (CBF) increase might limit or abolish adverse acidaemia effects. Furthermore, neonatal animal models have noted acidaemia to increase or maintain CBF, as well as umbilical venous po Acidaemia promotes O 2 release from fetal haemoglobin by shifting the O 2 dissociation curve to the right (Bohr Effect). Decreased haemoglobin O 2 affinity promotes O 2 diffusion into surrounding tissues. In vitro studies have shown that moderate acidosis can optimise myocardial function preservation in isolated neonatal, 144 and adult hearts/myocardial tissue, although benefits are lost with profound acidosis. 145 Further, acidaemia has been noted to ameliorate the effects of excitotoxic amino acids on murine cerebral cortex cultures. 149 Mild acidosis has been shown to limit hypoxic neuronal injury in vitro by delaying depolarization onset in adult rat hippocampal slices. 150 Additionally, studies have noted increased umbilical venous erythropoietin levels with mild umbilical artery acidaemia, 151 with significant correlations between umbilical artery ph values and serum erythropoietin levels Acute acidaemia was found to have no effect on basal cardiovascular, metabolic or endocrine function in a chronically instrumented fetal ovine model, but markedly enhanced bradycardia, femoral vasoconstriction, metabolic and endocrine responses to acute maternal hypoxemia. 155 Thakor and Giussani postulated that acute acidaemia enhanced the bradycardia and femoral vasoconstriction response by sensitising carotid chemoreceptors. During hypoxaemia, glomus cells within carotid bodies uncouple, resulting in decreased junctional conductance leading to neurotransmitter release (e.g. dopamine, noradrenaline, acetylcholine, substance P and encephalins) toward the carotid sinus nerve sensory terminals. 156 Acidaemia directly influences glomus cell junctional channel proteins with low ph values, increasing uncoupling. 157 Therefore, acute acidaemia could sensitise the carotid body to arterial po 2 changes culminating in an increased autonomic response. This hypothesis is supported by the more profound bradycardia amongst acidaemic fetuses suggesting greater vagal tone. Additionally, there is evidence of increased sympathetic tone amongst acidotic neonates due to increased plasma adrenaline and noradrenaline acute hypoxaemia responses. Other 12 P a g e

35 authors have demonstrated similar findings in different animal models Thakor and Giussani theorised that increased plasma catecholamine response to acute hypoxemia in acidaemic fetuses might maintain a greater overall peripheral vasoconstriction. In contrast to the effect on fetal systemic circulation, Thakor and Giussani demonstrated that acute acidaemia caused umbilical vessel vasoconstriction in response to maternal hypoxemia. 155 This concurs with Wood and Chen who noted increased fetal arterial pco 2 following acidic infusions cannot be totally compensated for by placental gas exchange. 161 In the Thakor and Giussani study, fetal arterial ph decline was not as profound (-0.05 vs ), which they suggested was indicative of umbilical vessels sensitivity to catecholamine-induced vasoconstriction. The authors concluded that acidaemic fetuses exposed to hypoxaemia are at greater risk of adverse outcomes due to increased catecholamine response interfering with umbilical perfusion, resulting in further hypoxaemia. Others have noted increased maternal catecholamine levels and sympathetic nervous stimulation can potentiate fetal injury by reducing uterine blood flow, and interfering with myometrial activity. 166 While acidaemia did not affect the arterial blood pressure (BP) response to hypoxaemia, rebound hypertension following the insult occurred in acidaemic fetuses, which did not occur in controls. Given that vagal tone typically opposes catecholamine effects, the increased catecholamine drive without equivalent vagal tone might cause increased arterial BP during recovery in acidaemic fetuses. Higher catecholamine concentrations persist for longer in fetal circulation thus having a longer effect duration, which is reflected by prolonged femoral vasoconstriction and elevated fetal arterial BP during recovery in acidaemic fetuses. A combination of the sympathetic nervous system and catecholamine concentrations are responsible for the fetal glycaemic response to acute hypoxaemia insults Given that acidaemia increases glucose-stimulated insulin release, 169 any effect of acidaemia on plasma glucose concentrations is likely to be tempered by increased insulin concentrations. There was no difference between controls and acidaemic neonates in lactic acidaemia, despite increased fetal peripheral vasoconstriction amongst acidaemic fetuses. 155 It was hypothesised this was due to acidaemia enhanced lactate uptake by various organs, such as the liver, 170 or transport into the maternal circulation. Fetal acidaemia might enhance placental transport due to reduced umbilical vascular perfusion, which would slow placental transit time allowing time for placental lactate transport into maternal circulation. 13 P a g e

36 Thakor and Giussani demonstrated no difference between control and acidaemic endocrine responses to maternal hypoxaemia; however, several authors showed that acute acidaemia stimulates hypothalamus-pituitary-adrenal (HPA) axis production of adrenocorticotropic hormone (ACTH) and cortisol. 161,171 Others have noted significant correlations between umbilical artery ph values and cord plasma free cortisol values. 172 The divergence could be due to failure to exceed an acidaemia threshold necessary to trigger ACTH, and cortisol production, as the acidaemia in the Thakor and Giussani study was comparatively milder. Thakor and Giussani also noted while acidaemic fetuses had increased plasma ACTH and cortisol responses, there was no effect on adrenal cortical response to ACTH, which concurs with another study s findings. 173 It was hypothesised that the sensitising effect of acidaemia on the fetal HPA axis occurs at the hypothalamus and/or pituitary gland. Hypothalamic release of corticotrophin-releasing hormone and arginine vasopressin has been shown to stimulate ACTH production; thus acidaemia might alter hypothalamic hormone release. Whilst there is no direct evidence for this, fetal ovine studies have noted that acidaemia stimulated anti-diuretic hormone (ADH) release, 161 while an increased ADH response to hypoxaemia was noted in a spontaneously acidaemic model. 176 Hypothalamic catecholaminergic neurons have been identified as functional during acute hypoxaemic insults; 177 thus fetal acidaemia has the potential by increasing sympathetic tone to increase hypothalamic corticotrophin releasing hormone production. There is evidence that acidaemia directly stimulates adult ACTH production; however, whether this is applicable to the fetus is unknown. The beneficial effects of mild to moderate acidaemia are unlikely to persist in neonates with severe acidaemia or co-morbidities such as prematurity or low birth weight. 181 Severe acidaemia can have detrimental effects on a number of organ systems including the central nervous system (CNS), gastrointestinal tract (GIT, pulmonary system, and cardiovascular system (CVS) Consequently, neonates with severe acidaemia are at a higher risk of low Apgar scores, neonatal seizures, neonatal death, and long-term neurodevelopmental deficits Furthermore, as the ph decreases below 7.00 the risk become progressively higher Pathologic fetal acidaemia Whilst fetuses have adequate compensatory mechanisms to cope with acidaemia without injury for short periods, severe fetal acidaemia is associated with increased mortality and increased risk for later neurodevelopment injury. 138, Fetuses exposed to chronic antenatal acidosis are at particular risk of long-term morbidity. Low et al. found that the 14 P a g e

37 incidence and severity of newborn complications following acidaemia increased with the escalating severity and duration of metabolic acidaemia. 191 That being so, unless there are other adverse events, such as a coexistent fetal hypotension, acidaemia alone does not produce adverse long-term developmental outcomes Fetal and neonatal acidaemia has been historically defined as an umbilical artery blood ph of less than Most neonates with such a definition of acidaemia will grow to be vigorous and healthy with no permanent neurodevelopmental sequelae. 186,199 Consequently, several alternative definitions have been considered. Initially some suggested a ph two standard deviations (SD) below the mean ph (7.10 to 7.18) should be the cut-off for pathological acidaemia. 63,66,69 Much like the 7.20 threshold, most neonates with an umbilical artery blood ph less than or equal to 7.10 are healthy, with 86% having normal five minute Apgar scores. 67 Currently the most used definition of pathological acidaemia is an umbilical artery ph less than 7.00 with a significant metabolic component, 186, which has become an integral part of defining birth asphyxia, with the severity associated with severity of injury. Issues persists with this threshold, namely most neonates with a ph of 7.00 are neurologically healthy. 190,201 Most neonates with a ph greater than 7.00 are healthy; several studies have found that even mild to moderate acidaemia is associated with an increased risk of low Apgar scores. 186,202 Consequently, the International Cerebral Palsy Task Force (ICPTF) and American Congress of Obstetrics and Gynaecology (ACOG) Committee on Obstetric Practice and others have suggested intrauterine hypoxia, severe enough to cause HIE and CP, requires an arterial ph less than , It appears that there is a temporal component to the fetal and neonatal effects of acidaemia. Casey et al. studied 1,691 neonates with UCBGA and another blood sample two hours later, to evaluate the influence of prolonged acidaemia on neonatal outcome (Figure 1.3.). 209 Neonates with umbilical artery acidaemia had an increased relative risk (RR) of neonatal seizures (RR 2.5; 95%CI 1.2, 5.3); however, there was no increased risk of respiratory distress (RR 1.0; 95%CI 0.8, 1.4), meconium aspiration syndrome (MAS) (RR 1.2; 95%CI 0.8, 2.0), or neonatal death (RR 0.6; 95%CI 0.1, 3.5). Those with neonatal acidaemia had a significantly increased RR of neonatal seizures (RR 5.7; 95%CI 2.2, 14.5), respiratory distress (RR 5.6; 95%CI 3.7, 8.5), MAS (RR 2.4; 95%CI 1.1, 4.8), and neonatal death (RR 7.2; 95%CI 1.6, 33.0). Neonates with prolonged acidaemia were more likely to experience respiratory distress (RR 4.4; 95%CI 3.1, 6.2), MAS (RR 3.7; 95%CI 2.2, 6.3), neonatal seizures (RR 13.0; 95%CI 15 P a g e

38 6.3, 26.7), and neonatal death (RR 10.7; 95%CI 3.3, 35.3) than neonates without acidaemia. Consequently, it is appears neonates with prolonged acidaemia, which extends beyond delivery, are at greater risk of morbidity and mortality. Figure 1.3. Distribution of the various directions of the ph change following delivery Term Neonates (n=1,691) Prolonged Acidaemia (UA ph<7.20 & Neonatal ph<7.20) Fetal Acidaemia (UA ph<7.20 & Neonatal ph 7.20) Neonatal Acidaemia (UA ph 7.20 & Neonatal ph<7.20) Normal (UA ph 7.20 & Neonatal ph 7.20) n=178 (11%) n=594 (35%) n=110 (7%) n=809 (48%) Adapted from Casey et al., Respiratory and metabolic acidaemia Generally, fetal or neonatal acidaemia is classified as a respiratory, metabolic, or mixed respiratory and metabolic acidaemia. Respiratory acidosis results from fetal CO 2 accumulation; while metabolic acidosis develops when insufficient fetal oxygenation causes a change from aerobic to anaerobic metabolism. Acidaemia classification was previously - based on fetal pco 2 and HCO 3 values, with a high pco 2 indicative of respiratory acidaemia and a high HCO - 3 indicative of metabolic acidaemia. These definitions did not account for the compensatory HCO - 3 increase that can accompany elevated pco 2 values, which is considered to be 1 meq/l for every 10 mmhg pco 2 increase. 186 If the compensatory increase is not corrected, respiratory acidaemia can develop into a mixed metabolic and respiratory acidaemia. Currently, metabolic acidosis is routinely evaluated using standard base excess (SBE), actual base excess (ABE) or BD. Actual base excess and BD are equivalent values except for the 16 P a g e

39 former having a negative sign. Actual base excess reflects blood sample buffering capacity by calculating the acid required to return ph to a set value while CO 2 within the sample is maintained constant. Standard base excess is similar except it adjusts for haemoglobin levels thus reflecting extracellular fluid s buffering capacity. While SBE is technically preferable, 188 ABE tends to be more widely utilised and reported. The BE threshold of metabolic acidaemia is somewhat controversial. Low et al. evaluated 174 term neonates, stratified by umbilical artery BE values, with no significant difference between groups in cardiovascular and renal complications. 210 There was a significant increase in CNS (p=0.01) and respiratory (p=0.001) complications as BE decreased. Together with earlier findings, 191 Low et al. proposed a BD of 12 mmol/l as a cut-off as complications occurred in 10% of neonates with arterial BD values of mmol/l. Pure respiratory acidaemia is usually not associated with serious morbidity despite the umbilical artery ph being indicative of acidaemia Potential causes of respiratory acidaemia include umbilical cord compression, decreased fetal cardiac output, and insufficient placental perfusion. Respiratory acidaemia is not an entirely benign event as if prolonged the resultant hypoxia can produce a metabolic acidaemia. In fetuses, without maternal acidaemia, the fetal acidaemia will predictably change from normal to a respiratory acidaemia then if the insult persists to a metabolic acidaemia secondary to lactate accumulation. Thus, while respiratory acidaemia is usually transient and non-pathological, it can be a potential harbinger of later pathological metabolic acidaemia. There is some suggestion that hypercapnia might be neuroprotective; CNS blood flow is directly proportional to blood CO 2 levels, namely hypocapnia lowers and hypercapnia increases CBF, with the response particularly profound in the young. 213 Hypercapnia has also been noted to suppress oxidative metabolism, by inhibiting cerebral energy utilization and limiting glycolytic flux, with reduced tissue lactate production noted with hypercapnia Hypercapnic rats have been found to have greater high-energy phosphate reserve conservation and decreased energy expenditure. 219 Klinger et al. noted amongst neonates with HIE, severe hypocapnia significant increased the likelihood of neurodevelopmental deficits or neonatal death (OR 2.34, 95%CI 1.02, 5.37; p=0.044). 220 Further, Pappas et al. noted that increasing severity and duration of hypocarbia was associated with worse outcomes. 221 Together, increased CBF and reduced metabolic rate linked to hypercapnia can act synergistically to protect neural tissue from hypoxia and ischaemia. 17 P a g e

40 Mixed respiratory and metabolic acidaemia Acidaemia is rarely clear-cut often being a mixed metabolic and respiratory acidaemia. Notwithstanding the importance of a metabolic component, Herbst et al. noted a greater proportion of NICU admissions amongst neonates with combined respiratory and metabolic acidaemia compared to those with metabolic acidaemia alone; however, arterial ph values were significantly lower in those with mixed acidaemia. 222 While the authors suggested this might be due to hypercapnia induced ph decrease; it is a significant confounding factor. Four-year follow-up revealed no significant neurodevelopmental differences. In acidaemic (arterial ph<7.00) term non-anomalous singletons a higher proportion of adverse early neonatal outcomes occurred with mixed acidaemia (Table 1.7.). 201 This concurred with ovine studies noting worse renal blood flow in hypercapnic fetuses. 223 The effects of respiratory acidaemia need further study before greater emphasis can be placed on this finding Birth asphyxia Definition of birth asphyxia Asphyxia is a poorly defined and vague term that is often misused and misunderstood No uniform definition has emerged until relatively recently, which complicates any literature review (Appendix B). Previous definitions included; 1) low Apgar scores; 69,200, ) cardiopulmonary resuscitation (CPR); ) resuscitation difficulties; 1 4) impaired spontaneous respirations; ) umbilical arterial, venous or early neonatal metabolic acidaemia; 67,69,229,234 and, 6) NE. 235 Currently, the term birth asphyxia is generally avoided where possible, primarily due to the medicolegal implications associated with labelling a neonate as having birth asphyxia. 205, , asphyxia as: The World Federation of Neurology Group Statement on Birth Asphyxia defined A condition of impaired gas exchange which if allowed to persist progresses to hypoxaemia and hypercapnia. 240 Conditions of impaired gas exchange may occur transiently without pathological consequences; however, a significant asphyxial insult will cause tissue O 2 deficiency resulting in anaerobic metabolism and metabolite accumulation and thus metabolic acidaemia. Consequently, Low added to the Bax et al. definition by suggesting fetal asphyxia is: 18 P a g e

41 Table 1.7. Relationship of umbilical artery acidaemia and acidaemia type with early neurological, renal, cardiac and pulmonary impairments Arterial Acidaemia Neurological Impairments Other Organ System Dysfunction ph Value Type HIE Seizures & Hypotonia Seizures Hypotonia Renal Cardiac Pulmonary Respiratory 3 (3%) 3 (3%) 0 (0%) 0 (0%) Mixed 29 (27%) 22 (20%) 2 (2%) 3 (3%) (n=109) Metabolic 1 (1%) 0 (0%) 0 (0%) 3 (3%) Total 33 (30%) 25 (23%) 2 (2%) 6 (6%) 30 (28%) 33 (30%) 30 (28%) (n=57) (n=27) (n=15) (n=10) Respiratory 1 (2%) 1 (2%) 0 (0%) 0 (0%) Mixed 5 (9%) 4 (7%) 0 (0%) 1 (2%) Metabolic 1 (2%) 0 (0%) 0 (0%) 1 (2%) Total 7 (12%) 5 (9%) 0 (0%) 2 (4%) 9 (16%) 10 (18%) 7 (12%) Respiratory 1 (4%) 1 (4%) 0 (0%) 0 (0%) Mixed 8 (30%) 5 (19%) 1 (4%) 2 (7%) Metabolic 0 (0%) 0 (0%) 0 (0%) 0 (0%) Total 9 (33%) 6 (22%) 1 (4%) 2 (7%) 7 (26%) 8 (30%) 8 (30%) Respiratory 1 (7%) 1 (7%) 0 (0%) 0 (0%) Mixed 8 (53%) 6 (40%) 0 (0%) 0 (0%) Metabolic 0 (0%) 0 (0%) 0 (0%) 2 (13%) Total 9 (60%) 7 (47%) 0 (0%) 2 (13%) 8 (53%) 9 (60%) 7 (47%) Respiratory 0 (0%) 0 (0%) 0 (0%) 0 (0%) Mixed 8 (10%) 7 (70%) 1 (10%) 0 (0%) Metabolic 0 (0%) 0 (0%) 0 (0%) 0 (0%) Total 8 (80%) 7 (70%) 1 (10%) 0 (0%) 6 (60%) 6 (60%) 8 (80%) Adapted from Goodwin et al., Note: Blank squares data not reported

42 A condition of impaired blood gas exchange leading to progressive hypoxaemia and hypercapnia with a significant metabolic acidosis. 243 Even this definition inspired some controversy, with the ICPTF noting it does not allow time of onset and progression to be easily determined Furthermore, the ICPTF does not advocate use of birth asphyxia, promoting its replacement with acute intrapartum hypoxic event, which has a series of definitive criteria (Table 1.8.). For neonates with an asphyxial insult not meeting these criteria, perinatal asphyxia is the suggested diagnostic label that encompasses the entire antepartum, intrapartum and postpartum period. They also suggest describing the time frame and insult course using terms such as acute, chronic, continuous or intermittent. The ICPTF recommends use of non-reassuring fetal status followed by a further description of the non-reassuring findings, rather than fetal distress. The ACOG and Society of Obstetricians and Gynaecologists of Canada have supported this opinion. 205,226, ,239 This phrase recognises it is the medical and midwifery staff members interpretation of fetal status rather than actual status that is described. Table 1.8. International Cerebral Palsy Task Force criteria for an acute intrapartum hypoxic event Essential Criteria Metabolic acidaemia in intrapartum fetal, postpartum umbilical cord artery, or early neonatal blood (ph < 7.00 and base deficit 12 mmol/l) Early onset of severe or moderate NE in infant s 34 weeks gestation. Cerebral palsy of the spastic quadriplegic or dyskinetic type Suggestive Criteria Sentinel hypoxic event occurring immediately before or during labour Sudden, rapid, and sustained deterioration of the fetal heart rate pattern typically after the hypoxic sentinel event when the pattern had previously been normal Depressed Apgar scores for longer than 5 minutes (five minute Apgar score < 7) Early evidence of multisystem involvement Early imaging evidence of acute cerebral abnormality Adapted from MacLennan, 1999 and MacLennan, The ICPTF definition of an acute intrapartum hypoxic event includes essential and nonessential yet suggestive criteria (Table 1.8.). Additionally, the ICPTF noted a set of factors suggestive of an event outside the intrapartum period (Table 1.9.). The ICPTF considers if no essential criteria are present; it is doubtful whether an acute intrapartum event occurred. Further, if blood gas data is not available then regardless of other criteria, one cannot assume diagnosis of an acute intrapartum hypoxic event due to the other essential criteria s poor 20 P a g e

43 specificity. If there is contrary or absent information regarding non-essential criteria, the intrapartum aetiology becomes increasingly doubtful. The non-essential criteria, all have other non-hypoxic aetiologies, and thus have only a weak association with an acute intrapartum hypoxic event. The ICPTF considers that contrary evidence would alter the balance of probabilities suggesting an intrapartum hypoxic event and most non-essential criteria should be present before making a diagnosis. Table 1.9. Factors potentially associated with neurological injury originating outside the intrapartum period 1. Umbilical arterial ph greater than 7.00 or base deficit less than 12 mmol/l 2. Infants with major or multiple congenital or metabolic abnormalities 3. Central nervous system or systemic infections 4. Early imaging evidence of long-standing neurological abnormalities e.g. Ventriculomegaly, Porencephaly, or Multicystic encephalomalacia 5. Intrauterine growth restriction 6. Reduced fetal heart rate variability from the onset of labour 7. Microcephaly at delivery (head circumference less than third percentile) 8. Major antenatal placental abruption 9. Extensive chorioamnionitis 10. Childhood congenital coagulopathy 11. Presence of additional major antenatal CP risk factors e.g. Preterm delivery (less than 34 weeks gestation), Multiple fetus pregnancy, or Maternal autoimmune disease 12. Presence of major postnatal CP risk factors e.g. Postnatal encephalitis, Prolonged hypotension or Severe respiratory disease associated hypoxia 13. Sibling with CP particularly if it is of the same type Adapted from MacLennan, 1999 and MacLennan, There has been some discussion about inclusion of metabolic acidaemia as an essential criterion Much of the debate is centred on UCBGA and potential issues surrounding this procedure. 242, Use of neonatal blood samples obtained after delivery rather than the umbilical cord at delivery is open to the influence of neonatal resuscitation. Finally, inclusion of metabolic acidosis might discourage clinicians from assessing acid-base balance after delivery. Other criticism involves the perceived limited nature of the definitions applicability. Phelan et al. noted only one neonate (N=28; 4%) had all essential and non-essential criteria (Table 1.10.), despite all 28 having CNS injury and normal admission EFM, followed by a rapid and sustained FHR deterioration P a g e

44 Table Application of International Cerebral Palsy Task Force definition of an acute intrapartum hypoxic event Population All Non- All Essential & Essential All Essential Essential Non-Essential Criteria Criteria Criteria Criteria Present Present Present Present Acute 60% (28/47) 32% (9/28) 11% (1/9) 4% (1/28) Mixed 77% (40/52) 25% (10/40) 0% (0/10) 0% (0/40) Adapted from Phelan et al., Note: Reactive FHR trace admission followed by sudden, rapid, and sustained FHR deterioration lasting till delivery; and, Heterogeneous group with different FHR patterns associated with permanent brain injury due to HIE. The ACOG published an updated version with the addition of another essential criteria, namely that other identifiable aetiologies should be identified and these neonates excluded (Table 1.11.). 203,248 This addresses the issue that many neonatal neurological injuries have causes other than intrapartum asphyxial injury; with intrapartum asphyxial injury responsible for a minority of neurological injuries. Evaluation of the 2003 combined ACOG and the American Academy of Pediatrics (AAP) statement has been conducted in 38,548 deliveries across two maternity units with 172 neonates (0.4%) meeting 1999 International Classification of Disease (ICD) Nine criteria for birth trauma, birth asphyxia, intrauterine hypoxia, or fetal distress. 249 The authors applied a modified ACOG guideline version, and found five neonates (2.9%) met guidelines for gestational age, cord blood gas values and Apgar scores (Figure 1.4.). Phelan et al. undertook a similar study on 39 term singleton neonates with HIE and permanent neurological injury. 250 All neonates had a reactive intrapartum FHR trace with a normal admission FHR, but experienced an abrupt and rapid FHR decrease, which did not return to baseline, was unresponsive to intervention, and persisted until delivery. In contrast, to the authors earlier evaluation of ICPTF guidelines, 88% of neonates (21/24) fulfilled all criteria (Table 1.12.). Six of 21 (29%) also satisfied all non-essential/suggestive criteria. Considering all 39 neonates, 36 (95%) met three or more essential criteria, and one or more nonspecific criteria. Unlike earlier definitions, Perlman considered a sentinel event to be critical and essential and included it as an inclusion criteria (Table 1.13.). 251 While, Perlman noted that all six criteria were present in greater than 90% of cases the presence of all criteria does not appear to be essential; hence, use of terms inclusion and exclusion rather than essential and non-specific/suggestive. The Perlman definition does not seem to have been widely accepted potentially due to the number of organisations supporting the preceding definitions. 22 P a g e

45 Table ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy acute intrapartum asphyxial hypoxic event criteria Essential Criteria Evidence of umbilical arterial metabolic acidaemia (ph <7.00 & base deficit 12 mmol/l) Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more weeks gestation Cerebral palsy of the spastic quadriplegic or dyskinetic type Exclusion of other identifiable aetiologies, such as trauma, coagulation disorders, infectious conditions, or genetic disorders Suggestive Criteria Sentinel (signal) hypoxic event occurring immediately before or during labour Sudden & sustained fetal bradycardia or absence of FHR variability in presence of persistent, late, or variable decelerations, usually after a hypoxic sentinel event with a previously normal pattern Apgar scores of 0-3 beyond 5 minutes Onset of multisystem involvement within 72 hours of birth Early imaging study showing evidence of acute non-focal cerebral abnormality Adapted from ACOG, 2003 and ACOG, ,248 Figure 1.4. Application of 2003 ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy acute intrapartum asphyxial hypoxic event criteria IDC-9 Criteria (N= 172) Gestation 34 Weeks (n= 82; 47.7%) Gestation < 34 Weeks (n=90; 52.3%) Arterial Metabolic Acidaemia (n=14; 8.1%) No Metabolic Acidaemia (n=68; 39.5%) Five Min Apgar 3 (n= 5; 2.9%) Five Min Apgar >3 (n=9; 5.2%) Adapted from Vance et al., Hypoxic Ischaemic Encephalopathy (n=5; 2.9%) 23 P a g e

46 Table Application of ACOG Task Force on Neonatal Encephalopathy and Cerebral Palsy acute intrapartum asphyxial hypoxic event criteria Essential Criteria Number (Percentage) Metabolic acidaemia Umbilical artery ph < /39 (97%) Umbilical artery base excess < -12 mmol/l 30/30 (100%) Umbilical artery ph < 7.00 & base excess < /30 (97%) mmol/l Moderate-severe neonatal encephalopathy 33/34 (97) Spastic quadriplegia/dyskinetic cerebral palsy 22/24 (92) No other identifiable aetiologies 39/39 (100%) Suggestive Criteria Number (Percentage) Sentinel hypoxic event 31/39 (80%) Bradycardia 39/39 (100%) Apgar score of less than four beyond five minutes 10/34 (29%) Multisystem organ dysfunction 34/34 (100%) Cerebral oedema 7/25 (28%) Adapted from Phelan et al., Table Perlman definition of intrapartum asphyxial event Inclusion Criteria Sentinel event e.g. Absent FHR variability with persistent late/variable decelerations/bradycardia, Ruptured uterus, Placental abruption, Umbilical cord prolapse, or Massive fetal maternal haemorrhage Evidence of metabolic acidosis in umbilical arterial cord or early neonatal blood e.g. Umbilical artery ph < 7.00 and base deficit >12 mmol/ml Ten minute Apgar score less than three Early onset moderate-severe neonatal encephalopathy Early evidence of multisystem organ dysfunction Neuroimaging consistent with an acute cerebral injury Exclusion Criteria Previous antenatal injury, Major or multiple congenital or metabolic abnormalities, Systemic or central nervous system infection, Congenital coagulation disorders, Focal cerebral infarction, and /or Traumatic brain injury Adapted from Perlman, P a g e

47 Neurological outcomes of perinatal asphyxia In addition to the mortality burden of intrapartum asphyxial injuries (Appendix C), there is a significant degree of morbidity. While asphyxia is a global insult, affecting the entire neonate, it effects some organs, such as the CNS, more than others and certain intra-organ areas preferentially. 252 The effected CNS regions and resulting outcomes depend on various factors including CNS maturity and resilience and insult duration and severity Animal models have demonstrated the importance of injury type; with global asphyxia, and cerebral ischemia, of as little as 10 minutes associated with injury. In contrast, CNS damage following sustained partial asphyxia injuries might take hours to manifest, if it occurs at all. 197, One of the earliest studies of long-term asphyxial outcomes followed 48 neonates, with 15 delivered without signs of life and 33 not establishing spontaneous respirations within 20 minutes of delivery. 233 Of the 48 neonates, 25 (52%) died within the neonatal period, with 13 deaths (52%) attributed to intrapartum asphyxial injury. Amongst the 23 survivors, at two to seven-year follow-up, six (26%) had CP. Mulligan et al. studied 133 neonates that took longer than a minute to establish spontaneous respirations noting 44% did not survive the neonatal period. 232 Amongst the 65 survivors, 12 children (18.5%) had severe neurodevelopmental sequelae, whilst six (9.2%) had mild but not handicapping disabilities. An even earlier study that classified perinatal asphyxia based on delayed or impaired respiration, noted significant differences in mobilisation, neurological disorders, perception, and personality between cases and controls. 268 De Souza et al. evaluated 53 term and post-term neonates with FHR abnormalities and/or MSAF as well as severe neonatal neurological abnormalities. 269 At follow-up two to five years later, 42 (78%) had no neurological abnormality. Seven (14%) had doubtful abnormalities, such as squints, febrile convulsions, large head circumference (greater than 90 th centile), hyperactive behaviour or minor motor dysfunction. Definite neurological abnormalities were noted in three (6%) without handicap, and, they together with the doubtful group were making appropriate scholastic progress. Only one child (2%) had a significant neurological abnormality considered severely handicapping. Fifty two neonates with umbilical/neonatal arterial BE values of less than -15 mmol/l and/or Sarnat and Sarnat NE were evaluated at one year old for neurodevelopmental status as well as undergoing magnetic resonance imaging (MRI) within a week of birth. 270 Of the 52 neonates, 15 (29%) died within a year of delivery. Seventeen of the survivors (46%) had 25 P a g e

48 normal neurodevelopmental status, three (8%) had minor neurodevelopmental abnormalities, three (8%) had a single major neurodevelopmental abnormality and 14 (38%) had multiple major neurodevelopmental issues. Brown et al. identified 760 live-born neonates from 14,020 neonates delivered at a Scottish maternity unit with a history suggestive of perinatal asphyxia. 271 Of these, 83 (11%) exhibited apnoeic/cyanotic attacks, apathy, convulsions, hypothermia, cerebral cry, persistent vomiting or needed tube feeding. An additional 11 neonates fulfilling this criteria but from external units were included. The asphyxial insult was localised to the antenatal (n=48; 51%), intrapartum (n=38; 40%), and postnatal (n=9; 9%) periods. Ninety-three neonates were available for follow-up during which 20 died (22%). Of the survivors, 24 (33%) were handicapped, 15 (21%) had neurological abnormalities but minimal impairment, and 34 (47%) were considered normal. Yudkin et al. studied 11,682 singleton deliveries between January 1984 and September 1985 to evaluate the perinatal asphyxia and CP relationship (Figure 1.5.). 36 There were 167 term infants with one-minute Apgar scores less than four, with nine neonates (5.3%) dying prior to five years old, two of which were thought to be due to perinatal asphyxia. Six neonates (3.5%) were considered to have been exposed to intrapartum asphyxial injury based on modified ACOG guidelines Of these six, two died during the neonatal period, three had neurodevelopmental abnormalities, and the remaining individual was considered normal. For the entire 11,683 cohort, there were 30 CP cases with only the three in the original cohort associated with intrapartum asphyxial injury. Thus, perinatal asphyxia was responsible for 20% of term CP cases and 10% of all cases in singleton births. In preterm neonates (<33 weeks gestation), Westgren et al. evaluated 108 neonates of which 30 had ominous FHR traces, which was considered perinatal asphyxia. 274 There was a significant difference in two-year mortality (14 [47%] vs. 11 [14%]; p<0.05). No significant difference in neurodevelopmental abnormalities was noted at two and four year follow-up (25% vs. 12%). When mortality and neurodevelopmental abnormalities were considered together, those exposed to perinatal asphyxia were more likely to have adverse outcomes (p<0.05). A similar study of 30 preterm neonates with metabolic acidaemia, noted significantly higher one year mortality (23% vs. 3%; p<0.006), and abnormal outcomes amongst those exposed to perinatal asphyxia (p<0.02). 275 In survivors there was no difference in minor motor or cognitive deficits; however, major deficits were more common with asphyxia (27% vs. 13%; p<0.03) 26 P a g e

49 Figure 1.5. Relationship between perinatal asphyxia and cerebral palsy in a cohort of singleton live births Singleton Live Births (N=11,682) Term with One Min. Apgar 3 (n=173) Term with One Min. Apgar>3 (n=10,937) Preterm (n=572) Neonatal Death (Birth Asphyxia) (n=2) Neonatal Death (Congenital Anomaly) (n=7) Available at Five Years Old (n=158) Lost to Follow-Up (n=6) Neonatal Death (Birth Asphyxia) (n=2) Cerebral Palsy (n=11) Cerebral Palsy (n=15) Cerebral Palsy (n=4) Birth Asphyxia Related (n=0) Other (n=11) Birth Asphyxia Related (n=3) Other (n=1) Adapted from Yudkin et al.,

50 Shankaran et al. followed 28 term neonates admitted to a tertiary level maternity unit with severe perinatal asphyxial injuries for five years. 276 Six neonates (21%) died during the neonatal period. The average height and weight was appropriate for age, although children with motor deficits had head circumferences less than expected. At one year old, 13 children (54%) were considered neurologically normal, increasing to 14 (58%) at the fiveyear follow-up. Amongst the 10 with severe motor deficits, eight had multiple handicaps and were not able to ambulate. Six severely handicapped children (60%) were visually handicapped, while all 10 had delayed expressive and receptive language development. Seizures were prevalent amongst the severely handicapped with nine (90%) requiring multiple anticonvulsants. At five years old developmental outcomes, were normal in nine children (38%), suspect in three (12%) and abnormal in 12 (50%) with the latter including all 10 with severe motor handicaps Neuropsychological, intellectual, and cognitive outcomes of perinatal asphyxia There is a relative dearth of information concerning the impact of perinatal asphyxial injury on neuropsychological, intellectual and cognitive outcomes. Until recently surviving neonates were considered as either having significant impairments and neurodevelopment issues or being normal. Such a dichotomous view of long-term effects of perinatal asphyxia probably originates from the perception of a critical threshold beyond which CNS damage occurs. 187,210, That being so, there is increasing support for a continuum of harm following intrapartum asphyxia, potentially after the attainment of a critical threshold. One area in which a continuum of harm would manifest itself is neuropsychological, intellectual, and cognitive difficulties in survivors, with several animal models suggesting learning behaviour can be affected by asphyxial injury. 261, Several early studies attempted to elucidate perinatal asphyxia s effect on intellectual development based on asphyxial definitions including apnoea, Apgar scores, and neonatal heel prick oxygenation. Amongst children studied from infancy to early school attendance those exposed to perinatal asphyxia had significantly worse intellectual abilities, although some noted no significant differences Conversely, in older school age children most studies showed no significant difference in intellectual performance; 268,288, however, there was a dissenting study with subjects at the younger end of the age spectrum. 294 Gottfried combined data from several studies, finding the average intelligence quotient (IQ) of individuals exposed to perinatal asphyxia was 4.6 points lower than their non-exposed counterparts. 295 The apparent disparity between studies using different age 28 P a g e

51 cohorts could be indicative of children s ability to compensate for and overcome intellectual deficits via CNS plasticity. 296 Alternatively, it could be a function of differences in intellectual and cognitive performance assessment, with children assessed prior to school typically tested using sensor-motor or perceptual-motor function rather than the verbal testing in school aged children. Further, the more profound an impairment, the easier it is to identify with cognitive and learning disabilities typically taking longer to manifest. 297 Early studies were limited by small cohort sizes, particularly for adverse outcomes. It can be assumed whilst there are definite intellectual consequences of perinatal asphyxia these tend to be minor and potentially transient. Several authors have noted memory impairments in adults following hypoxia, most likely due to hippocampal injury; 298, however, hippocampal injury and corresponding memory impairments occur in a minority of adults exposed to hypoxic injury. 305 Hippocampal injury is also thought to be responsible for memory impairments in children and adolescents, with a study of adolescents with a history of perinatal asphyxia demonstrating substantial bilateral hippocampal volume reductions Detailed MRI examination also noted abnormal putamen, ventral thalamus and brain stem findings, all suggestive of asphyxial brain injury. 308 Two MRI patterns of injury following perinatal asphyxial have been visualised in animals and neonates; 1) cerebral white matter injury following partial asphyxial injuries; and 2) thalami and basal ganglia injuries following acute profound asphyxial injuries. 252,257, Thalamus or basal ganglia injuries are likely to produce severe neurodevelopmental injuries; however, injuries affecting cerebral white matter can produce isolated cognitive impairments Reduced hippocampal volume has been associated with developmental amnesia; which is a severe episodic memory impairment (impaired context-rich event memory) accompanied by normal semantic memory (contextfree factual memory), working memory and scholastic performance. Substantial hippocampal injury is required for developmental amnesia; namely bilateral hippocampal volume reduction of 20-30%. 314 Insult timing does not appear to effect the severity of functional or pathological injury. 308 Studies concerning developmental amnesia should be contextualised as they often include preterm neonates with other risk factors for hippocampal injury and memory impairment. Additionally, these studies were retrospective, based on memory-impaired cohorts, which were evaluated for antepartum and intrapartum indicators of perinatal asphyxia. Consequently, while there is a link between perinatal asphyxial injury, bilateral hippocampal injury and developmental amnesia, it is not necessary a causative step-wise relationship. 29 P a g e

52 Several authors have attempted to circumvent these issues by prospectively recruiting cohorts of term neonates with evidence of intrapartum asphyxial injury independent of other injuries and conditions. One group evaluated 12 adolescents cognitive function at years of age, with the adolescents having experienced metabolic acidaemia and abnormal neurological findings but no major neurological abnormalities. 258,315 Eleven adolescents demonstrated normal cognitive function, while one demonstrated a mild developmental amnesia. In a cohort of term neonates with mild intrapartum asphyxial insults examined at four and eight years of age, no difference in motor development, cognitive development or serial memory tests was found between exposed and non-exposed children. 316 Given there were no significant differences between groups in socioeconomic status, family life and stresses, or child health and behaviour, it suggests term neonates exposed to mild asphyxial insults develop similar motor and cognitive deficits to the background population. A larger and more detailed study of 28 adolescents with evidence of perinatal asphyxial injury (eight mild and 20 moderate) and 28 controls matched for age, sex, education and socioeconomic status was conducted in Barcelona, Spain. 317 Based on the Wechsler Intelligence Scales all adolescents had normal intelligence levels, with no significant difference based on perinatal asphyxial injury or the injury grade. No significant difference was noted in memory, prefrontal and perceptual/motor function between control and mild perinatal asphyxia groups. Significant differences between control and moderate perinatal asphyxia groups were noted for memory, prefrontal and perceptual/motor function, although the later was only a single test out of a number. The only significant difference between mild and moderate perinatal asphyxia groups was a single test concerning memory function. Consequently, despite normal intelligence and lack of neurological abnormalities at birth or follow-up, neuropsychological impairments can persist amongst those exposed to moderate perinatal asphyxial injury. A subsequent MRI review at 16 years of age of 13 children who had experienced moderate HIE, found significant bilateral hippocampal volume reduction (p=0.015). 318 Normal immediate memory was noted when compared to matched controls, although long-term recall was impaired. The severity of long-term memory impairment was not significantly correlated with reduction in hippocampal volume in either hemisphere, although this could be due to the small cohort. Together these studies suggest long-term memory abnormalities can occur alongside normal immediate memory. To further support the hypothesis of a continuum of harm, the degree of impairment and hippocampal atrophy does not appear to be as severe as that 30 P a g e

53 noted in the developmental amnesia phenotype. Further long-term research is necessary, as issues associated with certain aspects of memory often take longer to manifest due to early childhood compensation, 258 and the clinical picture in severe injuries can often obscure memory deficits. Other than memory impairments there is evidence linking perinatal asphyxia with psychological and behavioural disorders Authors have suggested an association between perinatal asphyxia, CNS injury and schizophrenia, although the level of gene environment interaction responsible is debated; it s generally considered a combination is implicated in most cases. 322,328 This would fit with other studies that have noted contradictory evidence regarding the link between perinatal asphyxia and schizophrenia, 327, as well as the finding that at least 90% of neonates exposed to perinatal asphyxia do not develop schizophrenia. 320,325 One of the most comprehensive studies of long-term outcomes following perinatal asphyxial injury was conducted in Göteborg, Sweden on a cohort of term or near term neonates Seventy-one children were followed up at five, 10 and 18 months of age, with 12 children having significant neurodevelopmental abnormalities, such mild to severe mental retardation, CP or epilepsy. 230 The other 59 children were divided into 39 without neonatal neurological issues and 20 neonates with significant neonatal neurological events i.e. neonatal seizures, hypotonia, feeding difficulties, lethargy or depressed reflexes. Questionnaires were distributed to these 59 children together with 35 controls at 19 to 28 years of age. Controls had one and/or five minute Apgar scores greater than seven and no neurodevelopmental issues. There was no difference in social situation or scholastic achievements as young adults between controls and children requiring CPR. Furthermore, there was no difference between those with significant neonatal neurological deficits and those that did not. In neuropsychological testing no significant differences were found between controls and either study groups; however, there were statistically significant differences in eight of the 106 subtests. 231 Seven subtests demonstrated worse results amongst the mild group compared to controls (five in verbal functions, one in visual-spatial and visual-constructive functions, and one in freedom from distractibility). The other significant difference was in the maximum scores for design and learning between the moderate and control groups. No difference in intelligence occurred between the three groups; however, if mild and moderate groups were merged than controls had a significantly higher IQ than the merged group. While the definition of perinatal asphyxia was incongruous with other studies (CPR requirement and abnormal evoked 31 P a g e

54 electroencephalography [EEG] responses), this study provides a positive prognosis for neonates exposed to perinatal asphyxial injury. Despite the presence of minor neuropsychological deficits, the study suggests these do not significant impact on quality of life or long-term potential achievement. There is also a growing suggestion that perinatal asphyxia might play a role in behaviour abnormalities amongst survivors. Perinatal asphyxial insults can cause hippocampal and striatal injuries, with some linking such damage with behavioural issues, such as attentiondeficit hyperactivity disorder and autism spectrum disorders, 258, although this is not an exclusive mechanism of action. Animal models have noted hyperactivity and impulsivity amongst rats with a history of intrapartum asphyxial injury. 281,284, Furthermore, limited studies have noted children exposed to moderate NE have an increased rate of hyperactivity, autistic spectrum disorders, attention-deficit hyperactivity disorders and other behavioural issues. 225, The link between perinatal asphyxial injury and behavioural issues while possible is tenuous and requires more investigation and development of assessment tools prior to any definitive statement being made Multiorgan dysfunction Multiorgan dysfunction is found in nearly all infants with a post-asphyxial hypoxic-ischaemic injury Hypoperfusion of end organs together with hypercapnia and acidaemia produce multiorgan dysfunction, with the extent of damage proportional to the asphyxial insult s duration and severity. 347 This damage is produced as part of the fetus attempts to compensate for asphyxia with a response likened to a diving reflex. Blood is shunted away from non-essential organs, such as the integument & GIT, to essential organs such as the brain, heart and adrenal glands Animal models have suggested fetal hypoxia might also stimulate fetal ventricular output redistribution towards the placenta. 349,360 Increased CNS blood flow due to flow redistribution, whilst intended as a defensive mechanism may precipitate injury, such as intraventricular haemorrhage (IVH). 361 Therefore, it can be assumed that for a fetus to experience inadequate CNS or CVS tissue oxygenation, much greater oxygenation impairment and damage will have occurred in non-essential organs, such as the kidneys, GIT, and liver. Blood flow changes during an asphyxial insult are affected by the responsible mechanism, 357,362 and severity of resulting acidaemia. 354 Jensen et al. demonstrated in a fetal ovine model that during an asphyxial insult, secondary to reduced uterine artery blood flow, 32 P a g e

55 skin, carcass and lung blood flow decreased while blood flow increased to the myocardium, cerebral cortex and adrenals. 357,359 In the partial umbilical cord occlusion asphyxial models, blood flow to skin overlying the head and hindquarters increased three fold with concomitant increased fetal carcass blood flow. 350,362 Furthermore, these haemodynamic changes did not come at the expense of other cardiovascular adaptations to asphyxia. It is hypothesised that the increase in carcass blood flow (during hypoxaemic events associated with reduced umbilical perfusion) might be due to rapid blood flow through the carcass acting as a fast time-constant vascular bed. This would maintain venous return under restricted placental blood flow, such as may occur with umbilical cord occlusion. 350 Perinatal asphyxia has been found to have adverse effects on various organ systems (Table 1.14.). Gao et al. noted organ system dysfunction significantly increased with decreasing Apgar scores and umbilical artery ph values (p<0.05). 363 A strong negative correlation occurred between organ system dysfunction and one (r=-0.548; p<0.01) and five (r=-0.496; p<0.01) minute Apgar scores and umbilical artery ph values (r=-0.578, p<0.05). There are some conditions where there is a direct relationship with intrauterine asphyxia, such as acute tubular and cortical necrosis In other conditions, there are many aetiologies, of which asphyxia might only play a secondary role. For example, necrotising enterocolitis (NEC) is primarily due to IUGR and prematurity, but asphyxia can increase NEC incidence Considerable difference do exists in asphyxia induced multiorgan dysfunction (Table 1.15.); potentially due to lack of a consistent definition. 345 Martin-Ancel et al. evaluated the relationship between clinical and biochemical markers of perinatal asphyxia and multiorgan dysfunction in 72 term neonates with perinatal asphyxia. 379 No relationship was found between umbilical artery ph or MSAF and number of organs involved or severity of organ involvement. The lack of relationship between multiorgan dysfunction and umbilical artery ph had been previously reported in intubated term neonates, although one and five minute Apgar scores did have a significant relationship with frequency and severity of organ involvement (p<0.05). 344 A stepwise logistic regression model of the five-minute Apgar score found a significant association with the number of severely dysfunctional organs (OR 17.5, 95%CI 4.58, 66.9). All neonates with a five-minute Apgar score less than five had severe organ dysfunction in at least one organ, while 90% of those with a score greater than or equal to five had severe organ dysfunction (p<0.001). A relationship between abnormal FHR traces and number of dysfunctional organs was noted; however, further analysis was not possible due to insufficient FHR traces. Together these 33 P a g e

56 finding are consistent with animal models that have shown the diving reflex is not consistently activated, which in turn queries the level of protection that the reflex offers. 356 Table Effects of intrapartum asphyxia on various organ systems Metabolism Metabolic acidaemia Hypocalcaemia Hypoglycaemia Hyponatraemia Hyperinsulinism Elevated liver enzyme Inappropriate antidiuretic Elevated ammonia hormone secretion syndrome Central Hypoxic-ischaemic Brain oedema Nervous encephalopathy Neurodevelopmental System Neonatal seizures abnormalities Haematological Thrombocytopenia Coagulopathies System Disseminated intravascular Increased nucleated red coagulopathies blood cells Renal System Oliguria/anuria Haematuria Acute tubular/cortical Proteinuria necrosis Acute renal failure Myoglobinuria Pulmonary Hyaline membrane disease Pulmonary haemorrhage System Persistent fetal circulation Meconium aspiration Persistent pulmonary Apnoea hypertension of the Surfactant newborn deficiency/dysfunction Respiratory distress syndrome Gastrointestinal Feed intolerance Abnormal motility System Paralytic ileus Necrotising enterocolitis Ischaemic colitis Hepatic dysfunction Cardiovascular Bradycardia Ventricular dysfunction System Hypotension Myocardial necrosis Hypertension Myocardial ischaemia Shock Reduced ventricular function Tricuspid insufficiency Papillary muscle necrosis Congestive heart failure Adapted from Towell, 1988 and Gomella et al., P a g e

57 Table Neonates with perinatal asphyxia and evidence of organ system dysfunction Reference Organ System Central Nervous Gastrointestinal Cardiovascular Hepatic Renal Haematological Pulmonary Metabolic Sexson et al., % 20% 34% 15% 39% Fomufod et al., % 29% 24% 42% 42% 35% 65% Perlman et al., % 11-25% 11-57% 23% Roberts et al., % Shankaran et al., % 50% 54% 36% 86% Cordes, et al % 36% 88% 33% 49% Low et al., % 59% 24% 47% Karlowicz & Adelman, % Martin-Ancel et al., % 29% 29% 42% 26% Korst et al., % 26% 17% 23% 55% Mohan & Pai, % Hankins et al., % 80% 78% 72% 54% Aggarwal et al., % Talati et al., % 30% 43% 44% 36% Note: Blank spaces signify data that was not reported

58 If the diving reflex is a protective mechanism as initially proposed, non-essential organ dysfunction should be greater than essential organ dysfunction after asphyxial insults. There is some statistical evidence in humans to suggest this is not the case with the incidence of renal and cardiovascular dysfunction being similar to the incidence of pulmonary and hepatic dysfunction following severe intrapartum asphyxia. 345 In contrast, there is extensive evidence of consistent fetal ovine cardiovascular response to various asphyxial models and durations , ,357,369, Consequently, there is insufficient evidence to postulate about the role of the diving reflex in humans; however, experimental animal model evidence suggests there might be a protective role. A number of reasons could explain the absence of multiorgan dysfunction in an asphyxiated neonate. Phelan et al. postulated that sometimes asphyxial insults do not progress in a stepwise fashion, with fetal blood flow centralisation and end organ damage. 394 Instead, in acute situations characterised by sudden and profound cardiac output decreases, CNS injury could occur before peripheral damage. The average duration of FHR deceleration in the author s study of CNS injured neonates without multiorgan dysfunction of 32.1 ± 9.1 (range 19 51) minutes supports this hypothesis. Towell et al. postulated that the effects of asphyxia are most apparent on metabolic pathways and the CNS due to these systems being particularly sensitive to the internal biochemical milieu. 381 Others have observed that injury distribution is representative of tissues metabolic requirements, which is disrupted following interference in metabolic substrate supply in acute and severe asphyxial insults. This is reflected in imaging studies, which have noted more damage occurs in areas of the brain with higher metabolic rates. 395 Animal studies also noted increased lactate levels in organs with higher metabolic rates. 396 Accordingly, continual biochemical and clinical monitoring might not reveal multiorgan dysfunction initially but might do so later. 381 The non-linear insult progression proposed by Phelan et al. is consistent with several prolonged studies of multiorgan dysfunction in asphyxiated neonates. Overall, there is a strong association between acute asphyxial injury and multiorgan dysfunction. Occasionally there may be acute hypoxic episodes not accompanied by multiorgan dysfunction; however, most asphyxia will show some evidence of organ dysfunction. When disparities do occur, they tend to occur in neonates suffering from mild to moderate asphyxia, as neonates with severe CNS injuries nearly always exhibit multiorgan dysfunction. 24,250,276,346,369,379,382,385,394,397 reasonable indicator of potential CNS injury. Consequently, multiorgan dysfunction remains a 36 P a g e

59 1.2.5 Neonatal encephalopathy Neonatal encephalopathy is rapidly emerging as the favoured diagnosis for describing the neonate that is clinically unwell at delivery without implying a specific causal pathogenesis. 224,398 Many neonates previously diagnosed with birth asphyxia should now more accurately be diagnosed with NE. Neonatal encephalopathy is a syndrome of disturbed neurological function, based on clinical observations of a neonate born at or close to term. During the week after delivery, neonates typically have difficulty initiating and maintaining respiration, poor muscle tone, reflex depression, altered consciousness, and seizures ,225,399 While the concept of NE, was first delineated by Sarnat and Sarnat in neonates previously exposed to fetal compromise, 400 since then at least 12 definitions have been detailed, 401 complicating diagnosis and study. The aetiology of NE differs depending on the evaluated population and local medical care. 402 In developed nations, intrapartum hypoxia and ischaemia is responsible for only a small number of NE cases, with NE typically originating in the antepartum or postpartum period ,403 Badawi et al. found over 70% of term neonates with NE had no evidence of intrapartum asphyxial insult, 43 although other studies have noted evidence of intrapartum asphyxial injury in 50% of NE. 41 Magnetic resonance imaging studies suggest that despite the role of antenatal and genetic risk factors there is often imaging evidence of acute insults. 46 That being so, NE has been shown to have a heterogeneous aetiology including infections, congenital, placental, maternal and genetic anomalies or diseases. 41,43-44,235,402, Further, amongst neonates with NE attributed to perinatal asphyxia only 25-35% have identifiable sentinel events. 413 Few studies of neonatal outcomes following NE have been undertaken and those that have are typically retrospective and limited to populations that experience significant adverse outcomes, such as CP and death. 414 In those population studies it has been found that NE carries a significant risk of developmental delay, especially in speech and hearing by two years of age. 41 Of those without severe neurodevelopmental impairment it is estimated 10% have clinically significant developmental delay, with more subtle delays only apparent in later life. 414 In developed countries the prognosis of mild NE is good with little chance of significant morbidity or mortality. 399, In contrast, in developing countries, even mild NE has been associated with excess mortality. 417 As expected, neonatal outcome is worse with more severe NE In one study, abnormal neurodevelopment occurred in 25% of survivors of 37 P a g e

60 moderate to severe encephalopathy. 418 Interestingly, improvement in NE grade has been found to suggest increased neonatal resiliency to asphyxial injury and is a favourable prognostic indicator. 419 It s given that asphyxia on a scale significant enough to cause long-term CNS injury nearly always causes neurological dysfunction during the early neonatal period. In a Western Australian study of children at least five years old, Badawi et al. found at least 25% of children with CP had moderate or severe NE. 33 That being so, a follow-up study of 143 neonates with NE noted only 16 (12%) had CP (Figure 1.6.), although an additional 33 children (23%) died or experienced other neurodevelopmental issues. 420 Twelve (92%) CP cases had low Apgar scores, early onset acute evolving NE, acidosis, renal dysfunction and no antenatal risk factors suggesting an acute intrapartum event and potentially HIE. The former finding concurs with earlier studies, such as Gaffney et al. who evaluated 141 children with CP noting 100 (71%) had no signs of NE. 421 That being so, NE presence influenced the CP type, with neonates with NE more likely to develop quadriplegia (OR 4.8; 95%CI 2.2, 10.5), and less likely to have hemiplegia (OR 0.3; 95%CI 0.1, 0.8) than counterparts without NE. Amongst neonates exposed to NE, motor disability was more profound with a greater proportion of five year olds unable to walk independently (OR 4.0; 95%CI 1.8, 8.8). Additionally, there was an increased frequency of impairments in NE cases, such as visual impairment (OR 3.0; 95%CI 1.0, 8.6), intellectual delay (OR 2.5; 95%CI 1.1, 5.7), and swallowing difficulty (OR 3.1; 95%CI 1.4, 6.9). It is likely the relationship between NE and CP is stronger in developing countries due to increased prevalence of hyperbilirubinaemia, infections, and traumatic injuries, 422 which are significantly associated with both NE and CP. Pierrat et al. followed 90 neonates with moderate to severe NE for two years. 41 Twenty four (27%) died within the neonatal period with another three (3%) dying due to congenital abnormalities prior to follow-up. Amongst the 63 (70%) survivors, 40 (63%) were considered neurologically normal, eight (13%) had minor neurological dysfunction and 11 (17%) had CP with the remaining four lost to follow-up. A study of 1,099 high-risk NICU patients from a tertiary level neonatal unit noted those with NE were twice as likely to have a later CP diagnosis than their counterparts (OR 2.2, 95%CI 1.4, 3.5; p<0.001). 423 This difference persisted after multivariate analysis (OR 2.4, 95%CI 1.3, 4.6; p=0.008). The presence of NE also affected the nature of CP with non-spastic CP being more likely than spastic CP (OR=3.6, 95%CI 1.2, 10.9; p=0.02). Neonatal encephalopathy was the only 38 P a g e

61 significant neuroimaging and neonatal characteristic variable associated with CP severity (Severe vs. moderate/mild; OR=5.2, 95%CI 2.2, 12.4). Figure 1.6. Relationship between neonatal encephalopathy and cerebral palsy Neonatal Encephalopathy (n=143) Died (n=15; 10%) Neurodevelopme ntal Abnormalities (n=34; 24%) Normal (n=94; 66%) Cerebral Palsy (n=16; 12%) Adapted from Evans et al., Neurodevelopme ntal Disability & Handicap (n=12; 8%) Neurodevelopme ntal Disability without Handicap (n=6; 4%) Robertson et al. assessed 145 newborns with NE at 8 years of age. 424 The IQ, visuomotor integration and receptive vocabulary scores, reading, spelling and arithmetic grade scores for those with moderate and severe encephalopathy were significantly below controls. Unimpaired moderate encephalopathy survivors were more likely to be at least a grade level delayed than controsl. 424 Similar results were noted by Odd et al. when studying 426 neonates requiring resuscitation at delivery. 425 Significantly more neonates with NE had low performance (p<0.001) and full-scale (p<0.001) IQ scores than their asymptomatic counterparts. Barnett et al. collated information concerning the outcome of 123 neonates delivered at Hammersmith Hospital (London, UK) with NE between May 1991 and September Sixteen children (13.0%) died in the neonatal period or early infancy, and 10 (8.1%) had genetic, viral, metabolic or congenital associated abnormalities. Of the 80 available for follow-up, 32 developed CP (40%), primarily severe spastic quadriplegia (n=20; 62.5%) but also mild quadriplegia/diplegia (n=3; 9.4%), athetoid CP (n=3; 9.4%), hemiplegia (n=5; 15.6%), and ataxic CP (n=1; 3.1%). Of the children with CP, 25 (78.1%) had additional 39 P a g e

62 cognitive and sensory impairments. Fifty five children underwent testing at five to six years of age; with 37 children (67%) having scores above the 15 th centile for motor competence while 18 children (33%) had scores below, with 10 of the latter having scores less than the 5 th centile. Only 53 children had cognitive function assessed with 45 (85%) having an IQ greater than 84. Additional MRI examination of 39 children, found 17 neonates (43.6%) had white matter lesions without basal ganglia involvement, while 14 neonates (35.9%) had basal ganglia lesions with or without white matter changes. 427 Imaging of CNS visual areas revealed, 11 neonates (28.2%) had abnormal optic radiations and/or primary visual cortex injury. At follow-up, 16 children (41%) had abnormal results in at least one visual tests, with seven children having profound enough visual impairment to prevent further testing. A direct correlation between neonatal MRI injury severity and visual impairment was identified, with visual impairment present in all children with moderate-severe basal ganglia injury or significant white matter changes. Lindstrom et al. evaluated all 97,468 neonates delivered in Sweden in 1985 focusing on 684 neonates with a five minute Apgar score less than seven. 342 Review of obstetric and neonatal records identified 56 moderate-severe NE cases of which 43 were available for follow-up at years of age (Figure 1.7.). Fifteen (30%) neonates had major neurodevelopmental abnormalities, such as CP. Amongst those without major neurodevelopmental abnormalities, 20 (71%) had significant cognitive dysfunction, with eight neonates (19%) having no cognitive or neurodevelopmental abnormalities. Based on the Trent Neonatal Survey (UK) 1992 to 1994 database, Marlow et al. identified 65 neonates with moderate to severe NE that were followed for seven years. 343 Fifteen neonates (23%) were diagnosed with CP of which eight (12%) required specialised schooling due to severe cognitive impairment, with individuals exposed to severe NE at greater risk of later neurodevelopmental issues (6% vs. 42%). Of the 50 children without CP, there was a significant impact on cognitive development. The mean IQ difference to controls was greatest amongst with previous severe NE (-11.3 points; 95%CI -19.0, -3.6). For those exposed to moderate NE the average IQ was lower than non-ne controls (-1.7 points; 95% CI -7.3, 3.9), but the CI crossed zero. In neuropsychological testing, children exposed to moderate NE performed worse than those not exposed, with those exposed to severe NE performing worst. An earlier study noted amongst those with a NE history but no other significant medical conditions, a lower Griffiths developmental scale scores at one to two years old. 414 Further, there was a significantly greater proportion with clinically evident developmental delay. Consequently, it can be seen that following NE even without 40 P a g e

63 neuromotor abnormalities, a significant proportion suffers from cognitive impairments. While considerable attention is focused on neonates with NE that develop major disabling conditions, such as CP, there remains a large subset of less affected NE survivors with the potential to cause considerable financial and social costs. Figure 1.7. Swedish 1985 birth cohort and neonatal encephalopathy outcome at years old 1985 Swedish Deliveries (N=97,468) Low Five Minute Apgar Score (<7) (n=684) Available for Follow- Up at Years (n=560) Lost Neonatal Records (n=51) Died (n=73) Moderate-Severe Neonatal Encephalopathy (n=56) Neonatal Death (n=60) Childhood Death (n=13) Cerebral Palsy/Major Neurodevelopmental Abnormalities (n=15) No Major Neurodevelopmental Abnormalities (n=28) Declined Participation (n=13) Abnormal Cognition (n=20) Normal Cognition (n=8) Adapted from Lindstrom et al., P a g e

64 1.2.6 Hypoxic-ischaemic encephalopathy Hypoxic-ischaemic encephalopathy is a NE subtype first described in recognition that not all NE is due to perinatal asphyxial injury. 428 That being so, NE and HIE are often used interchangeably, despite being distinct clinical entities with different aetiologies, 399,401, with others avoiding HIE due to the difficulty in establishing hypoxic-ischaemic injury. 25,429,431 Although HIE by definition is due to a hypoxic-ischemic insult, the responsible hypoxicischaemic injury might occur throughout the perinatal period. Other conditions can produce a similar clinical picture to HIE, including haemorrhage, hypoglycaemia, infection and metabolic abnormalities. 428, At delivery the neonate frequently has low Apgar scores and difficulty initiating and maintaining respiration. Later there might be changes in muscle tone, appearance, heart rate, and stimulation responsiveness (Table 1.16.). By convention, HIE diagnosis is confined to term neonates as the immature CNS in preterm neonates often exhibits non-hypoxic-ischaemic injuries, 436 with clinical hypoxic-ischaemic injury markers often complicated by prematurity. That being so, HIE or similar post-asphyxial neurological injuries have been described in preterm neonates. 271, Despite this, HIE is generally regarded as the best clinical end point for evaluating intrapartum hypoxia. 438 While HIE is rare with an incidence of one to six per 1,000 deliveries (Appendix D), 38-39, it is not as rare as other adverse outcomes, and has a much less contentious aetiological link. 53 In fact, HIE is one of the essential characteristics of the guidelines of an acute intrapartum hypoxic event ,442 The prognosis of HIE is particularly dependent on the initial severity. Neonates with grade one HIE typically recover without long-term neurodevelopment sequelae, while most neonates with grade three HIE die in the neonatal period or suffer from long-term neurological sequelae. 316,415,424,438, Finer and Robertson et al. have completed one of the most extensive evaluation of neonatal prognosis following HIE in a series of articles published in the 1980s. 424,452,457, The first study by Finer, Robertson and colleagues of 89 term HIE cases followed for between three months and four year, noted 7% died prior to follow up. 462 Amongst the survivors, 65% were considered normal or minimally handicapped, while 28% were significantly handicapped. A significant relationship between HIE stage and neonatal outcome was noted (p=0.001), with no mild HIE case having significant morbidity or mortality, whilst all those with severe HIE either suffered from significant handicap or died. In 1983, the authors conducted a similar study on 49 term neonates followed up at P a g e

65 months of age, again identifying a significant association between encephalopathy grade and outcome (p=0.026) (Table 1.17.). 457 Table Grading of hypoxic-ischaemic encephalopathy Variable Stage I Stage II Stage III Consciousness Alert Lethargic Comatose Muscle Tone Normal, or Hypotonic Flaccid hypertonic Tendon Reflexes Increased Increased Depressed or absent Myoclonus Present Present Absent Seizures Absent Frequent Frequent Complex Reflexes Suck Active Weak Absent Moro Increased Incomplete Absent Grasp Normal Increased Absent Oculocephalic Normal Increased Depressed or absent Autonomic Function Pupils Dilated & reactive Constricted & reactive Respiration Regular Periodic and/or variable Heart Rate Normal or Bradycardia tachycardia EEG * Normal Low voltage, periodic, or paroxysmal Adapted from Hankins et al., Note: * Electroencephalogram Variable or fixed Ataxic and apnoeic Bradycardia Periodic or isoelectric Table Relationship between neonatal encephalopathy grade and neonatal outcome at months of age Outcome Encephalopathy Grade Mild Moderate Severe Normal 7 (14%) 21 (43% 0 (0%) Mild Handicap 0 (0%) 13 (27%) 0 (0%) Moderate Handicap 0 (0%) 7 (14%) 1 (2%) Severe Handicap 0 (0%) 0 (0%) 0 (0%) Adapted from Finer et al., The earlier studies by Finer et al. were amalgamated into a cohort of term neonates with HIE with detailed neurodevelopmental examination at six, twelve, twenty seven months and three and a half, five and a half, and eight years of age. 452 Detailed follow-up was available on 200 children (88.5%) at three and a half years (three children were seen after five years of age). Of the initial 226 children enrolled, 26 died due to HIE or associated complications with an 43 P a g e

66 in-hospital mortality rate for moderate HIE of 2.5% and 50% for severe HIE. At follow-up 38 children were diagnosed with some degree of HIE related handicap (Table 1.18.) Table Types of neurodevelopmental disorders experienced by the handicapped survivors Neurodevelopmental Disorders Number (Percentage) Cognitive Delay 22 (57.9%) Cerebral Palsy 20 (52.6%) Spastic Quadriplegia 14 (36.8%) Spastic-Athetoid Quadriplegia 2 (5.2%) Athetoid Quadriplegia 1 (2.6%) Spastic Right Hemiplegia 3 (7.9%) Convulsive Disorder 13 (34.3%) Visual Loss 11 (28.9%) Visual Impairment (< 20/60) 7 (18.4%) Legal Blindness (<20/200) 4 (10.5%) Deafness (>70 db) 4 (10.5%) Adapted from Robertson and Finer, Amongst children with mild HIE there were no reports of major neurodevelopmental handicaps, or mortality during the neonatal/early childhood period. Of those with moderate HIE, 24 (20.7%) survivors to discharge developed one or more handicaps, of which two with severe convulsive disorders died. Amongst those with severe HIE, seven died following discharge with only 25% surviving to three and a half years of age. Severe HIE survivors all had one to four major neurodevelopment handicap as well as significantly lower scores than those with moderate and mild HIE (Table 1.19.). Those with moderate HIE had significantly lower scores than mild HIE cases; while children with mild HIE had average scores on standardized measures. By eight years of age the cohort available for analysis was 77% of the original (n=174) with follow-up losses confined to mild (n=23), and moderate (n=29) HIE cases. 424 Those remaining were compared with 155 randomly selected control peers. Scholastically, 20% of controls were receiving educational assistance. Amongst those exposed to HIE, 11% of mild, 38% of moderate and 100% of severe were receiving similar assistance. Psychoeducation scores were significantly worse amongst those with moderate to severe HIE, but no difference was noted for mild HIE (Table 1.20.). Amongst those with a HIE history, 23 had significant neurodevelopmental disorders (16%), including CP, deafness, seizure disorders or cognitive delay. No mild HIE cases developed neurodevelopmental disorders; however, all those with severe HIE did. Amongst non-impaired children with 44 P a g e

67 moderate HIE there was no difference in visual-motor integration, or receptive vocabulary scores to controls, although IQ scores were lower (p<0.001). Those exposed to moderate HIE were likely to be at least one school grade behind control or mild HIE counterparts. These findings were echoed in a latter review that noted HIE survivors without motor disabilities were more likely to have a cognitive impairment. 463 Amongst children with neurodevelopmental disorders the majority had reading, spelling or arithmetic delay (72-100%). There was a significant correlation between HIE grade and eight year old reading (Pearson r=0.42; p<0.001), spelling (Pearson r=0.44; p<0.001) and arithmetic (Pearson r=0.41; p<0.001) levels. Table Influence of the grade of hypoxic-ischaemic encephalopathy on neurodevelopmental status at three and a half years old HIE Grade Mild (n = 66) Moderate (n = 94) Severe (n = 7) P-Value Handicapped 0% 21.3% 100% <0.001 Fine motor skill delay (>6 mths) 1.5% 14.9% 100% <0.001 Gross motor skill delay (>6 mths) 4.5% 18.1% 100% <0.001 Visual-Motor Integration (5.7) -4.7 (10.1) (3.3) <0.001 Stanford-Binet IQ (14.0) 92.3 (23.2) 37.1 (26.7) <0.001 Peabody Picture Vocabulary IQ (13.7) 92.8 (17.2) 71.7 (7.2) <0.001 Mean utterance length * 0.99 (1.4) (1.9) (0.4) <0.001 Adapted from Robertson and Finer, Note: Ordinal or continuous variables described with percentages; Continuous variables described with mean (standard deviation); * Expressed in standard deviations representing degree of deviation from chronological age prediction. Table Comparison of psychoeducation scores at eight years of age between encephalopathy grade and peers Encephalopathy Grade Peer Group Mild Moderate Severe (n=155) (n=56) (n=84) (n=5) Full-Scale Intelligence Quotient 112 (23) 106 (13) 95 (23) 48 (21) Visual-Motor Integration 9.3 (2.7) 9.0 (2.3) 7.4 (3.1) 0.4 (0.5) Receptive Vocabulary 100 (13) 99 (13) 87 (23) 36 (7) Adapted from Robertson et al., Note: Significantly different (p<0.001) from peers. Together it can be seen that, mild HIE has a good prognosis with no major neurodevelopmental handicaps, while most neonates exposed to severe HIE either die or experience severe neurodevelopmental handicaps. Presence of additional neurological problems at discharge does not seem to be predictive of adverse outcome; however, 45 P a g e

68 continuing presence of neurodevelopmental problems is associated with significantly worse prognosis. The presence of additional neurodevelopmental issues does not have as profound an influence on later outcome as the initial insults severity as demarcated by HIE grade. Even amongst neonates that do not develop major neurodevelopment issues there is a growing body of evidence noting cognitive, intellectual, and neurological deficits. Nagy et al. conducted MRI studies on nine adolescents delivered at term and subsequently diagnosed with moderate HIE. 464 All nine adolescents had seizures during the neonatal period with neonatal ultrasound revealing neurological damage in three of the eight it was performed on (38%). At follow-up, IQ tests noted three adolescents (33%) scoring below 70, three (33%) scoring between 70 and 85, and the remainder having scores greater than 85. Overall eight (89%) adolescents had some degree of cognitive problems, primarily with memory and attention. Similarly, Lindstrom et al. evaluated 43 adolescents (15 to 19 years of age) with previous NE, five-minute Apgar scores less than seven and no alternative aetiologies, and found 81% had cognitive dysfunction. 465 The MRI results demonstrated that even without significant and obvious neurological impairments, such as CP, significant white matter damage was still present. This damage persists despite neuronal plasticity and children s ability to adapt to severe neurological injuries suggesting that while impairment can be compensated to some degree (i.e. no major functional impairment) it is not completely effective. A recent review of outcomes following HIE evaluated term neonates that partially fulfil ICPTF guidelines for acute intrapartum hypoxic events. 448 The authors identified over 3,000 articles demonstrating neurological abnormalities following hypoxic-ischaemic insults; however, only 42 reported term neonatal outcomes that were not duplicated and had clear study inclusion criteria. Further evaluation revealed most studies described neonates with NE without readily identifiable intrapartum hypoxic-ischaemic insults. Amongst studies that did the finding was usually based on a single diagnostic marker. Thirteen studies were identified as meeting inclusion criteria, namely reporting term neonates with moderate-severe NE and metabolic acidosis. 41,187,192,271,316, Amongst the 13 studies there was significant heterogeneity (I 2 =87.7%; p<0.001). Overall, 47% of neonates (95%CI 36%, 57%) with HIE developed adverse outcomes, such as motor or cognitive impairment greater than two SDs below the norm, CP or death. If analysis was confined to neonates followed for less than three years than the proportion of adverse outcomes was 44% (95%CI 34%, 55%), although significant inter-study heterogeneity remained (I 2 =87.6%; p<0.001). 46 P a g e

69 Whilst HIE was originally defined to better distinguish neonates suffering from hypoxicischaemic insults, interchangeable utilisation of NE and HIE has lead to considerable confusion, which is regrettable given that once a neonate is diagnosed with a hypoxicischaemic induced injury it is difficult to revise the diagnosis based on later information. Consequently, there has been a move by some, such as the World Federation of Neurology Group for the Prevention of Cerebral Palsy and Related Disorders, towards wider (i.e. NE) rather than narrower definitions (i.e. HIE). 235,240, Neonatal seizures Numerous authors consider intrapartum asphyxia as a major aetiological factor for neonatal seizures within 48 hours of delivery, particularly amongst term neonates. 429, Some have postulated that early neonatal seizures might provide an indicator of the quality of perinatal care That being so, there is a diverse range of factors that can play a role in the aetiology of neonatal seizures (Table 1.21.), with aetiology appearing to vary with gestational age Clinically significant acidosis has been found in only 30% of neonatal seizures. 484 Imaging studies have noted that a significant proportion of seizures within 72 hours of delivery have MRI evidence of acute haemorrhagic or ischaemic injuries, 46 although antenatal and genetic factors cannot be ruled out. Together these factors appear to restrict neonatal seizures use as an index of perinatal care. The National Institutes of Child Health and Human Development concluded that early neonatal seizures were one of the best indicators of later neurological damage amongst term neonates. 485 Amongst neonates with NE, those with seizures were three times more likely to develop CP than their counterparts with NE alone (16% vs. 6%; OR 3.4; 95%CI 1.14, 10.2; p=0.04). 414 As part of the National Collaborative Perinatal Project (NCPP), Holden et al. reviewed 277 newborns with neonatal seizures, finding a mortality rate of 35%. 486 Amongst 181 survivors followed for seven years, 70% were normal. At one year of age, 13% had CP, 19% had significant mental retardation (IQ < 70), and 18% had epilepsy. Further, 13% of survivors had a combination of mental retardation, CP, and/or epilepsy. These findings concur with an earlier study noting neonatal seizures were one of the strongest independent predictors of neurological dysfunction at seven years of age. 487 Even amongst normal children significant deficits may persist, with follow-up of normal teenagers, attending normal schools with normal overall intelligence scores noting neuropsychological impairment in intelligence, spelling and memory P a g e

70 Table Selection of aetiological factors implicated in neonatal seizures Acute Metabolic Conditions Cerebrovascular Conditions CNS Infections Hypoglycaemia Hypocalcaemia Hypomagnesaemia Hyponatraemia Intracerebral haemorrhage Intraventricular haemorrhage Subdural haemorrhage Subarachnoid haemorrhage Bacterial meningitis Viral meningoencephalitis Hypernatraemia Neonatal withdrawal syndrome Iatrogenic fetal exposure to local anaesthetic Inborn errors of metabolism Arterial and/or venous ischaemic stroke Extradural haemorrhage Periventricular haemorrhage Intrauterine acquired congenital infections Acquired or Developmental Conditions Cerebral dysgenesis Hypoxic-ischaemic encephalopathy Hypertensive encephalopathy Genetic syndromes Benign neonatal familial convulsions Benign neonatal sleep myoclonus Early myoclonic encephalopathy Neonatal epileptic syndromes Congenital anomalies Idiopathic Benign idiopathic neonatal convulsions Adapted from Levene and Trounce, 1986; Evans and Levene, 1998; Tekgul et al., 2006; and, Silverstein and Jensen, , One of the earliest studies (N=131) investigating the relationship between neonatal seizures and adverse outcomes noted that 39% were normal, although 5% died prior to follow-up. 492 Amongst the remainder 13% had minor non-disabling neurodevelopmental abnormalities, 19% had moderately disabling abnormalities, and 23% had severely disabling abnormalities. Most children with motor handicaps had IQs below 70, as did a significant proportion of those with sensory abnormalities. Seventy-seven were considered to have been exposed to hypoxic-ischaemic insults (history of hypoxic-ischaemic events or early neonatal findings) with 41 (53%) developing moderate to severe neurodevelopmental handicaps. A study of 40 neonates with at least one seizure prior to 29 days of age, noted at four to six year follow-up that two had died (5%), 16 had adverse or borderline adverse outcomes (40%) but most were normal (n=22; 55%). 481 Another study of 89 term neonates with seizures within 48 hours, found 18% (n=15) died while of the 70 survivors, 30% (n=21) had significant handicaps, including CP, mental retardation, epilepsy or sensory deficits. 493 A retrospective cohort study of 227 neonates with five minute Apgar scores less than seven identified 27 neonates with seizures within 24 hours of delivery. 455 The majority of seizures occurred repeatedly but were of a short duration and responded to treatment. Eleven 48 P a g e

71 neonates (41%) died with five having repetitive seizures resistant to treatment. Of the survivors, nine (33%) were neurologically normal and seven (26%) had neurodevelopmental abnormalities. Studies of neonates with EEG seizure evidence noted that even neonates without clinical manifestations of seizures could have significant sequelae. Scher et al. studied 92 neonates with EEG confirmed seizures, with 46 (50%) dying within the neonatal period. 483,494 Amongst the 46 survivors followed up for between nine and seventy-two months, 48% (n=22) were considered to have significant neurodevelopmental abnormalities, while 7% (n=3) had mild clinical abnormalities without functional impairment. A similar study concurred noting unfavourable outcomes occurred in 70%; with 13 dying prior to followup. 495 Amongst survivors, 56% had epilepsy, 67% developmental delay, and 63% CP. More recent studies of neonates with seizures have noted reduced mortality in the first year; however, significant proportions of survivors still experience adverse long-term neurological outcomes. 491,496 There was a strong association between seizure aetiology and outcome, with seizures related to cerebral dysgenesis or global hypoxia-ischemia having a worse prognosis than other aetiologies. 491, Seizure timing has been found to be related to adverse neonatal outcome, with seizures within 24 hours of delivery associated with a higher degree of neurodevelopmental morbidity and mortality (48% vs. 24%; p=0.049) Cerebral palsy Cerebral palsy is a symptom complex rather than disease, which despite having an incidence of one to three neonates per 1,000 live births in developed nations, is the commonest childhood motor disorder (Appendix E) Cerebral palsy is not a distinct entity or diagnosis but rather a heterogeneous collection of conditions located on a continuum between minimal cerebral dysfunction and profound mental retardation and floppiness. These conditions are typically grouped together to allow better management of habitation and other support services. 506,508 Until the late 1990s, CP was defined as a non-progressive yet persistent neurological condition, due to brain defects or lesions acquired at the time of rapidest CNS development, manifesting with movement and/or posture disorders. 509 In 2005, the definition was revised to include, sensory, cognitive, communication, perception, behavioural, musculoskeletal or seizure disorders, although authors had been describing CP s association with such disorders for some time These co-morbidities result when lesions extend beyond the motor tract into other parts of the brain P a g e

72 Diagnosis of CP is based on clinical description independent of pathological and aetiological findings; therefore CP cannot be easily diagnosed in the neonatal period or those who die inutero. 34,516 Many clinical signs of CP are not readily apparent at birth, and those signs present can resolve spontaneously, thus the CP diagnosis cannot be made with great confidence until school starting age (approximately four-six years old, although others have suggested two years of age). 414,499,501, A variety of slowly progressive neurodegenerative disorders and metabolic conditions can mimic CP and cannot be readily differentiated till later childhood; these include Lesh-Nyhan Syndrome, Rett Syndrome and Glutaric Aciduria Type One. 513,521 Diagnosis is further complicated by a significant proportion of children with CP having other cognitive, sensory, neurological, gastrointestinal, and nutritional impairments. 510,518, While a perinatal history can raise suspicion of a CP diagnosis, single abnormal physical signs are not diagnostic, rather there must be a cluster of clinical findings acting together. 539 The most controversial aspect of CP remains its aetiology, while for most CP cases the aetiology is unknown, it has been estimated that approximately two thirds have at least a partial antenatal origin. 514,516, The aetiology of CP has been broadly divided into three areas in which causative insult occurs, namely antenatal, intrapartum, and postnatal. To consider each region as distinct discrete entities is incorrect. 544 A single aetiology directly causing CP in a particular period is a rare event, instead causal factors typically act in summation incrementally producing damage and/or increasing the fetus vulnerability to future insults Since, CNS development occurs throughout the antenatal period and extends into the postnatal period it is more vulnerable than other fetal organs, thus insults producing severe neurological deficits can occur at any time. In-depth discussion of the aetiology of CP is beyond the scope of this thesis; numerous factors have been implicated with different aetiologies postulated for different populations, 506,516,519, and different CP types. 510,518,554, The base pathology is probably white matter damage due to periventricular leucomalacia, cystic lesions, diffuse hypoxicischaemic injury, cerebrovascular accidents or intracranial haemorrhage with the CNS area affected related to injury onset. 487,554,560, Postulated aetiologies for CP involve endocrine pathways, 542, infections, 224,410,550,575, coagulation defects, iodine deficiencies, congenital anomalies, 35,614 and vanishing twin syndrome. 519,552,555, In developing countries acquired conditions, such as hyperbilirubinaemia, Rhesus isoimmunisation, perinatal asphyxia, and CNS infections, are the primary aetiological factors. 422,551, Cases due to infection and Rhesus isoimmunisation are relatively rare in developed countries, with 50 P a g e

73 cases associated with prematurity and low birth weight more prevalent. 506,627 That being so, even in developed countries, a higher CP risk can be found in neonates with unskilled manual workers as parents, indicating possible environmental factors as a causative agent, although this is debated by others. 631 Parental socio-economic status has been shown to influence CP prevalence, although this is once again controversial. 635 Aetiology of postnatal acquired CP is easier to ascertain and is typically trauma, cerebrovascular accidents, gastroenteritis, cerebral anoxia or infection occurring after the 28 th postnatal day. 629, In developed nations, post-natal CP has decreased due to advances in medicine, technology and public health Summary of adverse outcomes resulting from intrapartum asphyxial insults Adverse outcomes after labour are rare and include perinatal death, CP, multiorgan dysfunction, HIE, NE, neonatal seizures, and metabolic acidaemia. Of these conditions, HIE and metabolic acidaemia can be assessed at birth, have a strong link to intrapartum asphyxial injury and have a frequency adequate to evaluate in a study population of 20,000 to 30,000 deliveries. 1.3 Predictors of adverse outcomes associated with labour Current predictors of adverse outcomes Currently there is no gold standard test for perinatal asphyxia with fetal compromise, acidaemia, Apgar scores and other clinical predictors all having low positive predictive values (PPV). Moreover, many of these predictors are expensive and not applicable in developing nations where most neonatal deaths occur and few deliveries have skilled medical or paramedical staff members in attendance. 4 Predictors of asphyxial injury have evolved from initial process based forms (e.g. long labour) to more symptom based predictors (e.g. Apgar scores) to multifaceted outcome measures used today (e.g. UCBGA). These multifaceted outcome measures have greater clinical relevance as they are more likely to reflect adverse outcomes as well as being more objective and consistent Risk factor assessment In an ideal world there would be a failsafe screening method to identify those at risk of perinatal asphyxia, that is cheap, effective and able to be universally performed without extensive technological requirements. 640 Currently, this role is fulfilled by identification early 51 P a g e

74 in pregnancy or preconception of complications and factors associated with increased risk of fetal asphyxia While risk factor assessment is almost universally utilised to assess perinatal morbidity and mortality risk, there are several major limitations. 644 Given an accurate gestational age and fetal weight the probability of fetal metabolic acidaemia in a singleton can be estimated in 15-50% of neonates. 640 In developed nations, accurate determination of gestational and weight is typically done using ultrasonography. Disregarding that the expense of routine ultrasounds could be potentially limiting, 645 numerous authors have noted that there are additional issues with ultrasound prediction of fetal weight and gestational age Accuracy of gestational age assessment is dependent on gestation at which ultrasound is performed with the degree of error increasing with gestational age. 650 Fetal weight calculations are based on standardised neonatal formulas, with the inherent accuracies greatest at the extremes; however, accuracy can be improved by multiple measurements and fetal growth plots. 646, Predictive value of risk factor assessment Initially, risk factor assessment was intended to identify the fetus at risk of death, with scoring systems able to identify 30% to 35% of fetuses at risk of metabolic acidaemia. 640 Since this section of the population is at a substantially increased risk of perinatal mortality, these criteria identify 75% of total population morbidity and mortality. 654 That being so, studies have documented that to obtain sufficient sensitivity to predict perinatal mortality, a sizable proportion of pregnancies needed to be identified as at risk, usually greater than 50% , Low et al. asserted in 1981 that antepartum and intrapartum risk factors were an appropriate way to identify those at risk of metabolic acidaemia; however, such a criteria set would detect a 20% incidence of metabolic acidaemia. 640 Given that the incidence of intrapartum fetal asphyxia is 0.5% in the developed world, 32,39 any such assessment protocol will have a low PPV, while large numbers of false positives would potentially lead to unnecessary interventions. 642 More recently, Low et al. found a significant proportion of metabolic acidaemia occurs in pregnancies without antepartum and intrapartum risk factors At least 50% of neonates with metabolic acidaemia had no risk factors prior to labour and 30% had no antepartum or intrapartum risk factors. Those with no antepartum or intrapartum risk factors, composed 23% of neonates with moderate to severe asphyxia, while those without antepartum risk factors accounted for 40%. 643 There was no difference in asphyxia severity between those with and without risk factors. 642 Data from the NCPP suggests that 52 P a g e

75 while pre-pregnancy and antenatal factors are correlated with CP the predictive ability was very low (R 2 < 0.1), and remained low under multivariate analysis. 542 Low et al. concluded that risk factors might be secondary indicators for or suggest earlier intervention, and severe risk factors might in isolated cases be the primary indicator for intervention Relatively complicated predictive models have been developed to establish obstetric risk including demographic, obstetric, intrapartum and neonatal factors. An obstetric optimality score including 74 separate criteria, had a statistically significant relationship with neonatal neurological outcome (p<0.001); however, there was a poor correlation between the two (Spearman s r=0.144). 193 Another model was more sensitive (89.4%) and specific (92.4%); however, it encompassed ambiguous and subjective factors, such as dysfunctional labour and difficult delivery, were only able to be determined after labour had been established or neonate delivered. 658 Various early scoring systems were reported as having reasonable success in predicting adverse outcomes; however, these were evaluated using contemporaneous statistical methods, which are limited in comparison to those now available. Therefore, while formalisation of risk factor analysis is desirable, the cumbersome nature and volume of information required makes it practically difficult Role of risk factor assessment today Fetal asphyxial injury can occur in pregnancies with a history of antepartum or intrapartum risk factors; however, perinatal asphyxia also occurs in pregnancies without risk factors. Therefore, there are no pregnancies that can be stated as being, according to presence or absence of risk factors, at low risk for intrapartum asphyxial injury. Recently, the usefulness of clinical risk assessment has decreased due to the improvement in general maternal health status as well as the decreased incidence of perinatal asphyxia and its related complications. Risk factor assessment to predict fetal asphyxia and metabolic acidaemia suffers from limited sensitivity and specificity, 640,643 and therefore cannot be used reliably in a formalised manner. That being so, risk factor assessment will remain in use due to its ability to be rapidly utilised without extensive technological requirements Intermittent auscultation Whilst there is discussion over the responsibility for the incidental discovery that the fetal heart could be asucultated it is considered by many to be the beginning of modern obstetrics Fetal heart auscultation made it possible for the first time to accurately diagnose fetal death, multiple pregnancy, as well as fetal presentation and position prior to 53 P a g e

76 labour. 663 Intermittent auscultation (IA) was the prevailing method of intrapartum fetal assessment until EFM s introduction in the late 1960s, from which time its use has steadily declined That being so, IA use as a supplementary or preliminary method of intrapartum fetal monitoring remains relatively widespread due to the low resource implications involved. Further, there is a growing revival in utilisation following a series of RCTs in the later part of the 20 th Century comparing IA and EFM. A number of authors have noted that auscultation can detect fetal bradycardia and tachycardia as well as changes in FHR rhythm and FHR accelerations, although there is some debate about the quality of information obtained about the latter Part of the Collaborative Study of Cerebral Palsy, Mental Retardation, and Other Neurological Diseases and Blindness evaluated IA in 24,863 singletons. 672 Whilst they noted associations between FHR parameters and perinatal morbidity and mortality they concluded: No reliable single auscultatory indicator of fetal distress exists in terms of fetal heart rate (FHR), save in an extreme degree. 672 This is evidenced by NCPP studies that noted that while a bradycardia of less than 100 bpm occurred in 6% of fetuses it was not independently associated with later CP. 673 If the FHR was auscultated at below 60 bpm, which occurred in 1% of fetuses, then there was a significantly increased CP risk (5.7% of those with CP had a FHR < 60 bpm), although there was a 98% false positive rate. Auscultation provides insufficient information concerning FHR variability and while an impression of FHR decelerations might be obtained, specific information about duration, amplitude and recovery required to accurately describe deceleration types is lacking. 674 Intermittent auscultation requires technical expertise and skill. Some have noted that there is inadequate education and preparation prior to performing IA as well as insufficient on-going education. 665 Further others have highlighted the potential degradation in skills due to reliance on EFM Considerable variation in individuals interpretation of baseline FHR, as well as deceleration duration and nadir has been noted in non-clinical controlled environments even with prior warning about impending deceleration. 674 The requirement for a one to one staffing for IA is a major issue given the shortage of experienced midwifery and medical personal The majority of studies demonstrating the utility of IA have one to one midwife to patient ratios with a strict auscultation schedule. 54 P a g e

77 One study evaluating the utility of IA as the primary form of intrapartum monitoring found 49% of patients were not able to be monitored with IA due to the inability to meet one to one staffing requirements. 677 Additionally, in 2% of cases auscultation could not be performed due to maternal obesity or patient refusal. Of the 423 that commenced monitoring with IA, 392 (93%) were unable to complete monitoring due to frequency (50%; n=212) or recording (39%; n=163) requirements. Consequently, out of the initial cohort of 862 patients only 31 patients (4%) could be monitored entirely by IA. This degree of attrition is of particular concern, although it may be an over-estimation due to the influence of strong confounding factors. In mitigation, similar findings were noted in early EFM studies, albeit without such profound attrition Some authors have postulated that despite potential savings associated with IA s lower caesarean and instrumental delivery rate and decreased technology costs, these might be offset or exceeded by the one to one staffing costs. 676 The ability to hear the FHR is potentially limited by maternal obesity or polyhydraminos. 677 Intermittent auscultation can also alter the patient experience with its non-invasive nature allowing freedom of movement and position of the labouring mother; however, others might consider IA intrusive given the close contact and proximity of the healthcare provider required. The intermittent nature of IA combined with lack of automatic documentation can be considered a medicolegal positive and negative. The lack of a continuous trace might avoid potential inconsequential FHR variations being considered indicative of fetal compromise; however, there is the absence of what some consider an important documentation of the intrapartum period. The utilisation of Doppler based FHR monitoring systems in contrast to traditional Pinard, DeLee-Hillis or standard acoustic stethoscope FHR monitoring methods has been evaluated on a limited basis Mahomed et al. conducted a prospective RCT of 1,255 term singleton cephalic pregnancies with initial normal FHR. 681 The pregnancies were randomised into four groups intermittent EFM, Doppler FHR monitoring, Pinard stethoscope with a research midwife, or routine use of Pinard stethoscope by attending midwife. While there were significant study design, methodology and analysis limitations, the authors concluded FHR abnormalities were more reliably detected by Doppler FHR monitors, and its use potential resulted in better perinatal outcome (Table 1.22.). Simpson et al. noted use of a Doppler FHR monitor with a digital FHR display provided a more effective mechanism of FHR evaluation P a g e

78 Table Differences in intrapartum and neonatal outcomes between intermittent intrapartum fetal monitoring methods Intermittent EFM (n=318) Doppler Ultrasound (n=312) Research Pinard (n=310) Routine Pinard (n=315) Intermittent EFM (n=318) Doppler Ultrasound (n=312) Research Pinard (n=310) Routine Pinard (n=315) FHR Abnormality Caesarean Delivery Five Minute Apgar<6 OR OR OR n (%) n (%) n (%) (95%CI) (95%CI) (95%CI) 172 (54.1%) 100 (32.0%) 47 (15.0%) 6.1 (4.2, 8.8) 3.6 (2.4, 5.3) 1.7 (1.1, 2.7) 28 (9.0%) Reference 89 (28.0%) 76 (24.0%) 32 (10.0%) 46 (15.0%) 1.8 (1.4, 2.3) 1.6 (1.2, 2.0) 0.9 (0.6, 1.2) Reference 6 (1.9%) 3 (1.0%) 8 (2.6%) 9 (2.9%) 0.7 (0.2, 1.8) 0.3 (0.1, 1.2) 0.9 (0.4, 2.3) Reference Nursery Neonatal Stillbirth or HIE Admission Seizures Neonatal Death n (%) n (%) n (%) n (%) 51 (16%) 34 (10.9%) 47 (15.2%) 57 (18.1%) Adapted from Mahomed et al., (0.6%) 1 (0.3%) 7 (2.0%) 10 (3.0%) Note: Fetal heart rate. 0 (0.0%) 0 (0.0%) 6 (2.0%) 9 (2.9%) 8 (2.5%) 2 (0.6) 5 (1.6%) 9 (2.9%) Unfortunately, despite the studies detailed above there is a relative dearth of data, comparing different assessment protocols and nurse-to-fetus/mother ratios. Moreover, there is relatively limited research on the effectiveness of different IA devices. This dearth of evidence is reflected by Gilles et al. who noted that despite IA being the predominate intrapartum fetal monitoring form in Western Australia, 50% of maternity units had no written guidelines concerning method, indications for medical referral or fetal compromise management. 683 Of the units with protocols there was considerable divergence particularly in IA intervals in the first and second stages of labour. Despite this, FHR auscultation provides a relatively inexpensive and useful method of intrapartum fetal monitoring that is likely to be continued to be widely utilised for the foreseeable future. 56 P a g e

79 1.3.5 Electronic fetal monitoring The development of EFM in the 1950s provided a means to continuously monitor FHR and thus fetal condition throughout the intrapartum and late antepartum period. While EFM has been applied to the antepartum and intrapartum period, for the purpose of this thesis discussion will be confined to EFM use during the intrapartum period. Electronic fetal monitoring has been adopted amongst obstetricians and perinatal units worldwide, with it rapidly becoming a standard part of perinatal care and is now the commonest obstetric procedure. 684 Following EFM s introduction, studies documented associations between FHR patterns/parameters and short-term indicators of neonatal health and welfare, which in turn were considered to be reliably associated with long-term neurological wellbeing. 37,78,222,274,421,478,544,673, Authors have also noted significant relationships between adverse FHR traces and neonatal (or childhood) neurodevelopmental abnormalities Continuous EFM has been associated with an increase in caesarean and instrumental deliveries, 687,702,723, although others have noted a decrease or no change in operative and instrumental deliveries overall or for fetal compromise following EFM s introduction , Nevertheless, by the late 1980s and early 1990s, it was apparent that there has not been a significant decrease in CP and neurodevelopmental disorders following EFM s introduction That being so, there has been a significant change in CP distribution, 512,756, and other adverse neurological outcomes such as HIE. 443 Additionally, there has been a significant decrease in antenatal, intrapartum, and neonatal deaths since widespread utilisation of EFM, which may be related. 543,627,687,698, , ,741, , Limitations and issues associated with electronic fetal monitoring There are several major limitations associated with EFM, broadly being categorised into misuse, misinterpretation, and misapplication. Firstly, EFM is attempting to identify and predict adverse outcomes that are typically rare with diverse aetiological backgrounds. 778 There is a growing body of evidence that a significant proportion of adverse neonatal outcomes have an antenatal origin and consequently are unlikely to be altered by EFM prompted intrapartum interventions. 403,542,563,631,702, Electronic fetal monitoring is unlikely to make a major difference in prevalence of perinatal mortality, CP and neurodevelopmental deficits as only a small proportion are associated with intrapartum asphyxial injury. 36, Further, the occurrence of sudden acute total or near total asphyxial insults may be abrupt and unavoidable allowing insufficient intervention time P a g e

80 While EFM is technically relatively easy to operate and implement if the equipment is available, interpretation is subjective and there is considerable inter-observer and intraobserver variation, 793, although some have shown a reasonable consistency. 797,801, There is also debate about the most appropriate way to assess agreement within and between assessors. 810,814 Rather than being considered an imperfect screening test, an abnormal FHR pattern is often, erroneously, used as a diagnostic test for asphyxia, which can result in unnecessary and potentially harmful interventions. 752 That being so, reassuring FHR patterns are a reliable predictor of good neonatal outcome, suggesting EFM specificity not sensitivity may be the issue. Once a FHR abnormality has been identified there is at times disagreement about what action to take. 793, Finally, some suggest EFM is unable to produce the reliability, and validity necessary to allow timely intervention; 793 however, if FHR patterns are interpreted within their clinical context the correlation with neonatal outcomes improves A variety of reasons have been proposed for the increase in caesarean deliveries, including increased EFM use. A number of RCTs have found when compared to IA, continuous EFM is associated with significantly more instrumental and operative deliveries. 749,751,791,820 In an attempt to reduce the risk of unnecessary operative intervention, numerous forms of supplementary monitoring have been utilised including fetal pulse oximetry, automatic ST segment analysis of fetal electrocardiography, and FBS. To date these EFM adjuncts have met with mixed success Based on perinatal mortality reviews, incorrect EFM use and interpretation has been cited as an important contributor to adverse perinatal outcomes. Failures in EFM use and interpretation were found in more than 50% of intrapartum-associated mortalities. 812, The UK Maternal and Child Health Research Consortium (MCHRC) reported that substandard care, although not just EFM associated, occurred in almost 75% of intrapartum fetal/neonatal mortality ,832 Consequently, inadequate surveillance as well as inaccurate EFM interpretation and response are major components of medico-legal action worldwide Studies of medicolegal claims have identified that EFM associated issues are found in a substantial proportion of cases. A Danish study of approved medicolegal claims for perinatal 58 P a g e

81 brain injury found 76% involved EFM associated issues. 836 Other studies have noted EFM associated issues in 45-80% of cases reviewed with issues including missing FHR traces, lack of action following FHR abnormality, technically unsatisfactory EFM traces, and lack of FHR abnormality recognition. 465,790,792, Additionally, studies have noted long pattern recognition lag times, with Murphy et al. noted average FHR abnormalities recognition times of 91 minutes. 812 With severe FHR abnormalities the recognition time was longer on average 128 minutes, although recognition intervals of eight hours were reported. Furthermore, studies have noted the high proportion of junior medical and midwifery staff members involved, which emphasises the importance of adequate supervision and education of junior staff in EFM use and interpretation It is apparent, that education is necessary to provide staff members with the skills required to apply, interpret and act upon intrapartum monitoring, such as EFM. A recent survey of public maternity units in the Australian state of Victoria, found only a third of major obstetric units and even fewer smaller units were providing formal education. 839 Moreover, at least a third of the education programs were considered inadequate. In the USA, most obstetricians in training learn through clinical practice instead of a formal program. 840 A 1989 Canadian survey found only 40% of Canadian hospitals have a formal intrapartum fetal surveillance education program. 665 In contrast, greater than 96% of surveyed UK perinatal units provided some EFM education to medical and midwifery staff members, although compulsory attendance only occurred in 56% of units for midwifery and 71% for medical staff members. 828 Intrapartum monitoring education programs are essential, yet to date are often poorly implemented and under resourced. For any education program to be successful a standard set of guidelines must be established for a clear interpretation and action based EFM approach. Until recently, 20% of hospitals using EFM had no written guidelines, 665 despite the relative profusion of different guidelines concerning FHR trace interpretation. 796,825, The significant number of guidelines, the inter-guideline differences, their sporadic utilisation and lack of simplistic definitions may have actually served to complicate rather than improve EFM trace interpretation. 855 Further, the number of units reporting having guidelines for EFM interpretation does not appeared to have increased with a recent study of Irish maternity units finding that 27% of units using EFM had no departmental guidelines, 856 with similar findings from studies of UK maternity units. 857 Interestingly, guideline availability was not influenced by unit size, with 16 UK maternity units having no guidelines despite having more than 3,000 deliveries annually P a g e

82 This is in contrast to Swedish studies that have noted significant increases in maternity units with EFM guidelines to 100% Less common issues associated with internal EFM include the risk of intrauterine catheter damage, which may result in catheter parts being retained in the uterine cavity. 860 Additionally, there have been rare reports of placental abruption, placental perforation, umbilical cord entanglement, perforated placental or umbilical cord vessels as well as uterine perforation by intrauterine pressure catheters There is also the potential for pathogenic organisms to be introduced into the uterus These adverse outcomes are rare especially as intrauterine catheters are rarely utilised, with external tocodynamometer preferred due to its less invasive nature and the lack of significant difference in outcomes between internal and external tocodynamometry Fetal scalp electrode (FSE) misapplication is an additional, rare issue with reports of implantation through anterior and posterior fontanelles resulting in cerebrospinal fluid (CSF) drainage, although no adverse outcomes were reported. There have been a number of reports of localised hematomas and abscesses following FSE application. 740, A single significant intrapartum haemorrhage following iatrogenic FSE associated scalp laceration has been reported, although no significant sequelae resulted. 879 Unusually, a second degree fetal scalp burn following internal fetal monitoring has been described, although the responsible mechanism wasn t established. 880 Another rare issue with internal EFM is being unable to apply FSEs due to fetal skin diseases, namely ichthyosis, although only two cases have been reported. 881 There have also a number of case reports of localised and disseminated neonatal bacterial and viral infections as well as maternal endomyometritis following FSE use. 866, Adverse sequelae that have resulted included osteomyelitis, meningitis, septicaemia, hydrocephalus and intracranial abscesses. 882,886, ,902 While this link between internal monitoring and infections has been documented it is unlikely that EFM is the sole aetiological factor in anything apart from a small number of infections Furthermore, few infections required operative intervention as they quickly respond to topical treatment with most relatively minor and not leading to increased neonatal nursery length of stay. 896 Given that internal EFM is no longer standard practice and the type of FSE utilised has changed, 876,898,905 the significance of these risks is not as profound today. 60 P a g e

83 Electronic fetal monitoring versus intermittent auscultation There is considerable debate concerning the best method of intrapartum fetal monitoring particularly comparing EFM and IA. While a detailed comparison of EFM and IA is beyond the scope of this thesis further details are provided in Appendix F. The latest Cochrane review comparing continuous EFM and IA, included over 33,000 deliveries from 11 RCTs and seven countries (Australia, Denmark, Greece, Ireland, Pakistan, UK, and USA). 751 Amongst neonates monitored with EFM there was a significantly increased caesarean delivery rate, with a difference in risk of caesarean delivery of 5% (95%CI 2%, 8%). An increased risk of FBS, instrumental delivery and caesarean delivery for abnormal FHR/fetal acidaemia was also noted those with EFM. There was an additional caesarean for every 58 deliveries (95%CI 43, 87) monitored using continuous EFM. The most profound difference in the Cochrane Review was regarding neonatal seizures with continuous EFM associated with a halving of the risk of seizures. Despite considerable variation in neonatal seizure incidence (0.03%-5.69%), the reduction was consistent across all of the RCTs and subgroups. In terms of numbers needed to treat, 661 deliveries (95%CI 384, 2002) would have to be monitored with continuous EFM to prevent one neonatal seizure. The findings of reduced neonatal seizures with continuous EFM concur with a number of other studies of EFM. 820, ,742 The debate about intrapartum monitoring will continue for the foreseeable future, with the debate focusing on the caesarean delivery and neonatal seizure aspects. The perceived conflict between maternal risk (increased caesarean and instrumental vaginal delivery rate) and neonatal benefit (decreased incidence of neonatal seizures), makes it exceptionally difficult to make quality judgments as to which effect and resultant issues are more important Electronic fetal monitoring today Today EFM is an almost ubiquitous feature of maternity care in developed health care systems, with numerous studies noting increased EFM use over the last 40 years. 666, , These changes potentially reflect a change in EFM s role since its introduction; initially it was intended to decrease perinatal morbidity and mortality. Currently, with advent of effective centralised monitoring, 914 some suggest EFM has taken on a babysitter role. 915 So while IA might be as effective in low risk pregnancies, EFM requires less staff Initially, central monitoring was noted to significantly increase instrumental and operative deliveries for fetal compromise (p=0.02; p=0.05) as well as overall caesarean delivery rates (p=0.01). 918 That being so, a more recent and larger study found no difference in operative delivery rate (14.5% vs. 15.7%; p=0.13), NICU admissions (4.6% vs. 5.1%; p=0.21) or five minute Apgar scores 61 P a g e

84 less than seven (1.5% vs. 1.6%; p=0.87). 919 Whether or not centralised fetal monitoring is an appropriate monitoring method is debated but as of now appears to be an integral practice in many maternity units. Despite widespread EFM use for over 30 years, the prevalence of CP and other neurodevelopmental diseases has not declined significnatly. 543,776 There has been some acknowledgement that together with the increasingly litigious obstetric environment, EFM has been at least partially responsible for the increase in caesarean deliveries. 752 There is no specific FHR pattern that allows accurate prediction of neurological outcome. While EFM might provide early indication of perinatal asphyxia, alone it is inadequate in proving a diagnosis. The efficacy of EFM is based on a number of assumptions that require a series of relationships between FHR abnormalities and fetal compromise, fetal compromise and fetal asphyxia, fetal asphyxia and HIE, and finally HIE and long-term neurodevelopmental sequelae. Given the complex aetiological relationships between these factors it is not surprising that at times EFM is not able to detect, ameliorate and prevent fetal injury. There is a growing questioning of EFM s efficacy in avoiding or ameliorating adverse neonatal outcome; however, there are no widespread alternatives. Fear of litigation, convenience, and inadequate staffing all contribute to continued EFM use despite conflicting opinions of its utility ,913, Meconium passage Meconium is composed of GIT secretions, proteins, mucopolysaccharides, cellular debris, bile acids and bilirubin, although it is primarily H 2 O (72-80%). 921 References of the association between fetal compromise and MSAF date from as early as 1858; 922 however, MSAF s significance has been fiercely debated Meconium occurs in 7-29% of deliveries, with meconium found in amniotic fluid (AF) from 10 weeks of gestation although it is rare before 34 weeks At least a third of neonates exposed to MSAF have meconium below the vocal cords; however, MAS only develops in 2%. 923 Previously meconium was considered harmful to the fetus; however, it s now thought that it s a combination of meconium and intrauterine asphyxia producing injury, 926,929, given that most non-hypoxaemic neonates exposed to MAS are asymptomatic. 923, Limitations of meconium passage While meconium has been utilised as a marker of fetal compromise since ancient Greece there a number of associated limitations. It is only possibly to observe MSAF if the 62 P a g e

85 membranes have been ruptured or on amnioscopy. One of the major confounding factors is gestational age since fetal defecation is most frequent between 28 and 33 weeks of gestation. Consequently, if there is even a minor impairment to clearance at this age it will become rapidly apparent. Closer to term as defecation becomes a less frequent occurrence and of a smaller volume; a relatively larger insult is required to make it as readily apparent. 933 Additionally, meconium can be observed in up to 50% of post-term fetuses with some hypothesising that if gestation was allowed to continue long enough that meconium passage would occur inevitably in all fetuses. 946 Assessment of MSAF is relatively subjective, with the potential for conflict over establishing presence and grading. Haemoglobin and its catabolic products can produce discolouration of AF. Several studies have noted that haemoglobin and its catabolites can produce green to brown AF, which could be mistaken for meconium One study of 1,227 amniocentesis samples identified 83 discoloured samples (6.8%), of which 38.6% had vaginal bleeding prior to amniocentesis. 948 Twenty samples were spectrophotometrically analysed, with all discoloured samples having significant total and fetal haemoglobin concentrations present. Haemoglobin and its catabolites within AF is not a benign event, with its presence suggestive of maternal or fetal intrauterine bleeding. Consequently, while there is the potential for misrecognition of meconium and haemoglobin; in both situations there would be concern about fetal condition. Other confounding factors include maternal ingestion of traditional medicines, namely bowel purgatives Experimental prolonged cholic acid infusion produced meconium in a fetal ovine model suggesting potential confounding in mothers with hepatic disease. 953 Similarly, vaginal misoprostol has been associated with increased meconium prevalence possibly due to direct stimulatory effect of the drug or its metabolites on bowel motility. 954 Meconium staining is more common in mothers from Pacific Islands, South Asian and African- American backgrounds; 924,955 potentially due to differences in diet or maturation rate of fetal GIT innervation Predictive value of meconium passage It is generally considered there is a poor association between MSAF and acute hypoxic episodes, thereby negating the use of meconium passage as an acute asphyxial marker. Westgate et al. in a ovine model found that despite repeated umbilical cord occlusion producing severe metabolic acidaemia and episodic hypotension, no previously healthy near term fetuses passed meconium. 956 Other ovine studies have found similar outcomes, with 63 P a g e

86 acute inhalational hypoxaemia not associated with MSAF; instead it s often accompanied by reduced GIT peristalsis Poor correlations have been noted between asphyxial markers, e.g. umbilical artery blood gas and lactate levels, and meconium passage. 937,958, That being so, several authors have noted an increase in one and five minute Apgar scores less than seven amongst neonates with MSAF. 929,937 Furthermore, numerous studies have noted an increased likelihood of low umbilical artery ph values in neonates with MSAF. Similarly, MSAF is significantly more common amongst neonates with umbilical artery acidaemia; however, 80% of acidaemic neonates have been found to have clear AF. 964 Interestingly, Steer et al. only noted a significant association between MSAF and umbilical artery ph values when there was an abnormal EFM trace during the first stage of labour. 937 Others found neonates with MSAF had higher scalp blood ph values and one-minute Apgar scores than those with MSAF and FHR abnormalities or FHR abnormalities alone. 968 Significantly increased risks of neonatal seizures, 479 NE, 421 CP, 577 and perinatal mortality 966 have all been reported in neonates with MSAF. Similarly, there is evidence linking thick meconium with increased perinatal morbidity Conversely, thin meconium is considered to have no or minimal increased associated risks; however, this is disputed by others that suggest a correlation between risk, MSAF colour and time that the fetus has been exposed to the meconium. 969,971 In postdate pregnancies; fetuses with thick meconium had significantly lower fetal scalp ph values in late labour than those with thin meconium, with the likelihood of an umbilical artery ph less than 7.10 was doubled with thick MSAF. 705 Sienko et al. found that contrary to widespread belief, the most clinically important meconium colour is not green but long-term meconium, which is a greenish tan, muddy brown or light tan colour. 971 Amongst preterm neonates there have been limited studies on MSAF s significance. Scott et al. evaluated perinatal outcome in 506 singleton preterm (<37 completed weeks) neonates; finding no significant differences in gestational age, birth weight, and umbilical artery ph and BE between clear and MSAF (Table 1.23.). 972 There were statistically significant differences in one and five minute Apgar scores, but these were not clinically significant. The significantly higher proportion of NICU admission amongst those exposed to MSAF potentially reflects concern about MAS. Meconium s presence could influence NICU admission decisions with combination of prematurity and MSAF leading staff to believe the neonate warranted more intensive observation and care. Neonates with MSAF are often 64 P a g e

87 suctioned at birth, which could lead to increased supplementary O 2 demand resulting in nursery admission (4.7) -4.0 (1.4) 0.20 Table Comparison of perinatal outcomes between those exposed and not exposed to meconium Meconium (n=24) Clear (n=481) P-Value Birth Weight (g) 2049 (883) 2250 (820) 0.25 Gestational Age (wk) 33.2 (3.4) 32.2 (4.5) 0.18 One-minute Apgar 6 (3) 7.2 (2.7) 0.01 Five Minute Apgar 7.7 (1.9) 8.4 (1.3) 0.01 Umbilical Artery ph 7.27 (0.01) 7.29 (0.001) 0.34 Umbilical Artery Base Excess NICU Admission 75% (18/24) 53% (255/478) 0.04 Adapted from Scott et al., Note: Mean (SD); % (n/total n) Spinillo et al. identified 40 cases of CP and 59 neonatal deaths in 450 singleton preterm (24-33 completed weeks) evaluated at two years of age. 516,973 Amongst neonates exposed to MSAF CP prevalence was significantly higher (41.2% [7/17] vs. 10% [33/328]; p=0.006). Multivariate logistic regression found MSAF and prematurity were associated with a nearly sevenfold increased risk of CP (RR 6.9, 95%CI 2.32, 20.81; p=0.001), while there was no significant association between MSAF and neonatal death (RR 3.24, 95%CI 0.73, 14.50; p=0.120). Wong et al. assessed the RR of non-reassuring cardiotocography or fetal distress in pregnancies complicated by MSAF at various gestations in 9,542 singleton pregnancies. 974 Meconium occurred in 1,946 (20.4%), with 191 (9.8%) having EFM indicative of fetal compromise. Non-reassuring EFM traces were significantly less common amongst those without MSAF (n=438; 6.6%; p<0 001). Amongst premature neonates there was no significant difference in non-reassuring EFM traces between those with and without MSAF. The RR of fetal compromise (MSAF vs. no MSAF) increased with gestation beyond 38 weeks, which is in contrast to the suggestion that MSAF is an entirely physiological event, as in the later circumstance the RR of fetal compromise would be equivalent across all gestational ages. This concurs with other studies that have noted a correlation between gestational age and MSAF presence , While placental insufficiency could explain the higher risk amongst post-term neonates (compared to term and preterm neonates) it would not produce a progressive increase in risk with gestation (RR 0 92 at < 37 weeks; RR 3 29 at 42 weeks). Further, post-term neonates regardless of MSAF s presence are equally likely to 65 P a g e

88 have been exposed to placental insufficiency and thus should have an equivalent RR of fetal compromise. Meconium staining independent of EFM signs of fetal asphyxia, is not likely to be indicative of fetal compromise and should not be considered an indication for expediting delivery. 825,848 Conversely, if the FHR pattern is abnormal, MSAF is indicative of a higher chance of neonatal acidaemia, poor condition at birth, low Apgar scores and requirement for resuscitation. 917,929,939,966,969,980 Most studies concerned with MSAF and fetal/neonatal outcome have investigated meconium as a risk factor rather than a predictor so there is little evidence either for or against its use as a predictor of adverse neonatal outcomes. Further, there is now a growing body of evidence that the diagnostic utility of MSAF is different between preterm and term/post-term neonates Role of meconium passage today While use of meconium as an indicator of fetal compromise holds great appeal as it requires little expertise or technology, thus being ideal for the developing world where most perinatal morbidity and mortality occurs, there remains reservations about its effectiveness. While authors have proven an association between meconium and chronic hypoxia this does not appear to be present for acute asphyxial injury. Therefore, while MSAF is associated with increased perinatal morbidity, its absence cannot be considered to exclude potentially adverse outcomes. Conversely, while meconium passage might be a physiological event it is potentially implicated in pathological outcomes. Accordingly, MSAF should be considered a risk factor for adverse neonatal and fetal outcome, and consideration should be given for EFM and FBS where necessary in all deliveries with MSAF, 825,848,929 although studies suggest MSAF alone is not a valid indication for FBS. 944, Fetal scalp ph analysis Intrapartum collection of fetal scalp capillary blood was developed from attempts to improve neonatal resuscitation in the early 1950s. 981 Saling and colleagues developed a way to rapidly measure oxyhaemoglobin saturation in blood samples obtained from central neonatal circulation via umbilical catheters From there they took the step of obtaining blood samples from the presenting part in fetuses with Rhesus incapability induced erythroblastosis allowing determination of haemoglobin concentration, haematocrit and blood group and allowing exchange transfusions within five to ten minutes of delivery. 985 Finally, development of ph analysers able to utilise small blood samples allowed the first intrapartum fetal blood 66 P a g e

89 analysis with ph and oxyhaemoglobin saturation measurement and pco 2 calculation to occur on the 21 st of June Initially it was hoped that FBS would reduce perinatal mortality and morbidity, although it is now primarily used to guide intrapartum interventions by more accurately identifying fetal compromise Fetal scalp blood ph normally lies between fetal arterial and venous ph values and decreases as labour progresses (Table 1.24.) In an ovine model, scalp ph tended to resembled venous ph as the fetus became more hypoxic. 991 A primate model had similar findings with scalp blood ph being units greater than venous ph and units less than arterial ph, over a ph range of Human studies are limited by the delay between FBS and cord gas analysis, with only one study managing to obtain near simultaneous FBS and central ph values. 993 Scalp blood samples were obtained five minutes before delivery, with the findings consistent with animal studies. Additionally, other studies have noted strong correlations between fetal scalp ph values and umbilical artery values (r=0.99; p<0.001), even in neonates with low scalp ph values. 994 Scalp ph continued to be indicative of fetal status even during active pushing of the second stage. 995 Table Change in mean fetal scalp blood and tissue ph values over the peripartum N Early First Stage Late First/Early Second Stage Late Second Stage Umbilical Artery Umbilical Vein Saling, Kubli, Beard et al., Rooth et al., Weber & Hahn Pedersen, (7.26 * 7.30 (7.18 ) * 7.28 ) (7.16 * ) Smith et al Adapted from Weber and Hahn-Pedersen, Note: * Scalp tissue ph value During the first stage of labour, fetal scalp ph values range between 7.25 and ,998, The RCOG considers intervening on scalp ph of less than 7.20 is appropriate, although this is a point of contention amongst some authors. 848 Eliot and Hill initially suggested that a ph of 7.20 merits a repeat FBS within five minutes and delivery should be expedited only when ph reaches In a later study they revised the cut-off of concern to being less than or equal to 7.24, 1006 which concurs with findings of another study, 1007 while others choose the 7.20 cut-off. 728, P a g e

90 Reliance on critical cut-off levels has several disadvantages. Most fetuses that develop intrapartum hypoxia have normal ph at the beginning of labour with acidaemia developing during labour. 998,1008 Prevention of fetal asphyxia requires detection before injury, early in progressive ph decline. Consequently, values in the lower normal range should be considered suspicious. Bretscher and Saling defined pre-acidaemia as the range , which would indicate heightened concern for neonatal wellbeing It is considered there is no incentive for intervention if ph is greater than 7.24, while a decision regarding obstetric management is necessary if ph is less than This has been affirmed in NICE guidelines, with a ph value of less than or equal to 7.20 considered abnormal and greater than or equal to 7.25 normal Limitations and issues associated with fetal scalp blood sampling A number of issues and limitations have been identified since the introduction of FBS into clinical practice in the 1960s, including issues surrounding infection and haemorrhage Fetal and neonatal haemorrhage following fetal scalp blood sampling Excessive bleeding following FBS has been reported in 15 cases, with five resulting in fatalities due to intrapartum exsanguination Excessive bleeding has been reported following aponeurotic puncture (inadvertent deep scalp penetration through galea aponeurotica) and in fetuses with coagulopathies. Punctures have also occurred through scalp, dura and arachnoid meninges allowing CSF drainage Aponeurotic puncture have been found to frequently occur despite use of guarded two millimetre blades It is unlikely that aponeurotic puncture is a major cause, especially since FBS has been modified to prevent this More likely to be involved are coagulopathies, which have been implicated in most cases , Fetal and neonatal infection following fetal scalp blood sampling There is extensive documentation of infections following fetal scalp electrodes; information on similar infections following FBS is rather more limited. Localised infections following FBS have been described ranging from harmless infection of the coccyx to scalp abscesses. 901,988,995,1013,1015,1019 The prognosis of FBS associated localised infections has been uniformly good, with no long-term adverse sequelae reported. The potential for maternalfetal infection transmission is of concern, particularly Human Immunodeficiency Virus (HIV) and Hepatitis viruses. Vertical transmission occurs in around 13-40% of HIV cases, with transmission occurring via: 1) placental transmission (antepartum); 2) maternal-fetal 68 P a g e

91 fluid transfer during delivery (intrapartum); and, 3) transfer via breast milk (postpartum) Most vertical transmission occurs through intrapartum maternal-fetal fluid transfer, 1022 therefore any disruption of the fetus external integrity by invasive procedures could increase transmission risk. Some studies have found an increased risk of vertical transmission with invasive fetal procedures, while others have noted no differences Potential conflict between fetal scalp blood sampling and vacuum delivery Several authors noted that FBS in combination with vacuum extraction potentially leads to an increased risk of cephalohaematoma, and that vacuum deliveries should possibly be avoided when there has been previous FBS. 1015, Lee studied 63 neonates delivered by Malmstrom vacuum extractors at full dilatation, five minutes to 22 hours after FBS (most sampling to delivery intervals were less than an hour) There was no significant difference in cephalohaematoma incidence between vacuum deliveries that were and were not (n=1,891) preceded by FBS (9.5% vs. 8.2%, respectively). Examination of neonates scalps showed no bleeding and in most the sampling site was not easily located. Unfortunately the authors, possibly due to small cohort size, were not able to stratify the cases based on sampling to delivery interval or number of sampling sites. While the concerns about the increased likelihood of bleeding and cephalohaematoma when FBS is followed by vacuum delivery might be unfounded, it would be wise to be cautious particularly with multiple sampling sites, or short sampling to vacuum delivery intervals Delay in delivery for compromised fetuses Anecdotally there has been concern that obtaining a fetal scalp blood sample might delay delivery of a compromised fetus Studies have noted FBS can take up to 70 minutes, although most take less than half an hour This must be taken into account during the decision making process regarding whether to conduct FBS. While some have suggested FBS should be undertaken prior to operative delivery for abnormal FHR patterns in the absence of a clear contraindication Several groups and institutions have published guidelines indicating FBS should not be performed in situations where there is clear evidence of sustained fetal compromise. 825,841,848 This concurs with the current practice of FBS being an EFM adjunct to clarify FHR traces considered to be suspect and acts to minimise the likelihood of delaying intervention Additional limitations of fetal scalp blood sampling Other issues associated with FBS include sample contamination with meconium, AF or air bubbles. At times the sampling site might be inaccessible due to a closed cervix, fetal hair, 69 P a g e

92 high presenting part, or intact membranes Several cases of blades breaking and lodging in the scalp requiring surgical removal have been reported. 1012, In addition, blood gas analysis is costly, requires frequent calibrations of equipment, trained technical staff, and relatively large blood volumes Authors have noted that the technique and equipment utilised can alter FBS effectiveness Maternal hypertension has also been noted to affect scalp blood gas values with lower ph and higher pco 2 values Correlation of fetal scalp and central blood gas values Several paediatric and adult studies have shown correlations between capillary, venous and arterial blood gases, in various clinical situations Human studies have demonstrated significant correlations between scalp and umbilical artery ph values with coefficients ranging from 0.61 to 0.99; 269, however, FBS utility relies on scalp values reflecting central fetal circulation values. Morgan et al. correlated fetal scalp blood gas values with pre-ductal arterial blood gas values in an ovine model Maternal hypoxaemia was induced by stepwise fractional inspired O 2 reduction from 20% to 5% O 2 by nitrogen addition. Significant correlations were noted between fetal scalp and brachial artery ph values (r=0.70), only a poor correlation was noted for fetal scalp po 2 (r=0.42) and pco 2 (r=0.11) values. A number of animals had mean brachial artery pco 2 values less than scalp pco 2 values. Given that scalp blood is a mixture of arterial, venous and capillary blood, scalp pco 2 should be greater than fetal pre-ductal arterial pco 2. Morgan et al. postulated that air contamination produced a diffusion gradient encouraging CO 2 diffusion out of the scalp sample prior to analysis artificially lowering its value. Another analysis (n=21) excluding samples with scalp pco 2 values less than arterial pco 2 value noted a good correlation between scalp and brachial artery po 2 (r=0.80) and pco 2 (r=0.88) values, with the correlation between scalp and arterial ph values becoming more profound (r=0.95). The authors concluded that provided physiological limitations are considered when interpreting scalp blood gas values there was good correlation between scalp and arterial blood gases. Adamsons et al. studied 11 pregnant rhesus monkeys to establish the relationship between fetal blood from the scalp, carotid artery and jugular vein during labour Thirty seven simultaneous samples were collected from all three sites, with 27 obtained during delivery and the remainder following delivery of the head. Good correlations were noted between scalp ph and carotid artery ph values (r=0.955) as well as with the jugular venous ph (r=0.973). Furthermore, correlation was noted between po 2 and pco 2 values from the 70 P a g e

93 scalp and carotid and jugular blood samples. This significant relationship persisted when the fetus experienced significant acidaemia. Despite the significant correlations, Adamsons et al. noted that during induced labour in monkeys, fetal scalp ph overestimated carotid arterial ph by an average of ph units Others have reported scalp blood ph values in human fetuses that are lower than umbilical arterial ph by up to 0.06 ph units. 1002,1058 Taken together this suggests the additional acidosis within the fetal scalp (as suggested by lower scalp ph values) during asphyxial episodes is of respiratory rather than metabolic origin. This is further supported by scalp po 2 not being significantly different from arterial po 2 while fetal scalp pco 2 levels are significantly higher during hypoxia Limited scalp perfusion, as with caput succedaneum and severe head compression, is believed to alter ph; however, there is no clear supportive evidence. In an ovine model, scalp perfusion increased during asphyxia like situations, 359,362 although others have noted decreased scalp perfusion In the adult scalp, tissue oxygenation significantly declined once capillary blood flow was less than three millilitres per 100 grams of tissue per minute Analysis of fetal scalp blood gas values prior to and during contractions found no difference in blood gas values provided FHR did not alter by more than 15 bpm If there were significant FHR changes then a significant decrease in po 2 values occurred (-4.1 mmhg; p<0.01), whilst other values remained the same. Findings are more contradictory regarding caput, with one study finding an occasional increased incidence of scalp acidaemia with caput, 1062 whilst another noted little overall scalp ph change Fetal scalp ph was found to vary by up to 0.10 ph units; however, this was postulated to be due to changes in maternal acid-base balance from pain associated hyperventilation. 59 The most recent study of the effect of caput effect encompassed 20 fetuses with simultaneous samples obtained from oedematous and normal parts of their scalps The mean sample ph value obtained from caput areas was significantly lower than that from normal areas (7.190 vs ; p<0.005). Scalp ph changes are amplified if there has been fetal scalp pressure from a vacuum extractor or an amnioscope, although scalp massage has been found to correct acute hypoperfusion Role of fetal scalp blood gas sampling Fetal scalp blood sampling was first described in the early 1960s; at this time IA was the only intrapartum fetal surveillance method as EFM was in its early experimental phase. 986 By the 1960s and 1970s, FBS was primarily used to clarify the diagnosis of fetal comprise, thereby preventing unnecessary operative and instrumental interventions. 693,770,988,1064 Consequently, 71 P a g e

94 FBS was never employed as a primary fetal surveillance method rather it has been an adjunct to clarify other methods findings Currently, the major role of FBS is clarification of adverse FHR traces to differentiate fetuses in need of intervention from those that might be managed expectantly. 841 Lower caesarean deliveries rates have been noted in fetuses monitored with continuous EFM and FBS compared to those monitored with EFM alone. 749,917, The reduction in neonatal seizures noted with EFM have primarily been found in studies where there was access to 750, FBS.. Use neonatal outcomes of FBS as an adjunct has been noted by some to improve short term There is circumstantial evidence that FBS might reduce umbilical arterial acidaemia with studies with higher FBS rates having higher mean cord artery ph values One limited study noted a decline in perinatal mortality rates following FBS introduction, 1075 although this has not been replicated and there is a strong confounding likelihood. Some have recommended that if EFM is available then there should be FBS facilities to limit operative intervention with continuous EFM. 750,1076 Perkins was one of the first to critique FBS s role in intrapartum management; managing 7,158 deliveries in a tertiary level hospital between 1978 and 1980 without FBS. 822 Compared with other institutions using FBS there was no major increase in stillbirths, operative interventions or neonatal compromises. Goodwin et al. recreated Perkins study in 1994 with the proportion of deliveries undergoing FBS declining from 2.17% to 0.03% over five years. 823 Despite this, they noted no increase in caesarean delivery rate for fetal compromise and no increase in indirect asphyxial markers, such as MAS or NICU admission with low Apgar scores. An early theoretical paper postulated that FBS might reduce perinatal mortality; however, any reduction in perinatal asphyxia would require a significant proportion of individuals to be exposed to FBS The most recent Cochrane review evaluating EFM and IA found that there was no evidence that FBS availability decreased caesarean delivery rate or incidence of neonatal morbidity. 751 Earlier studies noted that FBS use with EFM reduced the caesarean delivery rate, although this was primarily due to intervention being delayed to the second stage (Table 1.25.). 59,1078 While Perkins and Goodwin were criticised for the high caesarean delivery rate and the uncontrolled retrospective study, it appears that together with the Cochrane review, this might have contributed to the disinclination towards FBS. Brandt-Niebelschutz and Saling noted FBS had a sensitivity of 93% and a false positive rate of 6% for umbilical artery ph values equal to or less than Hon et al. found the 72 P a g e

95 correlation between fetal scalp ph values and one and five minute Apgar scores greater than six was poor (Table 1.26.) Conversely, there were significant correlations between fetal ph values and Apgar scores less than seven. The correlation between fetal ph values and Apgar scores increased as the interval between obtaining ph values and delivery shortened. Further study noted no significant correlation between scalp BE values and one-minute Apgar scores less than seven; however, there was a significant correlation with five minute scores less than seven Significant correlations also occurred between fetal scalp BE values and one and five minute Apgar scores greater than six. This concurs with other studies, with 85-90% of fetuses with a scalp ph greater than 7.20 having Apgar scores greater than six. 998,1058,1082 Table Fetal blood sampling s impact on maternal and neonatal outcome Caesarean Delivery Rate Odds Ratio (95%CI) Neonatal Convulsions Odds Ratio (95%CI) EFM without FBS 4.14 (2.29, 7.51) 0.79 (0.21, 2.97) EFM with FBS 1.98 (1.33, 2.94) 0.49 (0.29, 0.82) Adapted from Green, based on Murphy et al., 1990 and Thacker et al., , Fetal scalp blood gas sampling today The role of FBS came under attack by a number of prominent American obstetricians in the 1980s and 1990s who detailed FBS elimination from their centres The decline in use has been accentuated by development of other non-invasive methods of assessing fetuses with abnormal FHR traces Currently, FBS use tends to be confined to major tertiary centres and within these centres to high-risk cases with sampling rates of 0-22% of the population. 189,1073,1084 Thirty six percent of maternity units from the Republic of Ireland use FBS if the EFM trace is non-reassuring. 856 A survey of 92% of UK obstetric units (caring for 84% of all UK deliveries), that 44% of units used FBS in the first stage of labour whilst 11% utilised it in the second stage. 911 Interestingly, 49% of units had equipment capable of measuring ph; therefore 5% of units had the ability to conduct ph analysis but did not do so. An earlier survey found FBS was utilised by 40% of UK maternity units with an additional 16% having access to equipment for ph analysis. 910 A subsequent study of all UK maternity units noted that amongst the units using EFM, 81% also utilised FBS. 857 Amongst the 42 maternity units that didn t use FBS, 13 (31%) had less than 1,000 deliveries per annum, six (14%) had greater than 3,000 deliveries per annum and four units (10%) transferred all suspicious 73 P a g e

96 EFM traces to other units. A 1984 survey of all Swedish maternity units noted 42% of units used FBS. 908 Since this earlier survey, two further surveys have been conducted concerning intrapartum fetal monitoring The first noted 84% of Swedish maternity units (covering 94% of all deliveries) used FBS when the EFM trace was considered suspicious. By the next survey, all units were using FBS although only 72% had written guidelines concerning its application and utility. In 2008, 61% of units (28/46) analysed lactate alone, 28% analysed blood gas and lactate values and 11% analysed blood gas alone. In units using blood gas analysis, 61% analysed all blood gas parameters representing a significant increase since 1999 (49%). Overall, 3-20% of deliveries were exposed to FBS, although some units did not keep records of FBS, thus a more realistic range may be 3-14%. Table Correlation between fetal scalp ph values and one and five minute Apgar scores. Interval Before Delivery (Minutes) Correlation Category Actual Coefficient Number P-Value One-minute Apgar greater than Six All (114.50) < (13.64) > (10.49) > (7.15) > (4.18) > (1.35) >0.05 Five Minute Apgar greater than Six All (118.90) > (14.31) > (10.63) > (7.35) > (4.17) > (1.34) >0.05 One-minute Apgar less than Seven All (171.49) < (15.23) < (10.31) < (8.50) < (4.25) < (1.32) <0.005 Five Minute Apgar less than Seven All (240.04) < (8.69) < (8.69) < (8.38) < (4.44) < (1.44) <0.05 Adapted from Hon et al., Note: Mean (Standard Deviation) 74 P a g e

97 Theoretically FBS utilisation should be much greater as several authors and institutions have strongly encourage[d] maternity units employing EFM to have access to FBS facilities. 750,825,841,846,848,1071 Despite these recommendations, FBS is rarely used outside tertiary centres, with there being little consensus regarding its role in intrapartum fetal surveillance. It appears that this will remain so, and use might even decline further in the face of new fetal stimulation tests, which are applicable in the antepartum and intrapartum periods, and are more easily learnt and organised There have been a number of studies looking at FBS utilisation, but there is a paucity of studies looking at how FBS is utilised. Murphy et al. found FBS was indicated in 57.9% of fetuses later diagnosed with perinatal asphyxia and 20% of fetuses that did not develop perinatal asphyxia; however, it was only undertaken in 15.8% and 8.3%, respectively. 812 A retrospective review of 1,208 high risk pregnancies with continuous EFM compared FBS indication and performance (Figure 1.8.) It is apparent most fetuses did not require FBS and did not undergo FBS; in those that underwent FBS (n=114) it was unnecessary in 39% while it was not performed in 33% of indicated cases. Of the four, birth asphyxia cases only two underwent FBS and in one case FBS occurred after two hours of progressive EFM abnormalities. Of the 30 caesarean deliveries performed due to suspected fetal compromise, 17 were not preceded by FBS. The authors concluded that there were clinical circumstances in 10 cases that would warrant operative delivery; however, the other operative deliveries were potentially due to overhasty intervention. Failure to obtain a FBS occurred in seven fetuses. Particularly interesting was staff members acceptance of physiologically implausible scalp ph values (7.82 and 7.56), without attempting further FBS. In most cases, sampling was performed appropriately in a timely manner; however, the number of times it was applied inappropriately was unexpected. Fetal blood sampling and EFM are not independent entities, given that the decision to undertake FBS is typically based on the EFM trace. Further the FBS results only provide an indication of fetal status at the time of sampling. Consequently, it is important to note that effective FBS utilisation depends on the ability of medical and midwifery staff members to correctly interpret EFM traces. A way to ensure most acidaemic neonates are identified is to have high FBS rates. 812,1073 There is some evidence that higher FBS rates are associated with higher mean cord arterial ph values, 1074 although there s no evidence that this translates to improved clinical outcomes. The high FBS rates necessary are unlikely to be widely accepted or practical particularly given the current FBS scepticism and accompanying limited utilisation. Westgate and Greene 75 P a g e

98 concluded that improved FBS utilisation and interpretation would most likely arise out of a better understanding by medical and midwifery staff of the relationship between intrapartum events and fetal/neonatal acid-base as well as improved EFM trace interpretation Figure 1.8. Appropriate utilisation of fetal scalp blood sampling in a tertiary centre FBS Utilisation n=1,208 (100%) FBS Indicated n=105 (8.7%) FBS Not Indicated n=1,103 (91.3%) FBS Performed n=70 (5.8%) FBS Not Performed n=35 (2.9%) FBS Performed n=44 (3.6%) FBS Not Performed n=1,059 (87.7%) Adapted from Westgate and Greene, Fetal scalp blood sampling provides what is generally considered the gold standard marker of fetal status during labour; however, its use is limited although potentially growing. While scalp and vibroacoustic stimulation may provide an alternative to FBS they are unlikely to replace FBS as the gold standard marker of intrapartum asphyxial injury; thus FBS is likely to remain in use. The other alternatives to FBS whilst showing promise in some cases are unlikely to be widely utilised outside the academic spectrum due to technological limitations at this point in time. Furthermore, with the development of microanalysis technology allowing blood gas analysis on smaller sample volumes it is possible that utilisation might increase in the near future, particularly expanding from the confines of tertiary hospitals into secondary level maternity units. Consequently, FBS if interpreting clinical context is an accurate EFM adjunct, 750,825 with its use potentially associated with decreased operative interventions and neonatal seizures. 76 P a g e

99 1.3.8 Apgar scores Traditionally, the primary means of identifying perinatal asphyxia has been the Apgar score developed by Virginia Apgar in The Apgar score was rapidly adopted due to its ease of use and ability to provide a quick result, it has been said no neonate delivered in a modern hospital will escape being allocated an Apgar score The Apgar score is based on five key criteria: 1) heart rate; 2) respiratory effort; 3) reflex irritability; 4) muscle tone; and 5) colour, with each scoring up to two points to give a total score of 10 (Table 1.27.). The score is usually assessed at one and five minutes following delivery; however, the assessment has been performed up to 20-minutes. Table The Apgar score Heart Rate Respiratory Effort Reflex Irritability Muscle Tone Zero One Two No heart beat seen, felt, or heard Apnoea No response Completely flaccid < 100 bpm bpm Slow and/or irregular Some extremity flexion Breathing and crying lustily Facial grimacing, sneezing, &/or coughing following nasopharyngeal suctioning Spontaneous limb flexion and the ability to resist extension Colour Pale Cyanotic Entire neonate is pink Adapted from Apgar, 1953; and, Azra Haider and Bhutta, ,1091 Note: beats per minute Apgar developed the score primarily to focus attention on the neonate s condition after delivery, as well as monitor the effect of anaesthesia, presentation, delivery methods and resuscitation. 1087,1089,1092 Soon afterwards, she noted the ability of one-minute Apgar scores to predict neonatal condition after delivery, as well as predicting neonatal mortality and outcome up to 28 days post-delivery. Following on from this, it was used quite contentiously as a predictor of long-term neonatal neurological outcome. Apgar herself noted the Apgar score was not a good predictor of long-term outcome; 1087,1092 however, it took some time for the enthusiasm for the Apgar as a potential tool for all occasions to be replaced by scientific studies of large neonatal cohorts. During this period the Apgar score was considered a good predictor of perinatal asphyxia and long-term neurological outcome and until recently formed 77 P a g e

100 a major component of the International Classification of Diseases definition of birth asphyxia. 67,202,1089, More recently, there has been a recognition that Apgar scores are indicative of a lack of neonatal vigour at delivery rather than birth asphyxia. 242, Limitations of the Apgar score Virginia Apgar when devising her scoring system used criteria that were easily assessed without extensive equipment, able to be performed without interfering with neonatal resuscitation and requiring minimal training. 1087,1092 While this is a strength it s also a weaknesses with considerable discussion, including by Apgar, of the lack of consistency and subjective nature of several criteria ,1092, Various confounding factors for Apgar scores have been identified including birth weight, gestation, geographical location, infection, resuscitation, ventilation, maternal smoking, time of delivery, personnel assigning the score, anaesthesia, analgesia, and congenital abnormalities. 225,435,794,1090,1092,1098,1102, The Apgar score is an indicator of the neonate s condition at a particular point in time and has a limited time frame Given that the Apgar score was developed in the 1950s when the practice of intubation during neonatal resuscitation was a relatively rare occurrence there is conflict over how to assess intubated neonates. Further, several criteria are dependent on the neonate s level of physiological maturity, namely muscle tone, colour, and reflex irritability; therefore preterm neonates can potentially be allocated a low Apgar score due to physiological immaturity alone Whilst there have been attempts to alter the Apgar score to minimise confounding, these have not met widespread acceptance. Furthermore, the predictive ability of modified criteria have not been widely studied One proposal suggested removal of one or more Apgar score criteria based on the assumption that there are complex relationships between the various criteria; so removing a single criterion might not profoundly alter the utility of the overall score. 710,1118,1122,1125 Another proposed modification is development of a weighted Apgar score; however, this does at least partially remove the simplicity of the original Apgar score. Others have suggested an expanded Apgar score including additional resuscitative measures Heygi et al. conducted the largest to date study of the various Apgar score components based on 1,105 preterm neonates with a birth weight less than 2,000 grams, from three NICUs Significant linear correlations (p<0.01) were noted between all one-minute Apgar score criteria, with respiratory rate, muscle tone, and reflex irritability having the strongest 78 P a g e

101 correlations with each other and the total score. Neonatal heart rate did not correlate well with the other criteria, whilst colour had the lowest correlation with other criteria. Further, the authors constructed a model that compared each criterion s contribution by examining a hypothetical rate of increase for each criterion. The respiratory rate, tone, and reflex criteria produced the largest increases in total score (unit increase [UI] = 0.20), followed by heart rate (UI=0.16), and finally colour (UI=0.14). Interestingly, heart rate had a variable effect with a larger contribution at lower Apgar scores and a smaller contribution at higher scores. The lack of utility of the colour criterion has been alluded to by a number of authors, including Apgar, 1087,1090, ,1127 with Marx et al. noting that removing colour increased the score s correlation with umbilical artery ph values Crawford et al. found the one-minute Apgar criteria were closely related, with colour having the weakest link with the other criteria Each criterion, except colour, correlated well with umbilical artery ph, pco 2 and BE values. The authors concluded the most informative components in regards to neonatal acid-base status were heart rate, muscle tone and reflex irritability with inclusion of colour potentially reducing the score s discriminatory value. Some authors have suggested that pulse oximetry, should be substituted for colour, although this detracts from the original scores simplistic utility Predictive value of the Apgar score A considerable body of the negative opinion concerning Apgar scores is due to the apparent lack of strong relationships with other measures of perinatal compromise and the subsequent poor relationship with neonatal morbidity and mortality. This criticism needs to be placed in the context of other measures of perinatal wellbeing and merits further discussion. Early neonatal acidaemia, asphyxia, NE, neonatal mortality and long-term neonatal outcome have all been shown to be predicted by Apgar scores, with almost every correlative study finding an association between Apgar scores and neonatal neurological outcome. 225, Short-term neonatal outcome The relationship between Apgar scores and short-term neonatal outcome has been evaluated using several large cohorts. Sykes et al. in 1,210 consecutive deliveries found the Apgar score had limited application with few neonates suffering from respiratory depression at five minutes due to improved neonatal resuscitation techniques. 67 Therefore, it can be assumed that rapid improvement in scores by five to ten minutes indicates that the insult was unlikely to have been sufficiently severe to produce neurological injury Hogan et al. found that in neonates with a five minute Apgar score less than four there is sufficient evidence for Apgar scores to be used as a proxy for asphyxia; however, in neonates with Apgar scores between 79 P a g e

102 four and six, only half suffered from asphyxia. 202 This definition of birth asphyxia, utilising five minute Apgar scores, has been used in other studies, such as Ergander et al. who noted in a two year follow-up of 116 neonates, a mortality rate of 30% with 23% of survivors having neurodevelopmental sequelae Ellis et al. evaluated the one-minute Apgar score as a screening method for NE (n=91) in 14,371 live births at Prasuti Griha Maternity Hospital, Kathmandu, Nepal One-minute Apgar scores less than four had a sensitivity of 92.3% and specificity of 95.4% in predicting NE (Table 1.28.). The authors concluded that oneminute Apgar scores overestimate the number of neonates with significant birth asphyxia but are still a useful screening test. Table One-minute Apgar score as a predictor of neonatal encephalopathy One-minute Neonatal Encephalopathy n (%) Apgar Score Mild Moderate Severe Total 3 (n=734) 28 (3.81%) 33 (4.50%) 23 (3.13%) 84 (11.44%) > 3 (n=13,637) 2 (0.01%) 3 (0.02%) 2 (0.01%) 7 (0.05%) Adapted from Ellis et al., Note: All neonates with NE had one-minute Apgar >3 and <7. For neonatal acid-base status, divergence has been noted between Apgar scores and umbilical cord blood gas values. Sykes et al. noted in 1,210 consecutive term neonates, only 19% with five minute scores less than seven had umbilical artery acidosis (arterial ph < 7.11 and BD > 12 mmol/l). 67 Conversely, 14% of those with arterial acidaemia had five-minute Apgar scores less than seven. This concurs with other studies of one and five minute Apgar scores. 435, Socol et al. evaluated 28 neonates with five minute scores less than four, noting most (n=17; 61%) had arterial ph values greater than 7.00, with 15 (54%) neonates having ph values greater than Additionally, around 50% of those with one-minute Apgar scores less than seven had normal umbilical ph values, whilst those with Apgar scores greater than six, 6% had cord ph values less than ,1139 That being so, studies have noted that neonates with low one and five minute Apgar scores were significantly more likely to have umbilical cord blood gas or lactate values that were consistent with acidaemia. 705,1140 Further, correlation studies of the relationship between umbilical artery ph values and Apgar scores have identified statistically significant correlations (Table 1.29.). The association but lack of strong correlation between cord blood gas values and Apgar scores is not entirely unexpected in that they evaluate different aspects of neonatal condition. Apgar scores evaluate neonatal condition at delivery in a general manner, while umbilical cord blood gas values reflect a particular aspect of neonatal 80 P a g e

103 condition, namely the neonatal biochemical milieu. While there s is to an extent overlap in particular scenarios there is also divergence, which probably explains the lack of strong correlation between the two measures of neonatal condition. Table Correlation between Apgar scores and umbilical artery ph values One-minute Apgar Five Minute Apgar Correlation P-Value Correlation P-Value Coefficient Coefficient Gao, Yuan et al < <0.01 Hoffmann, Hjortdal et al <0.001 Steer, Eigbe et al < Marx, Mahajan et al < <0.001 Note: Modified one-minute Apgar score with exclusion of colour Amongst studies of neonates containing a general population with a significant proportion of low-risk neonates, the one-minute Apgar score is a very specific predictor of neonatal mortality, although not particularly sensitive (Table 1.30.). Amongst high-risk neonates with low birth weights the sensitivity of one-minute Apgar scores increases, although the specificity declines. Casey et al. conducted a retrospective study of 151,891 live-born singleton infants without major malformations delivered at equal to or greater than 26 weeks gestation between 1988 and Five-minute Apgar scores were available for 145,627 neonates, of which 13,399 were delivered between 26 and 36 weeks gestation. Amongst preterm neonates the average five minute score was related to gestational age; however, the average score for week neonates was not significantly different from those delivered at or weeks. In term and preterm neonates, neonatal mortality was related to five-minute Apgar scores (Table 1.31.). Low Apgar scores (0-3) were significantly associated with neonatal death within 24 hours of delivery in preterm (p<0.001) and term (p=0.009) neonates. These findings concur with another preterm study (25 weeks gestation) that noted a significant correlation between every one step increase in one, five and ten minute Apgar scores and survival without severe brain damage An earlier study of low birth weight neonates ( 1000 grams) noted a statistically significant relationship (p<0.05) between five minute Apgar scores and neonatal survival; 1142 however, the difference was not particularly clinically significant. Amongst neonates requiring resuscitation, Saugstad et al. found that neonates surviving a week had significantly higher one (p<0.001) and five minute (p<0.001) Apgar 81 P a g e

104 scores. 444 This did not translate into a higher likelihood of dying in the first week in those with one-minute scores less than four (OR 1.6; 95%CI 0.8, 3.0), although it did for neonates with five-minute scores less than four (OR 14.0; 95%CI 6.7, 29.2). It was noted that oneminute Apgar scores had a greater sensitivity but lower specificity than five-minute scores. Amongst neonates with HIE and treated with neuroprotective hypothermia, 10 minute Apgar scores of zero were strongly associated with mortality in the neonatal period (Multivariate OR 32.7; 95%CI 6.4, 166.5; p<0.001) and first nine months (Multivariate OR 51.7; 95%CI 9.9, 269.5; p<0.001) Further, a 10-minute score of zero was a sensitive predictor of both mortality outcomes (93% and 96% respectively) with specificity values of 58% for neonatal mortality and 75% for mortality within the first nine months. Table Relationship between one-minute Apgar scores and neonatal mortality Study Study Period N Sensitivity Specificity Positive Likelihood Ratio Negative Likelihood Ratio General Population Apgar & James, ,715 59% 93% Colburn & Salzman, ,597 27% 98% Collaborative Perinatal Project, ,698 56% 95% Ikonen, ,698 35% 99% Jennett et al., ,124 52% 98% Low Birth Weight ( 1500 gm) Population Apgar & James, % 69% John et al., % 79% Behnke et al., % 68% Myers et al., % 73% Luthy et al., % 73% Adapted from Schmidt et al., The latest National Institute for Clinical Excellence (NICE) intrapartum care guidelines included a meta-analysis of five cohort studies and one systematic review (encompassing 16 cohort studies) regarding one and five minutes Apgar scores ability to predict neonatal mortality. 841 They concluded that Apgar scores were moderately effective predictors of neonatal mortality (Table 1.32.). Further, Van de Riet conducted a meta-analysis of P a g e

105 studies ( ) noting low one-minute Apgar scores (0-3) were associated with a 15% mortality rate, which was six times higher than those with scores of four to six and 40 times higher than those with scores greater than or equal to seven. 415 A similar trend was exhibited for five, ten and twenty-minute Agar scores (Table 1.33.). Table Prevalence and relative risk of neonatal death for five minute Apgar scores in term and preterm neonates Five Minute Apgar Live Births Neonatal Deaths Relative Risk n n (%) (95% Confidence Interval) Term ( 37 wks) Singleton Live Born Neonates (N=132,228) (24.42%) 1460 (835, 2555) (0.89%) 53 (20, 140) , (0.02%) Reference Preterm (26-36 wks) Singleton Live Born Neonates (N=13,399) (31.52%) 59 (40, 87) (7.19%) 13 (9, 20) , (0.53%) Reference Adapted from Casey et al., Table Predictive value of one and five minute Apgar scores for neonatal mortality Sensitivity (95%CI) Specificity (95%CI) Odds Ratio (95%CI) One-minute Apgar Score 0-3 vs % 95.4% (43.7%, 48.3%) (95.3%, 95.5%) (16.07, 19.51) 0-6 vs % 84.2% (64.7%, 69.1%) (83.9%, 84.4) (9.72, 11.85) Five Minute Apgar Score 0-3 vs % 99.7% (34.9%, 37.5%) (99.7%, 99.8%) (203.09, ) 0-6 vs % 98.7% (54.1%, 56.8%) (98.7%, 98.8%) (91.58, ) Adapted from National Collaborating Centre for Women s and Children s Health, Wennergren et al. evaluated the relationship between one and five minute Apgar scores and neonatal respiratory problems in 4,656 neonates Unfortunately, the data was stratified into delivery mode and gestational age with no overall results reported. That being so, amongst term neonates there were significantly more neonates with respiratory disturbances amongst those with one and five minute Apgar scores less than seven. Further, Piekkala established a significant relationship between respiratory distress syndrome (RDS) and 15 minute Apgar scores in a regional Finnish population of 5,380 neonates with birth weights greater than 499 grams P a g e

106 Table Meta-analysis of the association between Apgar scores and neonatal mortality Mortality Rate by Live Births Odds Ratio (95% Confidence Lower Score Higher Score One-minute Apgar Score Interval) 0-3 vs /5, /11, (5.0, 6.5) 4-6 vs /11, /85, (4.0, 12.8) Five Minute Apgar Score 0-3 vs ,761/3, /6, (4.2, 7.9) 4-6 vs /6,510 2,113/370, (10.8, 38.6) Ten Minute Apgar Score 0-3 vs / / (4.3, 7.6) 4-6 vs / /5, (1.8, 20.5) Twenty Minute Apgar Score 0-3 vs /178 95/ (6.1, 17.3) 4-6 vs. 7-95/233 91/1, (10.1, 19.7) 10 Adapted from van de Riet et al., Long-term neonatal outcomes One of the earliest studies of neonatal outcome of children assessed at one year of age found a significant relationship between one and five minute Apgar scores and neurological abnormality, motor retardation, muscle tone, and prehensile grasp, with a stronger relationship between five minute scores and adverse outcome Drage et al. found 12.7% of neonates with five minute Apgar scores less than seven and 1.7% of those with Apgar scores greater than seven had abnormal neurological findings. 67,1154 A later study evaluated underlying causes of neonatal mortality in those with low one and five minute Apgar scores, found five minute scores had the greatest influence on neonatal mortality That being so, neonates with an abnormal one-minute Apgar were still three to four times more likely to die during the neonatal period than counterparts with normal scores. Nelson et al. as part of the NCPP found no correlation between low Apgar scores and increased risk of death or CP; with 80% of neonates with 10 minute Apgar scores less than four that survived to school commencement having no major handicap That being so, this needs to be considered in context as 69% of neonates with 10 minute Apgar scores less than four died during early infancy. Consequently, 75% of neonates with a 10-minute Apgar scores less than four died or suffered a significant disability. These findings concur with another NCPP study noting a significant relationship between severe handicap at seven years and five minute Apgar scores that persisted under multivariate analysis. 487 Nelson and 84 P a g e

107 Ellenberg concluded based on the NCPP cohort, that if the Apgar score was low at both one and five minutes then there was a definite increased risk, which also applied to infants with persistently low scores at 10, 15, & 20 minutes A 15-minute Apgar score of less than four was associated with a 53% mortality rate and 36% CP rate amongst survivors. If the low score persisted for 20 minutes, mortality rose to 60% and 57% of the survivors had CP. A persistently low Apgar score has been found in other large cohort studies to be a strong predictor of adverse outcome. 1094,1102,1108, As noted above the high mortality rate amongst infants with low scores suggests that if more neonates survived to assessment there could have been more CP cases In what is probably a reflection of the recent advances in neonatal and perinatal care, the NICE guidelines regard one and five minutes Apgar scores as moderately effective CP predictors (Table 1.34.). 841 Table Predictive value of one and five minute Apgar scores for cerebral palsy Apgar Score Sensitivity (95%CI) Specificity (95%CI) Odds Ratio (95%CI) One-minute Apgar Score 0-3 vs % (18.1%, 31.6%) 95.3% (95.1%, 95.5%) 6.67 (4.63, 9.61) 0-6 vs % (34.9%, 50.4%) 81.9% (81.5%, 82.2%) 3.36 (2.44, 4.61) Five Minute Apgar Score 0-3 vs % (5.9%, 11.1%) 99.8% (99.8%, 99.8%) (28.37, 56.11) 0-6 vs % (21.0%, 29.0%) 98.9% (98.9%, 98.9%) (23.80, 36.78) Adapted from National Collaborating Centre for Women s and Children s Health, Twenty six neonates with one-minute Apgar scores less than two, requiring intensive resuscitation prior to establishing regular respiration were assessed at two to five years of age Eight children (31%) were diagnosed with neurological abnormalities of varying significance (Table 1.35.). A single child (4%) had consistent bilateral symmetrical sensorineural hearing loss, while of the 24 assessed for speech and language, five (21%) had delayed language development, three (13%) had speech defects, and one (4%) had no speech due to a gross physical handicap. While most children with one-minute Apgar scores less than two did not have severe neurodevelopmental abnormalities approximately a third of survivors without handicaps had speech or language deficits. A similar study, using one-minute Apgar scores of zero or five minute scores less than four, evaluated 31 neonates at 5-10 years of age Two neonates (7%) had severely handicapping neurodevelopmental abnormalities, while one (3%) had a definite abnormality without significant handicap. At follow-up there was no difference in the psycholinguistic quotient. A recent Australian case-control study of 587 CP cases and 85 P a g e

108 1,154 controls noted a significant relationship between CP and one (38.2% vs. 3.0%; OR 20.27; 95%CI 11.29, 36.42; p<0.001) and five (9.5% vs. 0.2%; OR 51.27; 95%CI 12.20, ; p<0.001) minute Apgar scores less than four. 583 Levene et al. evaluated Apgar score s ability to predict adverse outcomes amongst 122 term neonates with HIE. 446 They found the general utility of Apgar scores was not particularly high, although high specificity does provide a role as a screening agent (Table 1.36.). Table Neurological condition at two to five years of severe perinatal asphyxia survivors Neurological Condition Number (Percentage) Normal neurological findings 16 (61%) Neurological findings of slight or doubtful significance 6 (23%) Neurological disorder producing little or no physical 2 (8%) handicap Definite and obvious neurological disorder * 2 (8%) Note: Squints, breath-holding attacks, hyperactive behaviour, or head circumference >97 th centile at 1-10 months; Increased lower limb extensor tone or sensorineural deafness; and, * Microcephaly, spastic quadriplegia, severe mental retardation, and epilepsy, or spastic quadriparesis and athetosis. Table Sensitivity and specificity of Apgar scores in predicting adverse outcomes at one to five years of age. Apgar Score n Sensitivity Specificity One-minute 3 & five minute > % 38% Five minute 5 & ten minute > % 67% Five minute 3 & ten minute > % 90% Ten minute 5 & twenty minute 15 43% 95% >5 Ten minute 3 & twenty minute 5 17% 99% >5 Twenty minute % 100% Adapted from Levene et al., Moster et al. in a cohort of 235,165 Norwegian children found that despite improvements in neonatal care there remains a strong association between low Apgar scores and death and CP (Table 1.37.) Furthermore, the authors noted that those who developed CP had both clinical problems and low Apgar scores; however, 80% of children with very low 20 minute Apgar scores survived without significant disabilities. 225,1108 This was in contrast to earlier studies, such as Ergander et al. who followed 116 neonates with five minute scores less than four, finding amongst the 81 (70%) survivors, 16 (20%) with a severe disability and 3 (4%) with a mild disability P a g e

109 Table Relative risk of mortality and morbidity according to the five minute Apgar score Relative Risk (95% CI) Outcome Apgar Scores Apgar Scores Morbidity Cerebral palsy 81 (48-138) 31 (22-44) Mental retardation without cerebral palsy 9.4 (3-29) 4.4 ( ) Neurological disability without cerebral palsy or mental retardation 8.8 (4.7-17) 2.1 ( ) Non-neurological disabilities 1.7 ( ) 1.3 ( ) Mortality Neonatal death 386 ( ) 45 (30-68) Infant death 76 (56-103) 8.9 (6.4-12) Death between one and eight years 18 (8.539) 2.2 ( ) Adapted from ACOG, 2003 based on data from Moster et al., ,1108 Note: Five minute Apgar 7 used as reference category. The largest study to date evaluating the link between CP and five minute Apgar scores, is a cohort of 543,064 singletons without malformations alive at one year of age Of the cohort, 988 neonates (0.18%) were diagnosed with CP prior to five years of age. There was a strong stepwise inverse relationship between five-minute Apgar scores and CP, which persisted after adjusting for neonatal birth weight (Table 1.38.). Approximately 90% of those with five minute scores less than four did not have CP, and in those with CP, around 80% had five-minute scores greater than six. Table Odds of cerebral palsy diagnosis by five years of age based on five minute Apgar score Apgar Score Prevalence n/n (%) Unadjusted Odds Ratio (95% Confidence Interval) Adjusted Odds Ratio (95% Confidence Interval) One/Two 39/369 (10.6%) (90.8, 188.6) 53.1 (35.2, 79.9) Three 29/268 (10.8%) (88.7, 203.4) 49.5 (31.2, 78.6) Four 39/445 (8.8%) (74.0, 152.9) 34.7 (23.1, 52.1) Five 34/964 (3.5%) 40.5 (27.8, 58.9) 12.6 (8.4, 18.8) Six 47/2,150 (2.2%) 24.7 (17.8, 34.3) 8.3 (5.9, 11.8) Seven 79/4,716 (1.7%) 18.9 (14.4, 24.7) 7.0 (5.2, 9.3) Eight 128/16,536 (0.8%) 8.6 (6.8, 10.9) 4.4 (3.5, 5.7) Nine 431/338,101 (0.1%) 1.4 (1.2, 1.7) 1.3 (1.1, 1.6) Ten 162/179,515 (0.1%) Reference Reference Adapted from Lie et al., Note: Adjusted for neonatal birth weight Thornberg et al. followed 227 term neonates with five minute Apgar scores less than seven delivered between 1985 and 1991 to 18 months of age. 455 Sixty-five (29%) had HIE retrospectively diagnosed, with 36 mild (16%), 17 moderate (7%), and 12 severe (5%) cases. 87 P a g e

110 Thirty-five neonates required NICU admission with 12 (34%) dying prior to follow-up, and five (14%) had neurological injuries. Seizures occurred in 27 neonates (12%) of which most, whilst repeated, were of short duration and responded to treatment. At follow-up, 199 neonates (88%) were considered normal with 12 neonates (5%) having neurodevelopmental abnormalities. Thirteen neonates (6%) died, with 11 dying within a month of delivery, and the remainder within a year, all of who exhibited signs of neurological damage. As part of a whole-body hypothermia randomised controlled trial (RCT) the outcome at months of term or near-term neonates with NE and evidence of hypoxic-ischaemic injury was related to 10-minute Apgar scores A significant proportion of neonates with 10- minute Apgar scores less than five died and amongst survivors there was a significant degree of disability (Figure 1.9.). Of those with a 10-minute score of zero, 24% survived without significant disability. Multivariate analysis concluded for each point decrease in 10-minute Apgar scores there was a 45% increase in likelihood of significant morbidity or mortality. These studies only included neonates that survived long enough to be randomised and included into the RCT thus could be a relatively healthier population of neonates. Figure 1.9. Relationship between ten-minute Apgar scores and neonatal morbidity and mortality Term Neonatal Encephalopathy (N=188) Ten Minute Apgar (70%) Ten Minute Apgar 5 56 (30%) Normal/Mild Disability Death/Significant Disability Normal/Mild Disability Death/Significant Disability 46 (35%) 86 (65%) 39 (70%) 17 (30%) Adapted from Laptook et al., Van de Riet s meta-analysis noted that associations between Apgar scores and CP were much weaker than the association between Apgar scores and neonatal mortality. 415 Low twenty 88 P a g e

111 minute Apgar scores were predictive of CP; however, amongst those with five minute Apgar scores less than four, less than 5% of survivors had CP. Similarly, for low one-minute scores (0-3) only 2% develop CP. That being so, those with low Apgar scores were at significantly increased risk of developing CP than their counterparts with normal scores (Table 1.39.). Gurbuz et al. conducted a retrospective case control study of 101 term neonates diagnosed with CP and 308 controls. 577 They noted that low (0-3) and low-moderate (<7) one-minute Apgar scores were associated with a significantly increased CP risk (Table 1.40.). Furthermore, if the Apgar score remains low or moderate-low at five minutes then the ORs are even greater. Table Meta-analysis of the association between Apgar scores and cerebral palsy and neonatal mortality Cerebral Palsy Rate by Live Births Odds Ratio Lower Score Higher Score (95% CI) One-minute Apgar Score 0-3 vs /2,285 28/6, (2.4, 6.5) 4-6 vs /6,421 90/39, (1.2, 2.9) Five Minute Apgar Score 0-3 vs /434 18/1, (2.1, 5.7) 4-6 vs /1, /46, (3.3, 8.9) Ten Minute Apgar Score 0-3 vs /114 11/ (2.6, 13.3) 4-6 vs /470 31/5, (2.8, 21.0) Twenty Minute Apgar Score 0-3 vs /22 6/ (5.7, 70.0) 4-6 vs /138 11/ (1.1, 40.1) Adapted from van de Riet et al., Table Relationship between one and five minute Apgar scores and cerebral palsy in a Turkish population Cerebral Palsy Controls Odds Ratio (95% (n=101) (n=308) CI) P-Value One-minute Apgar Score Less than 3 18 (17.8%) 5 (1.6%) (4.76, 36.69) Less than 7 21 (20.8%) 15 (4.9%) 5.12 (2.52, 10.40) Five Minute Apgar Score Less than 3 4 (4.0%) 0 (0.0%) (1.51, ) < Less than 7 22 (21.8%) 5 (1.6%) (6.19, 45.98) < Adapted from Gurbuz et al., Low one and five minute Apgar score have been considered early indicators of sensorineural and conductive hearing loss Correlations have been noted between Apgar scores and brainstem response to auditory input, 1164 with concurrent low Apgar scores and HIE being 89 P a g e

112 noted to produce central auditory impairment Evaluation of term neonates with transiently low Apgar scores without HIE revealed no abnormalities, after excluding maturational changes, in brainstem auditory evoked responses That being so, minor subclinical impairment to auditory function may have occurred, for which clinical and long-term implications are not readily apparent In 56 children with clinician diagnosed birth asphyxia, one-minute Apgar scores less than four were significantly more common amongst those without a hearing impairment (67% vs. 38%; p=0.01) The implications of transient low scores on auditory function are difficult to quantify; however, it appears that without significant neurological dysfunction, a transiently low score is relatively benign in terms of auditory function and impairment. This is emphasised by the finding that studies of neonates with coexistent encephalopathy noted the impairment was transient, resolving within a month In terms of cognitive status, a number of studies have followed neonates to later in life. Seidman et al. evaluated 1,942 subjects at 17 years of age and found no significant associations between IQ and Apgar scores, even after adjusting for demographic, obstetric, intrapartum, and neonatal covariates Further, there was no association between one and five minute Apgar scores and neurological, motor and general health. Low one and five minute Apgar scores (less than seven) were poor predictors of low IQ scores (<85) (Table 1.41.). An earlier case-control study of two and a half year old children with low Apgar scores matched for race, gender, and birth weight, found no significant difference in mean IQ values (86.92 vs ) The three children with the lowest IQ scores had low Apgar scores. Maternal questionnaires noted two significant differences between cases and controls, namely low Apgar males were rated as more active and low Apgar females were rated as more unpredictable. Table Predictive ability of low one and five minute Apgar scores of poor IQ scores at 17 years of age Apgar Score Sensitivity Specificity Positive Predictive Value Negative Predictive Value One-minute Score 7 8.1% 92.8% 7.8% 93.0% Five Minute Score 7 1.5% 97.6% 4.8% 92.9% Adapted from Seidman et al., The largest studies to date on cognitive outcome have been a series of Scandinavian papers Odd et al. linked brief (zero-five minutes) and prolonged (greater than five 90 P a g e

113 minutes) low Apgar scores (less than seven) with educational achievement and IQ in 212,606 male neonates delivered in Sweden between 1973 and The authors found neonates with prolonged, or even brief, low Apgar scores but without co-existing neurological abnormalities had a higher risk of poor IQ scores once they reach 18 years of age. While the overall effect was statistically significant there was only a limited effect on an individual s IQ and the effect probably had limited functional and clinical significance. Further, the study found a low Apgar score had little influence on later educational achievements. In contrast, if the neonate had concurrent encephalopathy and an Apgar score less than seven then there was a substantial increased risk of a poor IQ score. A study of 19,559 Danish men presenting for compulsory military service evaluated the relationship between five-minute Apgar scores neurodevelopmental and cognitive dysfunction The prevalence of neurological disabilities, disqualifying neurological disabilities (primarily epilepsy and CP) and low IQ scores was inversely related to the five minute Apgar (Table 1.42.). Multivariate modelling noted that individuals with five-minute Apgar scores less than seven were four times more likely to have neurological disability (OR 4.02; 95%CI 2.24, 7.24) and almost six times as likely to have a disqualifying neurological disability (OR 5.94; 95%CI 3.19, 11.06). Those with five-minute scores less than seven had IQ scores that were -2.6 points (95%CI -5.4, 0.3) less than those with scores of 10, while those with scores of seven to nine had scores that were -1.0 points less (95%CI -1.9, 0.0). Table Distribution of neurological disability and IQ by five minute Apgar score All Conscripts Conscripts with Assessed Cognitive Function N Neurological Disqualifying Lowest N Disability Neurological Disability Quartile IQ < (8.8%) 11 (8.1%) (34.9%) (2.5%) 20 (1.8%) (27.2%) 10 18, (2.2%) 242 (1.3%) (25.0%) Adapted from Ehrenstein et al., Stuart et al. evaluated the association between five minute Apgar scores and long-term cognitive function in 877,618 term singletons born to Swedish mothers between 1973 and 1986 inclusive A significant linear relationship (p<0.001) occurred between specialised schooling and five-minute Apgar scores (Table 1.43.). Those with five-minute Apgar scores less than seven were significantly more likely to attend specialised educational institutions (OR 1.93; 95%CI ). Amongst individuals attending standard schools, those with 91 P a g e

114 five-minute scores less than seven had an increased risk of finishing school without graduation grades or receiving the lowest possible grades. Table Relationship between five minute Apgar score and education at a specialised institution Five Minute Apgar Score Univariate Odds Ratio (95%CI) Multivariate Odds Ratio (95%CI) Zero 1.12 (0.60, 2.10) 1.26 (0.66, 2.38) One 1.60 (1.23, 2.07) 1.69 (1.30, 2.20) Two 3.19 (2.26, 4.48) 3.18 (2.24, 4.51) Three 3.12 (2.35, 4.16) 2.99 (2.34, 4.00) Four 2.55 (1.97, 3.31) 2.55 (1.96, 3.33) Five 1.74 (1.37, 2.21) 1.69 (1.33, 2.16) Six 1.76 (1.47, 2.10) 1.73 (1.45, 2.08) Seven 1.54 (1.35, 1.75) 1.51 (1.32, 1.73) Eight 1.36 (1.25, 1.48) 1.35 (1.24, 1.47) Nine-Ten Reference Reference Adapted from Stuart et al., Note: Adjusted for birth year, maternal age, parity, smoking, and maternal education Overall predictive value of the Apgar score The most recent ACOG statement regarding Apgar scores has stated that, particularly in preterm infants, the score should not be used for any purpose other than ongoing delivery room assessment This contrasts with the Neonatal Resuscitation Program guidelines that states that decisions regarding resuscitative interventions should be based on neonatal condition not the Apgar score That being so, Apgar scores that remain at zero for prolonged periods might have some role in determining whether discontinuation of resuscitative interventions is an appropriate. It has been anecdotally noted that there is considerable divergence in perceived and actual predictive ability of Apgar scores; however, there has not been extensive study. Paneth and Fox found respondents considered 44% of neonates with five minute Apgar scores less than four have intelligence outside the normal range, and 38% have CP In actuality, the National Collaborative Perinatal Project found 4% of neonates with five minute Apgar scores less than four were later diagnosed with mental retardation and 5% with CP Paediatric staff members were the most pessimistic about neurodevelopmental outcome, while nursing and midwifery staff members were the most optimistic (Table 1.44.). Doctors in private practice were more pessimistic about neurodevelopmental outcome; however, year of qualification had no effect. Sub-analysis should be interpreted cautiously as the cohorts were not randomly selected, no statistical analysis was reported and the cohort was relatively small. 92 P a g e

115 Since this study was published, almost 30 years ago, no other studies have assessed health professional s attitudes towards Apgar scores and resulting neurodevelopmental outcome. That being so, this study does provide insight at the time when medicolegal cases relating to perinatal asphyxial injury were beginning to be an issue. Table Estimates of the proportion of neonates with low five minute Apgar scores without neurodevelopmental abnormalities Background n Estimated Proportion Normal Intelligence No Cerebral Palsy Paediatrics % 42.6% Obstetrics % 65.9% Registered nursing % 67.3% Midwifery % 81.8% Other doctors and medical students % 55.5% Adapted from Paneth and Fox, Some have noted that the overall sensitivity and PPV of independent low five minute Apgar score has decreased in more recent studies and those studies with lower mortality rates In countries unable to provide widespread prompt and intensive neonatal resuscitative and subsequent care, a low Apgar score has been found to prominently identify neonates with a subsequent high risk of mortality and morbidity In contrast, most studies that have been conducted in countries with advanced perinatal services, have shown the predictive value of Apgar scores whilst still strong is less clear. Some authors have postulated that since the development of Apgar scores their predictive ability has been eroded by proliferation of NICUs and early and effective neonatal resuscitative protocols Therefore, Apgar scores should be considered a rough measure of a child s clinical depression during the first few minute of life and shouldn t be applied independently but with other markers of neonatal status to provide context and increase its prognostic utility. 225,1108, Use of the Apgar score today For a time after its introduction, the Apgar score was used to predict everything from a neonate s immediate outcome to their neurological wellbeing many years into the future. Due to this improper utilisation it came under significant criticism with some calling for its retirement from widespread use That being so, as of the late 1990s and 2000s there was a greater understanding of the Apgar scores strengths and limitations and it became popular again. Bharti and Bharti in a review of the Apgar score put forward several reasons why it has become so widespread and persisted: 1) its simplicity and ability to be used in the early 93 P a g e

116 postpartum period; 2) its statistical and teaching utility; and the 3) lack of knowledge of CP pathogenesis that produced excessive belief in Apgar scores potential predictive ability Furthermore, the Apgar score provides an ideal mechanism for establishing neonatal wellbeing at delivery, which is not excessively dependant on accoucher knowledge, and access to technological aids Consequently, it is likely to remain in extensive use throughout the world and an indispensible tool in less developed health systems When used correctly and in concert with other methods of assessing neonatal wellbeing then the Apgar score can be a useful tool particularly as a convenient shorthand method of reporting neonatal wellbeing as well as resuscitation effectiveness; however, if applied exclusively it can be falsely indicative of intrapartum compromise or dangerously reassuring Umbilical cord blood gas analysis Umbilical cord blood gas analysis is an objective measurement of neonatal status at delivery providing insight into neonatal stress response and potential presage of future outcomes. Blood gas values of umbilical cord samples reflect the last moment of fetal acid-base balance prior to delivery. Whilst it is unknown when UCBGA was first utilised it potentially could have been during Saling and colleagues early experimentation with FBS. 981 General consensus suggests that the umbilical artery provides the best insight into fetal biochemical milieu as it originates directly from the fetus rather than umbilical venous blood, which has passed through the placenta. Other authors have suggested that umbilical venous blood might be used as it has a similar ability to predict neurological morbidity, due to the correlation between venous and arterial ph and a comparable relationship with Apgar scores. 71,1185 Other authors have noted correlations between umbilical artery and venous blood and mixed arterial and venous blood samples, with mixed cord blood samples being more closely correlated with umbilical venous rather than arterial values (Table 1.45.) Standard practice is for both the umbilical artery and vein to be sampled in order to ensure the correct vessel has been sampled. 24,65,189,207,1187 This is due to umbilical vein samples being easier to obtain than umbilical artery samples, 71,189,211, thus the umbilical vein may potentially be sampled twice with one sample erroneously labelled arterial. This has potentially profound consequences, as the wrong reference ranges will be applied, resulting in incorrect conclusions about fetal status. 94 P a g e

117 Limitations and issues associated with umbilical cord blood gas analysis There are a number of issues associated with cord gas analysis including sample contamination, remote asphyxial insults, hidden acidosis, vigorous acidaemia, cord blood banking and delayed cord clamping. There is also the need for costly analysis equipment, relatively large blood volumes (30-50 microlitres [μl]), frequent equipment calibration, and technical support Table Relationship between umbilical arterial, venous and mixed cord blood gas values Umbilical Cord Blood Sample R 2 Parameter Arterial Mean (SD) Venous Mean (SD) Mixed Mean (SD) Arterial- Mixed Venous- Mixed ph 7.25 (0.09) 7.31 (0.09) 7.30 (0.09) po 2 (mmhg) 18.2 (10.2) 24.0 (9.0) 22.1 (8.1) pco 2 (mmhg) 52.1 (13.3) 43.4 (11.5) 44.9 (12.0) Bicarbonate (mmol/l) 22.2 (3.2) 21.4 (2.5) 21.1 (2.9) Base Excess (mmol/l) -4.6 (3.9) -3.8 (2.8) -4.4 (3.2) Adapted from Cusick et al., Sample contamination Cord blood sample contamination with meconium, AF or air can potentially alter blood gas values. Air bubbles often contaminate blood gas samples, especially if sample collection was technically challenging. This is often exacerbated by failure to expel air bubbles due to fears of aerosolisation. Air bubbles within the sample have the potential to increase po 2 and decrease pco 2 thus altering BE values. In contrast ph and HCO 3- levels would theoretically remain relatively stable. Adult studies have shown air bubbles within a sample alter po 2 and pco 2 values, although this depends on the sampling to analysis interval An air bubble comprising 10-20% of the sample will significantly increase po 2 while a air bubble in excess of 50% is required to decrease pco Gaskins et al. collected venous cord blood from 21 term neonates without evidence of fetal compromise Six samples of venous blood were obtained with various amounts of air contamination in similarly heparinised one and three millilitre syringes. These blood results were then compared with venous blood samples without any air bubbles. An additional 15 neonates had venous cord blood sampled in three millilitre syringes with 0.5 ml anaerobically collected while 0.5 ml of the same sample was combined with 0.1, 0.2, 0.3, 0.4 or 0.5 ml of air in order to determine what level of air contamination is necessary to cause alteration in blood gas values. Of the samples from 21 term neonates only the three-millilitre 95 P a g e

118 syringe with the 0.5 ml of retained air showed a significant increase in po 2 (p<0.05). No change occurred in regards to pco 2 in any of the bubbled samples. There were no - statistically significant difference in ph, HCO 3 or BE values between syringes with and without air bubbles. Amongst the 15 additional neonates a significant change was only found in po 2 and only when the air bubble exceeded 0.3 ml i.e. composed 37.5% of the sample. The authors postulated that the lack of pco 2 changes might be due to all samples being in normal ph (7.25 to 7.40) and pco 2 (24 to 60 mmhg) ranges, and that the air bubble never exceeded 50% of the sample. The ambient air pco 2 of 150 mmhg in contrast to the mean blood pco 2 of 30 mmhg leads to increased CO 2 affinity, as occurred in the three millilitre syringe which had a 1.75 times greater surface area than the one millilitre syringe and thus a greater area for gas exchange. Both syringe size and relative contamination amount could introduce pre-analytical errors into pco 2 analysis. This is mitigated by two factors, firstly in clinical practice a one millilitre rather than three millilitre syringe is recommended and most commonly used. 189 Secondly, the proportion of contaminating air must be in the region 37.5% of the total sample, which is a considerable and typically visually obvious amount. Consequently, air contamination of cord blood in one millilitre syringes does not profoundly alter ph, pco 2, HCO - 3, and BE values. The only value significantly altered is the po 2, and this is unlikely to alter neonatal clinical management Remote asphyxial insults Umbilical cord blood gas values might not accurately reflect intrapartum asphyxial insults that were remote from delivery. Some cases of HIE and hypoxia related mortality have no evidence of antepartum asphyxial insults or abnormal umbilical artery ph values. 202 This is potentially due to an asphyxial insult occurring several hours prior to delivery allowing time for hydrogen diffusion across the placenta down the concentration gradient into maternal circulation and subsequent normalisation of fetal ph levels. These situations are difficult to predict, prevent, and treat as they often occur without notice in the community prior to admission and are not apparent until injury has already occurred, typically after delivery. Consequently, while remote asphyxial insults should be considered in injured neonates without obvious aetiology; it is unlikely to be common Hidden acidosis Part of the fetal hypoxic-ischaemic insult response is preferential redistribution of fetal blood flow to vital organs at the expense of musculature and viscera. After delivery, once the neonate commences breathing and the hypoxic-ischaemic insult is resolved the hypoperfused 96 P a g e

119 tissues are reperfused. As part of this reperfusion process accumulated anaerobic metabolites that have been trapped in hypoperfused tissues are released into circulation. These metabolites include lactate, and have the potential to adversely affect the neonate s blood gas values. Consequently, authors have coined the term hidden acidosis to refer to the acidosis that might be trapped within tissues due to hypoperfusion. While hidden has been studied in emergency medicine, such as following severe haemorrhage or crush related injuries, there is a relative paucity of data in neonates. Wiberg et al. evaluated the effects of hidden acidosis as part of studying the effect of delayed cord clamping on umbilical cord blood gas and lactate values They found that in an unclamped cord segment that is serially sampled over the first ninety seconds following delivery that there was a delay between changes becoming apparent in the umbilical artery and the umbilical vein. Currently, it is not known how effectively the placenta can function in maintaining gas exchange and fixed acid transport after delivery of the neonate, although it is unlikely to be particularly profound. The greater increase in venous pco 2 over the second interval when compared to the first after taking into account corresponding ph, HCO 3-, BE and lactate changes suggests that placental function after delivery is insufficient to produce acid-base balance in umbilical venous blood. Hidden acidosis is in part due to discordance between tissue acidosis that is considered an integral component of asphyxia, and acidaemia. Hermansen postulated that acidaemia and acidosis are not synonymous, with neonates potentially having tissue acidosis without corresponding acidaemia. 137 While acidosis refers to production and accumulation of acidic metabolites within tissue, acidaemia refers to that within fetal circulation. Consequently, in partial and complete fetal circulatory arrest there might be a fall in tissue ph but the accumulated acid will not enter neonatal circulation until circulation has been restored, typically during neonatal resuscitation Animal experiments with conscious, normobaric, and pregnant Weddell seals found fetal ph declined relatively modestly during the simulated dive (maternal head submersion), but decreased significantly during the recovery period after the dive Fetal blood lactate concentrations only reached their peak minutes after the simulated dive ended. Thus the neonate can potentially develop acidaemia sometime after delivery that is not apparent in initial cord blood gas analysis Vigorous acidaemia Whilst rare, the potential exists for neonates to be delivered in apparently good clinical condition but with umbilical cord acidaemia. Evidence suggests that this occurs in less than 97 P a g e

120 1% of the population. 67,76, In the absence of other abnormal clinical features, such as that suggested by the ICPTF and ACOG, 24,203 umbilical arterial acidaemia in a vigorous neonate is regarded as having no major clinical significance. 66,1188,1202 The prognosis and aetiological background of the vigorous neonate with acidaemia is further examined in Appendix G. Medicolegal action is unlikely to occur solely based on an isolated abnormal umbilical blood gas value unless actual profound damage has occurred; as a successful action would require proof of all four elements of negligence Umbilical cord blood banking The growing interest in umbilical cord blood banking might interfere with collection of umbilical cord blood gas and lactate samples. Since blood gas analysis requires only a small blood volume in the region of micro-litres, this is unlikely to be of any real concern. Collection of an umbilical cord segment from which cord blood gas and lactate values can be elucidated, would still allow collection of umbilical cord blood for banking from the placenta and remainder of the cord without any substantial reduction in the yield of umbilical cord blood collected. Some authors recommend UCBGA prior to banking to exclude neonates with umbilical artery acidaemia from cord blood banking, 1204 although there is debate over whether acidaemia precludes banking Delayed umbilical cord clamping There is a growing discussion of the potential conflict between cord blood gas analysis and delayed cord clamping. One of the major concerns is the possibility of a significant change in blood gas values if the umbilical cord is not clamped as soon as possible after delivery (Table 1.46.). Most studies have focused on non-hypoxic neonates due to ethical implications of potentially impeding resuscitation with delayed cord clamping. While a decrease in arterial ph of 0.03 units in 90 seconds might be statistically significant it is unlikely to be of clinical importance in most neonates In these circumstances, where the neonate is in good clinical condition at delivery there is not the same impetus for immediate cord clamping That being so, there is a small proportion of neonates with near-abnormal ph values at birth for which the delay in cord blood collection and analysis could cause the value to become abnormal. The delay in obtaining umbilical cord blood samples might also make obtaining sufficient blood from umbilical vessels for analysis considerably more difficult. It has been postulated that a delay of seconds would lead to an increase in the number of umbilical vein only 98 P a g e

121 samples as the umbilical arteries have a tendency to rapidly empty unless clamped Wiberg et al. found that once cord pulsations ceased there was often insufficient arterial blood for blood gas and lactate analysis The authors found that umbilical cord pulsations typically ceased within 120 seconds post-delivery with three successive samples obtained in 79% and 89% of neonates for umbilical arterial and venous values respectively. Other authors have noted collapse of the umbilical vein and sometimes artery in most neonates within three minutes of delivery That being so, the largest evaluation of the effect of delayed clamping noted no significant difference in the proportion of validated paired samples between delayed and immediate calmping Table Impact of delayed umbilical cord clamping on umbilical cord blood gas values Study N ph po 2 pco 2 Base Excess Umbilical Artery Schruz et al., Ackerman et al., 1972; 1208 Ulrich et al., 1972; 1209 and, Chou et al., Lievaart and de Jong, Erkkola et al., Armstrong and 20 Stenson, Wiberg et al., De Paco et al., Andersson et al., Valero et al., Umbilical Vein Lievaart and de Jong, Armstrong and 18 Stenson, De Paco et al., Note: indicates significant (p<0.05) decrease over time, indicates significant increase over time, indicates no significant change over time, and blank indicates no information available Authors have postulated that immediate cord clamping might increase the likelihood of neonatal acidaemia. Hutchon suggested that in neonates with immediately clamped umbilical cords, H + are distributed into a smaller blood volume thereby producing a lower ph In neonates with delayed cord clamping there is the opportunity for anaerobic 99 P a g e

122 metabolites, such as lactate and H +, to be distributed into a much larger fetal placental blood volume, with the potential for continued placental transport in the moments after birth. While theoretically Hutchon s hypothesis is plausible the debate over the amount of blood transferred to the neonate and the ability of the placenta to continue transporting suggests that it s unlikely to be substantial. At this time, the literature is still divided over the benefit of delayed versus early cord clamping, particularly in term neonates Furthermore, amongst obstetricians there is a reluctance to perform delayed cord clamping in preterm neonates Given that cord blood gas and lactate analysis is only likely to be performed in developed countries, and that the greatest benefit of delayed clamping is currently found in developing countries it is unlikely these two procedures will come into large-scale conflict. On a smaller scale, with the growing popularity of less medicalised births where delayed cord clamping often occurs, there are a number of alternatives that could potentially allow accurate paired cord blood gas analysis and delayed cord clamping to coexist Umbilical cord acidaemia and adverse neonatal outcomes The link between umbilical cord acidaemia and adverse neonatal outcomes has been extensively studied in a range of populations. The majority of literature concerns umbilical artery blood gas values; however, there is a limited amount of information concerning umbilical venous values. Further, there is a distinct paucity of longer-term follow-up studies evaluating the relationship between umbilical cord blood gas values and long-term childhood and adulthood outcomes, with the majority of literature concerned with adverse outcomes within the neonatal period. Van de Riet et al. found umbilical artery ph values less than 7.00 had the strongest association with neonatal death compared with Apgar scores, and Sarnat NE grading; whilst there was also a significant association with CP (Table 1.47.). 415 To elucidate a threshold for umbilical artery acidaemia, Goldaber et al. evaluated 3,506 term singleton neonates with umbilical artery ph values less than As the ph decreased the likelihood of neonatal complications, such as special care nursery (SCN) admission, increased (Table 1.48.). In the ph less than 7.00 group, neonates were significantly more likely to have one and five minute Apgar scores less than four compared with other ph groups. Neonatal mortality was significantly more common amongst neonates with a ph less than 7.00 (p=0.03), with seven (50%) neonatal deaths in this sub-cohort. A similar study in term healthy singletons, noted an inverse correlation between umbilical artery ph values less than 7.00 and 100 P a g e

123 neurological, cardiac, renal and pulmonary issues. 201 Amongst neonates with seizures, hypotonia and organ system dysfunction there were significantly lower mean ph values than counterparts with non-neurological organ system dysfunction (6.79±0.11 vs. 6.90±0.08; p<0.05), and those without no organ system dysfunction (6.79±0.11 vs. 6.91±0.07; p<0.05). Table Meta-analysis of the relationship between umbilical artery ph values and cerebral palsy and neonatal mortality Morbidity or Umbilical Artery ph Mortality/Survivors Odds Ratio (95%CI) Lower Value Higher Value Cerebral Palsy < 7.00 vs /4 39/ (0.2, 24.8) < 7.10 vs /51 71/ (1.1, 5.1) < 7.20 vs /77 43/ (0.6, 4.6) Neonatal Mortality < 7.10 vs / /4, (3.3, 17.5) < 7.20 vs /145 42/ (2.2, 10.8) < 7.00 vs /87 1/ (4.1, 278.0) < 7.00 vs /87 7/3, (14.6, 124.2) Adapted from van de Riet et al., Table Relationship between early neonatal complications and umbilical artery ph value < 7.00 (n=87) (n=95) (n=290) (n=798) (n=2,236) SCN Admission 34 (39.1%) 12 (12.6%) 17 (5.9%) 22 (2.8%) 40 (1.8%) Intubation 12 (13.8%) 6 (6.3%) 5 (1.7%) 5 (0.6%) 13 (0.6%) One-minute Apgar Score 3 24 (27.6%) 8 (8.4%) 12 (4.1%) 19 (2.4%) 27 (1.2%) Five Minute Apgar Score 3 9 (10.3%) 1 (1.1%) 1 (0.3%) 0 (0.0%) 1 (0.04%) Neonatal Seizures 11 (2.6%) 4 (4.2%) 0 (0.0%) 2 (0.3%) 4 (0.2%) Neonatal Deaths 7 (8.0%) 1 (1.1%) 0 (0.0%) 3 (0.4%) 3 (0.1%) Adapted from Goldaber et al., One of the largest studies to evaluate the relationship between umbilical arterial ph values and adverse outcomes included validated arterial ph values from 51,519 singleton, term, non-anomalous deliveries between 1991 and 2009 (Table 1.49.) The absolute risk of adverse neurological outcome was significantly increased for ph values less than 7.10 (0.36%) with the lowest risk for the group (0.16%). For values less than 7.00, the risk of adverse outcome was 2.95%, with over 75% of neonates with adverse neurological outcomes having ph values greater than A small increase in risk was evident at higher ph levels. 101 P a g e

124 Table Relationship between umbilical artery ph values and encephalopathy, seizures and nursery admissions ph Range (n; %) n % risk RR (95%CI) NNH % Category Encephalopathy with Seizures and/or Death 7.00 (1,120; 2.17%) (10.50, 31.70) (1,364; 2.65%) (1.60, 8.22) (3,071; 5.96%) (1.06, 4.62) (5,622; 10.91%) (0.91, 3.39) NS (9,797; 19.02%) (0.64, 2.25) NS (12,903; 25.05%) (0.94, 2.83) NS (12,369; 24.01%) (4,581; 8.89%) (0.48, 2.45) NS (692; 1.34%) (0.80, 8.96) NS 1.97 Encephalopathy with Seizures (8.45, 32.49) (2.18, 12.33) (1.12, 5.98) (0.87, 4.07) NS (0.70, 2.95) NS (0.52, 2.51) NS (0.65, 3.68) NS (1.58, 11.21) Neonatal Unit Admission (5.72, 7.10) (1.38, 1.93) (1.49, 1.94) (1.27, 1.60) (1.08, 1.33) (0.96, 1.18) NS (0.82, 1.09) NS (0.51, 1.07) NS 0.76 Adapted from Yeh et al., Note: NNH = number needed to harm; NS = not significant. Sehdev et al. identified 73 neonates out of 10,705 (0.7%) born between July 1992 and October 1996 with an umbilical arterial cord ph less than Of the neonates with umbilical artery acidaemia 80% were admitted to the NICU. Thirty-five (48%) acidaemic neonates had organ system dysfunction resulting in death, seizures, severe IVH, respiratory distress, NEC, elevated liver enzymes or sepsis. The remaining 38 neonates (52%) without organ system dysfunction were considered controls. Comparing umbilical artery ph values revealed cases had significant lower average values and greater proportion of lower ph values (Table 1.50.). Those with organ system dysfunction had lower mean umbilical artery BD values, with a similar difference also present for one (p<0.001) and five (p<0.001) minute Apgar scores. This concurs with Gao et al. who noted that as umbilical artery ph 102 P a g e

125 decreased, the incidence of organ system dysfunction significantly increased (>7.20: 37%; : 60%; <7.00: 83%; p<0.05); with an inversely proportional relationship (r=-0.578, p<0.05). 363 Table Umbilical artery blood gas values in neonates developing complications Cases (n=35) Controls (n=38) P-Value Arterial ph 6.82 ± ± (43%) 31 (82%) (20%) 4 (11%) (17%) 1 (3%) (11%) 2 (5%) < (9%) 0 (0%) Arterial base deficit ± ± 2.4 < Adapted from Sehdev et al., Fee et al. studied all deliveries at Northwestern Memorial Hospital greater than or equal to 26 weeks gestation and 750 grams. 190 Of 15,896 deliveries, 1% had umbilical artery metabolic acidaemia, of which 39% required NICU admission (Figure 1.10.). Of those requiring NICU admission, 23% were abnormal at discharge and one died prior to discharge. In the abnormal at discharge cohort, 15 (65%) were followed up at 3-24 months with one neonate having persistent mild tone abnormalities and another mild mental developmental issues. Andres et al. correlated umbilical artery blood gas values with neonatal morbidity and mortality amongst 93 neonates with an arterial ph less than Lower arterial ph values were associated with HIE (p=0.03), CPR (p=0.03), seizure (p=0.02), intubation (p<0.001), and IUGR (p=0.01). This reflects Shalak et al. s findings in a cohort of 51 neonates admitted to a NICU with umbilical artery ph values less than Fifteen (29%) had abnormal outcomes (neonatal death or moderate-severe NE). The neonates with abnormal outcomes had significantly lower arterial ph (6.81±0.09 vs. 6.92±0.08; p<0.005), and BD values (-23±4 vs. -19±3 meq/l; p<0.005) and higher arterial pco 2 values (113±20 vs. 91±17 mmhg; p<0.005). Very low birth weight neonates were evaluated by Gaudier et al. using a cohort of 658 liveborn neonates weighing grams delivered between 1979 and Across all gestational ages, neonates with an arterial ph less than 7.05 were less likely to survive than those with a higher ph, although it was only significant for neonates at 27 and 28 weeks gestation. Multivariate logistic regression noted that the only significant relationship with 103 P a g e

126 neonatal mortality was low one and five minute Apgar scores and low arterial HCO - 3 values. The authors evaluated the 289 survivors at one year of age, with 11.8% having an IQ less than 70, 11.8% CP and 26.3% a major neurosensory abnormality There was not a significant relationship between arterial ph values and individual adverse neurological outcomes; however, when the major neurosensory impairments were grouped together the relationship became significant (Table 1.51.). Multivariate analysis identified an arterial ph less than or equal to 7.05 (OR 6.48; 95%CI 1.11, 37.83) as being associated with an increased likelihood of neurosensory impairment. Figure Neonatal biochemical and other outcomes in neonates delivered at Northwestern Memorial Hospital, WI, USA Deliveries (N=15,896) Metabolic Acidaemia (n=142; 1%) No Metabolic Acidaemia (n=15,386; 97%) Major Anomalies (n=368; 2%) Normal Nursery (n=87; 61%) Neonatal Intensive Care Unit (n=55; 39%) Normal at Discharge (n=31; 56%) Abnormal at Discharge (n=23; 42%) Neonatal Death (n=1; 2%) Adapted from Fee et al., Alternatively, a number of studies have conducted retrospective reviews of neonates that were considered to have been exposed to intra-uterine asphyxial insults, such as prolonged bradycardia, uterine rupture, maternal cardiac arrest or umbilical cord prolapsed, without any other explanation for their subsequent brain injury (Table 1.52.). These studies noted that whilst most neonates had umbilical artery acidaemia, there always were a number that did not. Perlman and Risser followed 39 term and 8 preterm neonates with umbilical artery phs 104 P a g e

127 less than 7.00, of which five (11%) died prior to discharge and four (9%) exhibited generalised hypertonia and hyperreflexia at discharge. 198 One neonate with early neonatal seizures was neurologically normal at discharge while five neonates (11%) had no adverse outcomes. The remaining 32 neonates (68%) all demonstrated transient neurological abnormality lasting four to 96 hours. That being so, Fisher s Exact Test and univariate logistic regression analysis found severe fetal acidaemia did not have a significant relationship with neurological dysfunction (Table 1.53.). Table Incidence of neurosensory impairments in surviving 500 to 1000 gm infants by umbilical ph Umbilical Artery ph Values < 7.05 (n=10) (n=35) (n=163) > 7.35 (n=11) P-Values Mental Retardation 28.6% * 3.2% 11.6% 12.5% NS Cerebral Palsy 30.0% 2.9% 12.3% 18.2% NS Neurosensory Impairment ** 60.0% 11.4% 25.2% 36.4% 0.01 Adapted from Gaudier et al., Note: Not significant; IQ < 70; * IQ was determined on seven individuals; ** Mental retardation, CP, blindness, deafness, and hydrocephaly and expressed as a percentage of affected individuals in each group. Table Umbilical artery ph and base excess values amongst neonates exposed to acute asphyxia like insults Study Umbilical Artery ph Umbilical Artery Base Deficit < & <7.10 >18 >-2 & 18 Korst et al % Korst et al % Pasternak & Gorey % 0% Hankins et al % 6% 45% 21% Hermansen % 6% Note: Blank spaces indicate information that was not available; and, mmol/l. The latest and largest meta-analysis to be conducted encompassed 51 articles containing 481,753 neonates The authors considered 45% (n=23) of studies high quality, 39% (n=20) medium quality, and 16% (n=8) low quality. Of the total, 13 cohort and two casecontrol studies with 469,395 neonates reported on the relationship between umbilical artery ph values and neonatal mortality. 181,192,209,1069,1151,1158, All studies when considered alone demonstrated a relationship between arterial ph values and neonatal mortality with significant heterogeneity (I 2 =61.0%). 105 P a g e

128 Table Relationship between adverse neonatal neurological condition and arterial ph and base excess values Adverse Neonatal Neurological Condition P-Value Odds Ratio (95% Confidence Interval) Arterial ph % (5/24) 2.8 (0.5, 16.0) % (2/23) Reference Arterial Base Excess % (4/22) 2.3 (0.4, 14.3) > % (2/23) Reference Adapted from Perlman and Risser, Note: Neonatal seizures followed by neonatal death or neurological abnormality at discharge; Base excess for one neonate with adverse outcome was not obtained Meta-regression analysis suggested that the populations influenced the relationship between arterial ph values and neonatal mortality. There was a strong relationship between neonatal mortality and arterial ph in a universal population (OR 16.9, 95%CI 9.7, 29.5; estimated predictive interval [EPI] ; I 2 =0.0%). 1069,1233, There was a similar, less profound relationship for at risk neonates (OR 4.2; 95%CI 2.6, 6.9; EPI 1.3, 13.7; I 2 =35.1%). 181,192,209,1151,1158, ,1234 Most cases in the universal population were obtained from a single study; 1235 exclusion of this study did not significant alter the arterial ph and neonatal mortality relationship (OR 17.0; 95%CI 4.4, 65.5); however, the predictive interval increased (EPI 0.0, ). The association between low ph values and neonatal mortality persisted in preterm and low birth weight populations (<32 weeks or <2,000 grams), with significant increased neonatal mortality with low ph values (OR 3.5; 95%CI 2.3, 5.4; I 2 =0.0%). 181,1069,1151,1158, ,1234 In term neonates, there was a significant association (OR 9.3; 95% 1.4, 63.2); however, the cohort demonstrated significant heterogeneity (I 2 =84.0%) and the predictive interval was wide. Sub-analysis based on study quality did not alter the significance or relationship between umbilical artery ph values and neonatal mortality. Further analysis evaluated the concept of a threshold; with the ph value of 7.00 not having a significant association with neonatal mortality (OR 6.1; 95%CI 0.9, 41.6). Using the 7.10 ph threshold there was a significant increased odds of neonatal mortality (OR 7.1; 95%CI 3.3, 15.3); however, the predictive interval crossed the line of no effect (EPI 0.8, 64.3). The final umbilical artery ph threshold (7.20) investigated noted similar findings (OR 4.3; 95%CI 2.2, 8.7; EPI 0.5, 40.6). The only study to simultaneously evaluate all three thresholds, 1235 noted the strongest 106 P a g e

129 association with neonatal mortality was present with the 7.00 threshold (OR 16.9; 95%CI 9.2, 31.1) while the weakest occurred with the 7.20 threshold (OR 3.1; 95%CI 2.3, 4.1). Thirty studies (n=10,904 neonates) were used to evaluate the relationship between artery ph and a composite neonatal morbidity outcome consisting of HIE, neonatal seizures, mechanical ventilation, IVH or periventricular leucomalacia. Most studies (n=28; 93%) demonstrated an independent association between ph values and neonatal morbidity, although significant inter-study heterogeneity (I 2 =58.2%) together with a significant Harbord test, is potentially indicative of the influence of numerous small studies. Amongst a high-risk population there was a weaker association between arterial ph and neonatal morbidity (OR 3.4; 95%CI 2.3, 4.9; EPI 1.4, 8.4; I 2 =26.4%) than in universal or undefined populations (OR 10.6; 95%CI 4.7, 24.1; EPI ; I 2 =66.4%). Analysis based on study quality noted that the significant relationship persisted amongst the 12 high quality studies (OR 6.6; 95%CI 3.7, 11.8; EPI 1.3, 32.6; I 2 =51.2%) and 18 low to medium quality studies (OR 4.6; 95%CI 2.6, 8.0; EPI 0.7, 29.2; I 2 =61.5%). In terms of a threshold effect the most significant association between a ph threshold and neonatal morbidity was for a ph value of 7.00 (OR 12.5; 95%CI 6.1, 25.6; EPI ). For the other thresholds similar results were noted with ph values of 7.10 (OR 2.4; 95%CI 1.3, 4.3) and 7.20 (OR 2.2; 95%CI 1.3, 3.7). Analysis of the relationship with specific outcomes within the composite outcome of neonatal morbidity noted significant relationships between arterial ph values and HIE (OR 13.8; 95%CI 6.6, 28.9), neonatal seizures (OR 8.1; 95%CI 3.0, 21.9), and IVH/periventricular leucomalacia (OR 2.9; 95%CI 2.1, 4.1). For venous ph values there was a significant relationship with neonatal morbidity (OR 4.0; 95%CI 1.2, 13.3; I 2 =44.5%) in five studies. 195,710,1185, The finding was complicated by the EPI crossing the line of no effect (0.1, 125.3). Other studies not included found contrasting results, with Dweck et al. finding no significant relationship between venous ph values and neurological injuries In contrast, Huisjes et al. found that below 7.20 neonates were eight times more likely to have neonatal neurological injuries (OR 8.2; 95%CI 4, 15). 71 For arterial BE values, meta-analysis of four studies, 210,599,1138,1240 revealed a significant association with neonatal morbidity (OR 2.5; 95% CI 1.3, 4.8); however, the EPI crossed the line of no effect (0.6, 10.4). Due to the small number of studies reporting ABE values it was not possible to examine the relationship between metabolic acidaemia and neonatal morbidity. 107 P a g e

130 The meta-analysis identified seven studies, containing 1,117 children, evaluating the relationship between umbilical artery ph values and CP. 598,1138,1151,1225,1232,1234,1236 Five studies independently demonstrated a relationship between umbilical artery ph values and CP. There was a significant association between low umbilical artery ph values and CP (OR 2.3; 95%CI 1.3, 4.1), without a significant degree of inter-study heterogeneity (I 2 =0.01%). Analysis to identify the presence of a threshold was not possible due to limited number of studies; however, bivariate meta-analysis noted the overall association remained significant (OR 2.1; 95%CI 1.2, 4.1). The authors of the meta-analysis concluded that the strength of association between umbilical cord blood gas values, primarily ph values, and adverse neonatal outcomes occurs across a wide population not just high-risk cases. Furthermore, regardless of neonatal clinical condition, the authors recommended increased initial surveillance for neonates with low umbilical ph values due to the significantly increased odds of later adverse outcome Predictive value of umbilical cord blood gas analysis There is a large body of evidence noting significant relationships between umbilical acidaemia and adverse outcomes, there is considerably less literature evaluating the ability of cord blood gas values to predict adverse outcomes, particularly long-term outcomes. As part of early UCBGA evaluation, several studies evaluated the link between umbilical artery ph values and Apgar scores. For one-minute Apgar scores, the studies generally demonstrated high specificity and low sensitivity (Table 1.54.). One of the most extensive studies of umbilical cord blood gas values ability to predict low five minute Apgar scores involved 13,735 validated samples obtained from singleton deliveries throughout Europe Similar findings to the one-minute scores there was a high specificity and negative predictive value (NPV) and lower sensitivity and PPV (Table 1.55.). Ruth and Raivio assessed the predictive value of umbilical artery ph and BE in 982 live born neonates delivered over a two month period. 69 Of the entire cohort, 12% of neonates (111/964) had an arterial ph two SDs below the mean for their mode of delivery, whilst 7% (70/964) had an arterial BD two SDs above the mean. The authors followed the cohort to one year of age, although 35 infants were lost to follow up and 22 had an adverse outcome unrelated to asphyxia. Of those that remained, 883 infants showed normal development, while there were four deaths, minor abnormalities in 28 neonates and major abnormalities in 10 considered to be potentially related to intrapartum asphyxia. Sensitivity and specificity 108 P a g e

131 analysis compared arterial ph, arterial lactate, five-minute Apgar scores, and combined Apgar score and arterial ph, in predicting neonatal outcome; however, all were found to be universally poor predictors of outcome at one year of age (Table 1.56.). The authors did utilise a relatively high arterial ph (7.16) and low arterial lactate (5.4 mmol/l) threshold, which could be partially responsible. Table Ability of umbilical artery ph values to predict low one-minute Apgar scores Study N ph Cut-Off Sensitivity Specificity Sykes et al., % 93% Josten et al., % 88% Lauener et al., , % 94% James et al., % 83% Fields et al., % 94% Suidan & Young, % 83% Silverman et al., , % 81% Page et al., % 88% Boehm et al., % 94% Dijxhorn et al., % 65% Vintzileos et al., % 92% Goldenberg et al., % 78% Perkins & Papile, % 90% Adapted from Schmidt et al., Note: One-minute Apgar <7, except Lauener et al. with <4. Table Ability of umbilical artery blood gas and lactate values to predict five minute Apgar scores less than seven and less than five Umbilical Artery Cut-Offs Sensitivity Specificity PPV NPV Five Minute Apgar Score less than Seven ph < % 96.0% 5.8% 99.4% ph < % 99.7% 9.1% 99.2% Lactate > 10 mmol/l 20.2% 97.8% 7.3% 99.3% ph < 7.05 & Base Deficit > % 98.9% 7.7% 99.2% mmol/l ph < 7.00 & Base Deficit > % 99.7% 9.1% 99.2% mmol/l Five Minute Apgar Score less than Four ph < % 95.8% 0.9% 99.9% Lactate > 10 mmol/l 26.3% 97.6% 1.5% 99.9% ph < 7.05 & Base Deficit > % 98.8% 1.2% 99.9% mmol/l Adapted from Wiberg et al., Note: Positive predictive value; Negative predictive value 109 P a g e

132 Table Ability of umbilical artery ph, umbilical artery lactate, and five minute Apgar scores to predict adverse outcome at one year of age Sensitivity Specificity PPV NPV Umbilical Artery ph 21% 89% 8% 96% Umbilical Artery Lactate 12% 91% 5% 96% Five Minute Apgar 12% 98% 19% 96% Five Minute Apgar & Umbilical Artery ph 7% 99% 27% 96% Adapted from Ruth and Raivio, Note: Positive predictive value; Negative predictive value Perlman and Risser evaluated the ability of a variety of markers of neonatal status to predict neonatal seizures in term neonates that were considered at high risk following NICU admission An arterial ph value of less than or equal to 7.00 had a sensitivity of 100%, specificity of 81%, and a PPV of 23.8% in predicting seizures. Khoshnow and Mongelli evaluated the ability of umbilical artery ph values to predict five-minute Apgar scores less than seven and NICU admission finding an area under the curve (AUC) of 0.75 and 0.67, respectively Suidan and Young also evaluate arterial ph s ability to predict five minute Apgar scores less than seven finding a sensitivity of 50%, specificity of 81% and PPVs and NPVs of 8.4% and 98%, respectively Westgren et al. evaluated the predictive ability of umbilical cord blood gas values using 4,045 samples obtained from 3,932 consecutive deliveries at two Swedish maternity units. 29 Umbilical artery ph and BE values were comparable with each other with sensitivity and specificity varying with the cut-off utilised (Table and Table 1.58.). The study was limited by relatively small numbers of adverse neonatal outcomes; only six neonates had neurological abnormalities (one case of HIE, two hypotonia and three seizures). Further, for all outcomes studied intrapartum asphyxial injuries are typically an aetiological agent in a minority of cases Role of umbilical cord blood gas analysis Multiple academic and clinical organisations advocate UCBGA following delivery either in a selective or universal manner ,49,841,912,1250 Despite these recommendations, the uptake of UCBGA into maternity units has been poor, especially outside tertiary centres. Additionally, considerable debate exists about whether UCBGA should occur following all deliveries in a universal manner or selectively on a proportion of the population. 110 P a g e

133 Table Predictive ability of umbilical artery ph values Parameter < 1 st Percentile (6.98) Cut-Off Limits < 2.5 th Percentile (7.04) < 5 th Percentile (7.08) <10 th Percentile (7.14) <25 th Percentile (7.21) NICU Admissions Sensitivity 4% 6% 11% 16% 29% Specificity 99% 98% 95% 90% 75% Meconium Aspiration Syndrome Sensitivity 11% 33% 33% 33% 56% Specificity 99% 98% 95% 90% 75% Idiopathic Respiratory Distress Syndrome Sensitivity 0% 0% 0% 11% 15% Specificity 99% 98% 95% 90% 74% Assisted Ventilation Sensitivity 0% 8% 8% 17% 42% Specificity 99% 98% 95% 90% 75% Neurological Abnormality Sensitivity 17% 17% 17% 34% 67% Specificity 99% 98% 95% 90% 75% Neonatal Deaths Sensitivity 29% 29% 29% 43% 57% Specificity 99% 98% 95% 91% 75% Adapted from Westgren et al.,

134 Table Predictive ability of umbilical artery base excess values Parameter < 1 st Percentile (-19.2 mmol/l) < 2.5 th Percentile (-16.3 mmol/l) Cut-Off Limits < 5 th Percentile (-14.0 mmol/l) <10 th Percentile (-11.9 mmol/l) <25 th Percentile (-8.4 mmol/l) NICU Admissions Sensitivity 3% 6% 9% 15% 31% Specificity 99% 98% 96% 91% 76% Meconium Aspiration Syndrome Sensitivity 11% 22% 44% 56% 56% Specificity 99% 98% 95% 90% 76% Idiopathic Respiratory Distress Syndrome Sensitivity 0% 0% 4% 11% 15% Specificity 99% 98% 95% 90% 75% Assisted Ventilation Sensitivity 0% 0% 17% 17% 25% Specificity 99% 98% 95% 90% 76% Neurological Abnormality Sensitivity 17% 17% 17% 34% 67% Specificity 99% 98% 95% 90% 76% Neonatal Deaths Sensitivity 29% 29% 43% 43% 57% Specificity 99% 98% 95% 90% 75% Adapted from Westgren et al.,

135 Universal versus selective umbilical cord blood gas sampling The latest ACOG guidelines on UCBGA advocate isolating an umbilical cord segment at all deliveries but only sampling if a: 1) serious abnormalities arise during delivery; or, 2) problems with neonates condition are present at or beyond 5 minutes of age Another selective sampling protocol proposed by Gilstrap et al. included clamping an umbilical cord segment for all deliveries and then waiting for the five minute Apgar If the neonate is vigorous and crying with a normal five minute Apgar then the cord segment can be discarded without sampling. A third selective approach is to perform UCBGA on premature neonates, those with MSAF and instrumental or caesarean deliveries for fetal compromise. The RCOG and Royal College of Midwives (RCM) in a joint statement suggested that all caesarean and instrumental deliveries for fetal compromise should have UCBGA while consideration should be given to measurement of cord blood gases following all deliveries. 912 In contrast, the SOGC recommends collecting and conducting UCBGA on all deliveries Currently there is no consensus on whether UCBGA should be performed in a universal or selective manner. A concern with selective sampling is sampling algorithm complexity. It is widely acknowledged the more complex a policy, the less likely it will be applied correctly or at all, particularly when staff and resources are limited. Wong and MacLennan noted in a tertiary hospital that even with simplistic guidelines, namely all neonates with five minute Apgar scores less than seven should have UCBGA, only 52% had samples collected and analysed Application of the guideline that all neonates require UCBGA produces an anecdotally reported more efficient and easier process This is particularly important in tertiary settings where a large amount of teaching and rapid staff turnover occurs. Case selection for cord blood gas sampling based on risk factors, whilst an appealing proposal, is unlikely to result in blood gases being collected on cases with adverse outcomes after labour. A significant proportion of perinatal mortality or morbidity occur in neonates were assessed as low-risk following pregnancies and deliveries without obvious complications. 511, ,812, One review of 103 CP cases undergoing medicolegal action noted only 38% of cases had UCBGA Absence of antepartum or intrapartum risk factors is rarely an exclusion criteria for sampling but risk factors presence may be used as a sampling indication. Khan et al. identified primiparity, prolonged labour, assisted delivery, and fetal compromise on FHR traces as highly sensitive markers of neonatal acidaemia post-delivery; 113 P a g e

136 however, the specificity was universally poor recommend criteria for selective umbilical cord blood gas sampling. Consequently, the authors were unable to The ACOG considers that since only severely impaired neonates are at risk of HIE and neurological dysfunction, UCBGA adds little to evaluation of vigorous term newborn with normal Apgar scores. 49 Instead they consider UCBGA to be most useful in neonates with low Apgar scores or following serious abnormality in the delivery process. 49, More recently, the AOCG advocated UCBGA on all neonates undergoing caesarean delivery for fetal compromise, low five minute Apgar scores, severe growth restriction, abnormal FHR tracings, maternal thyroid disease, intrapartum fever, and multi-fetal gestations Unfortunately, the ACOG have not defined each criteria, leaving it to the clinician what circumstances would fulfil the criteria with other organisations having been similarly vague. 848 Use of Apgar scores to select neonates for UCBGA is controversial. Firstly, the Apgar score is subjective and it has been some suggested scoring might be affected by individuals desire or distaste for UCBGA. 49,1187 Secondly, such a method would miss neonates suffering an asphyxial insult who appear vigorous at delivery, for example due to catecholamine release These neonates form a significant proportion of those developing neurodevelopmental morbidities. 1155, It has been estimated that 75% of all neonates developing CP have normal five minute Apgar scores, 1155 although others have noted higher proportions Even with a UCBGA policy based on low Apgar scores, 50% will not have cord blood gas samples collected Thirdly, Apgar scores are influenced by factors such as birth weight, infection, gestational age, resuscitation, recreational drugs, anaesthesia, analgesia, and congenital abnormalities. 225,794,1092,1098,1102, Role of umbilical cord blood gas measurement in early neonatal management Opponents of UCBGA often point out it occurs post-insult and therefore is unable to prevent neonatal injury. That being so, results of umbilical cord blood gas and lactate measurement can be used in neonatal management of those with or at risk of neurodevelopmental injuries. Cord blood gases can also play an important role in determining causes of non-vigorous neonates at birth to allow effective resuscitation and neonatal care. For example, while most unwell neonates require basic respiratory support, the cause of respiratory depression can be varied. Normal blood gas values assist in excluding acidaemia as the cause of respiratory depression and shifts attention to other 114 P a g e

137 aetiologies such as narcotics or infection. Conversely, if blood gas values indicate significant metabolic acidaemia then early interventions to prevent or minimise injury can be instigated. Over the previous decade there has been considerable development in neuroprotective treatment options with early intervention and care having the potential to have profound influence on long-term neonatal outcome One of the most promising is use of neonatal hypothermia as a form of neuroprotection following exposure to potentially asphyxiating events It has been postulated that hypothermia might reduce injury severity by lowering cerebral metabolism, preventing tissue acidosis, inhibiting cellular apoptosis, impairing excitatory amino acid release, combating ischaemia associated glutamate release and uptake, and reducing free radical, platelet activating factor and nitric oxide (NO) production. 182, Several animal studies found that reducing brain temperature helps to inhibit or ameliorate neurological injury Additionally, one meta-analysis noted a reduction in the risk of death associated with HIE following neonatal hypothermia There was some concern that a decrease in neonatal mortality would be accompanied by an increase in neurodevelopmental abnormalities in survivors; 1296 however, this has not occurred as survivors have lower rates of neurodevelopmental abnormalities, 1295, and radiological evidence of the benefits of neuroprotective hypothermia. 1299, Hypoxic-ischemic insults produce a biphasic cerebral energy failure. During the primary phase, immediately after the insult, cell death occurs as a result of exhaustion of cellular energy metabolism. The primary phase is then followed by some degree of recovery following restoration of perfusion to the affected region. Next there is a latent period of 8-48 hours post insult, over which time delayed cellular injury will steadily become more obvious. Finally, secondary cell death will commence with release of excitatory amino acids, generation of reactive oxygen free radicals, mitochondrial dysfunction, intracellular calcium accumulation, cellular apoptosis, and cytotoxic activation of microglia Given that hypoxic-ischaemic injury occurs in two phases with a latent phase between there is a potential window for intervention. How long this window lasts is debatable but general consensus based on animal models is between four to six hours post-insult, ,1294,1316 with no human data suggesting efficacy of neonatal hypothermia beyond this time period The intervention period is shorter than the latent period as intervention is required to commence prior to the latent phase finishing and must account for insults occurring sometime before delivery. There is animal evidence that the greater the severity of the hypoxic-ischaemic insult the shorter the intervention window Consequently, a quick and accurate test is required that allows identification of neonates that might benefit from intervention. One of 115 P a g e

138 the major controversies surrounding neuroprotective hypothermia is this; how to identify neonates that would obtain greatest benefit, 204,413,1295, especially given the potential cardiovascular, respiratory, hepatic and haematological adverse effects. 1296,1298, , Hypothermia can also affect pharmacokinetics, pharmacodynamics and therapeutic utility of various drugs Whether NE is secondary to antepartum and intrapartum causes needs to be differentiated at delivery due to the short potential intervention period; hypothermia is unlikely to benefit neonates with antenatal hypoxic-ischaemic injuries. Further, it is particularly difficult to distinguish NE due to intrapartum hypoxia from that due to antepartum factors, or congenital abnormalities Currently, the only objective mechanism to differentiate between these is UCBGA. Consequently, any inclusion criteria for neonatal hypothermia should include an umbilical cord blood gas profile indicative of an acute intrapartum asphyxial episode. This concurs with most large RCTs evaluating neonatal hypothermic neuroprotection which used umbilical cord or early neonatal blood gas values, 1296 with umbilical artery ph values of less than 7.00 and a BE less than -16 generally considered indicative for inclusion ,1304, With the development of pharmaceutical and other agents for the prevention or amelioration of hypoxic-ischaemic injury, the early identification of neonates is only going to become more important. 433,1266, Neonates can be identified with a reasonable efficacy on the basis of their umbilical cord blood gas and lactate measurements as being at risk of HIE therefore allowing the prompt intervention and potential stabilisation and damage mitigation using the latest neurological therapeutics. This has profound implications in the ability of resource limited NICUs to allocate in a timely manner the limited resources to those best able to derive benefit. It can thus be seen that umbilical cord blood gas and lactate measurement has the potential to significantly alter neonatal management Educational role of universal umbilical cord blood gas analysis Whilst the provision of umbilical cord blood gas values does not have the ability to alter the intrapartum care of the fetus from which it is derived, it has the potential to influence clinician s interpretation of their intrapartum management. 47 The availability of quantifiable biochemical indicators of fetal well-being immediately after delivery provides the opportunity for direct feedback about intrapartum management practices (Figure 1.11.). 116 P a g e

139 Figure Action of positive and negative biochemical reinforcement on clinical behaviour Adapted from White et al., Note: Fetal heart rate; High pco 2 but normal lactate and BE values; * Increased pco 2 as well as increased lactate and/or decreased BE levels; ** Normal pco 2 values but increased lactate and/or decreased BE levels; *** Potential modifiable factors include maternal position, maternal hydration, oxytocin management, FHR trace interpretation, earlier fetal wellbeing assessment (e.g. scalp stimulation or FBS), vaginal examination of labour progress, earlier assisted/operative delivery and BP management following regional anesthesia. Biochemical reinforcement can act in a positive or negative manner, reinforcing behaviour associated with favourable fetal outcomes while identifying and modifying behaviour associated with adverse outcomes. Such a system is not unprecedented in obstetrics, with an Apgar score based system meeting with some success in a North Staffordshire (UK) maternity unit Most clinicians review their clinical care after the delivery of an infant in poor clinical condition sometimes formally, other times informally. The presence of cord blood gas results provides information about respiratory and metabolic acidosis across a continuous scale allowing identification of near-misses (e.g. arterial ph or lactate mmol/l). Many of these near-misses would result in neonates born in good or relatively good condition; however, the potential to learn from review of these cases provides 117 P a g e

140 the opportunity to gain a greater degree of insight into clinical care and its effect on neonatal wellbeing. This would mirror the approach to such near-miss incidents in the aviation industry, with incidents typically investigated in a de-identified manner with non-punitive reporting followed by widespread distribution of findings Good biochemical outcomes provide direct positive reinforcement by endorsing and encouraging successful management behaviours. Conversely, non-reassuring biochemical outcomes provide the clinician with information about the potential asphyxial insult s duration and severity. Clearly some adverse outcomes will be unavoidable regardless of intrapartum care. For the remainder, rapid biochemical feedback allows immediate identification of instances where intrapartum care might have been suboptimal, and reinforces the need for review and improvement of clinical practices. Management of future similar cases might be modified by simple strategies such as changes in maternal position and hydration, as well as avoiding more complex factors such as uterine hyperstimulation, prolonged second stage, and suboptimal timing of intervention To establish UCBGA s utility in biochemical reinforcement and subsequent improvement in neonatal outcomes following changes in clinical practice, UCBG values must be considered indicative of sub-optimal care in some circumstances. Jonsson et al. noted that amongst neonates with metabolic acidaemia, almost half were exposed to sub-optimal care, whilst amongst non-acidaemic vigorous controls only 13% were considered to have been exposed to suboptimal care (p<0.001) For neonates that developed metabolic acidaemia there was a significant more delayed responses to persistent EFM abnormalities (20% vs. 1%; p<0.001). Pathological EFM traces where significantly more common amongst those that developed metabolic acidaemia (68% vs. 22%; p<0.001), from which it may be inferred that the delayed response potentially contributed to later development of metabolic acidaemia. Similar findings regarding sub-optimal EFM utilisation occurred in studies looking at antenatal and intrapartum courses of neonates that developed NE or died, 1361 and amongst neonates with seizures or terminal apnoea To determine to what degree metabolic acidaemia is preventable is not a straightforward proposition; however, Jonsson et al. postulated that 40-50% of metabolic acidaemia could be potentially avoided due to presence of sub-optimal intrapartum care, which concurs with other studies. 643,792,1363 Numerous authors have noted the relationship between suboptimal EFM utilisation, injudicious use of oxytocins and adverse intrapartum and neonatal outcomes, , so the risks are not new with most units having guidelines on oxytocins and EFM and appropriate responses. That being so, it is apparent guidelines are 118 P a g e

141 not uniformly followed in all circumstances. It is unlikely that medical and midwifery staff members are unaware of guidelines concerning intrapartum care and are probably generally familiar with the contents. In some circumstances divergence from intrapartum guidelines is unavoidable and unforeseen; however, it is likely a proportion of divergence is potentially avoidable and use of an objective end-point, such as UCBGA, allows identification of such circumstances and involvement of bio-feedback Other benefits of universal umbilical cord blood gas analysis Routine UCBGA allows determination of site population distributions for measures of fetal acidaemia. These distributions and reference ranges can be utilised in auditing clinical care. The proportion of neonates with low umbilical cord phs or other indicators of metabolic acidaemia, such as BE or lactate, could potentially be used to indicate the quality of intrapartum care if used with other obstetric and neonatal data. Umbilical cord sampling also maintains and develops medical and midwifery skills regarding labour management as well as providing objective foci for training and ongoing up-skilling of EFM interpretation particularly in units with an active education program Inter-hospital and intra-hospital comparisons can be made if routine sampling is performed utilising a similar technique across sites. This would provide a objective endpoint in order to examine the influence of labour management advances on the fetus and neonate. 189 Universal UCBGA allows the process of sampling to become routine ensuring that even during obstetric, fetal or neonatal emergencies UCBGA is less likely to be missed as it has become a habit. The benefits of routine sampling can also be more immediately apparent in that early neonatal blood gas data is available in the event of a rapid deterioration in neonatal condition Umbilical cord blood gas analysis today Umbilical blood gas analysis is an objective method of evaluating neonatal condition and fetal metabolic condition. One of the most useful UCBGA applications is in non-vigorous neonates. Sykes et al. found 80% of all neonates with low one minute Apgar scores who might have been previously assumed to have suffered from birth asphyxia can have birth asphyxia ruled out if a umbilical cord ph is obtained. 67 Low Apgar scores are common amongst preterm neonates who are at much great risk of later neurodevelopmental issues, without UCBGA these could be inaccurately attributed to birth asphyxia. Obtaining an early neonatal blood sample from the umbilical cord via UCBGA can also help guide immediate neonatal management. 119 P a g e

142 Umbilical cord blood gas analysis has been met with scepticism and consequently uptake into clinical practice has been at times slow. In the early 1980s, 6% of UK obstetric units used UCBGA on greater than 20% of deliveries, whilst a further 35% indicated they obtained cord blood samples in some situations. 911 A 1999 UK survey found 14 maternity units (6%) did not use UCBGA, while 162 (68%) did so after emergency caesarean deliveries and 105 (44%) after instrumental deliveries. 857 A survey of 144 university obstetric units in Canada, Puerto Rico, and USA found all institutions used UCBGA, with 27% sampling % of deliveries and 40% sampling less than 25% of their deliveries Centres typically analysed the umbilical artery and vein separately (61%) with 29.9% of centres only sampling the umbilical artery. Representatives from almost all (96%) centres considered UCBGA was of clinical benefit, while 93.1% were of the opinion that it reduced the risk of medicolegal action. A more recent study of 215 UK maternity units, 84% of units performed some form of UCBGA Of these, 74% had a selective sampling policy, with 54% obtaining an arterial and venous sample. In terms of analysis type, 54% performed full blood gas analysis, while 24% performed ph analysis only. Eighty percent considered UCBGA clinically useful, 85% useful for auditing and teaching purposes and 90% useful for medicolegal reasons. Three percent of units felt UCBGA had no role in obstetrics, but 16% of units did not perform UCBGA. An Eire study found 46% of units routinely conducted UCBGA following emergency caesarean deliveries while 64% did if the neonate was in poor condition at delivery. 856 There is limited data on UCBGA utilisation, with the data mainly confined to whether sampling is performed universally or selectively. Skelton et al. studied how selective sampling is utilised in a clinical environment, in all deliveries at tertiary hospital and community hospital in Portland, Maine, USA Indication for sampling was based on 1994 ACOG guidelines, namely that sampling should be performed if neonates show signs of depression at birth, with the authors equating neonatal depression with a five minute Apgar less than seven. A number of factors were identified as being associated with UCBGA utilisation (Table 1.59.). A multiple logistic regression model was developed and identified factors that significantly impacted the likelihood of UCBGA including maternal age, presence of medical staff members at birth, birth weight and gestational age. The tertiary level hospital was 32 times more likely to conduct UCBGA than the community hospital. Overall, ACOG guideline compliance was relatively poor with 97% (n=1,125) of 1,170 blood gas analyses, performed on neonates with five minute Apgar scores greater than or equal to seven. Amongst those with Apgar scores less than seven, 15 (25%) neonates did not have UCBGA, although seven neonates were managed in a palliative manner. 120 P a g e

143 Table Factors affecting the utilisation of umbilical cord blood gas analysis in a selective model P- Adjusted OR Factor Variable Number (%) Value (95%CI) Race Caucasian 1134/3078 (37) Reference Non-Caucasian 35/84 (42) 0.98 (0.90, 1.06) Education (Grades < /1284 (40) Reference completed) /1870 (35) 0.97 (0.93, 1.01) Maternal age < /215 (52) /2462 (36) /489 (36) Birth weight (g) /290 (84%) ( /2491 (32%) 3999 if DM) 4500 ( 4000 if 133/382 (35%) DM) Gestational age < /380 (79%) (wks) /2744 (31%) Maternal medical conditions Abnormal neonatal condition Congenital anomalies Intrapartum complications /42e2 (43%) Present 439/840 (52) Absent 703/2251 (31) Present 118/152 (78%) Absent 1044/3002 (35%) Present 34/53 (73%) Absent 1126/3105 (36%) Present 650/1141 (57) Absent 478/1942 (25) < (0.96, 0.99) < (0.94, 0.99) < (0.90, 0.99) < < < < (1.76, 2.55) Five minute Apgar < /3103 (36%) 1.70 (0.87, 3.32) score < /60 (75%) Reference Facility Tertiary 1149/2332 (49) 32.11(20.54, 50.20) < Community 21/834 (3) Reference Birth attendant Obstetrician 1041/2544 (41) Reference General 70/294 (24) 0.73 (0.52, 1.04) Practitioner < Midwife 57/311 (18) 0.37 (0.26, 0.53) Other 2/15 (13) 1.57 (0.06, 41.05) Adapted from Skelton et al., Note: 100 g differential Umbilical cord blood gas analysis provides information on the neonate at delivery as well as an insight into the period prior to delivery including intrapartum biochemical and metabolic milieu. Use of UCBGA is increasing as the benefits become increasingly apparent. It 121 P a g e

144 provides an objective method of evaluating neonatal condition as well as becoming an integral part in diagnosis of many disorders related to intrauterine hypoxic-ischaemic insults. There is a significant and growing body of evidence to suggest universal UCBGA at all deliveries can have medicolegal, financial, and educational benefits. Despite this, most obstetric units (supported by several major obstetric colleges), use selective UCBGA, an approach that has a number of major limitations Assessment of fetal and neonatal lactate levels Use of lactate to assess neonatal and fetal wellbeing was first broached in the 1930s; 1373 however, it has been in the last 30 years, that major efforts have been made to evaluate lactate s role in intrapartum fetal surveillance and neonatal assessment at delivery. These efforts have been constrained by the laborious and technically demanding methods of lactate analysis. Consequently, although lactate assessment has been utilised in adult critical care setting for many years, it has only been since the development of micro-volume hand held lactate meters in the 1990 s that it has begun to be widely utilised in obstetric and neonatal medicine Lactate physiology Lactate production and its effects on the fetus, neonate and mother were originally considered relatively simplistically with lactate consider to have a detrimental physiological effect. In contrast, it has more recently become apparent that the production and physiological effects of lactate are more complex than first supposed with production under hypoxic and non-hypoxic conditions and positive and negative fetal, neonatal and maternal effects Hypoxic lactate production Lactate is produced in the fetus when tissues undergoing periods of hypoxia and/or ischaemia with a change from aerobic to anaerobic metabolism (Figure 1.12). Glucose is broken down along the glycolytic pathway to form pyruvate. When there is sufficient fetal tissue oxygenation, pyruvate enters the citric acid cycle where nicotinamide adenine dinucleotide (NAD + ) accepts a H + with an additional electron, a hydride ion (H: - ), to produce NADH. The corresponding catabolism of NADH consumes O 2 and produces NAD + and H 2 O. This reaction takes place along the inner mitochondrial membrane and is responsible for releasing large amounts of energy necessary for oxidative phosphorylation. Oxidative phosphorylation in turn produces ATP and H 2 O. The glycolytic process is dependent on 122 P a g e

145 intracellular NADH concentration, since NAD + is the major hydrogen carrier in catabolism. During anaerobic metabolism, pyruvate is converted into lactate which results in formation of H + but is less efficient in ATP production. Figure Aerobic and anaerobic metabolism. Cytosol Glucose 2 ADP 2 NAD + 2 ATP 2 NADH 2H: - 36 ATP 2 Pyruvate 2 Lactate - + 2H + 36 ATP 2 H 2 0 Citric Acid Cycle CO 2 CO 2 36 ADP 4NADH 4NAD + 4H + + O 2 + 4e - 4e - Mitochondrion O 2 Adapted from Pennell, electron. Note: H: - is a hydride ion, containing an extra unpaired While exact lactate production sources are often difficult to identify in the fetus, 438 lactate in fetuses/neonates with hypoxia is most likely to have been produced by the fetus Animal models have suggested that in non-hypoxic situations lactate can be produced in the placenta with the substrates sourced from the mother and fetus Placental lactate can enter uterine and umbilical circulation with 60-75% ending up in fetal circulation. As fetal plasma lactate levels are higher than maternal lactate, release from uteroplacental tissues does not operate on a simple kinetic basis. Instead it s suggested an active lactate transport system exists across the placenta and is responsible for carrying lactate from fetal into maternal circulation ,1378 Cordocentesis has been used in human and animal models to establish the 123 P a g e

146 placenta s role in lactate production; however, studies have been conflicting on fetal lactate s primary origin. Higher umbilical venous lactate suggest a predominantly placental lactate origin, 56,1375, while higher umbilical artery lactate prior to labour suggesting fetal origin even in aerobic conditions. 1378, Radiolabelled lactate in a fetal ovine model has provided the best method for determining fetal lactate s origin; indicating placental and fetal production even in normoxia, with net fetal consumption As part of the hypoxia protective response the fetus prioritises certain organs, directing blood flow to them at the expense of other organs Seidl et al. in a murine model demonstrated that ATP depletion was considerably greater in the kidneys than in the CNS or heart when exposed to a graded perinatal asphyxial insult This suggests non-essential fetal organs that are negatively affected by the fetal response to hypoxia are the primary source of endogenous lactate Non-hypoxic lactate production While lactate is usually produced under hypoxic conditions, production also occurs in aerobic conditions as lactate and pyruvate are in a steady state relationship. Consequently, elevated pyruvate levels, as may occur with hyperglycaemia, could cause lactic acidaemia without hypoxia or ischaemia. 438 Further support for this is found via the significant correlation between cord lactate and neonatal and maternal glucose concentrations The relationship between lactate and pyruvate is maintained in anaerobic conditions with an increased lactate/pyruvate ratio While some have investigated the lactate/pyruvate ratio as a marker of neonatal wellbeing the general consensus is that it is not any more useful than lactate levels alone. 1387, Experimental fetal hyperglycaemia models have been developed utilising high dose glucose infusions, 115,1391 or beta-mimetic drugs, 1392 to induce glycogenolysis. Philipson et al. randomized 32 elective caesarean cases into receiving a litre of 5% dextrose (containing 50 grams of glucose), Ringer's lactate or isotonic saline solution before epidural anaesthesia. 115 A significantly lower umbilical arterial and venous ph was found in neonates exposed to a glucose infusion even after accounting for potentially confounding perinatal factors. Additionally there was an increase in cord blood lactate concentrations amongst those exposed to dextrose. In contrast, Nordstrom et al. utilising a continuous 5% dextrose infusion at 180 millilitres per hour (nine grams of glucose per hour) found no significant difference in lactate levels in maternal, fetal, and neonatal cord blood samples Similarly, Lunell et al. found that acute maternal metabolic change resulting from a salbutamol infusion during the third trimester was unlikely to have a significant effect P a g e

147 The birthing process has been noted to induce fetal catecholamine release, as part of the stress of being born The increased catecholamine levels lead to glycogenolysis in the fetal liver with concomitant hyperglycaemia; however, no related lactate increases have been found, in normal, 1396 or complicated 1397 deliveries. Maternal hyperventilation has been noted to influence lactate levels by increasing maternal and fetal lactate levels by up to one mmol/l; due to a maternal CO 2 decrease depleting HCO 3 levels secondary to carbonic anhydrase buffering. To maintain electroneutrality following the decrease in negatively - charged HCO 3 ions, lactate serves as a supplementary source of anions Effect of lactate on tissue Lactate has a contentious effect on the body appearing in some circumstances to protect against hypoxic insults and mitigate its effects while possibly instigating additional neurotoxic effects. Recently, thinking about lactate has changed in that rather than being a dead end anaerobic metabolism product detrimental to the fetus, lactate may actually have a beneficial effect and could be indicative of an endogenous response to protect the fetal brain from injury Effect on neural tissue It has long been known that there is a strong association between lactic acidosis and ischemic injuries; despite this the role of lactate in CNS injuries has remained contentious The first major study regarding lactate s detrimental effects was in adult glucose and lactate treated primates Myers et al. noted that lactate produced CNS oedema and necrosis in mature primate fetus. One study noted irreversible damage in vulnerable CNS regions following lactate accumulation of μmol per gram of neural tissue, 1405 while others required 25 to 30 μmol per gram of neural tissue Several others have noted that lactic acid injection into the cerebral cortex of adult rats produces histology similar to an ischaemic infarction. 183,1399,1407 This histological appearance was not produced when other organic acids of similar ph values were injected. It has been postulated that the detrimental effect of glucose on the adult animal brains during hypoxic-ischaemic injuries is due to high tissue lactate concentrations or alterations in H + homeostasis. A direct relationship has been identified between circulating glucose levels and lactate accumulation within the brain during hypoxic-ischemic episodes. 1406, Moreover, authors have noted higher lactate concentrations are associated with more severe subsequent blood flow and metabolism alterations after the initial insult finishes. Other authors have refuted the hypothesis that lactate is the critical factor in determining the presence and extent 125 P a g e

148 of tissue injury. 1406,1408,1410 Rice et al. noted in an immature rat model that the widespread infarction and oedema resulting from common carotid artery occlusion, is confined to the cerebral hemisphere ipsilateral to the occluded common carotid artery Lactate accumulation in CNS tissue is effectively identical amongst both cerebral hemispheres despite only one being injured This concurrent lactic acidaemia leads to a concentration gradient encouraging blood lactate to shift into the CNS. Cremer et al. demonstrated in immature rat models that there is enhanced blood-brain barrier permeability compared to equivalent adults Vannucci et al. noted that while lactate concentrations were similar there was a considerably lower intracellular ph in the damaged hemisphere Consequently, Vannucci et al. hypothesised that acidosis rather than lactic acidosis, correlates better with CNS injury, which has been supported by other experimental models It has been postulated this effect doesn t exist to the same extent in more immature models due to age-specific differences in cerebral glucose uptake and metabolism. Glucose penetrates into the immature brain more slowly, 1416,1419 due to glucose transport carrier immaturity. Rat models have shown that under normoxic conditions, glucose penetration into the brain in a newborn is a fifth of the adult rate Murine experiments have shown that during hypoxic episodes, glucose transport into the brain is not able to keep up with the increase in cerebral anaerobic glycolysis Correspondingly, the immature brain uses glucose at a lower rate than the mature brain. Under non-hypoxic conditions the cerebral energy consumption for a week old rat is a tenth of an adult Consequently, a lesspronounced increase in the glycolytic rate under hypoxic conditions is expected compared to the mature model, which would result in a depression of anaerobic glycolytic activity and less tissue lactic acidosis. The decreased glucose, lower glycolytic rate, and increased ability of lactate to move out of the brain suggests lactate might not accumulate to the same degree in the immature brain as it does in the adult. An alternative explanation was proposed by Xiang et al. who suggested the discriminatory factor for whether lactic acidosis is a neurotoxic or neuroprotective factor might be neuronal age Most in vitro studies use embryonic or neonatal neurons, whereas Xiang et al. used hippocampal slices derived from day old rats. Xiang et al. postulated that age modulated lactate s effect on neurons via the varying abilities of neurons to utilise lactate as a fuel source. Wada et al. noted that neural activity could be maintained in immature hippocampal neurons when lactate was the only source of energy; however, mature hippocampal neurons were unable to do so Authors have also noted that neurons derived from adult animals are less effective in their buffering ability of in intracellular ph 126 P a g e

149 changes than those derived from younger animals This difference in neonatal response to hypoxic-ischaemic insults has been noted in various animal models. 1428,1432 Studies utilising organotypic hippocampal slice cultures demonstrated that lactate does not support synaptic transmission Xiang et al. showed that lactic acidosis is toxic to hippocampal neurons at acid-base conditions that can occur during cerebral ischemia It was noted that acidosis independent of lactate concentration was toxic, but lactate further potentiated acidosis instigated neurotoxicity. The potentiation of acidosis toxicity was not universally present with the effect only observed at ph values less than Potentiation of acidosis neurotoxicity by lactate was not due to intracellular ph differences but N-methyl-Daspartic acid and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor activation producing excitotoxic neuronal death. Excitotoxicity might be due to increased glutamate uptake inhibition that was noted when lactate was present at lower ph levels. This was not expected as both metabolic acidosis and excitotoxicity were previously believed to be entirely independent occurrences during cerebral ischemia Previously, it was considered neuronal energy requirements were primarily met by glucose production of ATP; however, lactate may also be a source of CNS energy. 1375,1384,1400,1403, Pellerin and Magistretti hypothesised that this may be due to an astrocyte-neuron lactate shuttle, where astrocytes produce lactate that is then utilised by neurons as an energy substrate More recently, the additional hypothesis of CNS lactate production and utilisation has been developed, including a lactate-alanine shuttle, within the glutamineglutamate cycle. Studies of critically ill adults have found that lactate is not only produced in the CNS by astrocytes, but also appears to be the main neuronal metabolic substrate Fetal ovine studies using MRS to monitor fetal brain lactate concentrations during hypoxic insults have indicated anaerobic metabolism starts relatively early in acidaemia, beginning at an arterial ph of less than 7.28 or a BE less than negative eight mmol/l This suggests that anaerobic metabolism begins before the threshold of pathological acidaemia. Whether this is due to anaerobic metabolism causing acidaemia or anaerobic metabolism is acting as an early survival phase manoeuvre is unknown. Lactate has been proposed as an important fetal energy source, 1384 being second only to glucose and if completely oxidised it is postulated to account for around 15% of fetal O 2 consumption For functional recovery in adult rats following prolonged hypoxia, the utilisation of lactate as an energy source is essential Glial cell lactate release is enhanced by glutamates presence, which stimulates neuronal 127 P a g e

150 glycolysis Consequently, neuron released glutamate could ameliorate its own neurotoxicity in a negative feedback loop by stimulating astrocyte lactate production. Wyss et al. demonstrated that lactate alone can sustain in vivo neuronal activity, with the loss of voltage-sensitive dye signal during severe glucose deficiency (produced by insulin administration) attenuated by IV lactate infusions Similar findings have been noted in murine hippocampal slices with field potentials maintained with lactate as the sole metabolic substrate Additionally, Wyss et al. noted there was an activity dependent lactate oxidation, together with increased lactate uptake from the blood stream and transport efficacy. Finally, the authors noted that increased blood lactate concentrations reduces cerebral glucose metabolism and reduced glucose utilisation was compensated for by increased lactate utilisation. This latter increase in lactate and decrease in glucose consumption becomes even more pronounced during brain sensory stimulation. Maus et al. demonstrated that lactate can protect cultured murine striatal neurons from neurotoxicity Furthermore, Maus et al. s data concurred with other studies in noting that lactate can act as metabolic substrates for striatal neurons because it increases neuronal mitochondrial dehydrogenase activity as well as substituting for glucose in restoring high ATP levels. Maus et al. s observations when considered alongside other literature suggests lactate can be taken up by neurons via monocarboxylic acid transporters, to preserve hippocampal histological integrity and synaptic function when glucose is deficient or glycolytic metabolism impaired The increase in lactate levels following injury might act to attenuate brain injury. Studies in rats with L-lactate and glutamate cortex infusions, demonstrated significant reductions cortical lesion size when compared with rats exposed to glutamate only infusions. When L- lactate was replaced with D-lactate, the lesion size was greater than a glutamate infusion only Similarly, IV lactate infusions 30 minutes after a moderate brain injury, resulted in significantly less cognitive deficits when assessed two weeks later This finding was confirmed by Holloway et al. who quantified the optimal lactate dose and mitochondrial preservation following traumatic brain injury based on brain ATP content The optimal dose was found to be a 100mM IV L-lactate infusion, which significantly improved cognitive recovery and preserved cerebral ATP generation. Interestingly, there does not necessary appear to be a clinical improvement in cognitive outcome, despite the dose-dependent effect of lactate on mitochondrial O 2 consumption P a g e

151 In fact, Holloway et al. noted that low L-lactate concentrations appear to be of little or no cognitive benefit, while abnormally high lactate concentrations were injurious even in the absence of blood gas and BP perturbations The authors noted that the absence of any measurable systemic acidosis in rats combined with humans ability to tolerate high lactate concentrations with complete functional recovery suggests that adverse effects of high lactate concentrations might be secondary to neurological effects. It was believed that supplying supraphysiological lactate concentrations, to enzymes fulfilling a rate-limiting role within the oxidative phosphorylation pathway (i.e. lactate and pyruvate dehydrogenase) could increase their functionality Authors have also postulated, as an alternative mechanism, that high lactate concentrations could activate the malate-aspartate dehydrogenase shuttle, which re-oxidises cytosolic NADH by indirectly transferring reducing equivalents to neuronal mitochondria Such a mechanism would suggest that electron transfer is coupled to ATP productions outside the traumatically damaged mitochondrion The increased degree of ATP preservation noted in the Holloway et al. study with the 100mM lactate dose would support the latter mechanism Further, support has been provided for the latter mechanism by Zeng et al. who suggested that pyruvate infusions might effectively replace oxidised nicotinamide adenine dinucleotide by its cytosolic conversion to lactate In contrast to the traditional thought that lactate is a dead end product of anaerobic metabolism, in vitro studies have demonstrated neurons ability to function with lactate as the only available carbon source Fowden proposed that lactate is such an important fetal energy source that it is second only to glucose and if completely oxidised accounts for 15% of fetal O 2 consumption Indeed, IV lactate when administered after neuronal injury, has been shown to be taken up at the injury site, leading to preservation of extracellular glucose levels after injury After brain injury, lactate levels rise while glucose levels decline in extracellular fluid, suggesting that lactate might be preferentially produced in injured tissue. Lactate s beneficial effect might be to provide neurons with an easily metabolised carbon source to more rapidly replenish energy stores after injury when there is a large energy demand to re-establish ionic homeostasis Normally, cells will catabolise glucose to pyruvate using two ATP molecules but generating four ATP molecules. If ATP levels are depleted, then glucose might not be as readily metabolised due to the requirement for ATP. Providing neurons with lactate bypasses this initial ATP requirement and might help them to recover more quickly. 129 P a g e

152 Effect on vascular tissue Vasodilatation and decreased vascular smooth muscle responsiveness to contractile agonists has been noted in conditions with increased tissue lactate concentrations Lactate s effect on vascular tissue is complicated by high lactate values rarely occurring in isolation. Under most physiological and pathophysiological conditions of increased lactate levels there is a concomitant acidaemia, which has been known to produce vasodepression. Despite this, lactate alone has been noted to experimentally produce vasodilatation independent of extracellular ph, with acidaemia potentiating lactate s vasodilatory effects A number of mechanisms responsible for lactate s effect on vascular tone and muscular contractility have been investigated including intracellular calcium shifts, 1469, reductionoxidation potential, 1472,1474 and intracellular signalling involving NADH/NAD reductionoxidation induced superoxide production. 1471, The literature on the effect of lactate on membrane potential and intracellular calcium ions on muscle and other cells is contradictory over the exact nature of effects. 1470,1473, Favero et al. found that intense muscle activity, which produces high physiological lactate concentrations, can disrupt excitation-contraction coupling This may lead to decreases in calcium ion transients producing decreased tension development and contributing to muscle fatigue. Posterino and Fryer in contrast noted that L-lactate had minimal effects on voltagedependent calcium ion release or sarcoplasmic reticulum calcium ion handling and exerts a modest inhibitory effect on muscle contractility at the contractile protein level Barron and Nair incubated porcine carotid artery strips in solutions containing 10 millimole sodium lactate or sodium pyruvate, with strips in sodium lactate having a depressed rate and magnitude of contraction in response to K + induced depolarisation Decreased calcium ion concentration was not due to a selective effect of lactate on ph, membrane potential, or enhanced superoxide production. Removal of calcium ions from the incubation medium nullified the depressed contractile responsiveness and lactate had no effect on noradrenaline induced contractions that released intracellular calcium ions. Therefore, Barron and Nair concluded lactate inhibits arterial smooth muscle contraction by inhibiting calcium ions influx across the sarcolemma. Lactate has been found to dilate human placental arteries in the chorionic plate The authors postulate that relaxation occurs via an oxygen-dependent cyclic guanosine-3 :5 - monophosphate (cgmp) mediated pathway involving intracellular hydrogen peroxide (H 2 O 2 ) production. As part of the metabolic conversion of lactate to pyruvate, cytosol NADH is formed which results in H 2 O 2 production by NADH oxidase. The H 2 O 2 that is formed 130 P a g e

153 stimulates cgmp production causing vasorelaxation (Figure 1.13.). This relaxation is independent of ph, endothelial derived mediators, prostaglandins and NO related arginine metabolites. Consequently, it is thought that lactate may play a significant role in control of fetal-placental blood flow. Figure Potential mechanism of action of lactate in causing relaxation of placental vessels Adapted from Figueroa et al., This has been noted to be significantly inhibited and potentially abolished by gestational diabetes and pre-eclampsia Catalase inhibition in gestational diabetes and preeclampsia is likely to be responsible for attenuation of relaxation in response to lactate. Placental vessels from women with pre-eclampsia have increased NO, and peroxynitrite production; 1488 while gestational diabetics have shown increased NO production. 1481,1487 Animal models have shown that exposure of catalase to high physiological NO concentrations cause a prolonged inhibition of its activity through peroxynitrite formation Consequently, catalase inhibition might be responsible for the lessening of lactate s effect on placental vessels in gestational diabetes and pre-eclampsia. Lactate has also been noted to have a vasoactive effect on vasculature supplying the CNS. Experiments in neonatal goats, 140 noted increased CBF following lactic acid infusions; however, similar studies using neonatal and adult canine models noted no significant difference in blood flow. 141, These studies were complicated by the lack of differentiation between the effects of lactate and acidaemia. Following administration of a lactic acid/sodium hydroxide mix, to ameliorate the effects of acidaemia, Laptook et al. noted 131 P a g e

154 that CBF significantly increased and remained elevated 15 and 90 minutes after administration Fetal lactate levels during pregnancy and labour During pregnancy it was previously assumed lactate levels remain relatively stable until the later stages of labour. Nicolaides et al. performed a series of cordocentesis samplings on healthy fetuses between 17 and 38 weeks of gestation and found lactate values were not that different from values obtained postpartum in term neonates delivered by elective caesarean. 56 An earlier study of 200 pregnancies at weeks gestation noted no change in umbilical artery lactate levels but a significant increase in umbilical vein lactate levels. 79 This is in contrast to blood gas values, such as ph, po 2, pco 2 and BE, which all change with increasing gestational age ,1493 A more recent study by Wiberg et al. on postnatal umbilical cord lactate levels in 10,169 vigorous newborns has found that lactate concentrations in arterial and venous umbilical cord blood increased significantly with increasing gestational age after 34 weeks gestation The reasons underlying the discrepancy between these studies are most likely the different end points and methodologies used. Animal and human studies have demonstrated some degree of fetal lactate consumption most likely of lactate originating from uteroplacental glucose metabolism. 56,1375,1377,1495 Human studies have shown that before labour umbilical venous lactate levels are 7% higher than umbilical artery levels, while fetal ovine models have noted aerobic lactate production by the placenta with net transfer to maternal and fetal circulatory systems Further, lactate is the substrate responsible for a third of myocardial O 2 consumption in ovine fetuses; 1497 while oxidative lactate metabolism in the human fetus is responsible for 10-25% of metabolic activity Lactate transfer can occur both from the fetus to the mother as well as conversely although it does not occur to the same extent or speed as CO Given that lactate only equilibrates slowly across the placenta the maternal lactate concentration will have little effect on the fetal concentration except at the highest maternal lactate concentrations Placental lactate transport is generally considered to occur through facilitated diffusion coupled with proton transfer, 1378 with the presence of such carriers on maternal and fetal surfaces of the placental trophoblast It can logically be assumed that during labour there will be some increase in fetal lactate levels due to intermittent obstruction of fetal blood flow during contractions. Early studies noted 132 P a g e

155 increasing lactate levels in the fetus during labour, 990,1383 since then studies have noted no correlation between lactate levels and cervical dilatation or change in lactate levels during the first stage of labour. 28,1001,1043 Once the second stage is reached and the mother begins to actively push, both maternal and fetal lactate levels begin to increase. 1494,1498, Nordstrom et al. noted increases in maternal venous lactate concentrations by 0.07 mmol/l per minute and fetal blood lactate by 0.03 mmol/l per minute These data suggest that fetal lactate levels increase by one mmol/l for every 30 minutes of pushing. Fetuses with expulsion times equal to or greater than 45 minutes and high fetal lactate concentrations at the time of crowning typically had significantly greater umbilical arteriovenous differences. A larger study of 124 consecutive vaginal deliveries noted that umbilical artery lactates values were strongly correlated with duration of active pushing (R 2 =0.359; p=0.001), which persisted under multivariate analysis accounting for account parity, birth weight and gestational age (p=0.01) Neonates delivered following active pushing for greater than 20 minutes had significantly higher mean arterial lactate values than those pushing for a shorter period of time (4.9±1.4 vs. 3.3 mmol/l ±1.16; p<0.001). Additionally, the proportion of neonates with lactate values greater than six millimoles per litre was significantly higher amongst those with an active second stage greater than 20 minutes (3.03% vs %; p=0.006). An earlier study of 188 neonates noted a similar significant association between duration of active second stage and fetal scalp lactate values at time of crowning (p<0.001) as well as umbilical cord lactate values (p<0.001) Additionally, a significant relationship was noted between fetal scalp lactate values at crowning and umbilical arteriovenous lactate difference (p=0.03). Taken together these studies suggest increased fetal lactate production occurs with a prolonged active second stage particularly in fetuses with already high lactate levels. It s hypothesised that increased lactate levels in the second stage are due to maternal lactate being injected across the placenta into fetal circulation and the increasing duration of intermittent fetal hypoxia during maternal pushing. 1501,1503 That being so, the literature suggests that during fetal compromise increased fetal lactate levels are due to endogenous lactate production rather than transfer of maternal or placental origin lactate Higher scalp blood lactate and umbilical arterial lactate levels were found in those with non-reassuring rather than reassuring FHR patterns When the fetus is exposed to hypoxia then the increase in fetal lactate levels becomes more profound with a greater difference between umbilical arterial and venous lactate concentrations ,1390,1504 This concurs with findings of greater differences between umbilical arterial and venous lactate values in neonates exposed to longer active phases of the second stage Animal models have shown that the 133 P a g e

156 net lactate transfer during experimentally induced hypoxic situations is reduced to zero Thus it can be assumed that endogenous fetal lactate production occurs in response to hypoxia. During labour the fetus might experience a catecholamine surge as part of the normal response to the stress of labour The increased catecholamine levels induce glycogenolysis in the fetal liver increasing the amount of glucose in the fetal circulation Glycolysis then breaks down the glucose into pyruvate which then due to the steady-state relationship with lactate causes an increase in lactate concentration. Uterine muscle biopsies have shown that the lactate content is increased during pregnancy and is equivalent to a plasma concentration of 10 mmol/l. In comparison to other muscles such as the rectus abdominis the lactate concentrations are almost twice as high although the physiological and pathological significance of this is not known The relationship of lactate with fetal hypoxic-ischaemic brain injury There is a growing body of evidence that lactate has a role in fetal and neonatal assessment. Fetal ovine models have noted a significant correlation between lactate concentrations 24 hours after a 60 minute partial cord occlusion and brain injury assessed 72 hours later. 265 Intrapartum scalp lactate assessment has been shown to be more sensitive than scalp ph measurement for predicting a five minute Apgar score less than four and moderate-severe HIE In children, high lactate concentrations have been associated with increased morbidity and mortality Hyperlactacidaemia has been associated with increased morbidity and mortality in various neonatal populations, including NICU admission, 1509 suspected perinatal asphyxial injury, RDS/mechanical ventilation, congenital heart disease, 1515 therapeutic hypothermia, 1516 and extracorporeal life support Similarly, postnatal urinary lactate-creatinine ratio has been found to have uniformly high sensitivity and specificity for predicting HIE in neonates with perinatal asphyxia Furthermore, hypoxic canine models have showed higher blood and neural tissue lactate concentrations in comparison to their normoxic counterparts A number of proton MRS studies noted elevated fetal brain lactate concentrations after exposure to perinatal asphyxial insults. 311,1280, Elevated cerebral lactate levels have been found to be associated with adverse outcomes within 18 hours of delivery, hours of delivery, 1532 one week of age, 1533 two months of age, 1529 one year of age, ,1531 and into late childhood. 331,1534 Amongst infants with a history of birth asphyxia presenting with neurodevelopmental abnormalities at one year old, the commonest MRS findings at birth 134 P a g e

157 were elevated lactate and diminished N-acetyl aspartate peaks The maximum cerebral peak-area ratio of these two findings predicted one year outcome with a sensitivity of 79% and specificity of 93%. While neurological assessment did have a better sensitivity (100%) the corresponding specificity (31%) showed that neurological assessment had a tendency for false-positive predictions Worse outcomes have been noted amongst neonates with persistently elevated lactate levels, with MRS studies showing that infants exposed to birth asphyxia with elevated levels at one month were more likely to have abnormal neurodevelopmental outcomes Other studies have noted dose-dependent relationship between adverse outcome and cerebral lactate levels, with an increase in neurodevelopmental disabilities with increased CNS lactate levels It has been hypothesised that fetal and neonatal lactate levels might provide an indirect indication of the severity of hypoxic-ischaemic insults. Mitochondrial aerobic metabolism is disrupted by severe hypoxic-ischaemic insults, producing a shift to anaerobic metabolism. This leads to heightened conversion of glucose to lactate, and increased lactate that might enhance the CNS damage Severe asphyxial insults have been noted to reduce CBF, which is of particular importance since authors have suggested hypotension has a pivotal role in HIE pathogenesis. 197,433,1539 It is probable that the neuroprotective hypoxia related CBF increase cannot be maintained to the same extent during concomitant hypotension This would increase lactate accumulation by impairing supply of aerobic metabolism substrates and anaerobic metabolite removal. Fetal lactate levels might also be an indirect marker of fetal arterial pressure. High lactate levels have been associated with progressive cardiac function and output compromise An ovine model noted that for all permutations of arterial pressure response to umbilical cord occlusion, fetal lactate levels had significantly greater areas under the receiver operating curves (ROC) than traditional acid-base values. 196 Additionally, fetal lactate levels identified optimum cut-off values for prediction of three stages of cardiovascular deterioration during umbilical cord occlusion. The cut-off values progressively increased as BP control during umbilical cord occlusion deteriorated. In contrast there was no change in optimum cut-offs for ph, po 2, pco 2 or BE with cardiovascular deterioration during umbilical cord occlusion. Pennell hypothesised that due to this association, lactate could possibly predict the severity of neuronal injury; with fetal lactate concentration at delivery accounting for 58% (r=0.759, r 2 =0.576) of variation in neuronal injury 72 hours after repeated umbilical cord occlusion. In contrast the current markers of fetal wellbeing, umbilical artery ph and BE, accounted for only 19% and 23% of variability in neuronal injury, respectively. 135 P a g e

158 Pennell proposed that fetal lactate levels are better predictors of fetal BP instability during cord occlusion than other fetal acid-base values. 196 This is particularly important as the duration of fetal BP instability during umbilical cord occlusion accounts for 91% of variability in histopathological brain injury. Additionally, there is substantial evidence from adult critical care medicine that lactate is a better tissue hypoperfusion predictor than ph and BE As the understanding of mechanisms responsible for hypoxic-ischaemic brain injury has improved; it s become increasingly apparent that the severity of fetal BP and CBF changes during asphyxia has a much greater role in predict fetal brain injury than acid-base alterations. It is also consistent with animal, 197,261, and human studies, 191,199,1506 that suggest that fetal acid-base balance is a poor predictor of the severity of neuronal injury after asphyxia Lactate measurement Lactate levels vary between different body compartments, with erythrocyte lactate concentration 50-60% of that in plasma Foxdal et al. found that lactate concentrations are 35-40% lower in haemolysed venous blood compared to venous plasma, 24% lower in haemolysed fingertip capillary blood than in plasma, and 20% lower in venous and capillary whole blood with intact erythrocytes, than in haemolysed samples To further complicate measurements each lactate meter can be calibrated differently Variation is also introduced based on the sample analysed Consequently, it is difficult to recreate the testing environment in one clinical or experimental setting, hindering comparison of different meters Traditional lactate measurement Traditionally, wet chemistry was used to obtain blood lactate concentration by whole blood precipitation in perchloric acid. This was a time consuming process requiring large blood volumes, consequently it s use was limited to experimental situations Consequently, electrodes were developed for blood gas analysers allowing amperometric determination of lactate concentration by measuring current generated in a chemical reaction. While these electrodes are accurate and precise they require regular replacement. The requirement for blood gas analysers meant that there is still maintenance and expense issues and sample stabilisation is required if there is considerable collection to analysis delay P a g e

159 Handheld lactate meters More recently, handheld micro-volume single use test strip methods of analysis have been developed, such as the Lactate Pro, Accutrend Plus TM, Accusport, Nova Lactate Plus TM, and Lactate Scout TM. Handheld methods of lactate analysis have shown to be accurate, precise, effective and prognostically useful in a wide variety of clinical situations in veterinary medicine Furthermore, handheld lactate meters have been extensively utilised and evaluated in sports science, prehospital care and intensive care medicine The handheld meters are typically test strip based methods and operate in: 1) reflectometric, or 2) amperometric manner Amperometric lactate measurement The Lactate Pro manufactured by Arkray, KDK Corporation, Minami-Ku, Kyoto, Japan is one of the major commercially available amperometric test strip devices: it is not currently available in Australia. The test strip is printed with electrodes coated with lactate oxidase as well as ferricyanide as an electron mediator, which in the presence of lactate causes a series of reactions (Figure 1.14.). Figure Lactate Pro amperometric method of blood lactate analysis Lactate + Lactate Oxidase Oxidised Pyruvate + Lactate Oxidase Reduced Lactate Oxidase Reduced + [Fe(CN) 6 ] -3 Lactate Oxidase Oxidised + [Fe(CN) 6 ] -4 [Fe(CN) 6 ] -4 Fe(CN) 6 ] -3 + e - The first two reactions occur simultaneously with lactate oxidised to pyruvate alongside reduction of lactate oxidase, closely followed by oxidisation of lactate oxidase; allowing the first reaction to continually move to the right. As part of oxidisation of reduced lactate oxidase the electron mediator ferricyanide is changed to its reduced form ferrocyanide. Ferrocyanide is then oxidised by a +0.5V electrode back to ferricyanide with the anodic current measured. The current is then compared to a pre-programmed calibration curve giving the lactate concentration The process takes 60 seconds and requires a fixed sample volume of five micro-litres of whole blood Shimojo et al. compared the amperometric strip method with the conventional enzymatic method across lactate values of mmol/l, and found the between run coefficient of variation (CV) was % with a correlation coefficient of 0.98 between conventional and 137 P a g e

160 amperometric methods Studies of between run CV using the Lactate Pro TM has noted CVs of less than 6% across lactate values of clinical interest. 1376,1584 Luttkus et al. in the most recent evaluation of the Lactate Pro TM compared it with three other lactate analysis methods (RapidLab 865, Siemens Medical Solutions Diagnostics, Bad Nauheim, Germany; Radiometer ABL 625 and ABL 700, Radiometer Copenhagen, Denmark) All three biosensors had CVs between 1.55% and 3.16% with SDs from mmol/l, while the Lactate Pro TM had a CV of 3.99% and SD of mmol/l. When compared to the reference value, the Radiometer ABL 625 underestimated the value by 0.1%, the Radiometer ABL 700 underestimated by 6.2%, while the Siemens RapidLab 865 overestimated the value by 8.9%. The Lactate Pro TM typically underestimated lactate values by 3.7%. Ridenour et al. compared the Lactate Pro TM with the Nova Lactate Plus TM (Nova Biomedical, Waltham, Massachusetts, USA), 1586 using 118 cord blood samples which were analysed by each meter and a reference method (Vitros LAC slide assay; Ortho Diagnostics, Rochester, New York, USA). Over the range of values (1.3 mmol/l to 14.7 mmol/l), the Lactate Plus TM had an average bias of 1.0±0.7 mmol/l while the Lactate Pro TM had an average bias of 0.5±0.7 mmol/l compared to the reference method. If the values were restricted to the normal range ( mmol/l; n=72) the Lactate Plus TM showed an average bias of 1.1±0.6 mmol/l while the Lactate Pro TM had an average bias of 0.3±0.4 mmol/l. To establish a CV, control samples were run through each meter 20 times over five days. The Lactate Plus TM had a CV of 8.0% at low (1.2 mmol/l) and 4.3% at high (6.0 mmol/l) lactate concentrations while the Lactate Pro TM had a CV of 4.0% at low (3.2 mmol/l) and 3.2% at high (10.4 mmol/l) concentrations. The Lactate Plus TM had a number of practical advantages; requiring smaller blood sample volumes (0.7 μl vs. 5.0 μl) and the results were available much faster (13 seconds vs. 60 seconds) Reflectometric lactate measurement Reflectometric blood lactate analysis is a more recent development. Initially in the presence of lactate oxidase and O 2, lactate forms pyruvate and H 2 O 2. The H 2 O 2 then acts with 4- aminoantipyrine and N-ethyl-N-(2-hydroxy-3-sulfopropyl)-m-toluidine under the influence of horseradish perioxidase to produce a red-purple colour and H 2 O (Figure 1.15.). The lactate concentration is stoichiometrically related to the intensity of red-purple colour produced when a light at the colour s maximal absorbance (555 nm) is shone through the sample. The concentration is then calculated from a calibration curve programmed into the 138 P a g e

161 meter by a standard strip. 1550,1587 The commercially available Accusport meter, whilst reflectometric, uses a different reaction to early reflectometric metres (Figure 1.16.). Figure Reflectometric method of blood lactate analysis Lactate O 2 + Lactate Oxidase Pyruvate + H 2 O 2 2H 2 O AA + TOOS Horseradish Perioxidase Red-Purple Colour + 4H 2 O Note: 1) 4-AA: 4-aminoantipyrine; TOOS: N-ethyl-N-(2-hydroxy-3-sulfopropyl)-m-toluidine; 2) Text in italics are the reaction catalysts Figure Accusport TM reflectometric method of blood lactate analysis Lactate + Mediator Form One Pyruvate + Mediator Reduced Mediator Reduced + 2,18-Phosphomolybate Molybdenum Blue + Mediator Form Two Nordstrom et al. and Shimojo et al. both evaluated the early model reflectometric device and found the device was accurate within a 26-49% cord blood haematocrit. 1550,1587 Once over this level, five out of six neonates had values mmol/l lower than the enzymatic reference method There was an excellent correlation to the reference method (Monotest TM ; Boeringer Mannheim, Germany) for values in fetal scalp blood (r=0.90, p<0.001) and umbilical artery blood (r=0.95, p<0.001). Pennell et al. evaluated the Accusport TM device and found between run CVs of % over lactate value range of mmol/l Amperometric versus reflectometric lactate analysis Nordstrom et al. in, to the best of the author s knowledge, the only study comparing reflectometric (Accusport TM ) and amperometric (Lactate Pro TM ) devices found the amperometric method was unaffected by extreme lactate concentrations but the reflectometric method overestimated low lactate levels and underestimated high ones The Lactate Pro TM used a fixed five micro-litre sample volume, while the Accusport TM used a random blood drop, with significant underestimation occurring with the Accusport TM in samples less than 20 μl. The Lactate Pro TM also had a smaller between run CV. 139 P a g e

162 Factors influencing lactate measurement Sample contamination Amniotic fluid can contaminate blood samples and affect lactate analysis. Since, AF has high concentrations of lactate, contamination would produce an overestimation of fetal/neonatal lactate levels The significance of AF contamination is likely to be minimal as the same risk applies to scalp blood gas analysis due to AF s low ph Haematocrit Haematocrit affects most lactate analysis methods including electrodes, 1551 and test strips Test strip methods requiring diffusion into the reagent layer are particularly affected by higher viscosity (i.e. higher haematocrit) blood as it slows diffusion potentially producing falsely low values ,1584 Fetal and neonatal haematocrit have been observed to be influenced by factors including gestational age, IUGR, sampling location and labour. 990, Pennell noted that the Accutrend TM lactate meter s accuracy was not affected by haematocrit values between 41.5% and 62%. 196 For samples with a haematocrit higher than 62%, Accutrend TM meters underestimated lactate values by mmol/L. A weak correlation was identified between haemoglobin concentration and accuracy (r=0.199, 95%CI 0.044, 0.346; p=0.012), with an increase in haemoglobin of three grams per litre, resulted in an underestimation of 0.2 mmol/l Temperature Temperature has been postulated as a confounding factor primarily following delays between sample collection and analysis. Pennell found that lactate concentration increased from 4.84 mmol/l to 5.26 mmol/l over 160 minutes in partially chilled samples. 196 Another author noted that lactate concentrations increased at mmol/min at room temperature yet remained stable for the 20 minutes when the samples were kept in an ice slurry The issue of sample temperature is critical for fetal acid-base and lactate assessment because deliveries distant to the blood gas analyser or events after delivery can often precludes immediate cord blood analysis. If the Accutrend TM or other lactate meter is to be used samples have to be warmed to at least 10 C prior to analysis if they have been kept on ice for greater than five minutes. 196 Cooling of blood samples can affect lactate meter accuracy, as increased viscosity interferes with plasma separation in the test strip. Diffusion into the test strip or the enzymatic process in the strip s reaction layer might also be slowed. Conversely at temperatures greater than 35 o C the Accutrend TM may overestimate lactate concentrations possibly due to acceleration of the analysis process P a g e

163 Lactate in fetal scalp blood Relationship between scalp and central lactate concentrations Scalp lactate concentrations in the absence of asphyxial injury has been found to be similar to carotid arterial and jugular venous lactate levels; however, in fetuses exposed to asphyxial injury, the relationship between fetal scalp blood lactate and carotid arterial lactate is altered. 196 During asphyxia, fetal scalp blood lactate tends to underestimate carotid arterial lactate by on average 0.6 mmol/l. 196 These observations are mirrored by Yoshioka et al. who found no significant difference in mean scalp and umbilical artery lactate in fetuses at elective caesarean delivery In contrast, when samples were collected from those with one-minute Apgar scores less than six or delivered vaginally, scalp blood lactate was significantly less than umbilical artery lactate. In contrast to the relationship between scalp and carotid lactate values, scalp blood lactate is similar to jugular venous lactate in an ovine model with the relationship not being influenced by asphyxial insults or fetal condition changes. 196 Other fetal ovine and primate studies concurred when evaluating ph, po 2 and pco 2 values with similarities between scalp and jugular values remaining with ph levels as low as ,1059 Whilst this disparity appears to be disadvantageous the close relationship between jugular venous and fetal scalp capillary blood may be advantageous, as jugular venous blood composition is influenced by arterial blood composition, CBF and brain metabolic needs. Consequently, jugular venous blood and fetal scalp blood lactate levels might be more informative than arterial lactate levels regarding the fetal brain s operational milieu. Pennell noted that scalp-arterial lactate differences were not influenced by fetal arterial ph, po 2, pco 2, BE, glucose or noradrenaline; however, it was influenced by arterial lactate and adrenaline. 196 In ovine fetuses, it was found that arterial lactate levels were directly correlated with scalp-arterial lactate difference. As fetal adrenaline increased, the scalp-arterial lactate difference became smaller. The relationship between arterial lactate, adrenaline and scalparterial lactate difference suggests that the difference between these sites during asphyxial insults might be due to fetal scalp perfusion changes. Whilst in the Pennell study, fetal scalp blood flow was not measured, it was postulated that increased scalp-arterial lactate difference during asphyxia might be due to increased scalp blood flow. 196 This has been described by Bobby and Santos, who demonstrated a three-fold increase in scalp blood flow following partial cord occlusion. 362 Fetal scalp lactate values are 141 P a g e

164 much like jugular venous lactate in that they are influenced by lactate in the supplying vessel (carotid arterial lactate levels), tissue blood flow (fetal scalp perfusion) and the metabolic process. Given that local lactate levels are determined by the balance between tissue lactate production and clearance, 1542 it would be logical to postulate that increased scalp blood flow during asphyxia might be partially responsible for lower lactate in scalp capillary blood when compared with arterial blood. An increase in the scalp-arterial lactate difference alongside an increase in arterial lactate levels might be secondary to arterial lactate s role as a marker of the asphyxial insult s severity. As the severity of the asphyxial insult increases, the cardiovascular response necessary to maintain cardiac output and redirect blood flow to vital organs increases. 357 Consequently, in a repeated umbilical cord occlusion asphyxial model, an increase in asphyxia s severity might increase scalp blood flow, which could potentially reduce scalp capillary lactate. A decrease in the scalp-arterial lactate difference due to increased adrenaline levels is expected if adrenaline s effect on fetal circulation is taken into account. Adrenaline release from the adrenal medulla occurs partly due to increased sympathetic tone, but also following a decline in po 2 values as the fetal adrenal gland is directly responsive to po 2 changes Given that adrenaline is a potent vasoconstrictor and can decrease scalp blood flow during asphyxia in ovine models, 359 fetal scalp lactate clearance might be impaired producing higher scalp capillary lactate concentrations Scalp lactate reference ranges Normal fetal lactate levels in the first stage of labour amongst fetuses with reactive FHR patterns prior to FBS are presented in Table The inter-study variation is most likely a product of the different sample types and measuring techniques. Higher lactate values are typically found in plasma, reflecting the uneven lactate distribution within the blood There is some divergence concerning scalp lactate cut-off values requiring clinical action between various studies. The earliest RCT comparing scalp ph and scalp lactate did not propose clinical guidelines preferring to encourage clinicians to interpret scalp lactate values with regard to maternal and fetal clinical condition That being so, scalp lactate values above the population 95 th centile (2.90 mmol/l) were considered suspicious and values above the 99 th centile (3.08 mmol/l) were abnormal. The more recent RCT utilised a higher threshold with values less than 4.2 mmol/l normal, values of mmol/l pre-acidaemic necessitating repeating FBS within half an hour, and values greater than 4.8 mmol/l as 142 P a g e

165 acidaemic; 1599 with these values based on Kruger et al. s ROC curve analysis Other ROC curve analysis, 1063 or prospective cohort, 1001 studies have suggested a lower cut-off of around 4.2 mmol/l. The Cochrane Review noted that the studies used different lactate meters, which may produce some of the variation in cut-off values; however, they did not identify an acceptable cut-off value for widespread use Furthermore, the various professional medical and midwifery bodies have not put forward any accepted guidelines concerning fetal scalp lactate cut-off values. Consequently, it is appears that at this point in time management of various scalp lactate values depends upon individual institutions guidelines. Table Normal ranges for scalp lactate in first stage of labour References Mean (mmol/l) 95 th Centile (mmol/l) n Sample Type Jacobsen & Rooth, Plasma Schmidt, Haemolysed Eguiluz et al., Whole Smith et al., Haemolysed Nordstrom et al., Whole Nordstrom et al., Whole Ramanah et al., Whole Adapted from Pennell, Note: Blank spaces signify data that was not reported or known Predictive ability of fetal scalp lactate Observational studies have shown that scalp lactate is as effective as scalp ph in predicting low Apgar scores at delivery. 1001,1043,1504 One of the earliest studies on fetal scalp lactate as a predictor of intrapartum hypoxia was by Smith et al. on 306 fetal scalp blood samples from 215 fetuses Significantly higher lactate and lower ph values were noted in samples obtained from fetuses with a one-minute Apgar scores less than six. These fetuses had higher umbilical cord lactate and lower ph values. A similar relationship was noted to exist with ominous FHR traces. That being so, the authors concluded lactate appeared no more sensitive a measure of asphyxia than the scalp ph. This should be considered in context as only four neonates were considered severely asphyxiated and statistical analysis was limited to comparison of means rather than ROC curve analysis. Westgren et al. in a RCT of 341 mothers compared fetal scalp lactate with fetal scalp ph using percentile cut-offs derived from Nordstrom et al. s study of fetal lactate during 143 P a g e

166 labour Whilst Westgren et al. noted a similar predictive ability, intervention rates, and short term neonatal outcome between lactate and ph, lactate was found to be significantly more practical, namely in the difference in failure rate and number of scalp incisions. Lactate analysis using relatively inexpensive handheld lactate meters allows quick bedside analysis with blood volumes of 5-20 μl, while ph analysis necessitates an expensive and technology intensive blood gas analyser with at least 35 μl. Failure rates for fetal scalp ph analysis were 21% while lactate only had a failure rate of 1% (OR 16.1, 95%CI 5.8, 44.7) Kruger et al. conducted a retrospective observational study of 1,709 fetal scalp samples to analyse the ability of lactate and ph to predict neurological disability When scalp ph and lactate analysis was conduct simultaneously there were no significant difference in areas under the ROC curve for most outcomes; however, scalp lactate had a greater efficacy in predicting five minute Apgar scores less than four (p=0.033) and moderate-severe HIE (p=0.015) (Table 1.61.). Table Area under ROC curves for scalp blood lactate concentration and ph value in patient samples obtained at the same sampling event Area Under ROC Curve (95%CI) Outcome n P-Value Scalp Lactate Scalp ph Umbilical Artery ph < (0.73, 0.83) 0.67 (0.61, 0.72) NS Base Deficit > (0.73, 0.82) 0.71 (0.66, 0.76) NS 16mmol/L Apgar Score < 7 at 1 min (0.65, 0.76) 0.71 (0.66, 0.76) NS < 4 at 5 min (0.74, 0.84) 0.55 (0.56, 0.66) < 7 at 5 min (0.64, 0.74) 0.61 (0.56, 0.66) NS Hypoxic-Ischaemic Encephalopathy Mild (0.79, 0.87) 0.75 (0.70, 0.80) NS Moderate-Severe (0.92, 0.97) 0.64 (0.58, 0.59) Adapted from Kruger et al., Note: Not Significant Kruger et al. found six cases with hypoxic brain injuries in their cohort Of these, five had fetal scalp blood sampling performed. Four neonates had lactate levels greater than 4.8 mmol/l, while two had acidotic ph values of 7.21 and It appears therefore that fetuses can have hyperlactaemia without a concurrent acidaemia. Ovine experiments have shown 144 P a g e

167 that lactate increases quickly after a hypoxic insult but takes much longer than ph levels to normalise once the insult has resolved. 265, Murine models have shown that subcutaneous lactate levels increase earlier than ph during hypoxic-ischaemia insults and earlier than brain lactate levels Consequently, lactate might be an earlier marker of fetal hypoxic-ischaemic injury than other current markers, allowing earlier intervention. These studies also suggest scalp lactate is a better marker than ph for intermittent acute insults because ph can be normalised by the placenta and buffering systems whereas lactate can only be cleared by active placental transport. One of the more recent comparisons of ph and lactate analysis of fetal scalp blood was conducted on 2,992 singleton pregnancies with a cephalic presentation, gestational age greater than or equal to 34 weeks and non-reassuring or ominous FHR traces Each fetus had one to nine scalp blood samples. There was a significantly higher failure rate with ph determination, which led to 155 (10.4%) protocol violations. In comparison, there were 18 (1.2%) protocol violations amongst those with lactate blood sampling. There were no significant differences between groups in umbilical artery metabolic acidaemia (ph 3.6% vs. lactate 3.2%; RR 0.91, 95%CI 0.61, 1.36) or umbilical artery ph less than 7.00 (ph 1.8% vs. lactate 1.5%; RR 0.84, 95%CI 0.47, 1.50). The two arms had similar modes of intrapartum management, with no significant difference in the operative and instrumental delivery rates. The authors noted that if there was not such a high rate of crossovers amongst those supposedly only having scalp ph analysis (i.e. having lactate analysed following failed ph sampling or analysis) a much higher intervention rate would have occurred. For neonatal outcome there was no difference between the study arms for operative interventions, low five-minute Apgar scores, and NICU admissions. This concurs with a previous RCT although the smaller number of cases in the Westgren et al. study did not allow evaluation of significant neonatal outcomes as well as a lower lactate level to define acidaemia (4.2 mmol/l vs. 4.8 mmol/l) That being so, the low incidence of adverse outcomes meant that even in the Wiberg-Itzel et al. cohort there was only six HIE cases in each study arms. In 387 paired scalp ph and lactate samples, a significant correlation between scalp ph and lactate values was noted as well as correlations between scalp ph and lactate values and umbilical cord blood gas values (Table 1.62.). 74 No correlation was noted between scalp lactate values and one (r=0.28; p>0.05), five (r=0.18; p>0.05), and ten (r=0.15; p>0.05) minute Apgar scores. There were only eight abnormal Apgar scores, which limits the study s 145 P a g e

168 clinical applicability. Similar findings were noted by Borruto et al. with a significant correlation between scalp ph and lactate values (R =0.49; p=0.01), but no significant correlation with one (R=-0.21; p>0.05) or five (R=-0.11; p>0.05) minute Apgar scores Table Correlation between scalp ph and scalp lactate values and umbilical cord blood gas values Scalp ph Values Scalp Lactate Values Parameters Correlation Correlation P-Value Coefficient Coefficient P-Value Scalp ph Umbilical artery ph Umbilical artery lactate Umbilical artery base deficit Adapted from Ramanah et al., The most recent and only Cochrane review concerning intrapartum fetal scalp lactate analysis combined the studies by Westgren et al., 1042 and Wiberg-Itzel et al found no significant difference in NE or death Furthermore, there were no differences in any other markers of neonatal or maternal outcome, including Apgar scores, NICU admissions, umbilical artery ph values, umbilical artery BD values, metabolic acidaemia, or delivery mode. The sole difference between scalp ph and lactate analysis was the FBS success rate, which was significantly but not profoundly higher amongst those using lactate analysis (RR 1.10; 95%CI 1.08, 1.12). This later result was not derived from both studies as only Wiberg-Itzel et al. reported sufficient data for analysis Lactate in neonatal cord blood While UCBGA has been relatively widely practiced for a considerable period of time, umbilical cord lactate analysis is only a relatively recent development. To date there have been a number of studies of umbilical cord lactate levels using various cohorts, sample sizes, blood samples (whole versus haemolysed blood), and method of reporting results (some studies using means and SDs, others medians and percentiles). Consequently, it is difficult to establish a single reference range due to variation in the literature (Table 1.63.). Lactate concentrations in umbilical cord vessels are closely correlated; 1506 with the arteriovenous difference typically positive (i.e. umbilical artery lactate concentrations are greater than venous). 1390, A significant correlation also exists between umbilical artery lactate and the arteriovenous difference, which is indicative of an increasing fetal lactate origin as the fetus exhibits a progressively larger lacticacidaemia P a g e

169 Table Normal reference ranges for umbilical artery lactate values after labour Mean (SD) 95 th Percentile Blood Sample Type Reference 2.8 Rooth & Nilsson, Jouppila & Hollmen, Haemolysed blood Low et al., (0.09) Haemolysed blood Smith et al., (1.23) Haemolysed blood Suidan and Young, (1.20) 3.20 Haemolysed blood Ruth & Raivio, (1.20) Whole blood Nordstrom et al., (0.94) Whole blood Westgren et al., (1.40) Whole blood Shirey et al., Whole blood Nordstrom et al., (1.53) Whole blood Yahyaoui et al., (2.33) Whole blood Gjerris et al., (1.53) Whole blood Dessole et al., Whole blood White et al., (2.03) Whole blood Ramanah et al., (1.92) Whole blood Khoshnow et al., Holzmann et al., Adapted from Pennell, Note: Blank spaces signify data that was not reported; Median A number of animal models have evaluated the correlation between tissue and umbilical artery lactate values. Using guinea pigs, Kastendieck et al. induced fetal asphyxia by intermittent apnoea, operative stress and placental abruption then obtained umbilical artery blood samples as well as cerebral, heart, liver, lung, abdominal muscle and fascia, bowel and kidney tissue samples. 396 Given that simultaneous sampling was not possible a corrected lactate value was calculated. A significant correlation was found between umbilical artery lactate values and heart (r=0.84; p<0.001), cerebral (r=0.78; p<0.001), lung (r=0.59; p<0.02) and bowel (r=0.68; p<0.01) tissue lactate concentrations. Heart lactate concentrations were greater than other tissues being 70% greater than umbilical artery levels, while cerebral lactate concentration was 30-50% higher. The authors postulated that increased heart lactate was due to increased cardiac tissue glycolysis during acute fetal hypoxic insults, which also occurs in ovine and canine models Further the authors noted that tissue from the kidney, liver, lung, bowel and abdominal wall had lactate concentrations similar or even significantly lower (bowel and lung tissue) than umbilical artery lactate. Together this 147 P a g e

170 suggests that during hypoxic episodes there might be a lactate efflux out of cardiac and cerebral cells. Consequently, the authors concluded that umbilical artery lactate concentrations accurately reflect intracellular cardiac, cerebral, gastrointestinal and pulmonary lactate values Predictive ability of umbilical artery lactate values One of the largest studies to evaluate umbilical artery lactates ability to predict adverse neonatal outcome found lactate levels were significantly correlated with fetal ph, haemoglobin, and BE values but not fetal po 2, gestational age or birth weight. 29 Interestingly, not only SGA neonates but also large for gestational age (LGA) neonates had increased lactate concentrations, although this does not occur in a more recent study Intrauterine growth restricted and SGA neonates often experience hypoxia resulting in increased baseline lactate, which are further increased due to haemoconcentration. 56,1595, This explains the correlation between haemoglobin and lactate as haemoconcentration is a response to tissue hypoxia allowing increased blood O 2 carrying capacity. Large for gestational age neonates are also more likely to exhibit haemoconcentration than AGA counterparts This might explain the higher lactate levels in LGA neonates with the high metabolic demand producing a coexisting O 2 depletion and tissue hypoxia. It is possible that lactate is often used as an energy source in LGA neonates especially those with hypoglycaemia Alternatively, amongst LGA neonates exposed to higher blood glucose levels there could be a corresponding increase in lactate levels. Labour has been found to increase lactate, with one study noting neonates delivered via emergency caesarean or instrumentation had significantly higher lactate while elective caesarean deliveries had lower values. 29 Numerous significant correlations have been noted between arterial and venous lactate values and other blood gas values, 27,690,1140 and Apgar scores. 1140,1386 These strong and significant correlations suggest that arterial lactate values could be used either in a supplementary role to blood gas values or to replace them. Westgren et al. found that ph, BE, and lactate had approximately the same ROC curves and predictive ability for neonatal morbidity. 29 Interestingly, combining lactate and other blood gas values, such as ph or BE, did not improve the ability to predict neonatal morbidity. Ruth and Raivio in 931 neonates reported similar findings concerning sensitivity and specificity of umbilical lactate compared to a depressed Apgar score. 69 Amongst, depressed neonates (five minute Apgar scores less than four) it was found that lactate had a higher sensitivity than ph or BE. Suidan and Young found a higher degree of sensitivity in predicting low Apgar scores The predictive ability of lactate for five minute Apgar scores 148 P a g e

171 less than seven was diminished somewhat in a more recent study with an arterial lactate cutoff of 5.75 mmol/l having an area under the ROC curve of 0.76 and a sensitivity and specificity of 61% and 85%, respectively Wiberg et al. in the largest study to evaluate the predictive ability of umbilical artery lactate (13,735 validated umbilical cord blood gas results from singleton deliveries) evaluated the effect of adjusting values for gestational age The use of gestational age-adjusted values to predict five minute Apgar scores less than seven was slightly, albeit not statistically, better than non-adjusted values, while there was no difference for scores less than four. While the PPV and sensitivity was poor, gestation adjusted lactate values were considered to be the most accurate way to predict low five-minute Apgar scores. While analysing lactate s ability to predict Apgar scores is important, it is the ability to predict HIE and neonatal seizures that is particularly significant. This is partly because these outcomes are pathological in their own right and are responsible for considerable morbidity and mortality but they also have a much better correlation with long-term neurodevelopmental outcome. 53 In this regard, umbilical artery lactate has been found to be an effective predictor of the later development of NE and HIE. 29,1626 Elevated arterial lactate values have been noted to have a significant correlation with NICU admission (OR 2.91; 95%CI 2.08, 4.06; p<0.001) in term and post-term neonates Further, ROC curve analysis noted that an umbilical artery lactate cut-off of 5.75 mmol/l had an AUC of 0.66, a sensitivity of 39% and a specificity of 86% for predicting NICU admission. In terms of predicting long-term neonatal outcome even less information is available. Ruth and Raivio in a small study noted that lactate and ph both had equivalently poor predictive values in terms of neurodevelopment at one year of age. 69 Consequently, it appears that much larger cohorts of neonates need to be followed to examine the long-term predictive value, especially in terms of outcomes such as CP, and neonatal death Limitations of umbilical cord lactate analysis There appears to be relatively few confounding factors for umbilical cord lactate levels although this might be due to a lack of study rather than lack of confounding. Much like for fetal scalp lactate levels, labour by itself does not appear to increase umbilical cord lactate levels, 1043 instead it appears that second stage duration does Increased lactate levels have been noted amongst neonates presenting with septicaemia, suggesting that lactate might be produced as part of the infectious process. 1503,1627 Many of the issues that apply to UCBGA apply to lactate analysis; however, while blood gas values have been known to normalise 149 P a g e

172 following an insult via placental diffusion, lactate requires active transport so it persists longer after a hypoxic insult One of the advantages of UCBGA is that it provides more information regarding insult timing as well as the underlying mechanisms responsible for producing acidosis. Whilst this is not an issue when they are used concomitantly there is a growing desire given the roughly equivalent predictive ability and lactate s practical advantages to use umbilical lactate in place of umbilical blood gases. Whether the same amount of information can be gleaned from umbilical lactate analysis alone is unknown, but two major issues have been noted. Firstly, blood gases unlike lactate levels exhibit significant differences between umbilical arterial and venous values with the magnitude of difference giving an indication of acidaemia onset (i.e. large arteriovenous value difference suggests an acute insult that hasn t been able to equilibrate across the vessels) Secondly, there is evidence that cord blood gas values when combined with lactate values act as an objective assessment of intrapartum management and can influence staff member s management of similar cases in the future. 47,1200 Whether this occurs when only a lactate value is present is unknown but the information provided by blood gas analysis might be necessary to provide a better indication of the pre-pathological cases, which form a major component of any self-assessment protocol Use of lactate today There is a considerable amount of literature comparing blood gas and lactate values in fetal scalp blood samples, with several studies finding fetal scalp lactate to be a better predictor of adverse neonatal outcome in fetal scalp sampling than blood gas values. 26,1504,1506 Other studies have found that lactate is equivalent to ph at predicting these particular endpoints. 1042,1629 In one of the few studies of umbilical cord blood gas versus lactate analysis, Westgren et al. obtained 4,045 umbilical cord blood gas and lactate samples from 3,932 consecutive deliveries. 26,29 Umbilical artery lactate was found to have a similar efficacy to umbilical artery ph and BE in prediction of MAS, NICU admission, idiopathic RDS, assisted ventilation, neurological abnormalities and neonatal death. Further, there is some animal evidence that lactate might be a better indicator of adverse outcome than ph as lactate levels in subcutaneous tissues have been shown to increase before ph changes becomes apparent Intervention, guided by FBS, could then take place earlier with the neonate potentially being exposed to a less severe insult, or no insult at all. Both umbilical cord blood gas and lactate values can differentiate between acute and chronic insults; however, to be effective UCBGA requires accurate paired umbilical arterial and venous blood samples. In contrast, some authors have suggested that lactate values can be obtained from arterial, 150 P a g e

173 venous, or mixed arteriovenous samples as lactate values from all three sources have been found to be closely correlated That being so, this has not been widely adopted and has been anecdotally treated with considerable scepticism, thus whilst this could make cord lactate analysis even technically easier and cheaper, no studies have evaluated the predictive ability of anything other than arterial lactate. Consequently, the umbilical artery will remain the preferred sampling site until further research is conducted. Overall, literature concluded that lactate and blood gas values have a similar efficacy in predicting adverse neonatal outcomes consequently either of these methods can be utilised to predict neonatal outcome. One factor that all studies evaluating the efficacies of lactate and blood gas values detailed was that lactate has a number of practical advantages over blood gas values. 29,1042,1504,1506,1629 The advent of handheld lactate meters means it is now possible to measure lactate levels in a minute at the patient s bedside with only 5-20 μl of blood required depending on lactate meter. In contrast, blood gas analysis requires considerably larger blood volumes in the region of 35 μl. In terms of fetal scalp sampling there was a considerable reduction in the number of failed attempts when lactate rather than ph values were sought, 1042,1506,1611,1629 with one author stating that failure of fetal scalp blood sampling has almost been abolished It could be possible that a similar reduction in the number of inaccurate or failed umbilical cord sampling procedures could occur with the use of cord lactate rather than blood gas analysis. The size and expense of blood gas analysers means that analysis will typically have to occur outside the labour and delivery ward increasing the delay between collection and analysis and therefore potential pre-analytical changes in umbilical cord values. That being so, automated blood gas analysers that automatically calibrate and require only relatively small sampling volumes have been around for some time Paradoxically, the handheld nature of lactate meters means blood can be immediately drawn and analysed allowing rapid action on the results. One disadvantage of cord lactate analysis is that blood gas values stay relatively constant in a clamped umbilical cord segments at room temperature for minutes, and potentially longer when stored on ice Umbilical lactate analysis needs to be carried out within 10 minutes of clamping the cord as lactate values remain constant at room temperature for only that period. 28,1213 This is not a major issue, as the ability to conduct beside analysis means it is unlikely that there will be considerable delays between collection and analysis. Further, placing the sample on ice can further delay any change if necessary. The fact that lactate is directly measured has a considerable advantage over BE which is calculated. Base excess can be calculated from a number of formulae depending on the 151 P a g e

174 machine utilised with each brand of blood gas analyser using a different algorithm, which might in part explain why values from different analysers are not readily comparable. 27,83,1632 Furthermore any error in the variables within the formula will create errors in the final result. For example, air bubbles would produce artificially low pco 2 values that in turn falsely elevated BE. Therefore if a maternity unit is to introduce either UCBGA or umbilical cord blood lactate analysis, then lactate might represent a valid alternative. While there are benefits of performing both umbilical blood gas and lactate analysis, such as the ability to differentiate between acute and chronic asphyxial injury, small maternity units with limited resources and numbers of deliveries might not be able to afford to introduce both forms. If a maternity unit has 1,000 deliveries or less annually it would be difficult to justify the purchase of a blood gas analyser for about AU$40,000 as well as ongoing service costs. In comparison, a lactate meter costs AU$400, and each test costs in the region of one Australian dollar. Most individuals would consider the cost of lactate analysis for a biochemical endpoint that provides a progressive improvement in outcome as well as identifying neonates in need of specialised care, a worthwhile expense. The use of lactate in obstetrics as a marker of fetal and neonatal wellbeing is growing in popularity. The development of reliable, accurate, and relatively inexpensive handheld lactate meters has allowed lactate analysis to occur in the delivery room with the results in a minute allowing instant feedback and action on the results. Overall it can be seen that analysis of fetal blood lactate is a rapid, simple, and inexpensive process that requires only a small amount of whole blood Summary of the current predictors of adverse outcomes. Currently, there are number of techniques that have been developed to predict adverse perinatal outcomes. Risk factor assessment although widely, almost subconsciously, used has issues with sensitivity and specificity. Similarly, although MSAF has been considered a marker of fetal compromise since Ancient Greece, it s a poor predictor of adverse intrapartum outcomes. Electronic fetal monitoring is one of the commonest obstetric procedures and although it has been associated with a reduction in stillbirths, its introduction does not appeared to have decreased the incidence of CP and other neurodevelopmental disorders. 543, Apgar scores, although an effective method of describing neonatal condition at birth were never intended to be used as a predictor of long-term neonatal 152 P a g e

175 outcome. Cord blood gases and lactate measures are currently considered the most sensitive reflection of birth asphyxia Cord blood gas and lactate measurements also correlate with other adverse neonatal outcomes including neonatal seizures, HIE, cardiopulmonary and renal dysfunction, and abnormal neonatal development. 186,199,201,1225,1236, That being so, measurement and analysis occurs after delivery and thus after the event. Therefore, although universal cord blood gas and/or lactate analysis might be useful in optimising neonatal care and administrative practice there is no data in primary and secondary level maternity units to suggest that the widespread UCBGA at delivery might reduce the incidence of adverse outcomes associated with labour, or even how introduction of universal UCBGA will effect obstetric practice in non-tertiary environments. Given the importance of intrapartum asphyxia and its consequences as well as the potential universal UCBGA benefits, this is an area that requires future study. 153 P a g e

176 CHAPTER TWO THESIS AIM AND OUTLINE It is widely accepted that umbilical cord blood acid-base status at delivery provides a sensitive reflection of birth asphyxia with the absence of acidaemia effectively excluding birth asphyxia as a potential diagnosis. Despite this belief being widely held, there have been no studies to date evaluating the impact of the introduction of universal UCBGA at delivery into nontertiary level obstetric centres. Further, there remain a significant number of questions about the predictive capability, cost-effectiveness and most effective manner in which to undertake umbilical cord blood sampling and analysis, which are preventing widespread adoption of universal UCBGA. 2.1 Aim The primary aim of this thesis was to evaluate the impact of measuring blood gases and lactate levels from umbilical cord blood at delivery on all neonates delivered at a series of metropolitan and regional centres. Further, this thesis seeks to develop a greater understanding of the benefits and implications of introducing a universal umbilical cord blood gas and/or lactate analysis program into a maternity unit. The general hypothesis for this thesis is that the measurement of umbilical cord blood gas and/or lactate values will accurately identify neonates that will have an increased risk of an adverse outcome and lead to improvements in intrapartum management with a resulting improvement in neonatal outcomes. 2.2 Studies performed Umbilical cord blood gas and lactate analysis at delivery: Stability of results over time An ideal cord sample is drawn from each vessel, anaerobically, immediately after birth and chilled immediately. It is then taken with minimal time delay to the blood gas analyser, which is often in a laboratory and not at the point-of-care, where it is well mixed and quickly analysed. Unfortunately, the ideal sample rarely occurs in any delivery suite. Consequently, 154 P a g e

177 routine practice is to collect a loop of cord at the delivery from which samples are collected sometime after the delivery. These samples are sometimes analysed immediately, but there is often analysis delays due to issues such as deliveries in the operating theatre, postpartum complications and other practicalities. Given the increasing support in the literature to perform blood gas analysis on umbilical cord arterial and venous blood from all deliveries, and the potential implications of litigation from intrapartum asphyxia, it is critically important that issues regarding the stability of routine blood gas and lactate values be further evaluated in a clinical setting reflecting current practice. This study evaluated the stability of umbilical cord blood gas results, and lactate concentrations over one hour, with repeated analysis of cord blood that has been collected from: 1) Umbilical cords kept at room temperature; 2) Umbilical cords kept on ice; 3) Plastic syringes from immediate cord sampling kept at room temperature; and, 4) Plastic syringes from immediate cord sampling kept on ice Prediction of adverse neonatal outcome using umbilical artery blood gas and lactate values There is a growing body of evidence to suggest that lactate levels in the fetus are directly correlated to fetal brain injury. 196 Consequently there has been increasing support for analysis of umbilical cord lactate levels at all deliveries. 66,207,211,234 To date there have been few studies linking umbilical cord lactate levels to outcomes. Therefore, if universal umbilical cord blood sampling is to be introduced, the ability of umbilical cord blood gases and lactate levels to predict a variety of adverse neonatal outcomes including neonatal HIE requires appraisal. To address this aim, this study evaluated the ability of umbilical artery cord blood gas and lactate measures to predict neonatal HIE both independently and in a variety of predictive models Evaluation of selection criteria for validating paired umbilical cord blood gas samples: an observational study The majority of previous studies evaluating umbilical cord blood gas sampling included all samples obtained from a specific population. They did not, however, take into account the fact that some samples might not be valid representations of umbilical arterial or venous blood due to pre-analytical sampling errors. The proportion of sampling errors range from five to twenty five percent of the total number of samples. 65,72,207,1140,1189,1635 The most common mistakes are inadvertent switching of the umbilical artery and vein samples or sampling the same vessel twice (typically the umbilical vein). Westgate et al. developed a model to exclude results with a high likelihood of incorrect sampling. 207 This model is based on a series of minimum accepted differences between arterial and venous ph and pco P a g e

178 values. The optimum minimum difference between arterial and venous ph is a contentious issue with considerable divergence in opinion. 68,71-72,134 More recently, Kro et al. developed a model based on similar principles to Westgate et al., albeit more complicated This study seeks to evaluate the issue of accuracy in UCBGA and establish the most effective method to identify potentially invalid samples (Westgate, Kro or other methods) The impact of introducing universal umbilical cord blood gas analysis and lactate measurement at delivery Numerous publications have suggested value in performing cord blood gas analyses at delivery; 24-25,49,211,825,912,1250 there have been few evaluating cord lactate at delivery. To my knowledge, there has been no published studies evaluating the impact of introducing universal cord blood gas and/or lactate analysis into a non-tertiary level maternity unit. To address the primary aim of this thesis, this study evaluated the introduction of universal cord blood gas and lactate measurements into a number of primary and secondary level maternity units in metropolitan and regional locations with a variety of models of care. The primary outcome of this study was evaluating both the accuracy of sampling and rates of metabolic acidaemia over the study period. The changes over time were analysed with both univariate and multivariate analyses taking into account a variety of potential confounding demographic and obstetric covariates Universal umbilical cord blood analysis: Is it worth the hassle? To date no comprehensive cost-effectiveness evaluation of cord blood gas analysis has been undertaken. Numerous ad-hoc analyses of the potential cost-effectiveness of universal blood gas analysis have been undertaken, ,1631,1635 with some degree of divergence in their conclusions regarding costs and benefits. These analyses have, for the most part, suggested that the potential averted costs (in terms of deflecting or ameliorating medicolegal actions) would easily absorb the incurred costs associated with a universal blood gas analysis program. 1188,1635 Additionally, authors have postulated that universal sampling would, via economies of scale, result in a cheaper per unit cost than a selective program In contrast, a number of organisations and authors have suggested that universal analysis is not a costeffective proposition, 49,189 despite the lack of any studies to support this tenet. Consequently, this study sets out to conduct the first cost-effectiveness evaluation of universal cord blood gas and lactate analysis in a tertiary maternity unit. 156 P a g e

179 2.2.6 Attitudes and barriers to universal umbilical cord blood gas and lactate analysis Currently, there is a significant and growing body of evidence and support for collection of umbilical cord blood samples and subsequent blood gas analysis. 24,49,841,912,1250 The biochemical data provided by cord blood gas analysis forms an integral part of diagnosis and exclusion of conditions arising from perinatal hypoxic-ischaemic insults, with the absence of umbilical artery metabolic acidaemia effectively excluding birth asphyxia as a diagnosis. 24,203 Additionally, there is evidence to suggest that universal analysis of umbilical cord blood gases at all deliveries can have significant medicolegal, financial, and educational benefits. Despite this, there remains reluctance on the part of many maternity units and organisations to adopt a universal approach to cord blood gas analyses. 47,211,1187,1635 The final experimental chapter of this thesis aims to identify perceived barriers and impediments as well as attitudes towards introduction of universal umbilical cord blood gas/lactate analysis. 157 P a g e

180 CHAPTER THREE THE EFFECT OF TIME, TEMPERATURE AND STORAGE DEVICE ON UMBILICAL CORD BLOOD GAS AND LACTATE MEASUREMENT: A RANDOMIZED CONTROLLED TRIAL 3.1 Introduction There is increasing support in the literature to perform blood gas analysis on umbilical cord arterial and venous blood samples from all births. 47 Paired cord blood analysis provides an objective measure of neonatal condition at delivery that can be used as an objective measure for the audit of intrapartum care. 68,97,1637 The international consensus statement for defining a causal relationship between acute intrapartum events and CP stated that a severe metabolic acidosis, with an umbilical artery ph < 7.00 and a BD 12mmol/L, is one of the three essential criteria to define an acute intrapartum hypoxic event. 24 Currently, umbilical cord ph at birth provides the most sensitive reflection of perinatal asphyxia injury with the absence of acidosis effectively excluding asphyxia as the diagnosis; 24,203 thus umbilical cord blood gas assessment has an important diagnostic and medico-legal role. That being so, there are a number of factors that can interfere with the collection of good quality results from the umbilical cord, including: 1) the type of container in which the blood is collected and stored; 2) the temperature at which the sample is stored; and 3) the time of sample analyses after birth. Ideally umbilical cord blood gas analyses should be conducted immediately after birth, although the clinical environment will sometimes result in a delay. Often these delays occur in the circumstances of the sickest neonates as staff members are focussed on early neonatal care. It is these neonates who at the greatest risk of adverse neonatal outcomes. Recent data are defining a potential role for lactate assessment in cord blood after delivery in clinical conditions that may have resulted in critical tissue hypoxia and/or under-perfusion. Umbilical artery lactate concentration has been shown to have a similar efficacy to acid-base assessment in predicting perinatal outcome. 29 With advances in technology, lactate measurement can be performed using relatively inexpensive handheld meters (AUS$300) that provide a point-of-care method of measuring plasma lactate levels in 60 seconds These meters require as little as 15 l of blood and are significantly cheaper than other assay 158 P a g e

181 methods. The size and cost of these units makes them ideally suited for both small and large obstetric units where access to conventional blood gas analysis can be associated with considerable cost. Given the support in the literature to perform blood gas analysis on umbilical cord arterial and venous blood samples, and the potential medico-legal implications of litigation from intrapartum asphyxia, it is important that the issues regarding the stability of routine blood gas and lactate measurements are evaluated in a clinical setting that reflects current practice. A number of previous studies have evaluated the impact of temperature and/or time on the stability of cord blood gas measures. 28,126,1213,1596,1617,1631, The results from these studies, were inconsistent, possibly due to the limited sample size and methodological issues in many of the studies. In the present study we have evaluated the stability of cord blood gas and lactate measures over a one hour period with repeated analyses of blood samples from umbilical cords randomised to one of four study groups: 1) umbilical cords stored at room temperature (CR); 2) umbilical cords stored in ice (CI); 3) plastic syringes from immediate cord sampling stored at room temperature (SR); and, 4) plastic syringes from immediate cord sampling stored in ice (SI). 159 P a g e

182 3.2 Materials and Methods After informed consent, each participant selected an opaque sealed envelope from a selection of 20 envelopes (block randomisation) assigning the umbilical cord to one of four experimental groups. Random allocation for consecutive women was obtained using a computer-generated sequence. Cord segments were collected from 80 women delivering at KEMH, Perth, Western Australia. This study had been granted ethics approval prior to commencement by the Women s and Children s Health Service Ethics Committee Cord collection technique After delivery of the fetus, the umbilical cord was clamped immediately, approximately 10 centimetres from the umbilicus. A second clamp was applied adjacent to the first and the cord then cut separating the baby from the placenta and distal umbilical cord. A second set of clamps was then placed on the cord five centimetres from the introitus or uterine incision. The cord was then cut between these clamps producing a free loop of cord clamped at either end that was approximately centimetres in length Serial clamping technique The free loop of cord was taken immediately to the blood gas analyser in delivery suite where four additional clamps were applied to the cord; with one clamp every two centimetres to divide the cord into five identical segments for analyses. The routine arterial and venous blood gas samples were collected from the first segment within five minutes of the delivery and were designated as time zero. Each sample underwent routine acid-base and lactate analysis within 15 minutes of delivery using a Bayer Chiron Diagnostics Model 840 Blood Gas Analyser (Bayer Diagnostics, Germany) with an additional lactate electrode. The blood gas analyser was located in the Labour and Birth Suite adjacent to the room where the experiment was being conducted. Hospital technical staff members maintained the blood gas analyser daily with automatic calibration occurring every two hours. The umbilical cords were randomised to one of four experimental groups: 1) umbilical cords kept at room temperature; 2) umbilical cords kept on ice; 3) plastic syringes kept at room temperature; and 4) plastic syringes kept on ice. 160 P a g e

183 In the experimental groups (CR and CI) where the umbilical cord was kept for one hour, cord sampling from separate segments occurred every 15 minutes (+15, +30, +45 and +60 minutes). These samples were tested immediately after collection for acid-base and lactate levels. The cord segments in the CI group were stored in ice slurry between sampling for the duration of the protocol. Samples for the syringe groups (SR and SI) had arterial and venous samples collected from each of the four clamped cord segments immediately after the time zero samples were collected. The SR samples were then stored in syringes at room temperature: the syringes from SI samples were stored in ice slurry. Repeated analyses were performed from these samples every 15 minutes Statistical analysis Within each experimental group, 16 umbilical cords sampled five times had an 80% power with an overall type I error rate of 5% to identify a change of one SD in any of the parameters measured during routine blood gas analyses. We elected to increase the sample size to 20 per group to allow for up to 10% missing samples within each experimental group. Cord blood gas measurements were summarised using means, SDs and standard errors of the mean. To establish the magnitude of change in cord gas parameters over the study period, mean absolute and relative differences were calculated. Categorical outcomes including demographic, obstetric, and intrapartum characteristics were summarised with frequency distributions, and univariate comparisons of outcomes between the experimental groups were conducted using univariate analyses. Simultaneous evaluation of the independent effects of time, temperature, and storage device on the stability of blood gas measures was performed using a repeated measures analysis of variance with fixed and random effects that models repeated cord gas measurements over time. All hypothesis tests were two-sided with p-values less than 0 05 considered statistically significant. Generalised estimating equation analysis used the more conservative p-value cut-off of 0.01 to account for the multiple testing (four comparisons to baseline measures) utilised. Analyses were performed using SPSS statistical software (SPSS Inc., Version 15.0, Chicago, IL) and SigmaPlot (Systat Software Inc., Version 11.0, Chicago, IL). 161 P a g e

184 3.3 Results Over a period of 10 months (May 2008 to June 2009), umbilical cord segments were collected from 80 mothers. There were no significant differences between the four experimental groups in maternal, obstetric or intrapartum factors including: gestational age (p=0.656), parity (p=0.498), onset of labour (p=0.417), maternal analgesia/anaesthesia (p=0.821), mode of delivery (p=0.332), birth weight (p=0.238), and one and five minute Apgar scores (p=0.677 and p=0.386, respectively). Statistically significant but clinically insignificant differences were observed between study groups in baseline umbilical blood gas and lactate values (Table 3.1.). Baseline measures of blood gas and lactate parameters were within the normal range in all four groups. Table 3.1. Baseline mean (standard deviation) umbilical arterial and venous blood gas and lactate values Cord Ice Cord Room Syringe Room Syringe Ice Temperature Temperature P-Value Umbilical Artery ph 7.31 (0.05) 7.31 (0.04) 7.33 (0.03) 7.30 (0.03) <0.001 po (9.13) (5.74) (6.10) (4.47) <0.001 pco (8.04) (5.94) (6.01) (5.69) <0.001 Bicarbonate (2.23) (1.85) (1.27) (1.74) Base Excess (3.25) (2.27) 0.11 (2.06) (1.93) <0.001 Lactate 2.22 (0.67) 2.04 (0.40) 1.82 (0.33) 2.50 (1.21) <0.001 Umbilical Vein ph 7.36 (0.03) 7.36 (0.04) 7.37 (0.02) 7.34 (0.04) <0.001 po (6.53) (4.87) (5.90) (6.51) <0.001 pco (4.39) (4.96) (4.39) (5.44) <0.001 Bicarbonate (1.32) (1.67) (1.08) (1.64) <0.001 Base Excess (1.70) (2.40) (1.68) (1.74) <0.001 Lactate 2.01 (0.47) 1.96 (0.46) 1.80 (0.38) 2.32 (1.12) <0.001 Table 3.2 presents a summary of the change in umbilical artery and vein blood gas and lactate measures for the four study groups with arrows indicating the direction of change and the numbers in brackets indicating the time at which the values became significantly different from the baseline values. Additionally, p-values for the comparisons between the four study groups are detailed in Table II, which indicate a significant difference between the four groups for all blood gas and lactate values (in both umbilical artery and vein) other than umbilical artery po 2 values that remained stable in all four experimental groups (p=0.440). 162 P a g e

185 The magnitude of change in the blood gas and lactate values are presented graphically in Figures 3.1 and 3.2 stratified by study group. Table 3.2. Generalised estimating equation change over time for umbilical artery and venous values by experimental group Cord on Ice Cord at Room Temperature Syringe on Ice Syringe at Room Temperature Inter-Group Comparison P-Value Umbilical Arterial Values ph (15) (15) (15) (60) <0.001 po pco 2 (45) (45) <0.001 Bicarbonate (30) (15) (15) (30) <0.001 Base Excess (45) (15) (15) (30) <0.001 Lactate (15) (15) (15) (15) <0.001 Umbilical Venous Values ph (30) (15) (15) <0.001 po 2 (45) pco 2 (60) (45) <0.001 Bicarbonate (45) (45) (15) (30) <0.001 Base Excess (60) (45) (30) <0.001 Lactate (15) (15) (15) (15) <0.001 Umbilical Arteriovenous pco 2 Difference Arteriovenous pco 2 (45) <0.001 Note: Arrows indicate the direction of change if a significant change (p<0.01 to account for multiple testing) occurred over the study period with the time (minutes) at which change occurred in brackets. The umbilical artery ph values deteriorated in three of the four study groups (CI, CR and SI) within 15 minutes (p 0.001). For the SR group, no significant change occurred until the sixty-minute analysis (p=0.002). There was no significant change in arterial po 2 values in any of the study groups (p>0.050). The arterial pco 2 results were divergent. There was no difference in the SR or CI groups over 60 minutes; however, both the SI and CR groups had a significant change in pco 2 values within 45 minutes (p 0.002). 163 P a g e

186 Figure 3.1. Change in arterial and venous ph, base excess and lactate values by experimental group. Arterial ph Venous ph Change in Arterial ph Change in Venous ph Time (Minutes) Arterial Base Excess Time (Minutes) Venous Base Excess Change in Arterial Base Excess (mmol/l) Time (Minutes) Arterial Lactate Change in Venous Base Excess (mmol/l) Time (Minutes) Venous Lactate Change in Arterial Lactate (mmol/l) Time (Minutes) Change in Venous Lactate (mmol/l) Time (Minutes) Note: Closed symbols indicate no significant change from baseline values; open symbols indicate a significant change from time zero. 164 P a g e

187 Figure 3.2. Change in arterial and venous po 2, pco 2 and bicarbonate values by experimental group. Arterial po 2 Venous po Change in Arterial po 2 (mmhg) Change in Venous po 2 (mmhg) Time (Minutes) Time (Minutes) Arterial pco 2 Venous pco Change in Arterial pco 2 (mmhg) Change in Venous pco 2 (mmhg) Time (Minutes) Arterial Bicarbonate Time (Minutes) Venous Bicarbonate Change in Arterial Bicarbonate (mmol/l) Time (Minutes) Change in Venous Bicarbonate (mmol/l) Time (Minutes) Note: Closed symbols indicate no significant change from baseline values; open symbols indicate a significant change from time zero. 165 P a g e

188 Umbilical arterial BE values deteriorated in all four groups, with significant change occurring within 15 minutes for samples stored in CR and SI (p 0.009), while the change in the CI took 45 minutes to occur (p<0.001). The SR group had a significantly decreased arterial BE value within thirty minutes (p<0.001). Umbilical artery lactate value changes occurred within 15 minutes in all groups (p<0.001) with the greatest magnitude of change seen in the CR group. The patterns of change in blood gas values were less consistent in umbilical vein samples over time than their arterial counterparts. Venous ph values did not change significantly in CR and took 30 minutes to manifest a significant change in the CI group (p<0.001). Amongst the SI and SR groups where samples were collected at time zero, significant changes occurred within 15 minutes (p 0.003). Similar to arterial po 2 values, there was no significant change in venous po 2 values amongst samples in the CR, CI and SR groups: venous po 2 in the SI group increased by 45 minutes (p=0.009). No significant changes in venous pco 2 values occurred in those samples stored on ice (CI and SI); however, venous pco 2 increased by 45 minutes in SR (p<0.001) and decreased at 60 minutes in the CR group (p=0.008). Venous BE values were particularly divergent in the four study groups. There was no significant change in the SI group over the sixty-minute study period. Amongst the other groups, BE values significantly decreased in SR within 30 minutes (p=0.001), CR within 45 minutes (p=0.001), and CI within 60 minutes (p<0.001). For venous lactate values, all experimental groups demonstrated significant change within 15 minutes (p<0.002) with the smallest magnitude of change occurring in the SI group. There was no change in the umbilical arteriovenous pco 2 difference in CR, SR and SI groups whereas there was a significant decrease in umbilical arteriovenous pco 2 difference within 45 minutes in the CI group (p=0.006). Table 3.3 presents the mean and standard error for the magnitude of change in blood gas values in each of the four study groups after a 30-minute and a 60-minute delay in analyses. These data may be used to estimate the direction of change from time zero blood gas results when there has been a delay in analyses. 166 P a g e

189 Table 3.3. Prediction of baseline umbilical blood gas and lactate values following thirty or sixty minute delays Thirty Minutes Delay Sixty Minutes Delay Cord Ice Cord Room Temperature Syringe Ice Syringe Room Temperature Cord Ice Cord Room Temperature Syringe Ice Syringe Room Temperature Cord Ice Cord Room Temperature Syringe Ice Syringe Room Temperature Cord Ice Cord Room Temperature Syringe Ice Syringe Room Temperature Umbilical Artery ph Values (0.009) (0.009) (0.006) (0.008) Umbilical Artery Base Excess Values (0.445) (0.409) (0.478) (0.267) Umbilical Artery Lactate Values (0.175) (0.119) (0.110) (0.108) Umbilical Venous ph Values (0.003) (0.004) (0.004) (0.003) Umbilical Venous Base Excess Values Cord Ice (0.444) Cord Room Temperature (0.427) Syringe Ice (0.276) Syringe Room Temperature (0.163) Umbilical Venous Lactate Values Cord Ice (0.079) Cord Room Temperature (0.074) Syringe Ice (0.095) Syringe Room Temperature (0.055) Note: Significant difference from baseline values at time zero (0.010) (0.010) (0.006) (0.011) (0.495) (0.515) (0.425) (0.312) (0.179) (0.218) (0.122) (0.143) (0.004) (0.009) (0.004) (0.007) (0.381) (0.387) (1.915) (0.204) (0.098) (0.161) (0.097) (0.098) 167 P a g e

190 3.4 Discussion An ideal set of cord blood gas samples are drawn from the umbilical artery and vein immediately after birth and chilled without delay. These samples are then rapidly taken to the blood gas analyser, which is often in a laboratory and not at the point-of-care, where they are well mixed and quickly analysed. Unfortunately, the ideal set of samples may not necessarily occur in routine obstetric care. Consequently, it has become custom to collect a loop of cord at delivery from which samples are collected sometime between one and sixty minutes after birth. Delays in analysis frequently occur, especially where deliveries occur in the operating theatre. Moreover, delays can also occur when the neonate is born in poor condition or when the mother is medically unstable and staff members are preoccupied with providing clinical care. A number of previous studies have evaluated change in umbilical cord blood gas and lactate values over time and the various methods that can be employed to minimise these changes. 28,126,1213,1596,1617,1631, Many of these studies have a number of limitations including a lack of consistent sample collection and analysis. Further, most studies have limited sample sizes and do not compare all four sampling strategies evaluated in this study. Moreover, most studies do not report complete blood gas analyses results (i.e. ph, po 2, pco 2, HCO 3-, BE, and lactate values) for both umbilical vessels. This study has shown that significant changes occur in all umbilical arterial and venous blood gas and lactate measures over one hour with the exception of arterial po 2 values that remained stable in all four-study groups for the duration of the study. Further, for the first time, the utility of leaving the umbilical cord in slurry of ice until the time of analysis has been evaluated. This approach was found to be superior to leaving the cord at room temperature but not as effective as leaving blood in syringes until the time of analyses if there are any delays between delivery and cord blood gas analysis. Similarly, this study is one of the first to evaluate the effect of time, temperature and storage device on the arteriovenous pco 2 difference. Evaluating the stability of the arteriovenous pco 2 difference is important given its role in determining the temporal nature of asphyxial insults based on changes in paired umbilical cord blood gas values (i.e. acute vs. chronic insults). 24 The results of this study should be viewed in a clinical context with many changes achieving statistical significance but less that are clinically significant. For example, the changes in 168 P a g e

191 venous pco 2 values, whilst statistically significant, are unlikely to be clinically important as the change was of no more than four millimetres of mercury. In contrast, the changes in arterial and venous lactate values were statistically significant and as large as 2.5mmol/L, a magnitude of clinical importance given that the median arterial lactate level in our maternity unit was 3.7mmol/L. 47 A similar situation exists for arterial ph and BE values where the magnitude of change was up to 15% of the variation seen in these values in the normal range Effect of storage device It has previously been suggested that removal of blood from the umbilical cord vessels by immediate sampling reduces the number of blood gas parameters that change over time; 1648 hence, in most obstetric units, samples are taken from the cord as soon as possible after delivery to limit contact of the blood with the metabolically active endothelium in the umbilical cord vessels. Our data support this premise with smaller magnitude of change in cord arterial and venous lactate and BE levels in samples stored in syringes than those stored in cord segments. Further, greater deterioration occurred in cord arterial rather than venous values consistent with greater metabolic activity in the arterial endothelium and smooth muscle than in the tissue lining the umbilical vein. Interestingly, in this study no change was seen in arterial po 2 levels in any method of storage over time at any temperature and pco 2 levels did not change in a consistent manner across the four groups particularly amongst those samples stored in the umbilical cord for a period of time. Taken together these data suggest that the deterioration in BE values that occurs over time in blood samples stored in umbilical vessels is due to a progressive metabolic acidosis rather than respiratory acidosis Effect of temperature It is generally accepted that paediatric and adult arterial blood gas samples should be stored on ice until analysis can be performed, with the same principle applying to umbilical cord blood gas samples. Studies of adult blood gas samples have shown that leukocytes remain metabolically active and will continue to use O 2 and produce CO 2 over time It is thought that reducing the temperature of the blood sample will limit this process. Consistent with this hypothesis, a number of authors have shown previously that temperature affects the stability of blood gas results with the use of ice decreasing the magnitude of change in blood gas values over time. 1192,1596 Amongst samples stored in umbilical cords (CR and CI) the stability of cord arterial pco 2, HCO - 3 and BE levels as well as venous pco 2 and BE data is consistent with this premise. Interestingly, in this randomised trial, sample temperature alone during storage did not significantly alter arterial ph and po 2 values nor did it alter venous 169 P a g e

192 - po 2 or HCO 3 values. The observation that the markers of fetal metabolic acidosis, namely cord arterial lactate and BE, show greater magnitude of deterioration over time when umbilical cords are stored at room temperature rather than on ice provides support for the storage of samples on ice if there is likely to be a significant delay in analysis. In this study the greatest effect of temperature alone was seen on samples stored in the umbilical cord with little or no effect of temperature on blood stored in syringes for up to one hour. These data suggest the primary effect of storing samples on ice is mediated by the reduction in metabolic activity in the vessel walls rather than the metabolic activity of the leucocytes and red blood cells. Further, these data suggest that there is little benefit in storing blood gas syringes on ice in the delivery suite if these samples can be analysed relatively quickly Umbilical lactate values There are conflicting data describing the stability of umbilical artery lactate values: some studies suggesting lactate measures remain relatively stable at room temperature for 30 minutes, 28 with others noting significant changes within 20 minutes Dessole et al. (using a linear regression model) noted a significant increase over time in lactate levels of 0.062mmol/minute in samples stored in the umbilical cord at room temperature Our data are consistent with this rate of increase, albeit slightly less, with blood lactate stored in the umbilical cord at room temperature increasing at a rate of 0.037mmol/minute for 30 minutes. The data presented in this study and those of Dessole et al. suggest that lactate levels can change in as little as 15 minutes after the delivery, independent of temperature and storage device This problem can be ameliorated by use of portable, hand-held lactate meters that can be used at the bedside as point-of-care testing devices, and are widely utilised in sports medicine. These meters have been shown to be as accurate as larger, more expensive blood gas machines, 1550, ,1588 making them ideally suited to the delivery suites of smaller obstetric units that are not able to justify the expense of the equipment necessary to conduct a full blood gas analysis Combined effect of temperature and storage device Identification of the best method to minimise changes in blood gas and lactate values is not straightforward due to the divergent results for each individual blood gas measure in the artery and vein. Given that the umbilical artery blood gas values reflect those in the fetal circulation rather than the placenta, stability of the arterial values is more important than 170 P a g e

193 stability of the venous blood gas values. Arterial ph values are generally considered the most sensitive reflection of perinatal asphyxia injury, 24,203 with the syringe at room temperature group demonstrating stability for almost the entire study period. Establishing the presence of respiratory acidaemia relies on pco 2 values with there being no significant change in the syringe at room temperature group over sixty minutes. The arterial lactate values demonstrated a similar degree of stability in all four groups, while arterial BE values were most stable in cord on ice. Further, given the importance of the arteriovenous pco 2 difference in providing an indication of the timing of asphyxia insults as well as the validity of sampling, 207,1636 the least stable group was the cord on ice. Therefore, taken together these data, and those previously published, ,1646,1648 suggest that storing cord blood in syringes at room temperature is the best of the four approaches evaluated if there is a delay in analysis. There will always be clinical scenarios where there will be delays in the analysis of cord blood gas samples. While our data suggest that the smallest changes occur in the syringe at room temperature group, all methods of sample storage awaiting analysis are associated with changes in blood gas measures. The data presented in Table III may be utilised to predict the direction of change from blood gas measures at the time of delivery for the four approaches assessed. These algorithms can be used with some degree of confidence as they include an estimate in the error based on our sample size of 80 cords with five repeated measures. The findings also indicate that a more profound change than previously noted occurs in arterial ph and BE values within a 60 minute period These models should be interpreted with caution when considering the magnitude of change in blood gas and lactate values as they are reflective of the cohort in which they have been developed and require prospective replication and testing in a larger and more diverse cohort. The strengths of this study include the large sample size, the randomisation to four study groups, and the multivariate analyses that considered both the baseline blood gas measures as well as the potential covariates that may influence these results. Furthermore, the repetitive analysis of each umbilical cord without any missing samples provides a consistent manner in which to examine the changes in both arterial and venous blood gas values over time. One limitation of this study was that all of the baseline blood gas measures were in the normal range. Whilst our analyses did consider the variation within the normal range, we have not evaluated the stability of blood gas results in the pathologic range. 171 P a g e

194 3.5 Conclusion In conclusion, cord blood gas values change rapidly after delivery with changes occurring within 15 minutes in many parameters. Of the four options assessed, the smallest changes in blood gas measures were seen in syringes at room temperature. These data suggest that cord blood gas analyses should be conducted as soon as possible after delivery. If there is a delay in analysis, we present algorithms that may allow prediction of the direction of change in blood gas measures from the time of delivery for the four approaches assessed. 172 P a g e

195 CHAPTER FOUR ACCURATE PREDICTION OF HYPOXIC-ISCHAEMIC ENCEPHALOPATHY AT DELIVERY: A COHORT STUDY 4.1 Introduction Despite significant advances in midwifery, obstetric and neonatal care, birth asphyxia remains an important condition with major personal, medical, financial, and legal implications for families, health care professionals and communities worldwide. Hypoxic-ischaemic encephalopathy is one of the primary acute neurological manifestations of perinatal asphyxia injuries and is associated with a significant burden of morbidity and mortality. 424,452, Until recently there has been little that could be done to ameliorate injury amongst those with HIE; however, the growing utilisation of neonatal hypothermia for early treatment of neonates with HIE, has the potential to significantly reduce the morbidity and mortality associated with this condition. 204, One of the key factors enabling successful use of neuroprotective hypothermia is the early identification of neonates who would benefit. Under ideal circumstances treatment should be initiated within six hours of delivery. 204, Chapter aim The aim of this study was to develop a simple accurate method of predicting HIE, within minutes of birth, utilising clinical and biochemical measures that are widely available at delivery. In addition to univariate analyses, we have evaluated multivariate prediction models to predict HIE and moderate-severe HIE utilising two to four measures available at the time of birth. 173 P a g e

196 4.2 Materials and methods Umbilical cord blood gas and lactate samples were collected on all neonates delivered at 23 weeks gestation or greater, at KEMH, Perth, Western Australia between the 1 st of January 2003 and 31 st of December King Edward Memorial Hospital is the sole West Australian tertiary level maternity unit. This study received ethics approval from the Women s and Children s Health Service Ethics Committee (Reference Number EC07-46) on the 4th of September Neonates were excluded on the basis of fetal death in utero diagnosed prior to the onset of labour. Detailed maternal, obstetric, intrapartum, and neonatal information for all deliveries were abstracted from the institutional electronic database. Only those neonates with umbilical cord blood gas samples validated by the Westgate et al. criteria were included in the present study. 207 One-minute and five-minute Apgar scores were assessed by the primary accoucher, usually a Labour and Delivery Ward midwife, unless neonatology staff members were in attendance, in which case the senior neonatology team member was responsible for allocating scores. Oneminute and five-minute scores were recorded for all live-born neonates, apart from neonates born before arrival, fetal deaths, and terminations of pregnancy. The level of neonatal resuscitation was classified using neonatal flow algorithms from the neonatal resuscitation guidelines developed by the American Heart Association (AHA), the International Liaison Committee on Resuscitation, and the AAP. 1178,1650 The neonatal resuscitation levels were mutually exclusive with the highest level taking precedence over the lowest (Table 4.1.). Hypoxic-ischaemic encephalopathy was diagnosed by neonatology staff members and graded as stage one (mild), two (moderate), or three (severe) based on modified Sarnat and Sarnat definitions (Table 4.2.). 400 All HIE cases were reviewed by a single consultant neonatologist to confirm the diagnosis and grading. The primary study outcomes were HIE overall and moderate-severe HIE Statistical methods All statistical analyses were limited to neonates greater than 36 weeks gestation with paired umbilical artery and vein blood gas data that met the Westgate et al. criteria. 207 Descriptive data summaries were generated using frequency distributions (total number and percentage). Comparisons of outcomes observed in each year over the study period were conducted using Chi-Square tests. 174 P a g e

197 Table 4.1. Definitions of the various levels of neonatal resuscitation Level Description 0 No neonatal resuscitation undertaken in the delivery room 1 Neonatal resuscitation undertaken in the delivery room included administration of supplementary oxygen 2 Neonatal resuscitation undertaken in the delivery room included bag and mask ventilation 3 Neonatal resuscitation undertaken in the delivery room included endotracheal intubation and/or ventilation 4 Neonatal resuscitation undertaken in the delivery room included external cardiac massage 5 Neonatal resuscitation undertaken in the delivery room included administration of adrenaline Table 4.2. Criteria for the diagnosis of mild, moderate, and severe hypoxic-ischaemic encephalopathy Variable Mild Moderate Severe Level of Consciousness Alert Lethargic Comatose Muscle Tone Normal/Hypertonic Hypotonic Flaccid Tendon Reflexes Increased Increased Decreased/Absent Myoclonus Present Present Absent Seizures Absent Frequent Frequent Complex Reflexes Suck Active Weak Absent Moro Exaggerated Incomplete Absent Grasp Normal/Exaggerated Exaggerated Absent Oculocephalic Normal Overactive Reduced/Absent Autonomic Function Pupils Dilated Reactive Small Reactive Variable/Fixed Respiration Regular Periodic Ataxic/Apnoeic Heart Rate Normal/Tachycardia Bradycardia Bradycardia Electroencephalogram Normal Low Voltage Periodic /Paroxysmal Periodic/Isoelectric Receiver operating characteristic curve analysis assessed the ability of continuous biochemical measures, Apgar scores, and neonatal resuscitation levels to predict categorical outcomes. Areas under the ROC curve of % were considered to be excellent and those between 80-90% were considered good. Prediction accuracy of adverse neonatal outcomes was defined as the proportion of correctly classified cases (sum of true positives and true negatives) using the biochemical cut-off chosen to maximise the sensitivity and specificity. Optimal sensitivity and specificity were obtained for each predictor that maximised overall 175 P a g e

198 prediction accuracy. Positive and negative predictive value were calculated using the optimal determined sensitivity and specificity and outcome prevalence in the neonate subset with validated blood gas samples. Analyses of simultaneous HIE predictors were conducted using a stepwise process involving multivariable logistic regression and ROC curve analysis performed on the HIE probabilities obtained via logistic regression modelling. Forty-one different simultaneous predictor combinations were analysed for each outcome, with only the best performing predictor combinations reported. Given the number of HIE cases and to avoid over-fitting and improve clinical utility, all prediction models were limited to a maximum of four predictors for HIE overall and two for moderate-severe HIE. Multivariate models were retained if accuracy values were greater than or equal to 96% for predicting HIE overall and 97% for moderate-severe HIE. SPSS for Windows statistical software was used for all data analysis (SPSS Inc. 2006, Version 15.0, USA). All statistical hypothesis test were two-sided and p-values < 0 05 were considered statistically significant. 176 P a g e

199 4.3 Results Over the study period there were 30,574 neonates delivered at greater than 36 weeks gestation. A total of 109 neonates were excluded due to fetal deaths prior to the onset of labour. Paired validated umbilical cord blood gas values according to the Westgate et al. criteria, 207 were found in 70% (n=21,182) of the eligible population. Maternal, intrapartum, and neonatal characteristics of the validated cohort are presented in Table 4.3. Across the study period there was an increase in maternal age (p<0.001), and the number of multiple pregnancies (p=0.008). Additionally, there was a significant increase in the proportion of neonates with birth weights between 1500 and 2499 grams and a corresponding decline in the proportion of neonates with birth weights between 2500 and 3999 grams (all p<0.001). There was an increase in the proportion and number of neonates delivered operatively, with a corresponding decline in vaginal deliveries (p<0 001). There was no significant change in parity over the study period (p>0 05). A total of 60 cases of HIE were identified during the study period (1.97 per 1,000 live births). The incidence of HIE, and the specific grades of HIE, were constant across the seven years of this study (all p>0.05). Only 41 HIE cases (68%) were included in the final analysis with 19 cases excluded due to the absence of cord arterial or venous ph or pco 2 measurements or failure to meet the Westgate et al. criteria of minimum arteriovenous ph and pco 2 differences. 207 For moderate-severe HIE, there were 39 cases in the entire cohort (1.28 per 1,000 live births) and 28 in the validated cohort Univariate ROC analysis The AUC, sensitivity, and specificity for all predictors based on the maximal accuracy are presented in Table 4.4. The majority of the non-biochemical predictors had higher AUCs than those obtained for umbilical artery ph, BE, and lactate. For moderate-severe HIE, a similar situation existed with non-biochemical univariate predictors having higher AUCs than their biochemical counterparts. The one-minute Apgar score had the greatest AUC for both outcomes whilst umbilical arterial BE values had the lowest. The neonatal resuscitation level had the highest sensitivity of all factors for predicting all cases of HIE, followed by the one-minute Apgar score. Similarly, the neonatal resuscitation level had the highest sensitivity for prediction of moderate-severe HIE, followed by the one- 177 P a g e

200 minute Apgar score. The one-minute Apgar score had the highest specificity for predicting the absence of HIE, and the absence of moderate-severe HIE. Table 4.3. Maternal, obstetric, intrapartum and neonatal characteristics, n (%) Characteristic Number (Percentage) Maternal Age < 20 years 1,549 (7.3%) years 18,816 (88.8%) 40 years 805 (3.8%) Unknown 12 (0.1%) Nulliparous 8,995 (42.5%) Singleton Delivery 20,632 (97.4%) Mode of Delivery Vaginal 11,328 (53.5%) Instrumental 2,903 (13.7%) Caesarean 6,951 (32.8%) Birth Weight < 1500 grams 4 (0.0%) grams 836 (3.9%) grams 17,670 (83.4%) 4000 grams 2,672 (12.6%) The PPVs and NPVs for umbilical artery ph, BE, and lactate were calculated for predicting HIE and moderate-severe HIE (Table 4.4.). There were uniformly low PPVs ( 7%). The NPVs were never less than 99% and typically in the region of 99.9%. 178 P a g e

201 Table 4.4. Sensitivity, specificity, and AUC of univariate predictors of neonatal outcome Predictor AUC (95%CI) Cut Off Sensitivity Specificity PPV NPV Accuracy PLR NLR Hypoxic-Ischaemic Encephalopathy One Minute Apgar (0.956, 0.993) % 94.70% 3.20% 99.98% 94.69% Resuscitation Level (0.959, 0.987) % 88.32% 1.56% 99.99% 88.33% Five Minute Apgar (0.852, 0.981) % 93.02% 2.32% 99.97% 93.01% Arterial ph (0.823, 0.933) % 88.03% 1.21% 99.95% 88.00% Arterial Lactate (0.797, 0.921) % 88.19% 1.15% 99.94% 88.15% Arterial Base Excess (0.674, 0.870) % 94.69% 2.01% 99.91% 94.62% Moderate-Severe Hypoxic-Ischaemic Encephalopathy One Minute Apgar (0.952, 1.000) % 98.26% 6.34% 99.99% 98.24% Resuscitation Level (0.957, 0.994) % 88.27% 1.04% 99.99% 88.27% Five Minute Apgar (0.831, 0.996) % 97.49% 4.15% 99.98% 97.47% Arterial ph (0.797, 0.943) % 87.99% 0.82% 99.96% 87.97% Arterial Lactate (0.769, 0.933) % 88.17% 0.77% 99.95% 88.14% Arterial Base Excess (0.694, 0.907) % 94.67% 1.48% 99.95% 94.62% Note: Area under the Receiver Operating Characteristic Curve with 95% confidence interval

202 4.3.2 Multivariable ROC analysis After exclusions, 10 multivariate models remained for predicting HIE, and six models for moderate-severe HIE of the original 41 models evaluated (Table 4.5.). The combination of biochemical and non-biochemical predictors demonstrated superiority to the majority of univariate biochemical measures in predicting HIE overall and moderate-severe HIE. Considering AUC, number of predictors and the positive (PLR) and negative likelihood (NLR) ratios, the combination that was most effective in predicting HIE was the combination of one-minute Apgar scores and arterial lactate values. For moderate to severe HIE the most effective multivariate combination, was the combination of the neonatal resuscitation level and umbilical arterial lactate values. When the whole cohort was considered rather than just the validated cord blood gas cohort, ROC curve analyses produced similar results to that presented in Table 4.5. Sensitivity analyses including all UCBGA results found the combination of neonatal resuscitation level and arterial lactate remained one of the most effective predictors of moderate-severe HIE (AUC 0 981; 95%CI ) Multivariable prediction of the probability of moderate-severe HIE Equations for the final multivariable predictive models are presented in Table 4.6., allowing the calculation of a neonate s probability of later being diagnosed with HIE or moderatesevere HIE. Based on the probability equation for the level of neonatal resuscitation and arterial lactate model, Table 4.7. illustrates the percentage risk of a neonate developing moderate-severe HIE based on the individual neonate s umbilical artery lactate value and one-minute Apgar score. Combination of umbilical artery lactate levels from 1-12mmol/L and the requirement for intubation, external cardiac massage or administration of adrenaline produced a risk of moderate-severe HIE ranging from 0 3% to 81 0%. The highlighted section of Table 4.7. illustrates the combination of the two predictors that results in a risk of moderate-severe HIE greater than 2%; a level that may be considered as a candidate for further evaluation for further investigation/intervention to prevent adverse consequences of HIE. 180 P a g e

203 Table 4.5. Sensitivity, specificity, and AUC of multivariate predictors of neonatal outcome Predictor Model AUC (95%CI) Sensitivity Specificity PPV NPV Accuracy PLR NLR Hypoxic-Ischaemic Encephalopathy One Minute Apgar & ph (0.963, 0.997) 92.68% 96.38% 4.73% 99.99% 96.37% One Minute Apgar, ph, & BE (0.963, 0.997) 92.68% 96.45% 4.82% 99.99% 96.44% One Minute Apgar, & Lactate (0.961, 0.994) 89.47% 97.01% 5.49% 99.98% 97.00% One Minute Apgar, ph & Lactate (0.961, 0.996) 92.11% 96.67% 5.09% 99.98% 96.66% One Minute Apgar, Five Minute Apgar, ph & Lactate (0.957, 0.997) 92.11% 96.20% 4.49% 99.98% 96.19% One Minute Apgar, ph, BE, & Lactate (0.959, 0.996) 92.11% 96.40% 4.72% 99.98% 96.39% One Minute Apgar, Five Minute Apgar & Lactate (0.954, 0.997) 89.47% 96.48% 4.70% 99.98% 96.47% Five Minute Apgar & ph (0.902, 0.993) 87.80% 96.60% 4.77% 99.98% 96.58% Five Minute Apgar, ph, & BE (0.903, 0.993) 87.80% 97.00% 5.36% 99.98% 96.98% Five Minute Apgar, ph, BE, & Lactate (0.897, 0.993) 84.21% 97.36% 5.82% 99.97% 97.33% Moderate-Severe Hypoxic-Ischaemic Encephalopathy Neonatal Resuscitation & Five Minute Apgar 0.980(0.962, 0.998) 85.71% 98.13% 5.73% 99.98% 98.12% One Minute Apgar & ph (0.957, 1.000) 92.31% 98.05% 5.89% 99.99% 98.04% One Minute Apgar & Lactate (0.955, 1.000) 92.86% 98.08% 6.00% 99.99% 98.07% Neonatal Resuscitation & Lactate (0.960, 0.997) 84.62% 99.12% 11.31% 99.98% 99.10% Five Minute Apgar & ph (0.865, 0.998) 85.71% 97.85% 5.01% 99.98% 97.83% Five Minute Apgar & Lactate (0.838, 0.998) 84.62% 98.09% 5.55% 99.98% 98.08% Note: Area under the Receiver Operating Characteristic Curve with 95% confidence interval

204 Table 4.6. Probability equations for multivariate models. Predictor Model Logit Equations Probability Threshold Hypoxic-Ischaemic Encephalopathy One Minute Apgar & ph (One Minute Apgar) 8.012(pH) One Minute Apgar, ph, & BE (One Minute Apgar) 7.718(pH) 0.008(Base Excess) One Minute Apgar, & Lactate (One Minute Apgar) (Lactate) One Minute Apgar, ph & Lactate (One Minute Apgar) 6.209(pH) (Lactate) One Minute Apgar, Five Minute Apgar, ph (One Minute Apgar) 0.313(Five Minute Apgar) 5.432(pH) + & Lactate 0.123(Lactate) One Minute Apgar, ph, BE, & Lactate (One Minute Apgar) 4.962(pH) 0.043(Base Excess) (Lactate) One Minute Apgar, Five Minute Apgar & Lactate (One Minute Apgar) 0.354(Five Minute Apgar) (Lactate) Five Minute Apgar & ph (Five Minute Apgar) 9.675(Arterial ph) Five Minute Apgar, ph, & BE (Five Minute Apgar) (pH) (Base Excess) Five Minute Apgar, ph, BE, & Lactate (Five Minute Apgar) 6.772(pH) 0.028(Base Excess) (Lactate) Moderate-Severe Hypoxic-Ischaemic Encephalopathy Neonatal Resuscitation & Five Minute Apgar (Neonatal Resuscitation) 0.489(Five Minute Apgar) One Minute Apgar & ph (One Minute Apgar) 7.331(pH) One Minute Apgar & Lactate (One Minute Apgar) (Lactate) Neonatal Resuscitation & Lactate (Neonatal Resuscitation) (Lactate) Five Minute Apgar & ph (Five Minute Apgar) 8.967(pH) Note: Probability = exp(logit)/(1+exp(logit))

205 Neonatal Resuscitation Table 4.7. Percentage risk of moderate-severe hypoxic-ischaemic encephalopathy based on level of neonatal resuscitation and umbilical artery lactate values Umbilical Artery Lactate Values (mmol/l) <0.01% <0.01% <0.01% <0.01% 0.01% 0.01% 0.01% 0.01% 0.02% 0.03% 0.04% 0.06% % 0.01% 0.02% 0.02% 0.03% 0.05% 0.06% 0.09% 0.12% 0.17% 0.24% 0.33% % 0.07% 0.10% 0.14% 0.20% 0.28% 0.38% 0.53% 0.74% 1.02% 1.41% 1.95% % 0.44% 0.61% 0.85% 1.18% 1.63% 2.25% 3.09% 4.25% 5.81% 7.89% 10.64% % 2.58% 3.55% 4.87% 6.64% 9.00% 12.08% 16.03% 20.97% 26.93% 33.87% 41.58% % 13.68% 18.05% 23.43% 29.84% 37.15% 45.09% 53.30% 61.33% 68.78% 75.38% 80.97% Note: Risk calculated from exp( (Neonatal Resuscitation) (Lactate))/(1+exp( (Neonatal Resuscitation) (Lactate)))

206 4.4 Discussion This study represents one of the largest cohorts to evaluate the ability of biochemical and non-biochemical methods to predict HIE. We have shown that both biochemical and clinical methods are effective at predicting HIE. That being so, one-minute Apgar score and the neonatal resuscitation level had higher AUCs than umbilical artery biochemical measures suggesting superiority when single variables were used to predict HIE and moderate-severe HIE. The one-minute Apgar score had the greatest AUC for HIE overall and moderatesevere HIE. When multivariable models consisting of clinical and biochemical measures were developed to predict HIE, areas under ROC curves up to 0 98 with sensitivities up to 93% and specificities up to 99% were possible. There was no additional benefit conferred by including more than two predictors. Of the non-biochemical measures of neonatal wellbeing, the neonatal resuscitation level had the greatest sensitivity for predicting HIE and one of the highest sensitivities for predicting moderate-severe HIE. The need for high levels of resuscitation at delivery has previously been reported to be a sensitive predictor of later adverse outcomes. 389,425,486,1182, When the need for CPR coexisted with severe acidaemia, an adverse outcome was likely in over 90% of cases. 198 In a subsequent study, Perlman and Risser reported that initial resuscitation should be considered alongside post-delivery events for initial resuscitation to be an accurate predictor of outcome This is demonstrated by the observation that neonates born with normal blood gases that have a poor response to initial resuscitation followed by a rapid improvement once adequate ventilation and oxygenation has occurred, have positive shortterm neurological outcomes in greater than 95% of cases Taken together, these data suggest that the delivery room resuscitation level should not be utilised alone as a neurological outcome predictor: it performs best when combined with other assessments of neonatal wellbeing or response to resuscitation. When one considers the AUC and positive likelihood ratios of univariate predictors, the oneminute Apgar score was the most effective predictor of HIE and moderate-severe HIE. The positive likelihood ratio of the one-minute Apgar score for predicting moderate to severe HIE was almost double that of the five-minute Apgar score. This observation may be due to the one-minute score reflecting the neonatal condition at birth more closely that the fiveminute Apgar score, which may be influenced by the neonatal response to resuscitation. It is generally considered that the five-minute Apgar has greater value than the one-minute score 184 P a g e

207 in predicting outcome; however, the evidence supporting this is limited and typically arises from studies evaluating long-term outcomes, such as CP. 733 Taken together, these data provide further support to the ongoing utilisation of Apgar scores as a means of describing neonatal condition and predicting adverse outcomes despite the criticism the Apgar score has received for its subjective nature. 1089,1097,1181 When considering multivariable predictors of HIE, all of the predictive models had AUC greater than and overlapping 95% confidence intervals. Therefore, when deciding on the predictive model with the greatest clinical utility, PLR and NLR and the number of predictors utilised should be considered. For HIE, of the two variable predictors, the combination of one-minute Apgar score and arterial lactate had the highest PLR whereas for moderate-severe HIE, the combination of the level of neonatal resuscitation and umbilical artery lactate value was the best predictor. Both cord arterial lactate and ph are measures of acidaemia. Fetal arterial lactate values are a measure of anaerobic metabolism whereas fetal ph values represent both anaerobic metabolism and the acidaemia due to increasing fetal CO 2 levels (known as fetal respiratory acidaemia). Compared to ph, fetal lactate levels are relatively slow to normalise after a hypoxic insult as fetal lactate levels are dependent on the rate of anaerobic metabolism and placental lactate transfer, which is proton pump dependent and therefore rate limited ,1378 In contrast, most free H + are buffered within the cell by carbonic anhydrase forming carbonic acid that rapidly dissociates to CO 2 and H 2 O. Carbon dioxide diffuses rapidly across the placenta so that even large quantities produced by the fetus can be eliminated rapidly if maternal respiration, uteroplacental blood flow and umbilical blood flow are normal Collectively, these data suggest that fetal/cord lactate levels may be better markers of the long-term fetal condition than ph and pco 2 values, which can rapidly normalise after an insult. Until recently there has been little that could be done to minimise injury in neonates with HIE. Data from randomized controlled trials published over the last decade have demonstrated that the early treatment of neonates with HIE has the potential to significantly reduce the morbidity and mortality associated with HIE. 1295,1297, One of the key factors enabling successful use of neuroprotective hypothermia is the early identification of neonates who may benefit from this treatment. Under ideal circumstances treatment should be initiated within six hours of delivery, 1282,1316 with no human studies of neuroprotective hypothermia conducted beyond six hours after birth P a g e

208 This is not the first study to evaluate univariate and multivariable predictors of adverse neonatal outcomes. 99,389,486,578,697,1182, , Most of the previous studies have utilised small cohorts or subsets of clinical populations defined by clinical characteristics rather than an entire presenting population limiting their external applicability to other populations. Further, most previous studies did not utilise ROC curve analysis, considered the gold standard test method for comparing diagnostic tools. The predictors evaluated in this study were simple, inexpensive and available within minutes of delivery and were analysed over an entire presenting population suggesting that these results may be more applicable to the general population. The primary strength of this study is its large sample size as well as the universal sampling of an entire tertiary maternity unit population. Further, all neonates were assessed by clinical staff members at delivery rather than by members of the research team. The low PPVs and high NPVs reported in this study are a reflection of the low incidence of HIE. Whilst this cohort included 30,574 neonates greater than 36 weeks gestation, there were only 21,182 neonates with umbilical cord blood gas and lactate values that were validated according to the Westgate et al. criteria. 207 This subset was utilised for predictive model development; hence, 41 rather than the 60 cases of HIE were available for analyses. Sensitivity analyses using the entire cohort demonstrated similar results to those obtained in the analyses in the validated cohort suggesting that our predictive models are widely applicable. It is important to note that the sensitivities of all predictive models for predicting HIE were high (up to 93%) and for this condition, the consequences of false negative tests may be comparatively worse than false positive results. Despite the large sample size, this study was underpowered to detect differences in rare but serious outcomes, such as CP and perinatal death due to intrapartum asphyxia. The predictive data generated in this study has provided us with the opportunity to develop charts that can provide an individualised risk of HIE that can be used as part of the decision analyses to transfer patients to centres where neuroprotective therapy is available. The thresholds for consideration of transfer for neonates at risk of moderate-severe HIE should be considered as guidelines and should be interpreted within the clinical context. Moreover, individual centres are likely to have differing thresholds for transfer of at risk neonates depending on local access (and travel time) to tertiary support. 186 P a g e

209 Neonatal encephalopathy is a heterogeneous syndrome characterized by signs of CNS dysfunction in newborn infants. Clinical suspicion of NE should be considered in any infant exhibiting an abnormal level of consciousness, seizures, tone and reflex abnormalities, apnoea, aspiration, and feeding difficulties. 400 For many years it was accepted that fetal asphyxia during labour was the major cause of both NE and CP; 1657 however, the evidence for this is limited. Although few studies have adequately evaluated risk factors for NE other than HIE, a variety of prenatal and obstetric predictors have been identified in large cohort studies. In a large Western Australian Study of HIE, up to 69% of cases had antepartum risk factors, 25% had antepartum and intrapartum risk factors, 4% had evidence of only intrapartum hypoxia and 2% had no identified risk factors. Thus, approximately 70% of NE is associated with events arising before the onset of labour. 203 The diagnosis of cerebral hypoxia-ischemia during labour is difficult and is usually inferred from non-specific signs More precise assessment using specialist technologies like magnetic resonance imaging is possible but not widely available. Neonatal staff would benefit from a simple, quick, inexpensive, and accurate test that allows identification of neonates at risk of HIE that may benefit from interventions such as neuroprotective hypothermia. The predictive models presented in this study would be of greatest value to non-tertiary units and obstetric units located in rural, regional, and remote areas allowing the rapid identification of those most likely to benefit from interventions that need to be initiated within hours of delivery. 187 P a g e

210 4.5 Conclusion The simple combination of level of neonatal resuscitation and umbilical artery lactate values provide an accurate method of predicting moderate-severe cases of HIE within minutes of delivery. This approach can identify neonates for consideration for transfer to tertiary neonatal care who may benefit from neonatal hypothermia as a neuroprotective therapy. One of the key issues with neuroprotective hypothermia is early identification of neonates who would obtain greatest benefit. Under ideal circumstances, this treatment should be initiated within six hours of delivery. 204, The predictive tests developed in this study fulfil the criteria for early identification of neonates for consideration of neuroprotective therapies; they are simple, inexpensive and available within minutes of delivery. Moreover, the development of reliable, accurate, and relatively inexpensive handheld lactate meters allows lactate analysis to occur in the delivery room for as little as US$1 per test with the results available within minutes of delivery This approach for predicting the important adverse outcome of moderate-severe HIE should be widely applicable to all obstetric units. 188 P a g e

211 CHAPTER FIVE EVALUATION OF SELECTION CRITERIA FOR VALIDATING PAIRED UMBILICAL CORD BLOOD GAS SAMPLES: AN OBSERVATIONAL STUDY 5.1 Introduction There is a growing body of support for UCBGA to be undertaken on all deliveries to provide an objective marker of neonatal biochemical status at delivery, 47,66,211,912,1187,1658 that in turn can identify neonates that have been exposed to perinatal asphyxial insults. Whilst some authors have advocated sampling only the umbilical artery, 1189 the majority of authors and professional societies strongly advocate obtaining and analysing samples from both the umbilical artery and vein, 24,189,207,848,1250 in order to ensure the biologic validity of the blood gas values obtained. Most previous studies utilising UCBGA data have included all cases where blood gas data was available. This approach does not take into account pre-analytic sampling errors that may result in the analysed samples not being a valid representation of paired umbilical arterial and venous blood. Pre-analytic sampling errors are primarily due to inadvertent collection of mixed arterial and venous blood: less commonly, the same vessel can be sampled twice (usually the umbilical vein) or the samples may be mislabelled. In order to ensure the validity of paired UCBGA values, two methods have been developed: the Westgate et al. criteria and the more recent Kro et al. criteria. 207,1636 The Westgate et al. criteria are constrained by the small sample size and subpopulation from which it was developed. In contrast, the Kro et al. criteria was developed in a larger and more diverse cohort than the Westgate et al. criteria; however, some of the elements utilised in the Kro criteria are complex and may be difficult to apply in clinical situations. The validation of accurate paired UCBGA samples is unlikely to have clinically significant consequences for neonates delivered in good condition with uneventful neonatal periods. In contrast, for neonates born in poor clinical condition or those who have neonatal complications, the classification of paired UCBGA samples as valid (physiologically plausible) or non-valid (physiologically non-plausible) may have clinically significant consequences. This is of particular importance when considering the central role of UCBGA 189 P a g e

212 values in the diagnosis of perinatal asphyxial injury, 24,203 and its resulting medical, social, financial, and legal implications. Consequently, the development and evaluation of selection criteria for UCBGA values must take into account not just the overall proportion of neonates with valid and non-valid UCBGA values but also, and perhaps more importantly, the proportions amongst neonates with adverse neonatal and clinical outcomes Study aims The aim of this study was to compare four new selection criteria to the Westgate and Kro criteria for identifying accurate paired UCBGA samples in vigorous and non-vigorous neonates at delivery. Further, this study includes the first evaluation of the effects of different selection criteria on the number and proportion of neonates with UCBGA values available for interpretation amongst those that experience adverse clinical and neonatal outcomes. 190 P a g e

213 5.2 Methods The study was undertaken over a seven-year period (1st of January 2003 and 31st of December 2009) at KEMH, Perth, Western Australia, the sole tertiary level maternity unit for Western Australia. Paired arterial and venous umbilical cord-blood gas and lactate samples were collected on all neonates delivered at 23 or greater weeks gestation apart from: 1) therapeutic abortions for fetal anomalies; and 2) fetal deaths in utero diagnosed prior to the onset of labour. Detailed maternal, obstetric, intrapartum and neonatal information for all deliveries were extracted from the institutional electronic database. As soon as possible after delivery, with the placenta in-situ and ideally prior to the neonate s first breath, an umbilical cord segment was isolated utilising cord clamps. Arterial and venous samples were collected using a one-millilitre pre-heparinised plastic syringe (Rapidlyte TM ; Bayer Corporation, East Walpole, MA) and a 21-gauge needle. Analysis was performed as soon as possible after collection, typically within five to ten minutes after collection but occasionally extending up to 30 minutes. Blood gas analysis was performed on paired arterial and venous samples using a Bayer Chiron Diagnostics Model 840 Blood Gas Analyser (Bayer Diagnostics, Germany) located in the labour and delivery ward. Umbilical lactate was measured on the cord arterial sample using a Roche Accusport TM (Boehringer Mannheim, Germany). For the final two years of the study, a lactate electrode was installed in the blood gas analyser; however, the hand-held lactate meter was retained as a back-up mode of analysis. The blood gas analyser was serviced daily by hospital technical staff members while the lactate meters were calibrated with every 20 samples and serviced when necessary. Automatic one and two point calibration of the blood gas analyser occurred every 30 and 120 minutes, respectively. The midwifery staff, usually those who collected the samples, undertook all analyses. All staff members were required to meet minimum competency standards in sampling and measurement techniques prior to performing UCBG sampling and analyses independently. The six selection criteria for determining validated (biologically plausible) umbilical cordblood gas values were evaluated in this study (Table 5.1.). The first two selection criteria are the original Westgate et al. criteria, 207 and Kro et al. criteria The third is a modified version of the Westgate et al. criteria which utilises the KEMH population fifth percentile for arteriovenous (AV) ph difference ( 0.01pH units) and the KEMH population tenth 191 P a g e

214 percentile for AV pco 2 difference ( 3.4mmHg) rather than the fifth and tenth percentiles described in the original Plymouth study population. The KEMH criteria are similar to the Westgate and modified Westgate criteria: the KEMH fifth percentile AV differences in ph ( 0.01pH units) and pco2 ( 0.2mmHg) are utilised to confirm two-vessel sampling. The minimum information required for clinical interpretation of fetal acid-base status at delivery is a ph value, a pco 2 value and an indicator of metabolic acidaemia (either a BE or a lactate value). These three measures are utilised to define the minimal criteria. The sixth and final criterion evaluated is based on having at least one cord-blood vessel lactate measure available at delivery: the lactate criteria. Table 5.1. Definitions of various cord blood gas validation criteria Criteria Name Westgate al. 11 Kro et al. 13 Modified Westgate et al. King Edward Memorial Hospital et Criteria Details 1. Both arterial & venous vessel sampled 2. ph & pco 2 values present for both vessels 3. (Arterial ph Venous ph) (Arterial pco 2 Venous pco 2 ) 3.8 mmhg UAV 10th centile] [Westgate population UAV* 5th centile] 1. Both arterial & venous vessel sampled 2. (Arterial ph Venous ph) (Arterial pco 2 Venous pco 2 ) 5.25 mmhg 10th centile] [Westgate population [Kro population UAV 5th centile] [Kro population UAV 4. Venous pco mmhg 5. Arterial pco 2 value within gestational age adjusted normal range for arterial ph 1. Both arterial & venous vessel sampled 2. ph & pco 2 values present for both vessels [KEMH population UAV 5th centile] 3. (Arterial ph Venous ph) (Arterial pco 2 Venous pco 2 ) 3.4 mmhg 10th centile] 1. Both arterial & venous vessel sampled 2. ph & pco 2 values present for both vessels 3. (Arterial ph Venous ph) (Arterial pco 2 Venous pco 2 ) 0.2 mmhg 5th centile] [KEMH population UAV [KEMH population UAV 5th centile] [KEMH population UAV Minimal 1. Arterial or venous ph value present 2. Arterial or venous pco 2 value present 3. Arterial or venous base excess or lactate value present Lactate 1. Arterial or venous lactate value present Note: * UAV: Umbilical arteriovenous difference; Two standard deviations below the intrapartum mean maternal arterial pco 2 ; 30, 31 and, KEMH: King Edward Memorial Hospital The definition of neonatal umbilical acidaemia is based on the ICPTF, ACOG and AAP guidelines: an umbilical artery ph value less than 7.00 and an umbilical artery BE value less 192 P a g e

215 than -12mmol/L. 24,203 five-minute Apgar score less than seven. A non-vigorous neonate at delivery was defined as a neonate with a Descriptive data summaries were generated using frequency distributions (number and percentage). Comparisons of categorical outcomes were conducted using Chi-Square tests, whilst continuous outcome comparison was conducted by one-way analysis of variance. SPSS for Windows statistical software was used for all data analysis (SPSS Inc. 2006, Version 15.0, USA). All statistical hypothesis tests were two-sided and p-values less than 0.05 were considered statistically significant. 193 P a g e

216 5.3 Results During the seven-year study period, 38,404 neonates were delivered at 23 weeks gestation or greater at KEMH, Perth, Western Australia. Six hundred and forty one neonates were excluded due to therapeutic terminations for fetal anomaly or fetal deaths in utero diagnosed prior to the onset of labour. Detailed maternal, obstetric, intrapartum, and neonatal information was available for all deliveries (Table 5.2.). Across the study period there was an increase in maternal age (p<0.001) as well as variation in maternal parity (p<0.001). There was also an increase in operative deliveries with a corresponding decline in vaginal deliveries (p<0.001). No significant change in plurality, birth weight, or gestational age occurred over the study period (all p>0.05). Of the 37,763 neonates available for evaluation, umbilical cord-blood sampling and analysis occurred on 35,030 neonates (92.8%). A variety of reasons were noted for missing data including: no sample being collected (n=932; 2.5%); analyser associated technical difficulties (n=318; 0.8%); clotted samples (n=291; 0.8%); physiological third stage management (n=235; 0.6%); inadequate sample volume (n=210; 0.6%); and the neonate being born before arrival at KEMH (n=199; 0.5%). For the remaining 548 neonates (1.5%), no reason for missing data was recorded. Paired samples from both the umbilical artery and umbilical vein were available in 29,874 neonates (79.1%) representing 85.3% of all neonates with UCBG analysis. The application of the first four validation criteria to the KEMH population is presented in Figure 5.1. For the Westgate et al., Modified Westgate et al. and KEMH criteria, the proportion of neonates excluded from analyses are identical until the application of AV differences for ph and pco 2. The KEMH criteria classified the greatest proportion of neonates with valid UCBG samples whilst the Kro et al. criteria had the fewest. The Westgate et al. and Modified Westgate et al. criteria have similar proportions of neonates with validated UCBG values. The discriminating point in the selection criteria where there was the greatest reduction in the number of valid samples for analyses was at the one-vessel/twovessel stage. 194 P a g e

217 Table 5.2. Maternal, obstetric, intrapartum and neonatal characteristics for King Edward Memorial Hospital cohort Characteristic Number (Percentage) or Median (Inter-quartile Range) Maternal Age (Completed Years) 29 (24-33) Nulliparous 16,222 (43.0%) Singleton Delivery 34,978 (92.6%) Gestation Preterm 8,526 (22.6%) Term 28,833 (76.4%) Post term 404 (1.1%) Mode of Delivery Vaginal 20,827 (55.2%) Instrumental 4,340 (11.5%) Caesarean 12,596 (33.4%) Birth Weight (grams) 3,240 ( ) Gestational Hypertension 1,158 (3.1%) Preeclampsia/Eclampsia 2,050 (5.4%) Pre-existing Maternal Diabetes 696 (1.8%) Gestational Diabetes 2,652 (7.0%) Intrauterine Growth Restriction 2,133 (5.6%) Five Minute Apgar Score (0.7%) (2.1%) 7 37,431 (99.1%) SCN Admission Special Care Nursery 6,095 (16.1%) Neonatal Intensive Care Unit 3,685 (9.8%) Term Neonatal Intensive Care Unit Admissions 491 (1.3%) Umbilical Artery Blood Gas Values ph (7.230, 7.318) pco (47.70, 59.90) Base Excess (-4.90, -0.70) Lactate 4.00 (3.00, 4.94) 195 P a g e

218 Figure 5.1. Application of the Westgate et al., Modified Westgate et al.., Kro et al., and King Edward Memorial Hospital criteria 196 P a g e

219 The proportion of neonates with validated UCBG values varied in different clinical populations (Table 5.3.). The Kro et al. criteria have the lowest proportion of validated UCBG for each clinical outcome, while the Minimal criteria had the highest proportion. In comparison to the original Westgate et al. criteria the, modified Westgate et al., KEMH, minimal and lactate criteria had significantly higher proportions of neonates with validated blood gas values for each outcome (p<0.001). Conversely, the Kro et al. criteria define a significantly lower proportion of neonates with UCBG values for each clinical outcome when compared with the Westgate et al. criteria (p<0.001). Details of the proportion of neonates with validated UCBG values that experience adverse outcomes are summarised in Table 5.4. Similar to the nursery admission data, the Kro et al criteria provided UCBG data on fewer neonates that the Westgate et al. criteria (p<0.001) and the modified Westgate et al., KEMH, minimal and lactate criteria had significantly higher proportions of neonates with validated UCBG data (p<0.001). The proportion of neonates with normal UCBG values (arterial ph greater than 7.10 and arterial BE greater than -10mmol/L) was consistent across the Westgate et al., modified Westgate et al., and KEMH validated populations (95.6%). Application of the minimal and lactate criteria resulted in lower proportions of neonates with normal UCBG values (87.3% and 92.7% respectively), whilst the Kro et al. criteria resulted in a higher proportion (96.5%). The proportion of cases of severe umbilical artery metabolic acidaemia (arterial ph value less than 7.00 and BE values less than -12mmol/L) with valid UCBG utilising the Kro et al. criteria was 0.2% whereas it was 0.4% using the other five selection criteria (all p<0.001). The proportion of neonates with various clinical outcomes with valid UCBG data for the six selection criteria is presented in Table 5.5. The Westgate et al., modified Westgate et al. and KEMH selection criteria had similar proportions of healthy neonates at term with normal UCBG values. In contrast, the Kro et al. criteria had a higher proportion and the minimal and lactate criteria had lower proportions of neonates with normal UCBG values than the other selection criteria. The proportion of term healthy neonates diagnosed with abnormal UCBG values was identical utilising five of the six selection criteria with the Kro et al. criteria having a lower proportion (0.1%) than the other five (0.2%). 197 P a g e

220 Table 5.3. Cord blood gas values for clinical outcomes stratified by selection criteria Criteria Cohort for Evaluation (From N=37,763) Term Healthy Neonates (From n=23,536) Term Non- Vigorous Neonates (From n=338) Term Neonates to Ward (From n=25,630) Term Nursery Admissions (From n=3,203) Term Neonates to NICU (From n=491) n % n % n % n % n % n % Westgate et al. 25,378 * 67.2% * 16,202 * 67.2% * 226 * 66.9% * 17,787 * 69.3% * 2,263 * 70.7% * 344 * 70.1% * Kro et al. 21,824 * 57.8% * 14,127 * 60.0% * 188 * 55.6% * 15,535 * 60.6% * 1,915 * 59.8% * 287 * 58.5% * Modified Westgate et al. 25,290 * 68.6% * 16,489 * 68.8% * 234 * 69.2% * 18,104 * 70.6% * 2,308 * 72.1% * 350 * 71.3% * KEMH * 71.4% * 17,078 * 72.6% * 242 * 71.6% * 18,732 * 73.1% * 2,382 * 74.4% * 366 * 74.5% * Minimal 32,841 * 87.0% * 20,589 * 87.5% * 305 * 90.2% * 22,537 * 87.9% * 2,812 * 87.8% * 443 * 90.2% * Lactate 29,669 * 78.6% * 18,445 * 78.4% * 267 * 79.0% * 20,161 * 78.7% * 2,646 * 82.6% * 403 * 82.1% * Note: * p<0.05 compared to baseline Westgate et al. criteria; UA & UV ph & pco 2 present with UAV ph 0.01 & UAV pco 2 3.4mmHg; UA & UV ph & pco 2 present with UAV ph 0.01 & UAV pco 2 0.2mmHg; ψ UA ph, pco 2 & BE/lactate present or UV ph, pco 2 & BE present; UA lactate value present.

221 Table 5.4. Proportion of neonates with adverse outcomes stratified by selection criteria Criteria Hypoxic-Ischaemic Encephalopathy (N=84) Seizures (N=34) Metabolic Acidaemia (UA ph < 7.0 & BE <-12mmol/L) (N=127) Five Minute Apgar Score Less than Seven (N=1060) Neonatal Death (N=221) n % n % n % n % n % Westgate et al. 57 * 67.9% * 25 * 75.3% * 94 * 74.0% * 526 * 49.6% * 63 * 28.5% * Kro et al. 38 * 45.2% * 21 * 61.8% * 50 * 39.4% * 407 * 38.4% * 43 * 19.5% * Modified Westgate et al. 60 * 71.4% * 26 * 75.5% * 102 * 80.3% * 549 * 51.8% * 65 * 29.4% * KEMH ψ 62 * 73.8% * 27 * 79.4% * 103 * 81.1% * 581 * 54.8% * 72 * 32.6% * Minimal 75 * 89.3% * 31 * 91.2% * 127 * 100.0% * 786 * 74.2% * 118 * 53.4% * Lactate 63 * 75.0% * % % 680 * 64.2% * 93 * 42.1% * Note: * Significant difference (p<0.05) to baseline Westgate et al. criteria; Comparison not performed due to multiple groups with cell counts less than five; UA & UV ph & pco 2 present with UAV ph 0.01 & UAV pco 2 3.4mmHg; ψ UA & UV ph & pco 2 present with UAV ph 0.01 & UAV pco 2 0.2mmHg; UA lactate value present.

222 Table 5.5. Neonates with normal and abnormal blood gas values stratified by selection criteria and clinical outcome Criteria (N; % total cohort) Westgate et al. (N=25,378; 67.2%) Kro et al. (N=21,824; 57.8%) Modified Westgate et al. (N=25,910; 68.6%) KEMH (N=26,950; 71.4%) Minimal (N=32,841; 87.0%) Lactate (N=29,669; 78.6%) Population Normal Umbilical Cord Blood Gas Values * Borderline Umbilical Cord Blood Gas Values Abnormal Umbilical Cord Blood Gas Values Term Healthy Neonates (n=16,202) 15,547 (96.0%) 626 (3.9%) 29 (0.2%) Term Non-Vigorous Neonates (n=226) 172 (76.1%) 38 (16.8%) 16 (7.1%) Term Nursery Admissions (n=2,263) 2,038 (90.1%) 196 (8.7%) 29 (1.3%) Term Healthy Neonates (n=14,127) 13,682 (96.9%) 429 (3.0%) 16 (0.1%) Term Non-Vigorous Neonates (n=188) 152 (80.9%) 30 (16.0%) 6 (3.2%) Term Nursery Admissions (n=1,915) 1,754 (91.6%) 146 (7.6%) 15 (0.8%) Term Healthy Neonates (n=16,489) 15,822 (96.0%) 635 (3.9%) 32 (0.2%) Term Non-Vigorous Neonates (n=234) 178 (76.1%) 38 (16.2%) 18 (7.7%) Term Nursery Admissions (n=2,308) 2,078 (90.0%) 197 (8.5%) 33 (1.4%) Term Healthy Neonates (n=17,078) 16,377 (95.9%) 669 (3.9%) 32 (0.2%) Term Non-Vigorous Neonates (n=242) 184 (76.0%) 40 (16.5%) 18 (7.4%) Term Nursery Admissions (n=2,382) 2,144 (90.0%) 205 (8.6%) 33 (1.4%) Term Healthy Neonates (n=18,909) 18,013 (87.5%) 2538 (12.3%) 38 (0.2%) Term Non-Vigorous Neonates (n=305) 208 (68.2%) 73 (23.9%) 24 (7.9%) Term Nursery Admissions (n=2,812) 2,352 (83.6%) 419 (14.9%) 41 (1.5%) Term Healthy Neonates (n=18,445) 17,214 (93.3%) 1195 (6.5%) 36 (0.2%) Term Non-Vigorous Neonates (n=267) 192 (71.9%) 53 (19.9%) 22 (8.2%) Term Nursery Admissions (n=2,646) 2,303 (87.0%) 306 (11.6%) 37 (1.4%) Note: * Umbilical artery ph greater than 7.10 and umbilical artery base excess greater than -10mmol/L; Umbilical artery ph greater than or equal to 7.00 and less than or equal to 7.10 and umbilical artery base excess greater than or equal to -12mmol/L and less than or equal to -10mmol/L; Umbilical artery ph less than 7.00 and umbilical artery base excess less than -12mmol/L

223 A similar pattern of valid UCBG data was seen in term non-vigorous neonates (Table 5.5.). Westgate et al., modified Westgate et al., and KEMH criteria had consistent proportions of neonates with normal UCBG values (76.0%-76.1%) whereas the proportion was higher using the Kro et al. criteria (80.9%) and lower for the minimal and lactate criteria (68.2% and 71.9% respectively). Amongst term non-vigorous neonates, the six selection criteria had different proportions of neonates diagnosed with abnormal UCBG values ranging from 3.2% (Kro et al. criteria) to 8.2% (lactate criteria). Term neonates admitted to the nursery had similar patterns of valid normal UCBG values to the other neonatal outcomes previously described. The proportion of valid abnormal UCBG values was lower using the Kro et al. (0.8%) criteria than the other five criteria ( %). 201 P a g e

224 5.4 Discussion In this study we have compared six selection criteria to determine valid, physiologically plausible, UCBG data in 37,763 consecutive deliveries greater than 23 weeks gestation. Comparing the four validation criteria for paired UCBG samples, the KEMH criteria excluded the fewest samples from the study population and provided valid data for the greatest proportion of neonates for all clinical outcomes assessed from term healthy neonates to term neonatal deaths. This increase in the proportion of deliveries with valid UCBG data did not increase the proportion of healthy term neonates diagnosed with abnormal blood gas values (false negative UCBG data). It did, however, result in an increase in the proportion of non-vigorous neonates at delivery with umbilical artery metabolic acidaemia, likely to be true positive UCBG results. Single vessel UCBG data are obtained in approximately 14% of term deliveries, with single vessel data over-represented in babies with adverse neonatal outcomes. In this study we have evaluated two selection criteria to determine valid single vessel samples. Of these criteria, the minimal criteria excluded the fewest samples without any increase in the proportion of healthy neonates diagnosed with abnormal UCBG values. Moreover, the minimal criteria provided valid blood gas data to the largest proportion of babies with HIE, neonatal seizures, low Apgar scores and neonatal deaths. These valid UCBG results are likely to assist clinicians treating neonates with adverse outcomes; to identify the potential aetiology for their clinical status and to identify neonates for potential interventions. The presence of umbilical artery acidaemia was an inclusion criterion for many of RCTs evaluating the clinical utility of neonatal neuroprotective hypothermia, ,1304, and is one of the essential criteria for the diagnosis of acute intrapartum hypoxic events. 24,203 Changing from the Westgate et al. to the KEMH criteria for determining accurate paired UCBG samples would result in a 6% increase in the proportion of neonates with HIE considered to have valid cord-blood gas values. If the selection criteria were expanded to the minimal criteria, there would be a 23% increase in the proportion of neonates with valid paired cord-blood gas values available to consider for neuroprotective therapy. Similarly, amongst those infants that die within the neonatal period, there would be a 31% increase in the number of neonates with validated blood gas data if the minimal criteria for accuracy were adopted. 202 P a g e

225 In clinical care, one of the most problematic situations is a non-vigorous neonate with a single umbilical vessel sample or invalid values from paired samples using the current accuracy criteria. To address this issue, we have evaluated the impact of utilising the minimal criteria a ph, pco 2 and an indicator of metabolic academia (BE or lactate) available from one vessel. In a large population of 18,909 term healthy neonates, utilising the minimal criteria as a method of determining validity of results did not increase the proportion of neonates diagnosed with abnormal UCBGA results (0.2%). Of greater importance, the utilisation of the minimal criteria increased the proportion of term non-vigorous neonates with abnormal or borderline UCBGA results with a corresponding decrease in the numbers diagnosed with normal UCBGA results. Taken together, these data demonstrate that if paired cord blood samples are not available in non-vigorous neonates, the use of ph, pco 2 and BE/lactate from a single vessel is appropriate as it does not increase the number of false positives but does provide valuable acid/base data to the neonatal team. Historically, the proportion of samples declared non-valid varies from 5% to 37% of the population evaluated. 47,65,68,71-73,97,207,1189,1635, Apart from the inability to obtain an arterial and/or venous sample, the most common postulated mistake is the inadvertent switching of umbilical arterial and venous samples or sampling the same umbilical vessel twice (typically the umbilical vein). Early studies of UCBG values relied on the skill of the midwifery and medical staff members sampling technique, and typically only reported values from a single umbilical vessel. It was not until Westgate et al. developed a model to exclude results with a high likelihood of incorrect sampling, that consideration was given to sample accuracy. 207 The models derived to identify accurate sampling are based on a series of minimum accepted differences between arterial and venous values for ph and pco 2 derived from the underlying principles of hydrogen and CO 2 diffusion across the placenta. The optimum minimum difference between arterial and venous ph is contentious with considerable divergence in opinion. 68,71-72,134 The two previous studies to evaluate accuracy of paired UCBG values have concurred on a minimum difference of 0.02 ph units. The primary issue associated with the use of a percentile based umbilical AV difference to define accurate sampling is that a set percentage of the population are always going to be classified as having invalid UCBG values. The Westgate et al. and Kro et al. criteria utilise the fifth percentile AV ph difference and the tenth percentile AV difference for pco 2 as criteria to exclude paired single vessel samples. 207,1636 Westgate et al. detailed the choice of the tenth rather than fifth percentile for AV difference for pco 2 because the pco 2 electrode is less accurate than the ph electrode in standard blood gas machines. 207 The KEMH criteria 203 P a g e

226 described in this study also utilised the fifth percentile for AV ph difference to exclude paired single vessel samples; however, the fifth percentile AV difference in our large population of consecutive deliveries was 0.01 ph units. This small change in the exclusion criteria resulted in an additional 2.2% of samples remaining for subsequent analyses. The SD for the ph electrode in most blood gas machines is ±0.005 ph units. During routine calibration of the ph electrode, any values beyond two SDs (±0.01 ph units) for the calibration solutions results in a failure of quality control. Interestingly, the fifth percentile AV ph difference derived from the KEMH population is the same as the accuracy of the ph electrode. This provides further evidence for the AV ph difference of 0.01 to be utilised to exclude paired single vessel samples. In the KEMH criteria, the fifth percentile AV difference for pco 2 is utilised rather than the tenth percentile detailed in the Westgate et al. and Kro et al. criteria. This change, in conjunction with the change in ph AV difference in the KEMH criteria, resulted in an additional 4.2% of neonates having validated UCBG samples. The increase in valid samples did not result in an increase in false positive UCBG results: there was no increase in the proportion of healthy neonates diagnosed with abnormal cord blood gas results. The accuracy of the po 2 and pco 2 electrodes in most blood gas machines is ±0.5mmHg. The AV differences in pco 2 required to exclude paired single vessel samples is 7.6 SDs of electrode accuracy in the Westgate et al. criteria and 10.5 SDs in the Kro et al. criteria. Both of these AV differences are probably beyond that which is required to reliably identify paired single vessel samples. The Westgate et al. criteria were developed in a small cohort of 2,013 pregnancies 34 weeks gestation where each fetus was monitored with a FSE. Further, for the initial period of the Westgate et al. study, research personnel rather than clinical staff collected UCBG samples. There are also limitations in the population utilised by Kro et. al. to evaluate accuracy of paired UCBG samples. Although the Kro study population was larger (n=36,432 UCBG samples) than the sample used by Westgate et al., it was obtained from three different study populations: two low risk populations and one intensively monitored population. Each study subpopulation had different inclusion and exclusion criteria complicating the applicability of the results to a general obstetric population. In this study, we have addressed these limitations by collecting a large sample of consecutive deliveries (37,763) where all UCBG samples were collected and measured by clinical rather than research staff. 204 P a g e

227 During this study, UCBGA occurred in concert with the traditional approach to the management of the third stage, including early clamping of the umbilical cord, if delayed cord clamping was adopted more broadly, further analyses of arteriovenous differences would be required. It is important to note, however, that the greatest value of UCBGA is in the management of babies that are non-vigorous at birth. In such a clinical situation, typical management would entail early cord clamping and transfer of the newborn onto a resuscitation cot and into the care of neonatologists. At the present point in time, given the relative rarity of delayed cord clamping, it would be difficult to accumulate a database of the size in this manuscript for development of applicable validation criteria. 205 P a g e

228 5.5 Conclusions Utilisation of the KEMH criteria for identifying paired accurate UCBG samples results in an increase in the proportion of deliveries where UCBG results are considered accurate. This change occurs without increasing the rate of false positive diagnoses of acidaemia in vigorous neonates. It does, however, provide more valid data to aid clinicians where neonates are born in poor condition. If only one blood sample can be collected from the umbilical cord at delivery, utilising the minimal criteria described in this study results in a 31% increase in the number of neonates with valid blood gas data to aid clinicians in management of neonates born in poor condition. 206 P a g e

229 CHAPTER SIX THE IMPACT OF INTRODUCING UNIVERSAL UMBILICAL CORD BLOOD GAS ANALYSIS AND LACTATE MEASUREMENT AT DELIVERY 6.1 Introduction There is increasing support amongst academic organisations and professional colleges for performing UCBGA at delivery. 24,49,841,912,1250 The information provided by umbilical cord blood gas values is integral to the identification and classification of perinatal hypoxicischaemic insults. 24,203 Further, there is a growing body of data demonstrating the medicolegal, financial, neonatal and educational benefits of UCBGA performed on all deliveries. 47,211,1187,1635 The introduction of universal UCBGA into a tertiary level maternity unit with 19,426 deliveries over a four year period resulted in a progressive improvement in mean arterial ph, po 2, pco 2, base excess and lactate values (p<0.05). 47 Moreover, there was a 16% reduction in the number of neonates with arterial ph values <7.00, 27% reduction in arterial ph <5 th centile (ph=7.12), 25% reduction in arterial base excess <5 th centile (base excess <-9.3 mmol/l) and 60% reduction in arterial lactate levels >95 th centile (6.7 mmol/l) following universal UCBGA. These significant reductions in the proportions of individuals with metabolic acidosis remained significant after accounting for case complexity and demographic factors. The authors postulated that these improvements might be secondary to education and improvements in clinical practice resulting from biochemical biofeedback provided by objective markers of neonatal status; cord blood gas and lactate values. In some perinatal units, cord blood gas analysis may not be a feasible option, primarily due to the expense of equipment and small numbers of deliveries. In these units, umbilical cord blood lactate analysis has been proposed as an alternative that can be performed for a fraction of the cost. 29,1588 Significant correlations have been demonstrated between umbilical artery lactate values and a range of markers of neonatal status including Apgar scores, umbilical artery ph values, and umbilical artery base excess values. 27,69,690,1243,1626 Further, umbilical artery lactate values have been shown to be equivalent to arterial blood gas values in 207 P a g e

230 the prediction of a variety of adverse clinical and neonatal outcomes (Chapter Four). 29,1626,1661 A recent large cohort study demonstrated that combining umbilical artery lactate and neonatal resuscitation level produces the most effective predictor of moderate-severe hypoxic ischaemic encephalopathy, with a sensitivity of 85% and a specificity of 99% (Chapter Four) Despite the evidence demonstrating the value of universal UCBGA, there remains some reluctance towards implementation in obstetric units. The aim of this study was to evaluate whether the improvements in neonatal outcomes seen following introduction of universal UCBGA into a tertiary obstetric unit could be reproduced in primary and secondary level perinatal units in metropolitan and regional Western Australia. Further, this study provides the first evaluation of the introduction of a universal umbilical cord lactate analysis program into maternity units. 208 P a g e

231 6.2 Methods A prospective observational study was conducted at three obstetric units in Western Australia: one regional primary unit, one regional secondary unit and one metropolitan secondary unit. The Women s and Children s Health Service Research Ethics Committee, and the West Australian Country Health Board Research Ethics Committee granted approval for the study. All neonates delivered from 24 weeks gestational age were included, apart from fetal deaths in utero diagnosed prior to labour. Detailed information on all deliveries was recorded in institutional electronic databases, or in written birth registers at each location. Maternal, obstetric and neonatal characteristics available for use in analysis included maternal age, parity, mode of delivery, gestational age, labour induction and augmentation, maternal anaesthesia and analgesia, plurality, gestational age and neonatal birth weight. Paired umbilical arterial and venous blood samples were collected at all deliveries for blood gas or lactate analysis. Immediately after delivery, with the placenta in-situ and ideally prior to the neonate s first breath, an umbilical cord segment was isolated utilising cord clamps. Arterial and venous samples were collected using one-millilitre pre-heparinised plastic syringes and 21-gauge needles. Analysis was performed five to ten minutes after collection of samples. In the centres undertaking lactate analysis (primary and regional secondary units), umbilical lactate was measured using a Roche Accusport TM hand-held lactate meter (Boehringer Mannheim, Germany). In the centre undertaking full blood gas analyses (metropolitan secondary unit), measurement was performed on paired arterial and venous samples using a GEM Premier 3000 TM (Abacus ALS, Australia) analyser located in the Labour and Delivery Ward. The blood gas analyser was calibrated daily by hospital technical staff members while the lactate meters were calibrated with every 20 samples. The midwifery staff, usually those who collected the samples, undertook all analyses. All staff members were required to meet minimum competency standards in sampling and measurement techniques. Paired cord blood gas samples were evaluated for accuracy using the KEMH model to exclude results with a high likelihood of sampling error (Chapter Five), 1662 with all comparisons of blood gas data performed on paired samples validated with the KEMH criteria. For the centres in which umbilical lactate analysis occurred, no equivalent algorithm for minimum arteriovenous lactate differences exists. As a consequence all comparisons of 209 P a g e

232 lactate data were performed on the cohort of neonates that had both umbilical arterial and venous lactate values reported. To identify neonates at greatest risk of morbidity and mortality arising from metabolic acidosis, established pre-defined thresholds of umbilical artery blood gases and lactate values were utilised (ph < 7 0; ph < 7.1; BE < -12mmol/L; lactate > 6 1mmol/L; lactate > 6 7mmol/L). 28,47,210, Statistical analysis Categorical obstetric and neonatal characteristics were summarised using frequency distributions while continuous data was summarised with means and SDs. Univariate comparisons over the study period were conducted using Chi-square tests for categorical data and analysis of variance for continuous data. Logistic regression (presented as odds ratios [OR] and 95% confidence intervals [95%CI]) assessed the likelihood of cord arterial blood gas and lactate values falling outside pre-defined thresholds. Maternal, obstetric, and neonatal characteristics were considered as candidate outcome predictors as well as the time point within the study period that the neonate was delivered. Cord blood gas and lactate values were compared across the study period using multivariable linear regression, with adjusted means and their standard error of mean being estimated. The study period was divided into four epochs of six months for units A and C, and three epochs of six months for unit B that was only followed for 18 months. This approach to analysis was undertaken to minimise the effect of inter-month variations. All hypothesis tests were two-sided with p- values less than 0 05 considered statistically significant. SPSS statistical software was utilised for analysis (SPSS Inc., Version 15.0, Chicago, IL). 210 P a g e

233 6.3 Results Lactate measurement on umbilical arterial and venous blood was introduced into two maternity units, a regional primary obstetric centre (Unit A) and a regional secondary obstetric centre (Unit B). Unit A had 1,073 deliveries between December 2009 and February 2011 and Unit B had 1,891 deliveries over a period spaning between July 2009 and September At the secondary metropolitan obstetric unit (Unit C) universal UCBGA was undertaken on 3,340 deliveries between July 2009 and June During the study period there were two fetal deaths identified prior to labour at Unit A, five at Unit B and 14 at Unit C. Analysis of demographic, intrapartum and obstetric data revealed no significant change within each maternity unit in these covariates over the study period (Table 6.1.) Umbilical cord blood lactate analysis At the centres where umbilical cord blood lactate analysis was conducted, the regional primary level one obstetric centre (Unit A) had at least one value in 62.0% (n=811) of the population; the regional level two obstetric unit (Unit B) had at least one lactate value for 83.6% (n=1,394) of the population. Both arterial and venous lactate values were available for 59.7% (n=782) at Unit A and 78.5% (n=1,310) at Unit B. Over the duration of this study, there was variation in the proportion of neonates with lactate values in zero, one or two umbilical vessels at both Unit A and Unit B; the variation was around a point rather than a pattern of increase or decrease. At the regional primary obstetric centre (Unit A) there were no significant changes in the mean arterial lactate values over the three time epochs evaluated in univariate and multivariate analyses (Table 6.2). Significant variation in the mean umbilical venous lactate values occurred over the time epochs in both univariate and multivariate analyses (p=0.006 and p=0.001, respectively), although there was no pattern of overall increase or decrease. In the regional primary obstetric unit, there was a significant reduction in arterial lactates levels greater than the 95 th percentile (>6.1mmol/L, 16.3%-7.8%: OR=0.394, 95%CI= , p=0.005) and 99 th percentile (>6.7mmol/L, 8.5%-2.8%: OR=0.304, 95%CI= , p=0.019) (Figure 1.). These changes became apparent within the first twelve months of testing (Epoch One vs. Epoch Two). These differences persisted after adjustment for multiple maternal, obstetric and intrapartum covariates. (Table 6.3). 211 P a g e

234 Table 6.1. Demographic and intrapartum characteristics at cord blood gas analysis sites One Two Three Four P-Value Unit A (Primary Regional Obstetric Unit) Maternal Age < (6.7) 22 (5.1) 30 (7.0) (91.3) 395 (91.6) 390 (90.9) - >39 9 (2.0) 14 (3.2) 9 (2.1) - Nulliparous 173 (38.5) 158 (36.7) 159 (37.1) Term Gestation 437 (97.3) 418 (97.2) 419 (97.7) Birth Weight < (3.1) 9 (2.1) 10 (2.3) (86.4) 379 (87.9) 371 (86.5) - > (10.5) 43 (10.0) 48 (11.2) - Multiple Birth 8 (1.8) 6 (1.4) 0 (0.0) Induction/Augmentation 239 (53.2) 240 (55.7) 242 (56.4) Vaginal Delivery 252 (56.1) 238 (55.5) 237 (55.4) Instrumental Delivery 58 (12.9) 57 (13.3) 54 (12.6) - Caesarean Delivery 139 (31.0) 134 (31.2) 137 (32.0) - Unit B (Secondary Regional Obstetric Unit) Maternal Age < (7.3) 21 (5.0) 28 (7.2) 32 (7.3) (89.6) 385 (92.5) 35 (89.8) 390 (89.0) >39 13 (3.1) 10 (2.4) 12 (3.1) 16 (3.7) Nulliparous 157 (37.2) 161 (38.6) 164 (41.9) 176 (40.2) Term Gestation 407 (96.4) 393 (94.2) 366 (93.6) 416 (95.0) Birth Weight < (3.6) 17 (4.1) 16 (4.1) 10 (2.3) (83.4) 343 (82.3) 325 (83.1) 376 (85.8) > (13.0) 57 (13.7) 50 (12.8) 52 (11.9) Multiple Birth 8 (1.9) 6 (1.4) 10 (2.6) 8 (1.8) Induction/Augmentation 180 (42.7) 170 (40.8) 180 (46.0) 197 (45.0) Vaginal Delivery 222 (52.6) 241 (57.8) 215 (55.0) 233 (53.2) Instrumental Delivery 56 (13.3) 55 (13.2) 42 (10.7) 62 (14.2) Caesarean Delivery 1473 (34.0) 121 (29.0) 134 (34.3) 143 (32.6) Unit C (Secondary Metropolitan Obstetric Unit) Maternal Age < 20 years < (5.0) 26 (3.3) 24 (3.1) 37 (3.9) (92.8) 745 (93.6) 728 (94.5) 901 (93.8) >39 17 (2.1) 25 (3.1) 18 (2.3) 23 (2.4) Nulliparous 362 (45.7) 331 (41.7) 363 (47.2) 455 (47.3) Term Gestation 779 (97.1) 773 (96.9) 745 (96.5) 931 (96.7) Birth Weight < 2500g < (2.9) 10 (1.3) 19 (2.5) 24 (2.5) (85.9) 692 (86.9) 679 (88.2) 825 (85.8) > (11.2) 94 (11.8) 72 (9.4) 112 (11.7) Multiple Birth 8 (1.0) 12 (1.5) 4 (0.5) 12 (1.2) Induction/Augmentation 393 (49.0) 414 (51.9) 391 (50.6) 483 (50.2) Vaginal Delivery 442 (55.9) 457 (57.6) 446 (57.9) 560 (58.3) Instrumental Delivery 123 (15.5) 103 (13.0) 101 (13.1) 142 (14.8) Caesarean Delivery 226 (28.6) 234 (29.5) 223 (29.0) 259 (27.0) 212 P a g e

235 Table 6.2. Unadjusted and adjusted mean umbilical artery blood gas and lactate values Unadjusted Means (SD) Adjusted Means (SEM) One Two Three Four P-Value One Two Three Four P-Value Lactate Lactate ph 4.52 (1.51) 3.89 (1.50) (0.079) po (7.42) pco 2 (10.11) HCO 3 Base Excess Lactate (2.75) (3.53) 4.77 (2.00) 4.28 (1.30) 4.04 (1.41) (0.080) (8.30) (10.13) (3.14) (3.71) 4.94 (2.05) 4.47 (1.32) 3.82 (1.36) (0.079) (7.62) (10.57) (3.15) (3.62) 5.05 (2.70) Unit A (Regional Primary Obstetric Unit) (0.08) Unit B (Regional Secondary Obstetric Unit) 4.45 (1.50) < (0.09) Unit C (Metropolitian Secondary Obstetric Unit) (0.074) (7.27) (9.64) (2.97) (3.70) 4.83 (2.03) (0.003) (0.34) (0.44) (0.13) (0.15) 4.88 (0.09) 4.28 (0.07) 4.34 (0.09) (0.003) (0.34) (0.44) (0.13) (0.15) 4.86 (0.09) 4.46 (0.10) 4.16 (0.09) (0.003) (0.35) (0.46) (0.13) (0.16) 5.03 (0.10) (0.09) (0.003) (0.31) (0.41) (0.12) (0.14) 4.82 (0.08) <

236 Table 6.3. Unadjusted and adjusted logistic regression of umbilical artery biochemical outcomes following introduction of universal umbilical cord blood gas or lactate analysis. Unadjusted Logistic Regression, OR (95%CI) Adjusted Logistic Regression, OR (95%CI) Time Epoch One vs. Two One vs. Three One vs. Four One vs. Two One vs. Three One vs. Four Unit A (Regional Primary Obstetric Unit) Lactate > 6.1mmol/L (0.346, 0.904) (0.229, 0.821) (0.316, 0.852) (0.205, 0.759) Lactate > 6.7mmol/L (0.279, 1.032) (0.114, 0.825) (0.272, 1.024) (0.112, 0.823) Unit B (Regional Secondary Obstetric Unit) Lactate > 6.1mmol/L (0.569, 1.842) Lactate > 6.7mmol/L (0.388, 1.921) ph < (0.491, 1.303) BE <-12mmol/L (0.441, 3.007) Note: p-value < (0.547, 1.836) (1.010, 2.985) (0.608, 2.312) (0.345, 1.850) (1.052, 4.132) (0.410, 2.360) Unit C (Metropolitian Secondary Obstetric Unit) (0.550, 1.450) (0.491, 1.254) (0.426, 1.165) (0.283, 2.382) (0.271, 2.090) (0.368, 2.636) (0.498, 2.079) (0.319, (0.540, 1.458) (0.245, 2.163) (0.971, 3.471) (0.978, 4.657) (0.455, 1.201) (0.236, 1.898)

237 Percentage % Percentage % Percentage % Figure 6.1. Change in proportion of neonates with umbilical artery ph, base excess and lactate values outside the normal range. 20 Unit A Regional Primary Obstetric Centre Arterial Lactate > 6.1 Arterial Lactate > Epoch Unit B Regional Secondary Obstetric Centre Arterial Lactate > 6.1 Arterial Lactate > Epoch Unit C Metropolitan Secondary Obstetric Unit Arterial ph < 7.1 Arterial Base Excess < -12 mmol/l Epoch 215 P a g e

238 For Unit B, the regional level two obstetric centre, significant variation was noted in the average arterial and venous lactate values in both univariate and multivariate analysis (all p<0.001) (Table 6.2.): the variation was around a point rather than a pattern of increase or decrease. Across the study period there was significant variation in the proportion of neonates with an arterial lactate value greater than 6.7 mmol/l. Unadjusted logistic regression analysis noted a significant increase in the proportion of neonates with arterial lactate values greater than 6.1 mmol/l and 6.7 mmol/l when comparing epoch one with epoch four (Table 6.3.). After adjusting for demographic, obstetric and intrapartum covariates the changes were no longer statistically significant (Table 6.3.) Umbilical cord blood gas analysis At the metropolitan secondary level obstetric unit (Unit C), 84.5% (n=2,812) of the neonates had at least one cord blood gas result recorded, with 73.6% (n=2,451) having a set of results for both the umbilical artery and umbilical vein. Over the two years of evaluation, there was no significant difference in the proportion of neonates with paired validated umbilical cord blood gas values (p=0.429). Univariate comparison of mean umbilical cord blood gas values revealed significant variation in arterial po 2 (p=0.006) values around a point with no pattern of increase or decrease over the two-year study period. These changes remained significant after adjusting for maternal, neonatal and obstetric covariates. In the metropolitan secondary obstetric centre, there was a 21% reduction in arterial ph<7.10 (7.3% to 5.8%) which did not reach statistical significance. Similarly, univariate and multivariate logistic regression revealed no significant reduction in the proportion of neonates with measures of acidosis outside the predefined thresholds when the first time epoch was compared with each of the subsequent three (Table 6.3.) One, five and ten minute Apgar scores Evaluation of the one and five minute Apgar scores at Unit B over the study period revealed no significant variation in the proportion of neonates with Apgar scores less than four or less than seven. Unadjusted and adjusted logistic regression noted no significant differences between the first and any of the following time periods. At Unit C there were no significant changes in one, five or ten minute Apgar scores over the study period in univariate and multivariate logistic regression. No Apgar scores were available for analysis at Unit A. 216 P a g e

239 6.4 Discussion This study represents the first evaluation of the impact of introducing cord blood gas analyses into primary and secondary obstetric units in metropolitan and regional centres. The data presented demonstrate a 61% reduction in arterial lactate levels greater than the population based 95 th percentile and a 69% reduction in arterial lactate levels greater than the 99 th percentile. The introduction of universal UCBGA into a secondary level metropolitan maternity unit was associated with a clinically significant decrease in acidaemia, although it did not reach statistical significance. The reduction in the rate of metabolic acidaemia in the primary obstetric centre is of similar magnitude to that seen when UCBGA was introduced into a tertiary obstetric centre with more than 6000 deliveries per year. 47 In the larger study there was also a significant reduction in the number of admissions of term babies to the special care nursery. This study did not have adequate power to assess nursery admission in any of the three centres evaluated. The similar pattern and magnitude of change suggest that it is possible that the mechanism responsible for this improvement may be similar at both sites. The primary mechanism postulated for the reduction in moderate and severe metabolic acidaemia and nursery admission noted in the previous study was biochemical biofeedback. 47 It has been postulated that the additional biochemical information afforded by UCBGA provides an objective feedback mechanism in relation to intrapartum management practices. This in turn can reinforce behaviour associated with favourable fetal outcomes while potentially identifying and modifying suboptimal behaviour associated with adverse outcomes and nursery admissions. Consequently, UCBGA appears to have advantages outside the diagnostic and medico-legal field and the use of universal cord blood gas analysis could be considered in all maternity units. This hypothesis was supported by the observation that, as time progressed after the introduction of universal cord blood gas analyses, the use of tools to assess fetal condition (such as fetal scalp stimulation and scalp ph sampling) occurred in more timely manner. This subsequently resulted in the delivery of babies in better condition without and an increase in the rate of instrumental deliveries or caesarean section. Further studies are required to more carefully evaluate the potential mechanisms for the improvements seen in this study and that of White et al. Taking the findings of this study together with the previous evaluation of the introduction of universal UCBGA into a tertiary level maternity unit suggests that there is a reasonable body 217 P a g e

240 of evidence to support the introduction of universal UCBGA into all maternity units. For this to occur, universal UCBGA would need to be simple, quick, supported by the clinical staff and have demonstrated cost-benefit. Collecting blood for UCBGA is technically simple, takes several minutes to perform, and can be easily taught to staff. In this study the education package required for implementation, ongoing education and quality assurance required one senior registered midwife employed for eight hours a week. The timelines for processing of umbilical cord blood gas samples is relatively robust and should not interfere with clinical care. A recent randomised controlled trial demonstrated that cord blood gas values can remain stable for up to 60 minutes even if the segment of cord is clamped at both ends and left on the delivery tray by the bedside (Chapter Three) Cord lactate samples require analyses within 15 minutes to prevent statistically significant changes in values; this is however easily achievable with the availability of inexpensive point of care meters that can be kept at the bedside (Chapter Three) While lactate values are more likely to be influenced by delays in analysis, they are associated with a considerably smaller initial cost outlay than UCBGA, 1588 suggesting that lactate analysis may be a valid and cheaper alternative to UCBGA in primary level units where access to a blood gas analyser is not easily achievable. When this study was performed an evaluation of staff attitudes and barriers to the introduction of umbilical cord blood gas and lactate analysis at birth was performed simultaneously (Chapter Eight). This study demonstrated that, despite popular belief, most respondents considered UCBGA beneficial to perinatal care, with only 8% of staff believing UCBGA had no place in perinatal care. The information derived from this study may be useful in identifying and resolving concerns prior to the introduction of UCBGA. Further, it could be useful in the preparation of education and implementation packages necessary for introduction of UCBGA. A recent, cost-benefit analysis of the introduction of universal UCBGA into a tertiary unit in Australia demonstrated that, despite the significant initial and ongoing costs, the potential averted costs (due to reduced term SCN admissions) exceed the incurred costs utilising wide, clinically possible variations in parameter values for neonatal SCN admissions, magnitude of averted SCN admissions, cumulative number of deliveries and costs of SCN admissions (Chapter Seven). This benefit occurred without taking into consideration the potential averted costs in terms of deflecting or ameliorating medicolegal actions that have previously been shown to easily absorb the incurred costs associated with a universal UCBGA 218 P a g e

241 program. 1188,1635 Further cost benefit analyses are required for smaller primary and secondary units; however at a state level the existing data suggests strong economic benefit from universal UCBGA. This study has a number of limitations including its limited sample size and the short duration of evaluation after implementation of universal UCBGA. Larger sample sizes would be required to assess infrequent adverse obstetric and neonatal outcomes and to assess cost-benefit in terms of reducing the number of neonatal transfers to tertiary units. Only one study to date, to our knowledge, has follow obstetric and neonatal outcomes for a prolonged period of time after implementation of universal UCBGA. 47 This study monitored outcomes for four years after implementation and demonstrated sustained neonatal benefits. Longer follow-up studies in primary and secondary obstetric centres will be required to evaluate if the benefits of UCBGA are sustained. 219 P a g e

242 6.5 Conclusion The data presented in this study suggest that the benefits previously described of introducing UCBGA into a tertiary obstetric centre can be reproduced in a primary obstetric centre within 12 months of implementation. Larger studies are required in secondary units to assess infrequent adverse obstetric and neonatal outcomes. 220 P a g e

243 CHAPTER SEVEN UNIVERSAL UMBILICAL CORD BLOOD ANALYSIS: IS IT WORTH THE HASSLE? 7.1 Background Metabolic acidosis in arterial umbilical cord blood is considered an essential criterion for the diagnosis of birth asphyxia. 203,1664 Based on current evidence, umbilical cord arterial ph at delivery provides one of the most sensitive reflections of birth asphyxia with the absence of acidaemia effectively excluding birth asphyxia as a potential diagnosis. 203,1664 Additionally, authors suggest that universal blood gas analysis of umbilical cord blood samples at all deliveries can have significant medicolegal and educational benefits. 211,1187,1635 Furthermore, a recent meta-analysis noted that there was a significant, consistent, and temporal relationship between umbilical artery acidaemia and a variety of adverse neonatal outcomes We have shown that the transition from selective to universal UCBGA at the time of delivery was associated with a reduction in the incidence of umbilical artery acidaemia and improvements in perinatal outcomes, independent of obstetric intervention. 47 We postulated that the additional biochemical information provided by UCBGA provides an objective feedback mechanism in relation to intrapartum management practices. This in turn can reinforce behaviour associated with favourable fetal outcomes while potentially identifying and modifying suboptimal behaviour associated with adverse outcomes and nursery admissions. Consequently, UCBGA appears to have advantages outside the diagnostic and medico-legal field and the use of universal cord blood gas analysis could be considered in all maternity units. To date no comprehensive cost-effectiveness evaluation of UCBGA has been undertaken; however, several ad-hoc analyses of the potential cost-effectiveness of universal blood gas analysis have been performed ,1631,1635 These analyses have for the most part hypothesised that the potential averted costs in terms of deflecting or ameliorating medicolegal actions would easily absorb the incurred costs associated with a universal UCBGA program. 1188,1635 Additionally, some authors have postulated that universal sampling would, via economies of scale, result in a cheaper per unit cost than a selective program In contrast, there have been a number of professional organisations that have suggested that 221 P a g e

244 universal UCBGA is not a cost-effective proposition despite the lack of any studies that support this opinion. 49,189 Given the significant improvement in perinatal outcomes and associated reduction in neonatal admissions with universal UCBGA, this study aims to conduct the first in-depth cost-effective analysis to compare these benefits against the increased costs of implementing universal cord blood gas and lactate analysis. 222 P a g e

245 7.2 Methods Study Design Two UCBGA strategies, selective and universal, were considered for comparison of differences in costs incurred and proportion of term neonates (greater than 2499 grams) admitted to the SCN. Universal UCBGA was introduced in 2003 and remains standard practice at King Edward Memorial Hospital (KEMH) Western Australia (WA). Prior to 2003, selective UCBGA was standard of care at KEMH. Selective UCBGA was undertaken at the attending clinician s prerogative; however, for the purposes of this study, it was assumed that all neonates that would be subsequently admitted to the neonatal intensive care unit (NICU) would have had UCBGA performed. The improved health outcomes and declining nursery admission rates following the introduction of universal UCBGA in this study population between 2003 and 2006 has previously been published. 47 In this study, data collection and analyses have been extended from 2003 to 2009 to establish whether the previously described health benefits continued. Cost-effectiveness analysis was limited to admissions of term neonates (with birth weights greater than 2499 grams) to the SCN as these babies were the most likely to benefit from the availability of biochemical data provided by UCBGA. Admissions to the NICU were excluded from analyses, as these are more likely to be due to conditions such as prematurity and intra-uterine growth restriction that are unlikely to be affected by provision of cord blood gas results. Costs were evaluated from the state government perspective. Summary statistics and comparisons of pregnancy outcomes including SCN admissions between the time epochs (2002, , ) using multivariable logistic regression analysis was performed using SPSS statistical software (version 18 Chicago: SPSS Inc., Chicago, IL). The effects of time epoch were summarised using odds ratios (OR) and their 95% confidence intervals (CI). Modelling and cost-effectiveness analysis was performed using TreeAge Pro for Healthcare (2009 Edition. Williamstown, MA: TreeAge Software Inc) Study Population The analysis was based on the population presenting at KEMH, the sole tertiary level maternity unit for WA. Between the 1st of January 2002 and 31st of December 2009, 223 P a g e

246 inclusive, 42,857 neonates were delivered at 23 weeks gestation or greater. Out of the total population there were 757 neonates that were excluded from analysis based on therapeutic terminations of pregnancy, or fetal deaths in utero that were diagnosed prior to the onset of labour. Detailed maternal, obstetric, intrapartum, and neonatal information for all deliveries were extracted from the institutional electronic database (Table 7.1.). Across the study period there was an increase in maternal age, as well as significant change in the proportion of nulliparous mothers. There was an increase in the proportion and number of neonates delivered operatively, with a corresponding decline in vaginal deliveries (p<0 001). Further, there was significant variation in the gestational age, birth weight, and five-minute Apgar scores. There was a significant decrease in the proportion of neonates exposed to gestational hypertension, and a significant increase in those exposed to preeclampsia/eclampsia and gestational diabetes. Comparison of the period with the 2002 period revealed a number of significant differences in maternal age, parity, plurality, gestation, mode of delivery, birth weight, preterm birth weight, gestational hypertension, and SCN admissions. Comparing the cohort with the cohort revealed significant differences in maternal age, parity, plurality, gestation, mode of delivery, gestational hypertension, preeclampsia/eclampsia, gestational diabetes, five-minute Apgar scores and SCN admissions between the two cohorts. Over the study period there were significant changes in all categories of neonatal nursery admission (Table 7.2.). Univariate logistic regression indicated a significant reduction in term SCN admission of neonates greater than 2499 grams between 2002 and (OR 0.76; 95%CI 0.67, 0.85; p<0.001) as well as between 2002 and (OR 0.59; 95%CI 0.52, 0.66; p<0.001). After adjusting for obstetric and demographic covariates as well as intrapartum management over the study period, the reduction in SCN admissions remained significant between 2002 and (OR 0.74; 95%CI 0.63, 0.86; p<0.001) as well as between 2002 and (OR 0.58; 95%CI 0.49, 0.68; p<0.001). In comparison to the epoch, significantly more term neonates greater than 2499 grams were admitted to the SCN in 2002 (OR 1.33; 95%CI 1.18, 1.49; p<0.001). Conversely, significantly less term neonates greater than 2499 grams were admitted to the SCN in the epoch (OR 0.78; 95%CI 0.72, 0.84; p<0.001). Multivariable logistic regression analysis established the same pattern persisted after adjusting for obstetric, demographic and intrapartum factors with significantly more term neonates greater than 2499 grams admitted 224 P a g e

247 in 2002 (OR 1.36; 95%CI 1.17, 1.58; p<0.001) and significantly less in the period (OR 0.78; 95%CI 0.70, 0.88; p<0.001) in contrast to the period. The rate of SCN admissions of neonates greater than 2499 grams in 2002 before the introduction of universal UCBGA was at 9.3%. The SCN admission rate gradually declined following the introduction of universal UCBGA, and after the initial four years ( ) the rates of admission appeared constant at approximately 5.5% of all neonates. Four years after the introduction of universal UCBGA at KEMH, SCN admissions rates were constant; hence this study focuses on the first four years after its introduction. Further, the postulated mechanism for the improvement in cord blood gas results (biochemical biofeedback), 47 is likely to take a number of years to produce a significant change. Consequently, the viability of UCBGA program is linked with a reasonable time horizon to institute change - if the cost-effectiveness is unachievable within four years, UCBGA can be regarded as beyond feasibility Model structure A decision tree model was used to analyse the cost-effectiveness of universal UCBGA compared to selective UCBGA strategy (Figure 7.1.). The population of neonates was divided into term neonates with BW >2499 grams requiring SCN admission and all other neonates. The rates of SCN admission under each strategy were modelled as a cumulative probability over the study years, starting with year one alone. The total expected cost under each strategy over a given time period was calculated as the sum of weighted expected values for each individual year, allowing us to estimate the number of years required for universal UCBGA to be cost-effective. 225 P a g e

248 Table 7.1. Change in demographic, intrapartum, and neonatal characteristics over the study period Characteristic P-Value Maternal Age (yrs) 28 (6) * 29 (6) 29 (6) * <0.001 Nulliparous 1,801 (41.5%) * 8,545 (43.6%) 7,677 (42.3%) * Singleton Delivery 4,048 (93.3%) * 18,097 (92.3%) 16,867 (93.0%) * Gestation Preterm 929 (21.4%) * 4,531 (23.1%) 3,995 (22.0%) * Term 3,377 (77.9%) * 14,855 (75.7%) 13,978 (77.0%) * Post term 31 (0.7%) * 231 (1.2%) 173 (1.0%) * Mode of Delivery Vaginal 2,606 (60.1%) * 11,305 (57.6%) 9,522 (52.5%) * Instrumental 432 (10.0%) * 2,109 (10.8%) 2,231 (12.3%) * <0.001 Caesarean 1,299 (30.0%) * 6,203 (31.6%) 6,393 (35.2%) * Birth Weight (gms) 3,122 (776) * 3,091 (835) 3,107 (812) Term Birth Weight 3405 (503) 3412 (506) 3406 (503) Preterm Birth 2071 (691) * 2004 (789) 2035 (786) Weight Gestational Hypertension 263 (6.1%) * 735 (3.7%) 423 (2.3%) * <0.001 Pre-Eclampsia/Eclampsia 205 (4.7%) 1,003 (5.1%) 1,047 (5.8%) * Pre-Existing Maternal Diabetes 82 (1.9%) 341 (1.7%) 355 (2.0%) Gestational Diabetes 234 (5.4%) 1,208 (6.2%) 1,444 (8.0%) * <0.001 Intrauterine Growth Restriction 243 (5.6%) 1,069 (5.4%) 1,064 (5.9%) Five Minute Apgar Score (0.8%) 178 (0.9%) 90 (0.5%) * (1.5%) 338 (1.7%) 454 (2.5%) * < ,230 (97.8%) 18,949 (97.3%) 17,445 (97.0%) * SCN Admissions SCN 893 (20.6%) * 3,498 (17.8%) 2,597 (14.3%) * <0.001 Term SCN 437 (10.1%) * 1552 (7.9%) 1,159 (6.4%) * <0.001 Term SCN > (9.3%) * 1404 (7.2%) 1,025 (5.6) * <0.001 gm Note: Mean (Standard Deviation); Chi-squared (categorical) and one-way ANOVA (continuous) analysis of change over three time periods; and, * Significant difference to period in Chi-squared (categorical) or one-way ANOVA (continuous) analysis 226 P a g e

249 Table 7.2. Change in neonatal nursery and intensive care unit admissions over the study period stratified by gestation and birth weight 2002 n=4, n=4, n=4, n=4, n=5, n=6, n=6, n=5,765 Overall 1,271 1,198 1,426 1,319 1,356 1,502 1,550 1,433 (29.3%) (26.7%) (31.3%) (26.6%) (24.1%) (24.2%) (25.1%) (24.9%) SCN (20.6%) (18.1%) (21.5%) (17.4%) (15.1%) (15.1%) (14.2%) (13.5%) NICU (8.7%) (8.6%) (9.9%) (9.2%) (9.0%) (9.1%) (10.8%) (11.3%) Term Overall (11.2%) (9.5%) (11.6%) (8.8%) (6.6%) (7.6%) (8.3%) (7.9%) Term SCN (10.1%) (8.4%) (10.3%) (7.7%) (5.7%) (6.4%) (6.5%) (6.2%) Term NICU (1.1%) (1.1%) (1.3%) (1.1%) (0.9%) (1.6%) (1.8%) (1.6%) Term Overall gm (10.2%) (8.7%) (10.6%) (8.0%) (5.9%) (6.6%) (7.5%) (6.9%) Term SCN gm (9.3%) (7.7%) (9.4%) (6.9%) (5.1%) (5.6%) (5.8%) (5.5%) Term NICU gm (1.0%) (1.0%) (1.2%) (1.1%) (0.8%) (1.0%) (1.7%) (1.4%) P-Value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

250 Figure 7.1. Decision tree model for neonatal nursery admissions with and without universal umbilical cord blood gas analysis. Note: Costs of UCBGA sampling under selective strategy were included for NICU neonates only, in the All other neonates branch; SCN = Special Care Nursery; pscn_1,2,3,4 = probability of admission to SCN under selective UCBGA; and, RR = relative risk of SCN admission compared to the admission under selective UCBGA 228 P a g e

251 7.2.4 Probabilities The proportion of neonates admitted to the SCN under the selective strategy was based on that realised in the pre-universal UCBGA study year (2002: 9.3%) and was held constant in each year of the study period. The gradual decline in the rate of the SCN admissions after introduction of the universal UCBGA strategy, associated with the underlying effects of biochemical reinforcement and improved clinical management of semi-well neonates with normal UCBGA was estimated using a polynomial smoothing function over seven years (y = x x x x ; R 2 =0.78, Figure 7.2.) to model the true probabilities of SCN admission. These underlying estimated SCN rates were used to derive the relative risk of admission relative to the constant rate of 9.3% under selective UCBGA strategy (e.g. 8.9%/9.3% = 0.96 in year one) and standard error was based on the observed number of neonates each year (Table 7.3.). Table 7.3. Observed and modelled (first four years) number and proportion of all neonates admitted to the NICU and term neonates with birth weight greater 2499 grams admitted to the SCN under the universal UCBGA strategy. Observed Modelled All NICU SCN Year SCN Rate (99% CI) RR (99% CI) N N (%) N (%) 1 4, (8.6) 345 (7.7) 8.9% (7.8%, 10.0%) ( ) 2 4, (9.9) 427 (9.4) 8.0% (7.0%, 9.0%) ( ) 3 4, (9.2) 343 (6.9) 6.9% (6.0%, 7.8%) ( ) 4 5, (9.0) 289 (5.1) 6.0% (5.2%, 6.8%) ( ) 4+1 6, (9.1) 348 (5.6) 5.5% (4.7%, 6.2%) ( ) 4+2 6, (10.8) 361 (5.8) 5.4% (4.7%, 6.2%) ( ) 4+3 5, (11.3) 316 (5.5) 5.4% (4.7%, 6.2%) ( ) Note: SCN admission under universal strategy compared to SCN under selective strategy (9.3%); Modelled relative risks (RR) in each year were obtained relative to the fixed rate of SCN admission of 9.3% under selective UCBGA strategy (e.g. year 1, 8.9%/9.3% = 0.96) and standard error was based on the observed number of neonates each year. Confidence intervals (CI) were based on the total number of deliveries that occurred in each year. The NICU admissions for both UCBGA strategies were based on the admissions observed under universal UCBGA and were modelled directly from the data with the rates of 8.6%, 9.9%, 9.2%, and 9.0% observed in years one, two, three and four, respectively (Table 7.3.). The number of neonates born during each individual year, with the appropriate weighting of expected values for each individual year, was modelled using the observed data including 4,487, 4,550, 4,959 and 5,621 neonates in years one, two, three and four, respectively. 229 P a g e

252 Figure 7.2. Modelled proportions of SCN admissions under selective and universal CBGA strategies (with 99% confidence interval) Costs and utilities Current costs were calculated in 2009 Australian dollars (AU$) and used for all retrospective years; therefore, it was not necessary to include any discounting or inflationary measures. Incurred costs are detailed for selective and universal UCBGA (Table 7.4.). A Bayer Chiron Diagnostics Model 840 Blood Gas Analyser (Bayer Diagnostics, Germany) was used in both strategies. Cord blood was collected using 1-mL preheparinised plastic syringes (Rapidlyte ; Bayer Corporation, East Walpole, MA, USA) and 21-gauge needles. Three plastic cord clamps were used to isolate cord segments into two sections for sample collection. Sampling and analysing each neonate s cord blood took approximately 15 minutes. For costing purposes, the individual conducting UCBGA was considered to be an Australian Nursing Federation level 2.4 registered midwife (including on-costs). To provide initial and ongoing education an Australian Nursing Federation level 2.4 registered midwife was employed for eight hours a week whilst a consultant obstetrician was employed for an hour a week. Education occurred within allocated staff development time so no costs were associated with staff members receiving education. Fixed staff member training costs were considered to be equivalent for the universal and selective strategies. The cost of each neonatal admission was derived from Australian Refined-Diagnosis Related Groups (AR-DRG) Version 5.2, which are used to broadly categorise the level and type of care provided to an individual Australian Refined-Diagnosis Related Groups are 230 P a g e

253 indicative of the mean cost per event, in this case neonatal nursery admission, across a number of areas including medical clinical services, nursing clinical services, non-clinical salaries, pathology, imaging, allied health, pharmacy, critical care units, operating theatres, emergency departments, supplies, on costs, hotel and depreciation In a tertiary level maternity and neonatal unit it is potentially inappropriate to ascribe the P67D costing to a nursery admission, particularly when considering that KEMH is the sole WA tertiary level maternity unit, thus most neonates admitted have major medical issues or undergoing significant medical procedures. Correspondingly, it would also be potentially inappropriate to use the P06A and P06B costing for averted costs as these costs reflect neonates requiring significant levels of continuous ventilator support for prolonged periods (greater than 96 hours) Further, the lack of local data for the P06A and P06B costings provides additional support for other costings to be utilised. For this study the costs of an average admission to the neonatal nursery at KEMH was derived from the locally adjusted data (WA data) in the National Hospital Cost Data Collection Cost Round 13 Report, with a conservative cost for a single SCN admission at AU$2,558 (AR-DRG Version 5.2 P67D) Health outcomes Cost-effectiveness studies generally report quality adjusted life years (QALYs) as the primary health outcome. This measure was not appropriate for this study as no equivalent QALYs have been determined for admission of a term neonate with birth weights greater than 2499 grams to the SCN. Consequently, our primary study outcome was the proportion of neonates that did not require SCN admission. The difference between the rate of SCN admission under selective and universal policy was considered to be the rate of averted admissions. The time horizon for each individual neonate was confined to the time from delivery to discharge thus no discounting was required as no neonate s length of stay approached a year, and the majority of nursery admissions occur within the first 24 hours following delivery. The median length of stay for a term neonate at KEMH with a birth weight greater than 2499 grams was two days with 95% of the admissions being no longer than 12 days Cost-effectiveness analysis The expected additional costs of UCBGA and proportion of neonates requiring SCN admission were analysed cumulatively over the four study years. The cost of universal UCBGA was deducted from the cost of selective UCBGA to represent the incremental cost, 231 P a g e

254 while averted admissions represented the incremental effect. The incremental costeffectiveness ratio (ICER) was calculated by dividing the incremental cost by incremental effect and represents the additional cost of averting a SCN admission. Table 7.4. Base case assumptions of fixed and variable costs Factor Cost Fixed Costs Bayer Chiron Diagnostics Model 840 Blood AU$30,000 per machine Gas Analyser Analyser Servicing and Maintenance AU$15,000 per annum Midwife Education Officer AU$12,480 per annum (AU$30 by 8 hrs per 52 wks) Consultant Education Officer AU$10,400 per annum (AU$200 by 1 hr per 52 wks) Total AU$30,000 + AU$37,880 per annum Variable Costs Blood Gas Analyser Consumables AU$2.90 per sample or AU$5.80 per neonate (2 x sample per neonate) Needle & Syringe AU$3.12 per neonate 1-ml Pre-heparinised Plastic Syringes AU$1.25 per syringe (AU$2.50 per neonate) 21-Gauge Needles AU$0.31 per needle (AU$0.62 per neonate) Plastic Cord Clamps AU$0.73 per clamp (AU$2.19 per neonate) Staff Cost (15 minutes per sample of ANF AU$7.5 per neonate level 2.4 RM including on-costs) AR-DRG Coding Total AU$18.61 per neonate AR-DRG Description * Average Cost per Event P06A Significant problem or procedure and multiple major problems AU$67,655 P06B Significant problem or procedure without multiple major problems AU$22,977 P67A Without significant problem or procedure but with multiple major problems AU$18,574 P67B Without significant problem or procedure but with major problem AU$9,267 P67C Without significant problem or procedure but with other problem AU$4,721 P67D Without significant problem or procedure and without problem AU$2,588 Note: * All codings are for neonates with admission weights greater than 2499 grams; Costing sourced from National Hospital Cost Data Collection Cost Round 13 Report; 1665 and, Costing sourced from West Australian Adjusted National Hospital Cost Data Collection Cost Round 13 Report The ICER is typically compared to a willingness to pay (WTP) threshold value, the maximal cost a decision maker is willing to pay for the additional health benefit. Thus, if the ICER is less than the WTP, the strategy is said to be cost-effective, otherwise the strategy may be too 232 P a g e

255 costly for the gain in health benefit. A guideline WTP of 30,000/QALY (approximately AU$45,000) has been shown to be an acceptable figure in the UK; 1668 however, this may not be a comparable cost for averted SCN admissions (of term neonates with birth weights greater than 2499 grams) thus the conservative cost of SCN admission at AU$2,558 was used as the WTP threshold value. If universal UCBGA becomes less costly, whilst being more effective as previously indicated by the reduction in rates of admissions, then it is said to dominate the selective strategy. This clearly implies that a universal UCBGA program is cost-effective. Alternatively, the universal program may be more costly and less effective, in which case it is said to be an inferior strategy Sensitivity Analysis Two types of sensitivity analyses were performed to assess the uncertainty in model outcomes. Given that the probability of SCN admissions declined over the four years of universal UCBGA, univariate threshold analysis was performed to determine if there was a minimum rate of SCN admission at which universal screening would be the dominant strategy. This threshold value was obtained by varying the probability of SCN admission under selective UCBGA between 3% and 13%, and finding the minimum required reduction in rate of SCN admission under universal UCBGA which would equate to a zero net difference in cost per neonate between the two strategies. Probabilistic sensitivity analysis (PSA) was conducted via Monte Carlo simulation. For a given range in all parameter estimates, PSA allows for the recalculation of incremental costs and effects by sampling new parameter values from probability distributions during each simulation. The uncertainly around the expected cost-effective outcomes is quantified by conducting a large number of simulations and calculating the proportion in which a new strategy is cost-effective compared to the baseline strategy PSA of cost-effectiveness outcomes for selective and universal UCBGA strategies integrated parameters for the rate of SCN admissions under selective UCBGA, the magnitude of reduction in SCN admissions under universal UCBGA, the rate of NICU admissions, the proportion of DGR diagnoses P67C and P67D, and the number of deliveries per year (Table 7.5.). 233 P a g e

256 The SCN admissions under selective UCBGA strategy were modelled to range within ±4.3% from the baseline rate of 9.3% observed in 2002, and the rate of SCN admission was sampled at random from a uniform distribution ranging between 5% and 13.6% independently for each evaluation year. This rate represents a plausible range of SCN admission rates for term babies at a tertiary hospital. The reduction in SCN admissions under universal UCBGA was assumed to depend on the rate of SCN admissions projected under selective strategy. For each sampled selective SCN admission rate, the corresponding SCN admission rate under universal UCBGA was implemented at the appropriately reduced rate according to the relative risk and their 99% CI, as listed in Table These reductions in SCN admissions under universal UCBGA were implemented using lognormal distribution with parameters ln[rr] and standard error (SE) of ln[rr], as recommended by Briggs et al. for modelling of relative risks, 1670 which allowed a random selection of the probability of SCN admission such that 99% of sampled SCN probabilities are within the equivalent 99% CI intervals of the admission rates in Table The NICU admission rates were assumed to range within ± 2% of those observed under universal UCBGA in years one, two, and three and were sampled from a triangular distribution centred on the observed admission rates for the respective study years (Table 7.5.). For both strategies, the number of neonates born during any given year was allowed to range between 4,000 and 6,000 births, with all values within this range having an equal likelihood of being selected via a uniform distribution. Costs of admission were also varied during PSA. The primary costing associated with nursery admission was the most conservative costing for neonatal admissions detailed in the WA adjusted National Hospital Cost Data Collection Cost Round 13 Report The costing reflected admission of a neonate weighing greater than 2499 grams that had a medical indication for nursery admission but did not experience major health problems or experience significant medical procedures. As a tertiary level hospital was modelled, conservative costing was likely to underestimate the neonatal population s complexity both in terms of presenting problems and level of neonatal care required. Consequently, as part of sensitivity analysis the cost associated with nursery admission were varied to reflect neonates presenting with more severe conditions. This was reflected by changing the average cost of SCN admission in any given year, which was varied under a uniform distribution to include a mixture of P67C and P67D, ranging from 0% to 30% of population admissions costing 234 P a g e

257 P67C and representing a mean cost population of between AU$2,588 and AU$3,228 per admission. 235 P a g e

258 Table 7.5. Parameter distributions used during probabilistic sensitivity analysis in the cost-effectiveness SCN admission of term neonates with BW >2499 grams. Strategy Model Parameter Year Distribution Variation Median [min, max] Selective Probability of SCN admission 1,2,3,4 Uniform 9.3% ± 4.3% 9.3% [5.0%, 13.6%] Universal Both Relative risk of SCN admission compared to selective strategy Probability of NICU admission * 1 ln(0.961), % [6.3%, 12.4%] 2 ln(0.864), % [5.5%, 11.5%] Lognormal 3 ln(0.744), % [4.9%, 10.2%] 4 ln(0.656), % [4.1%, 8.6%] 1 8.6% ± 2% 8.6% [6.6%, 10.6%] 2 9.9% ± 2% 9.9% [7.9%, 11.9%] Triangular 3 9.2% ± 2% 9.2% [7.2%, 11.2%] 4 9.0% ± 2% 9.0% [7.0%, 11.0%] Number of neonates 1,2,3,4* Uniform [4000, 6000] Proportion of DRG P67C cost 1,2,3,4* Uniform 0% - 30% $2908 [$2588, $3228] Note: Independent parameter values were sampled for each year; Reductions in SCN admissions were implemented using lognormal distributions with parameters ln[rr] and standard error (SE) of ln[rr], where relative risk (RR) was calculated as the modelled SCN rate per year under universal compared to constant SCN rate of 9.3% under selective UCBGA and SE was based on the observed number of neonates each year. This distribution allowed a random selection of the SCN admission probability such that 99% of sampled SCN probabilities are within the equivalent 99% CI interval of the expected admission probabilities as shown in Table 7.3.; and, * Proportions of NICU admissions were based on the admissions observed under universal UCBGA.

259 7.3 Results Under the base case assumptions, in four years universal screening would be the dominant (less costly and more effective) strategy compared to selective screening saving $641,532 while adverting 376 SCN admissions (Table 7.6.). The strategy of universal cord gas screening appears to be cost-effective from the first year as the ICER<WTP; it cost $2,180 per averted SCN admission (an additional $34,874 to avert 16 SCN admissions) and became the dominant strategy from the second year after implementation. Threshold analysis indicated that a universal UCBGA strategy would be more effective and less costly than a selective strategy when the rate of SCN admission is reduced by at least an absolute 0.65% over the 4-year period (Figure 7.3.). The absolute reduction by 0.65% is no longer achievable over the 4 year period when the selective SCN rate is lower than 3.13%; this is unlikely given the rate of SCN admissions for the neonates >2499 grams in the tertiary institution is considerably greater than 3.13% and not likely to fall below 5%. In the first year, the universal strategy dominated the selective strategy 32.8% of the time or the ICER<WTP in 19.0% of all simulations, giving a total probability of that a universal strategy would be cost-effective compared to a selective strategy (Table 7.7. and Figure 7.4.). By the fourth year after introduction the universal strategy dominate the selective strategy in 99.9% of all simulations. Only in the first two year period was there a chance that universal UCBGA would be inferior or more costly compared to the selective strategy (48.2% and 16.7% of simulated outcomes in the first year (2003) and years one and two (2003 and 2004) combined respectively), and by the third year, universal would be at worst too costly in less than 0.5% of simulations. The cost-effectiveness acceptability curves summarise the likelihood that universal UCBGA is cost-effective compared to the selective strategy (Figure 7.5.). During the first year, a WTP value of zero indicates there is a 32.8% chance that universal would dominate selective UCBGA. The probability that universal UCBGA is cost-effective increases as the WTP increases, and this probability is approximately 50% when the WTP is $2,000 per averted admission. The probability that an averted admission would actually cost less than the cost of SCN admission ($2,588) was approximately 52% in the first year. After one year, the probability that universal UCBGA is dominant is greater than 71% and increases with time 237 P a g e

260 Table 7.6. Cumulative cost and effects under base case selective and universal cord blood gas screening strategies Year Neonates Strategy Cost, AU$ (%) Effect, N (%) ICER Consumables DRG Total SCN admissions Incremental- $/Averted N (All) Incremental Averted Admission 1 st 4487 Selective 7,221 1,076,608 1,083, (9.3) Universal 83,503 1,035,200 1,118,703 34,874 (3.2) 400 (8.9) 16 (0.4) 2,180 1 to Selective 15,596 2,168,744 2,184, (9.3) Universal 168,179 1,979,820 2,147,999-36,341 (-1.7) 765 (8.5) 73 (0.8) Dominant 1 to Selective 24,101 3,359,224 3,383, (9.3) Universal 260,466 2,864,916 3,125, ,943 (-7.6) 1,107 (7.9) 191 (1.4) Dominant 1 to Selective 33,517 4,710,160 4,743, (9.3) Universal 365,072 3,737,072 4,102, ,532 (-13.5) 1444 (7.4) 376 (1.9) Dominant Note: Consumables for selective = 18.61*(388, 450, 457, 506) representing selective testing on n overtly unwell (NICU) neonates in years 1, 2, 3 and 4 respectively. Consumables for universal =18.61*(all neonates for a given year). Dominant = comparative strategy is both less costly and more effective than baseline strategy; ICER = incremental (change) in effect/incremental cost, and represents the additional cost of averting an SCN admission on top off the number of admissions in the baseline strategy (the additional cost of lowering SCN admission).

261 Incremental cost ($AU) Figure 7.3. Threshold rate of averted SCN admissions where universal UCBGA strategy becomes dominant (incremental cost <0 when averted admissions is 0.653%) compared to any rate of SCN admissions under selective UCBGA strategy % 0.65% 0.70% 0.75% 0.80% Averted SCN admissions Table 7.7. Percent of simulations expected to be cost-effective during PSA with 50,000 sets of probability distribution samples drawn for each year. Year 1 Year 1 to 2 Year 1 to 3 Year 1 to 4 (All) Dominant 32.8% 70.3% 97.1% 99.9% ICER<WTP 19.0% 13.0% 2.5% <0.1% Total Cost Effective 51.8% 83.3% 99.6% 100% ICER>WTP 20.9% 9.1% <0.5% - Inferior 27.3% 7.6% - - Total Not Cost Effective 48.2% 16.7% <0.5% P a g e

262 Figure 7.4. Scatter plots of incremental universal UCBGA costs against effects Note: (Percent of expected averted admissions) and 95% confidence ellipse generated under PSA for each time period. Year 1 (top-left), years 1-2 (top-right), years 1-3 (bottom-left) and years 1-4 (bottom-right). Figure 7.5. Cost-effectiveness acceptability curves 240 P a g e

263 7.4 Discussion This study presents the first comprehensive cost effectiveness analysis of universal umbilical cord blood gas and lactate analysis. The results of this study reaffirm the continued clinical effectiveness of the introduction of universal UCBGA over a selective strategy. 47 Of greater importance, from an economic perspective the additional cost of universal UCBGA is off set against the significant reduction in SCN costs associated with averted nursery admissions within the first four years in policy implementation. The cost-effectiveness analysis in this study is based on seven years of experience with a universal UCBGA program and a selective analysis program prior to that. In contrast, the previous studies that have attempted to evaluate the cost-effectiveness of UCBGA are primarily based on speculation or limited analysis. The incurred costs of cord blood gas sampling are less than that postulated by other authors in ad-hoc cost-effectiveness studies. 1188,1631 Duerbeck et al. detailed the costs at the University of Arizona as being US$70.00 per umbilical artery sample Thorp et al. reported a range of costings from US$16.10 to US$58.00 depending on results required and location Further, Thorp et al. introduced the distinction between the actual cost of sampling and analysis and the amount that is charged to the patient or health service Other studies have postulated that the costs of cord blood gas analysis would be much lower than that seen in this study, such as Harris et al who proposed a cost of 0.41 per sample in universal UCBGA and 0.71 per sample in selective UCBGA or Garibaldi et al. with 4.00 per neonate. 1187,1635 These later estimates should be considered alongside the lack of detail supplied concerning what costs were included and how they were calculated and thus probably do not provide a realistic reflection of the incurred costs associated with cord blood gas analysis. Previously, a key impediment in the introduction of universal UCBGA was the consideration that the costs of universal sampling and analysis were prohibitive Further, others have postulated that for maternity units unable to afford the initial outlay associated with blood gas analysis then lactate analysis may provide a cost effective option as a result of lower incurred costs. 1565,1588 Additionally, a number of lactate analysis advantages may further influence its cost-effectiveness, including the practicality of point of care testing that has been found to confer significant costs savings in other clinical environments. 1565,1580,1671 Another practical advantage of lactate analysis is the smaller volume of blood required, which has been found in fetal scalp sampling to result in a significantly lower proportion of neonates with failed sampling and analysis. 74,1042 Anecdotal evidence suggests it would be reasonable 241 P a g e

264 that a similar situation exists for cord blood gas and lactate analyses. The missed opportunity cost of failed analysis on a sample due to insufficient blood volume is particularly hard to quantify. Given that collection of an adequate volume of blood is often most difficult on the sickest neonates, an approach that utilises smaller blood volumes for analyses has the potential to have a significant effect. Other authors and organisations have advocated selective rather than universal cord blood analysis, 912,1191,1250,1672 which may be in part due to its lower staffing costs and consumable use. To date the only study to evaluate the impact of universal cord blood analysis and to show a perceived benefit relied on a complete blood gas profile, 47 namely arterial and venous ph, po 2, pco 2, bicarbonate, base excess and lactate values. It is not known if the same benefits can be ascribed to a program that relies on cord lactate analysis alone or a selective analysis program. Consequently, at this point in time it is inappropriate to ascribe an equivalent perceived benefit in terms of reduction in nursery admissions to that which has been identified to follow a universal analysis program, and potentially inappropriate to ascribe any benefit at all to lactate analysis alone or selective blood gas analysis. Costing assumed that the individuals involved in the process of UCBGA were registered midwives, whilst this is the case at KEMH, other centres have demonstrated that other staff members are equally capable of performing UCBGA The shift of UCBGA responsibility to patient care assistants could reduce the associated staff time costs for collection and analysis of cord blood analysis. This study demonstrated the cost-effectiveness of universal UCBGA analysis from a government health care provider perspective; however, it is expected that the costeffectiveness would be even more compelling from a societal perspective. Such an approach would allow the inclusion of significant neurodevelopmental sequelae and associated costs that arise from hypoxic-ischaemic injuries in the perinatal period, such as cerebral palsy. A longer time horizon would also allow the inclusion of the medicolegal consequences of moderate-severe hypoxic-ischaemic encephalopathy. Given that median awards for moderate-severe HIE are AU$2.3 million and can be up to AU$15 million, 10,21-22 and that some authors place the annual cost of cerebral palsy in Australia being in excess of a billion Australian dollars, 1673 this could significantly contribute to the potential averted costs. Furthermore, study parameter expansion would allow the inclusion of costs associated with parental travel, accommodation and lost productivity that result from SCN admission, as well as accounting for equity issues associated with a complicated tertiary population in this study. 242 P a g e

265 7.5 Conclusion While the introduction of universal UCBGA is associated with significant initial and ongoing costs, the potential averted costs in terms of reductions in neonatal nursery admissions exceed the incurred costs in this study. Consequently, universal cord blood gas analysis can be considered a cost-effective proposition in a tertiary level maternity unit. 243 P a g e

266 CHAPTER EIGHT ATTITUDES AND BARRIERS TO UNIVERSAL UMBILICAL CORD BLOOD GAS AND LACTATE ANALYSIS 8.1 Introduction There is a growing body of evidence to support the collection of UCBGA at delivery. 24,49,912,1250,1674 Biochemical data provided by UCBGA forms an integral part of the diagnosis and exclusion of conditions arising from perinatal hypoxic-ischaemic insults: the absence of umbilical artery metabolic acidaemia effectively excludes birth asphyxia as a diagnosis. 24,203 Additionally, there are data demonstrating the benefits of universal sampling of umbilical cord blood gases at delivery with medicolegal, financial, and educational benefits. 47,211,1187,1635 For maternity units where UCBGA is not a feasible option, lactate analysis can be performed in its place for a fraction of the cost. 29,1588 Numerous studies have identified significant correlations between umbilical artery lactate values and early indicators of neonatal condition including Apgar scores, umbilical artery ph values, and umbilical artery base excess values. 27,69,690,1243,1386,1626 Further, cord blood lactate levels collected at delivery have been demonstrated to be equivalent to full blood gas analyses in predicting NICU admission, meconium aspiration, idiopathic RDS, assisted ventilation, neurological abnormality, neonatal encephalopathy, hypoxic-ischaemic encephalopathy (HIE) and neonatal death (Chapter Four). 29,1626,1661 Recently published data based on a large population study of 21,182 term neonates showed that cord blood lactate and the level of neonatal resuscitation was the best predictor of HIE of 47 different predictive models evaluated (Chapter Four) Despite the evidence demonstrating the value of blood gas analyses on cord blood from all deliveries, there remains reluctance in some maternity units to adopt a universal approach to cord blood gas or lactate analysis. Based on data from King Edward Memorial Hospital that demonstrated that the introduction of universal UCBGA improved perinatal outcomes, 47 the West Australian Department of Health financially supported the evaluation of the introduction of universal cord blood gas or lactate analysis into three maternity units that had previously only undertaken selectively UCBGA. As part of this study, questionnaires were distributed to staff members to identify perceived barriers towards the introduction of 244 P a g e

267 UCBGA through evaluation of attitudes of clinical obstetric staff across four obstetric units in metropolitan and regional Western Australia. 245 P a g e

268 8.2 Methods Medical and midwifery staff involved in intrapartum care at four level two maternity units completed questionnaires evaluating attitudes to universal blood gas analyses over a two year period between November 2008 and October One of these units was in metropolitan Perth, Western Australia (WA); the other three units were in regional WA, with one unit providing private care and the other three units providing mixed public and private care. The three maternity units within the public healthcare system comprised the three largest maternity units in terms of deliveries outside King Edward Memorial Hospital in Western Australia. The private maternity unit was included on the basis of being collocated with one of the public maternity units. Questionnaires included 13 statements with response options of strongly agree, agree, neutral, disagree and strongly disagree, as well as space for free text responses. Universal UCBGA was performed routinely at one regional centre prior to completing the questionnaire: the three other maternity units performed selective cord blood analyses at the discretion of attending medical staff. Descriptive data are presented using frequency distributions (total number and percentage). The influence of potential factors including age, gender, length of time providing intrapartum care; and previous experience with UCBGA on the introduction of universal UCBGA was examined in univariate analysis. Fisher s exact tests were utilised for evaluation of data. Frequency distributions were calculated using SPSS for Windows statistical software (SPSS Inc. 2006, Version 15.0, USA), while Fisher s exact test results were obtained from StatXact (Cytel Studio 2007, Version 8.0.0, USA). All statistical hypothesis tests were two-sided and p- values less than 0.05 were considered statistically significant. 246 P a g e

269 8.3 Results One hundred and seven questionnaires were available for analysis from a total of 127 that had been provided to staff (84% response rate). The majority of those replying were female, over the age of 40 and had been providing intrapartum care for over 10 years (Table 8.1.). Approximately two-thirds of those surveyed had previous experience with UCBGA (66.4%); of these most had only been exposed to selective analysis (77.5%). Table 8.1. Population demographics Characteristic Number (Percentage) Location Regional Public Hospital One 30 (28.0%) Regional Private Hospital 16 (14.9%) Regional Public Hospital Two 26 (24.2%) Metropolitan Public Hospital 34 (31.7%) Position Midwife 88 (82.2%) Student Midwife 7 (6.5%) GP Obstetrician 6 (5.6%) Consultant Obstetrician 2 (1.9%) Junior Medical Staff 2 (1.9%) Medical Student 1 (0.9%) Consultant Paediatrician 1 (0.9%) Age (12.2%) (15.9%) (41.1%) (30.8%) Gender Male 10 (9.3%) Female 97 (90.7%) Length of Time Providing Intrapartum Care (years) <1 15 (14.0%) (14.0%) (12.2%) >10 64 (59.8%) Previous Experience of Umbilical Cord Blood Gas Analysis None 36 (33.6%) Selective Universal Unknown 55 (51.4%) 15 (14.0%) 1 (0.9%) The respondents attitudes towards umbilical cord blood gas analyses are detailed in Table Of those who responded, the majority considered umbilical cord blood gas or lactate 247 P a g e

270 analysis beneficial to perinatal care (n=72; 67.3%), while 12 (11.2%) did not. Nine individuals (8.4%) considered that umbilical cord blood gas or lactate analysis had no place in perinatal care, although 61.7% of the population believed that it did have a place (n=66) or did not respond to this question (n=12; 12.2%). When respondents were asked to consider previously postulated benefits of cord blood gas and lactate analysis there were positive responses to the statements concerning objective neonatal status (n=64; 59.8%), medicolegal issues (n=74; 69.2%) and audit and teaching (n=64; 59.8%) (Figure 8.1.). The response to cord blood gas or lactate analysis being a cost effective proposition was more ambivalent with 58 individuals (54.21%) either not responding or responding in a neutral manner. The attitudes of respondents towards postulated barriers to the introduction of UCBGA are presented in Table 8.3. and Figure The majority of respondents considered universal cord blood gas or lactate analysis to be difficult to introduce due to insufficient time following delivery, increased workload, and encroachment of technology into birth. With regard to the cost of universal UCBGA being a barrier to introduction, there were few respondents that strongly agreed or disagreed: the majority of respondents either agreed (n=47; 43.9%) with this statement or provided a neutral response (n=40; 37.4%). When considering: (1) the level of expertise, (2) required equipment, and (3) the possibility of decreased patient contact time, approximately 20-25% of respondents provided a neutral response. The proportion of positive and negative responses to these statements was similar (45.8%, 41.1%, and 44.9% respectively). Respondents with a medical background were less likely to agree that UCBGA has no place in perinatal care (Positive Statement Response 0.0% vs. 9.5%; Negative Statement Response 83.3% vs. 58.9%; p=0.037). The profession of the respondents influenced the answers to perceived barriers to introduction of universal umbilical cord blood gas values. Midwifery respondents were more likely than medical respondents to provide positive responses to statements related to lack of time (57.9% vs. 16.7%; p=0.007), medicalisation (61.1% vs. 8.3%; p<0.001), and decreased patient contact (49.5% vs. 8.3%; p=0.025) as barriers to the introduction of universal UCBGA. 248 P a g e

271 Table 8.2. Attitudes towards the benefits of umbilical cord blood gas/lactate analysis Statement Strongly Agree Agree Neutral Disagree General Attitude Towards Umbilical Cord Blood Gas/Lactate Analysis Beneficial to maternity care (15.9%) (51.4%) (21.5%) (6.5%) No place in maternity care (2.8%) (5.6%) (17.7%) (38.3%) Potential Benefits of Umbilical Cord Blood Gas/Lactate Analysis Objective measurement of status at birth assists in neonatal care (9.4%) (50.5%) (25.2%) (11.2%) Objective record of status at birth is protective in the event of medico-legal issues (12.2%) (57.0%) (21.5%) (5.6%) Cord blood gas/lactate analysis is cost-effective (4.7%) (22.4%) (46.7%) (14.0%) Improved opportunities for audit & teaching (14.0%) (45.8%) (27.1%) (6.5%) Strongly Disagree 5 (4.7%) 25 (23.4%) 3 (2.8%) 1 (0.9%) 5 (4.7%) 4 (3.7%) No Response 0 (0.0%) 13 (12.1%) 1 (0.9%) 3 (2.8%) 8 (7.5%) 3 (2.8%)

272 Table 8.3. Perceived barriers and impediments to the introduction of universal umbilical cord blood gas/lactate analysis Potential Impediments Strongly Agree Agree Neutral Disagree Expense (8.4%) (35.5%) (37.4%) (8.4%) Insufficient time following delivery (17.8%) (35.5%) (21.5%) (18.7%) Increased workload (21.5%) (45.8%) (14.0%) (15.0%) Lack of necessary equipment (12.2%) (29.0%) (26.2%) (24.3%) Lack of necessary expertise (8.4%) (37.4%) (22.4%) (22.4%) Technological encroachment into birth ( medicalisation ) (24.3%) (30.8%) (24.3%) (12.2%) Decreased patient contact time (16.8%) (28.0%) (21.5%) (24.3%) Strongly Disagree 1 (0.9%) 3 (2.8%) 1 (0.9%) 3 (2.8%) 4 (3.7%) 6 (5.6%) 4 (3.7%) No Response 10 (9.4%) 4 (3.7%) 3 (2.8%) 6 (5.6%) 6 (5.6%) 3 (2.8%) 6 (5.6%)

273 Figure 8.1. Potential benefits of umbilical cord blood gas/lactate analysis 100% 90% 80% 70% 60% 50% 40% 30% 20% No Response Strongly Disagree Disagree Neutral Agree Strongly Agree 10% 0% Objective Measure Medicolegal Cost Effective Audit & Teaching Figure 8.2. Potential barriers to umbilical cord blood gas/lactate analysis 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% No Response Strongly Disagree Disagree Neutral Agree Strongly Agree 251 P a g e

274 The length of time the respondent had been providing intrapartum care influenced opinions relating to the potential benefit of UCBGA to maternity care. Similarly, opinions relating to potential barriers to universal UCBGA (increased workload, lack of necessary equipment, and medicalisation of birth) were also influenced by the duration a respondent had been providing intrapartum care. A higher proportion of the least experienced (<1 year, 73.3%) and most experienced staff (>10 years, 73.4%) agreed that UCBGA was beneficial to maternity care compared with those who had provided care for one to five years (53.3%) and six to ten years (46.2%) (p=0.019). Similarly, the lowest proportion of respondents that reported increased workload would be an impediment to universal UCBGA had <1 year (40%) or more than 10 years (67.2%) experience providing intrapartum care compared to those with one-five years (87.6%) or five-ten years (76.9%) clinical experience (p=0.033). Of those providing intrapartum care for six to ten years, 53.8% considered the lack of necessary equipment an impediment to universal UCBGA, while 48.4% of those with greater than 10 years exhibit a similar attitude. This is in contrast to the 20% of those with less than a year and 20% of those with one to five years experience of intrapartum care who reported that lack of equipment would be an impediment to universal UCBGA (p=0.004). As the length of time providing intrapartum care increased, more respondents disagreed with the statement that the medicalisation of child birth was an impediment to universal UCBGA (less than one year 13.3%, one to five years 13.3%, six to ten years 15.4%, greater than 10 years 20.3%; p=0.029). Of the 13 statements evaluated, the age of respondents influenced three: 1) the potential medicolegal benefits; 2) the lack of necessary equipment and 3) medicalisation of childbirth. Younger respondents were less likely to consider that the lack of necessary equipment was an impediment to universal UCBGA (20-29 years 23.1%, years 23.5%, years 40.9%, 50 years 57.6%; p=0.012). Furthermore, younger respondents were less likely to agree that universal UCBGA represented medicalisation (20-29 years 38.5%, years 47.1%, years 54.5%, 50 years 66.7%; p=0.017). There was significant variation (p=0.041) in response to the medicolegal benefits with regards to age, with 84.6% of respondents years old agreeing or strongly agreeing with a medicolegal benefit (74.4%), while 56.3% of year olds, 74.4% of year olds and 68.8% of greater than 49 year old respondents also responding positively. Gender of the respondent answering the questionnaire was only found to significantly affect the response to a single statement, namely that insufficient time following delivery would be 252 P a g e

275 an impediment to universal UCBGA. Female respondents were more likely to agree with the statement than their male counterparts (56.7% vs. 20%; p=0.042). Previous experience with UCBGA influenced responses relating to cost effectiveness and insufficient time at delivery. Those with previous UCBGA experience were more likely to have an opinion relating to the cost-effectiveness of universal UCBGA than those with no experience (74.2 vs. 40.3%; p=0.007). Moreover, considering barriers to the introduction of UCBGA, respondents with previous experience were more likely to disagree with the statement that there was insufficient time following delivery than those without experience (29.4% vs. 4.2%; p=0.009). 253 P a g e

276 8.4 Discussion This study represents the first evaluation, of which we are aware, of medical and midwifery attitudes to universal UCBGA at delivery. Generally, cord blood gas analysis was considered favourably with support for its use in perinatal care, although a minority believed that UCBGA had no place in maternity care. Most of the respondents were midwives, reflecting current staffing in the clinical environment within perinatal care in Western Australia; with the largest group of people being midwives. Further, the demographics of the midwifery respondents reflect that seen within the midwifery workforce throughout Australia, 1675 namely female midwives with significant experience of providing intrapartum care over forty years of age. The majority of the respondents agreed or strongly agreed with three of the four postulated benefits of UCBGA put to them, namely cord blood gas analysis role in establishing status at birth, medicolegal situations, and as audit and teaching tool. Whether cord blood gas analysis is a cost effective proposition was met with a less certain result with the most respondents not responding or having a neutral response. This may reflect the disconnect in the minds of many staff between the administration-associated financial costs and the clinical aspects of healthcare, and is emphasised by the response of one participant who stated that they were unable to comment [on the] costs involved in analysis, although others did state they believed that for the cost used for the machien [sic] we could use it on other thigs [sic]. When considering the barriers to introducing universal UCBGA there were three statements to which a majority of respondents expressed a definitive opinion, namely increased workload, insufficient time and medicalisation of birth. The first two barriers reflect the practical implications of introducing a new program into clinical practice. The actual and perceived time required to collect and analyse cord blood samples is likely to decline over time as clinical staff members become more experienced. The observation that individuals with previous experience of cord blood analysis were more likely to state that there was sufficient time following delivery to perform UCBGA supports this hypothesis. Further, developments in blood gas and lactate analyser technology have lead to production of portable analysers able to produce results at the bedside within minutes. The medicalisation of birth is a subjective concept with a considerable divergence between medical and midwifery staff members over its importance as an impediment to introduction 254 P a g e

277 of universal UCBGA. Some respondents described particularly strong responses including that they believed that this is destroying normal uncomplicated births [and interferes with] those beautiful, early precious moments, while others stated UCBGA was a good tool, part of the big picture for the neonate wellbeing. Given that it is likely to be a personal opinion it is unlikely to change over time, although experience over time with blood gas analysis may ameliorate or reinforce this concern. This study is limited by the lack of complete inclusion of all individuals providing intrapartum care at each study site. Further, there was only a small number of male respondents and a preponderance of midwifery responses, although this does reflect the relatively larger number of midwifery (rather than medical) and female (rather than male) staff involved in providing intrapartum care. Consequently, the comparisons between medical and midwifery attitudes should be interpreted with caution. That being so, the typical procedure for UCBGA in Western Australia is for the midwife at delivery to collect and analyse the blood sample. This also reflects the situation in Western Australia were a significant proportion of deliveries are conducted by midwives Consequently, the opinions and attitudes of midwifery staff members may provide a more accurate reflection of the issues surrounding the day to day practice of cord blood gas analysis. 255 P a g e

278 8.5 Conclusions This study evaluated the perceived barriers to universal UCBGA as well as providing an insight into medical and midwifery staff members perceptions of the benefits and general utility of UCBGA. The findings are broadly consistent with expectations with the majority of respondents indicating support for UCBGA. The information derived from this study may be useful in the identification and amelioration of areas of concern prior to the introduction of UCBGA. Further, it may be useful in the preparation of the education and implementation packages necessary for the introduction of UCBGA. 256 P a g e

279 CHAPTER NINE WHERE TO FROM HERE? THE FUTURE OF UNIVERSAL UMBILICAL CORD BLOOD GAS AND LACTATE ANALYSIS ON NEONATES AT DELIVERY: THESIS DISCUSSION AND CONCLUSION Perinatal hypoxic-ischaemic injuries have significant medical, legal, financial, and social implications for the healthcare sector; however, these implications also extend to the families of those involved as well as the wider community. The consequences of in utero exposure to hypoxic-ischaemic insults exist along a continuum ranging from no sequelae to extensive and debilitating long-term conditions such as CP, and perinatal death. This thesis has clarified and conducted the first comprehensive evaluation of a number of significant issues associated with the introduction of universal UCBGA into a perinatal unit. Further, it includes the first evaluation of the introduction of a universal lactate analysis program into a perinatal unit and the introduction of UCBGA into a non-tertiary perinatal unit. A plethora of literature has been published concerning the pre-analytical errors associated with delayed umbilical cord blood sampling and analysis. This literature is conflicting and has significant methodological and statistical issues. The RCT within this thesis is the first to comprehensive evaluate mechanisms to limit pre-analytical errors in UCBGA, and found that cord blood gas and lactate values change rapidly after delivery; changes occurring in some parameters within 15 minutes. Consequently, cord blood sampling and analysis should be conducted as soon as possible after delivery. Interestingly, umbilical artery lactate values were noted to significantly change within 15 minutes regardless of measures utilised to limit drift in lactate levels. In contrast, some measures in blood gas analyses remain stable for up to 60 minutes when cord blood that was stored in preheparinised syringes at room temperature. Methods to identify and predict neonates that will develop adverse neonatal outcomes are not a new concept; 99,389,486,578,697,1182, , however, the development of neuroprotective hypothermia has emphasised the importance of developing a simple, inexpensive and rapid method of identifying neonates for consideration of neuroprotective therapies. This thesis is novel in that it developed and evaluated its predictive models on an entire unselected presenting large population that had a reasonable number of adverse outcomes. The simple 257 P a g e

280 combination of level of neonatal resuscitation in the delivery room and umbilical artery lactate values was found to provide an accurate method of predicting moderate-severe HIE within minutes of delivery. Moreover, the practical advantages of the accurate and relatively inexpensive handheld lactate meters allows bedside analysis of the risk of HIE within minutes of delivery This approach for predicting this important adverse outcome has the potential to be widely applicable to all obstetric units. Standard practice with cord blood gas analyses are to ensure that paired umbilical cord blood samples are obtained, one from the umbilical artery and one from the umbilical vein. To confirm that these samples are from different vessels it is common to use a set of minimum arteriovenous differences. Prior to this thesis, two criteria were in use - the Westgate et al. or Kro et al. criteria. 207,1636 Both of these criteria have methodological issues associated with the sample populations utilised during their development. Further, the Kro et al. criteria are complex to apply and implement effectively. The KEMH validation criterion, developed in this thesis, was generated from on an entire presenting population and provides a simpler algorithm that can be universally applied to identify neonates with non-physiological UCBG values. Comparison of the historical criteria with a number of new criteria, demonstrated that the KEMH criteria identified the greatest proportion of deliveries as having accurate UCBGA without increasing the rate of false positive diagnoses of acidaemia in vigorous neonates. Further, it provided more valid data to aid clinicians where neonates are born in poor condition. Our research group has previously shown that introduction of universal UCBGA into a tertiary maternity unit resulted in improved neonatal outcomes and reduced nursery admissions. Further, there is evidence that lactate analysis may be a more practical alternative. In this thesis, I have evaluated the introduction of universal UCBGA into a metropolitan and two regional obstetric units. Whilst there was no significant changes in mean blood gas and lactate values at any centre following introduction of universal UCBGA or lactate analysis, there was a significant reduction in the number of neonates with moderate to severe elevations in their umbilical artery lactate values at the regional primary obstetric unit. There was also a clinically significant reduction in arterial ph values less than 7.10 and arterial ph values less than 7.00 at the secondary metropolitian centre following introduction of UCBGA; however, these reductions were not statistically significant. These data suggest that the benefits of introducing UCBGA previously described in a tertiary unit can be reproduced by introduction of universal lactate analysis into a primary (and possibly a secondary) obstetric centre. Larger studies in secondary centres are required to assess the 258 P a g e

281 impact of introducing universal UCBGA or lactate analysis into such centres, in part due to fact that adverse outcomes are infrequent. While a number of authors have postulated about the costs and benefits of UCBGA, ,1631,1635 this thesis contains the first comprehensive cost-effectiveness evaluation of UCBGA. It found that while universal UCBGA was associated with significant initial and ongoing costs, the potential averted costs (due to reduced term SCN admissions) greatly exceed the incurred costs in the majority of circumstances. Sensitivity analysis demonstrated that even when incurred costs exceeded averted costs, the cost per averted nursery admission was well below the cost of a nursery admission except for at the extremes of analysis. A key factor in the implementation of any new program or technique into clinical practice is the attitudes of the staff members that are required to abide by and implement the new idea. Consequently, this thesis set out to evaluate medical and midwifery staff member s attitudes to the introduction of a universal UCBGA analysis program. Throughout the evaluated population, there was a considerable divergence in opinions and attitudes towards UCBGA. While a small minority (8%) of individuals considered that UCBGA had no place in perinatal care, all medical and most midwifery staff members considered cord blood gas analysis favourably, with support for its use in perinatal care. Most respondents considered benefits of UCBGA exist in establishing neonatal status at birth, medicolegal situations, and as an audit and teaching tool. Further, those surveyed indicated that increased work-load, insufficient time and medicalisation of birth are all potential impediments to the introduction of universal UCBGA. Consequently, if a maternity unit is to successfully introduce universal UCBGA then these concerns need to be considered in the planning of any such introduction as well as addressed in the initial education and implementation packages. 9.1 Reasons to introduce universal umbilical cord blood gas analysis Umbilical cord blood gas analysis is an objective measurement of neonatal status at delivery giving an insight into how the fetus responded to the stresses of labour and delivery and providing a potential insight into its future outcome. Multiple academic and clinical organisations advocate UCBGA following delivery either in a selective or universal manner. 24,203,841 Furthermore, umbilical cord blood gas and lactate values are an integral part in the diagnosis and exclusion of many disorders related to intrauterine hypoxic-ischaemic insults, with the absence of umbilical artery metabolic acidaemia effectively excluding birth 259 P a g e

282 asphyxia as a diagnosis. 24,203 In addition to the biochemical biofeedback benefits detailed above, there is evidence in the literature to suggest that universal sampling of umbilical cord blood gases at all deliveries can have significant medicolegal, financial, and educational benefits. 47,211,1187,1635 Given that UCBGA occurs after delivery of the neonate and after intrapartum hypoxicischaemic injuries, its utility is often questioned given that it is unable to directly prevent or ameliorate injury in the neonate from which it was collected. That being so, the results of umbilical cord blood gas and lactate measurement are used in ongoing neonatal management of those with (or at risk of) neurodevelopmental issues such as HIE. Cord blood gas values fulfil an important role in assisting to determining the cause of non-vigorous neonates at delivery to allow the most effective resuscitation, and neonatal care. The presence of a normal umbilical artery blood gas values assists in excluding significant acidaemia as the cause of non-vigorous neonates and shifts attention to other aetiologies. Alternatively, if blood gas values indicate a significant metabolic acidaemia then early interventions to prevent or minimise potential damage (such as alkali therapy or whole body cooling) can be instigated. Universal UCBGA allows determination of site-specific population distributions for measures of fetal acidaemia. These distributions and reference ranges can then be utilised in auditing clinical care. The proportion of neonates with low umbilical cord ph levels or other indicators of metabolic acidaemia, such as BE or lactate levels, could potentially be used to indicate the quality of intrapartum care if used in conjunction with other clinical obstetric and neonatal data. Umbilical cord sampling also maintains and develops medical and midwifery skills regarding labour management as well as providing objective foci for training and ongoing up-skilling of EFM interpretation particularly in units with an active education program Inter-hospital and intra-hospital comparisons can be made if routine sampling is performed utilising a similar sampling technique across sites. This would provide a objective endpoint in order to examine the influence of labour management advances on the fetus and neonate. 189 Universal umbilical cord blood gas sampling allows the process of sampling to become routine ensuring that even during obstetric, fetal or neonatal emergencies, sampling is less likely to be missed as it has become routine. The benefits of routine sampling can also be more immediately apparent in that early neonatal blood gas data is available in the event of a rapid deterioration in neonatal condition. 260 P a g e

283 9.2 Obstacles to introducing universal umbilical cord blood gas analysis A number of impediments to introducing universal UCBGA into a maternity unit have been postulated including expense, concern regarding predictive ability, adverse staff and patient perceptions, and technical difficulties. While most medical and midwifery staff members involved in intrapartum care consider UCBGA benefitial to maternity care, a number of perceived impediments to its universal introduction have been identified in Chapter Seven including insufficient time following delivery, increased workload, and encroachment of technology into birth. One of the particularly pronounced impediments to the introduction of universal umbilical cord blood gas sampling is the cost of providing the service; both to the patient and to the health system. While the initial outlay in terms of purchasing the necessary equipment and staff training for universal UCBGA is not insignificant, Chapter Seven has demonstrated that universal UCBGA is a cost-effective proposition that will result in significant overall cost savings. Given that magnitude of the improvement in UCBGA results is similar in the primary and tertiary obstetric units, it is likely that the cost benefits detailed in Chapter Six are likely to persist outside the tertiary environment. Further, the lower initial outlay associated with lactate analysis, which may be more appropriate for smaller obstetric units, suggests that expense is even less likely to be a significant impediment to introduction of a universal analysis program. Following delivery the clinical situation, particularly when there are neonatal and/or maternal complications, often results in cord blood gas sampling and analysis being delayed or forgotten. It is just such situations that cord blood gas and lactate results are most important. To further complicate the issue there has been considerable debate about the most appropriate way to handle umbilical cord blood gas samples prior to analysis. Chapter Three has demonstrated that umbilical cord blood needs to be sampled as soon as possible after delivery; however, once this has occured analysis can be delayed for up to 60 minutes depending on the method used to limit changes. This provides an additional window of time in which to conduct cord blood gas analysis, and decreases the time demand on medical and midwifery staff members in the immediate post partum period. Further, use of the adjusting factors calculated in this thesis, if applied appropriately, can provide an indication of what blood gas and lactate values would have been 30 or 60 minutes prior depending on how blood is sampled and analysed. 261 P a g e

284 There is a growing demand for a less medicalised and more holistic birth in which activities such as delayed cord-clamping play a role. This is reflected in some of the attitudes demonstrated in Chapter Eight. Umbilical cord blood sampling could be perceived by some as unnecessary medical intervention and alternative procedures, such as delayed umbilical cord clamping and lotus births, may interfere with collection of umbilical cord blood samples. That being so, Chapter Eight demonstrated these views are currently only held by the minority and are unlikely to form a barrier to introduction of a universal analysis program. Furthermore, given medical and midwifery staffing shortages and growing workload, the universal application of a UCBGA program may be seen as an unnecessary burden to staff members. In practice, the small amount of time required obtaining and analysing the sample (five to ten minutes) is relatively inconsequential compared to the substantial benefits. 9.3 Umbilical cord blood gas analysis versus umbilical cord blood lactate analysis Numerous studies have reported the significant correlations between traditional cord blood gas measures (ph, po 2, pco 2, BE) and lactate values. 27,29,69,690,1140,1243,1626 Further, a number of studies have noted that cord lactate values are effective predictors of adverse outcomes. 69,1140,1243,1626 In contrast to FBS, where there is a considerable body of literature comparing traditional blood gas measurement with lactate measurement on fetal scalp blood to predict adverse neonatal outcomes, 26,1042,1504,1506,1629 there is very little evidence that directly compares the traditional umbilical cord blood gas values with lactate measurement as predictors of adverse neonatal outcomes. Ruth and Raivio in a cohort of 931 neonates reported equivalent sensitivity and specificity for umbilical artery ph and lactate values in predicting a depressed Apgar score. 69 Amongst, neonates with a five minute Apgar score less than four it was found that lactate levels had a higher sensitivity than ph or BE. Suidan and Young s results concurred with Ruth and Raivio although they found a higher degree of sensitivity in predicting low Apgar scores Wiberg et al. conducted the largest study to evaluate the difference in predictive ability of lactate and blood gas values The AUC for five minute Apgar scores less than four ranged from 0.77 for gestational age adjusted arterial lactate value to 0.69 for non-adjusted arterial ph values, although no significant difference was noted. When considered as a marker of the metabolic component of acidaemia (i.e. gestation adjusted ph and lactate versus gestation 262 P a g e

285 adjusted ph and BD), the lactate combination had equivalent or better PPV and sensitivity. Arterial lactate (10 mmol/l cut-off) had a higher PPV and equivalent sensitivity to a ph less than 7.10, in predicting five minute Apgar scores less than four. Considering Apgar scores less than seven, lactate (10 mmol/l cut-off) had a lower PPV but considerably higher sensitivity than a ph of 7.00, and a higher sensitivity and lower PPV than an arterial ph cut-off of While analysing the ability of lactate levels to predict Apgar scores is noteworthy, it is the ability to predict parameters like HIE and neonatal seizures that is clinically important. This is partly because these outcomes are pathologic in their own right and are responsible for considerable morbidity and mortality but they also have a much better correlation with longterm neurodevelopmental outcome. 53 The difficulty in correlating measures of acidaemia with long term outcome is reflected in the Wiberg et al. study who despite having a cohort of 13,735 cord blood samples only reported six neonates (0.05%) with HIE, none of whom had acidaemia Consequently, further analysis was not possible. With regard to predicting severe neonatal outcomes, the only two studies to directly compared umbilical arterial lactate to traditional acid base measures (ph and BE) published prior to the this thesis were conducted by the Westgren et al. and Ruth and Raivio. 29,69 Westgren et al. found that umbilical artery lactate had a similar efficacy to umbilical artery ph and BE in the prediction of meconium aspiration, NICU admission, idiopathic RDS, assisted ventilation, neurological abnormalities, and neonatal death. 29 Interestingly, combining lactate and other blood gas values, such as ph or BE, did not improve the ability to predict neonatal morbidity. The Westgren et al. study is limited by the relatively small number of neonates with adverse neonatal outcomes; only six neonates had neurological abnormalities. Further, only one of the six neonates with adverse neurological outcomes had a strong potential aetiological relationship with intrapartum asphyxial injuries (HIE). The other five adverse outcomes included hypotonia or seizures, all of which have been shown to have multifactorial aetiologies with intrapartum asphyxia only being responsible for a minority of cases. In terms of predicting long-term neonatal outcome, even less information is available. Ruth and Raivio followed 947 neonates for one year, with 42 neonates having adverse outcomes potentially related to perinatal asphyxial injury (28 minor adverse outcomes, 10 significant adverse outcomes and four deaths). 69 Umbilical artery lactate and ph were considered to have equivalently poor PPVs and sensitivity in predicting adverse neurodevelopmental outcome at one year of age. Given the significant changes in definitions of intrapartum asphyxial injury and associated condition, the reported adverse outcomes 263 P a g e

286 should be considered in context. All four neonatal deaths occurred in neonates with a gestation less than 29 weeks and birth weight less than 950 grams. Further, two of the neonates with significant neurodevelopmental issues (20%), and six of those with minor neurodevelopmental issues (21%) were also preterm deliveries. Given the limitations with previous studies comparing umbilical cord blood gas and lactate values in predicting adverse outcomes, Chapter Four has demonstrated in a sufficiently large cohort (N=21,182; HIE n=41) that umbilical artery lactate values are equivalent to arterial ph and BE values when considered independently. Further, when considered in combination with non-biochemical clinical markers of neonatal status (e.g. Apgar scores) arterial lactate is a more effective predictor of adverse neonatal neurological outcome than combinations involving arterial ph or BE. Most studies that compare the efficacies of lactate and blood gas measurement highlight the practical advantages of lactate analysis over blood gas analysis. 29,1042,1504,1506,1629 The development of handheld single strip lactate meters has allowed lactate analysis to take place in one minute, at the patient s bedside, on a sample of blood as small as five micro-litres. In contrast blood gas analysis requires considerably larger blood volumes in the region of 35 μl. For FBS a considerable reduction in attempt failure has been noted when lactate rather than ph values were sought, 1042,1506,1611,1629 with one author stating that the failure of fetal scalp blood sampling has almost been abolished The same reduction in the number of inaccurate or failed umbilical cord blood sampling procedures could potentially occur with use of cord lactate rather than blood gas analysis. Further, the direct measurement of lactate has a considerable advantage over the primary other marker of metabolic acidaemia, BE which is calculated. Base excess can be calculated from a number of formulae depending on the machine utilised, and any error in the variables within the formula will create errors in the final result. 27,83,1632 Given that lactate analysis can be undertaken at the bedside with handheld lactate meters, cord blood can be sampled and analysed immediately allowing rapid exploitation of the provided information. In contrast, cord blood gas analysis entails either sending the sample to a distant laboratory or a member of the perinatal team leaving the bedside to conduct analysis. Handheld lactate meters also act to mitigate one of the significant difficulties associated with umbilical vessel lactate analysis; stability of the measure over time (as seen in Chapter Three). No matter what actions are taken to try and limit changes in lactate values once samples are collected, they become statistically different within 15 minutes after delivery. In contrast, umbilical cord blood gas values remain stable for up to 60 minutes. 264 P a g e

287 The application of umbilical cord lactate analysis on universal scale has not met with the practical advantages that have been previously suggested. Whilst numerous studies have noted that handheld lactate meters are accurate, reliable and precise, the transition to clinical practice has revealed that there remain a number of significant technical issues when the meters are utilised outside the research arena. This is reflected in Chapter Six, where a significant proportion of neonates had no lactate values available due to technical difficulties associated with use of lactate meters not being able to cope with the comparatively large blood volumes associated with umbilical cord blood sampling. While Chapter Seven has conclusively demonstrated that cord blood gas analysis is a costeffective proposition, small maternity units with limited resources and numbers of deliveries per year may still not be able to afford to introduce a universal UCBGA program. In such a situation, the costs of a lactate meter, approximately AU$300, would represent a more tenable investment particularly given that each test costs in the region of one Australian dollar. These low incurred costs even if associated with a fraction of the improvements detailed in Chapter Seven would be suggestive of a cost-effective proposition. At this point in time, the majority of the information relating to the benefits of universal biochemical analysis is associated with cord blood gas analysis, and suggests where possible universal cord blood gas analysis should be considered. There is now a growing body of evidence that suggests that in environments where cord blood gas analysis may not be a viable option, a reasonable alternative would be cord lactate analysis. 9.4 Other biochemical and biological markers of perinatal asphyxial injury The number of potential markers of perinatal asphyxial injury is continually increasing as investigators expand their horizons into new molecular and biochemical arenas (Table 9.1.). Generally, the biochemical markers can be divided into two broad categories; those that measure factors involved in cellular metabolism and the hypoxic effects (i.e. purine metabolism and metabolic acidosis measures) and those measuring factors that are involved in or follow tissue damage (i.e. free radicals and excitatory amino acids). The potential exists that the combination of these two categories in the future, would allow exact insult timing to be elucidated; once it s known what the time lag after injury that various changes in factor concentrations occurs. 53,1678 This will allow a clear differentiation between antenatal and intrapartum insults that result in neurological damage. At this time; however, most markers are limited in clinical application, as they require samples that are not practicably obtained on 265 P a g e

288 large numbers of neonates, or extensive laboratory equipment and expertise that are also not practicably possible. That being so, studies such as that by Nagdyman et al. have noted that several biochemical measures are able to predict adverse neonatal outcomes, such as HIE, with a reasonable degree of sensitivity and specificity Table 9.1. Potential biochemical markers of intrapartum fetal hypoxia Cerebrospinal Fluid Plasma Other Aspartate Creatinine kinase isoenzymes Glial fibrillary acidic protein Glutamate Hydoxybutyrate dehydrogenase Lactate dehydrogenase N-Methyl-D-aspartic acid Neuron-specific enolase Hypoxanthine Glycine Kynurenic acid Erythropoietin Anti-diuretic hormone Erythropoietin Purine catabolic products Non-protein bound iron Astroglial calcium binding protein S100 Activin-A Platelet activating factor Lactate dehydrogenase Aspartate aminotransferase Alanine aminotransferase Neurokinin A Adenosine Adrenaline Dopamine Endothelin-1 Hypoxanthine Lactate/pyruvate ratio Malondialdehyde Noradrenaline Organic hydroperoxides Molecular predictors of hypoxia Given the growing use of molecular medicine, both in laboratory and clinical settings, it is inevitable that there will be attempts to utilise such methods in the identification of individuals at risk of hypoxic-ischaemic insults or are less likely to be able to manage such an insult. The presence of fetal ribonucleic acid and deoxyribonucleic acid in the maternal circulation, persists throughout the peripartum period and up to 15 minutes after delivery Some authors have suggested it might be possible to test a maternal blood sample for genes indicative of placental hypoxia and a fetus at risk This idea is based on the premise that tissue hypoxia being tightly regulated by hypoxia inducible factor that when released binds to a variety of promoter regions and up-regulates genes to produce a fetal response to the hypoxic conditions, 1686 any of these approximately 100 genes could be targeted to identify the fetus at risk. 9.5 Future research The studies within this thesis used a variety of outcomes; however, due to study size and time constraints the adverse outcomes evaluated were typically proximal to delivery. The implementation into metropolitian and regional secondary level maternity units was only able 266 P a g e

289 to evaluate cord blood gas or lactate values, and to a lesser extent Apgar scores as endpoints due to the relative scarcity of adverse neonatal outcomes. This reflects the smaller number of deliveries as well as the less complicated presenting population at secondary level maternity units. Further follow up of umbilical cord blood gas and lactate analysis at the regional and metropolitan study sites would increase the cohort size and provide a better delineation of potential benefit. The larger and more complicated KEMH cohort allowed the use of neonatal neurological outcomes, such as HIE as an outcome. The key outcome that most clinicians and parents are concerned about is survival and long-term neurodevelopmental function. For early predictors of neurodevelopmental function to be adequately assessed, a large cohort of neonates would need to be followed over an extended period of time, ideally until after the commencement of schooling. Such a study, whilst theoretically possible, would be associated with significant practical difficulties; not least the financial costs of establishing and following a cohort of sufficient size. Lactate acidaemia has been noted to be present in a number of neonatal conditions other than hypoxia and ischaemia, including septicaemia, hypovolaemia, cold stress and inborn errors of metabolism. 1627,1687 Despite this, there is a relative dearth of information concerning differential diagnoses for elevated lactate values. Consequently, factors influencing umbilical cord blood gas and lactate values need to be more thoroughly investigated particularly the impact of maternal, fetal and neonatal infection on cord blood gas and lactate values. The technical issues noted with cord blood lactate analysis in Chapter Six also need to be addressed, if cord lactate analysis is to be readily utilised in the clinical environment. This issue could be potentially ameliorated with the development of an analyser better able to cope with the relatively larger blood volumes of cord blood gas analysis. One potential modification to existing lactate meters could be the addition of a membrane or barrier to prevent ingress of blood. Alternatively, rather than placing blood on the lactate strip whilst it is in the meter, a mechanism to draw the blood from a syringe into the device by capillary or direct action, could be developed. Such a mechanism would also greatly aid FBS analysis when samples have been collected in capillary tubes, although may result in additional complexity and expense for lactate meters. 9.6 Conclusion The data presented in this thesis has for the first time provided objective evidence that the introduction in a tertiary centre of universal UCBGA is a cost-effective proposition. The 267 P a g e

290 benefits of universal UCBGA previously described in a tertiary centre have been found to extend to primary and secondary level maternity units. Introduction of universal lactate analysis into clinical practice for the first time has also revealed a number of technical issues that have not previously been reported and have limited its practical utility. That being so, umbilical artery lactate values when combined with measures of neonatal resuscitation are very effective predictors of later development of moderate to severe HIE. Together with previously published data, the data presented in this thesis supports the introduction of universal UCBGA to all deliveries with the expectation that it may improve perinatal outcome. 268 P a g e

291 APPENDICES Appendix A: Outcome of Neonates Exposed to Perinatal Asphyxial Injury Appendix B: Incidence/Prevalence of Perinatal Asphyxia Appendix C: Incidence/Prevalence of Perinatal Asphyxia Related Mortality Appendix D: Incidence/Prevalence of Neonatal Encephalopathy, and Hypoxic-Ischaemic Encephalopathy Appendix E: Incidence/Prevalence of Cerebral Palsy Appendix F: Electronic Fetal Monitoring versus Intermittent Auscultation Appendix G: Prognosis and Aetiological Background of Vigorous Neonates with Acidaemia Appendix H: Publications Arising From this Thesis 269 P a g e

292 Appendix A: Outcome of Neonates Exposed to Perinatal Asphyxial Injury Study N Asphyxia Definition Follow-Up Results Low et al., Umbilical arterial BB<34 meq/l 12 mths 9/41 (22% minor motor/cognitive deficits 4/41 (10%) major motor/cognitive deficits Low et al., Umbilical arterial BB <34 meq/l 12 mths 10/37 (27%) minor deficits 5/37 (14%) major deficits Moderate HIE: 4/10 (40%) deficits (3 minor, & 1 major) Severe HIE: 3/3 (100%) major deficits Niswander et al., Antenatal/perinatal catastrophic event 4 yrs 256/1125 (23%) perinatal deaths Scott, Intense resuscitation with: stillbirth; or delayed respiration>20 min 3-7 yrs 25/48 (52%) neonatal deaths 6/48 (13%) cerebral palsy Mulligan et al., Delayed (>1min) spontaneous respirations 4-5 yr 1/7 (14%) deaths 6/7 (86%) significant handicap D Souza et al., Intensive resuscitation>5 min 2-5 yr 6/26 (23%) slight/doubtful neurological abnormality 2/26 (8%) neurological abnormality without disability 2/26 (8%) neurological abnormality & disability Ergander et al., Five min Apgar yr 16/76 (21%) deaths 3/76 (4%) mild handicap 13/76 (17%) severe handicap Dennis et al., Umbilical artery metabolic acidaemia 4.5 yr No significant association between acidaemia & developmental outcome: however, greatest proportion of impairment was found in most acidaemic group Thomson et al., One min Apgar=0, or five min Apgar< yrs 2/31 (6%) handicap No difference between cases & controls Adapted from Dilenge et al., Note: HIE: hypoxic-ischaemic encephalopathy

293 Study N Asphyxia Definition Follow-Up Results Ishikawa et al., One min Apgar<6, & CNS complication 3-13 yrs 23/86 (27%) neonatal deaths 5/55 (9%) mild handicap 8/55 (15%) severe handicap Handley-Derry et al., Base deficit>12 mmol/l, & no/mild HIE 6-8 yr No difference between cases & controls Brown et al., Neurologic symptoms, with: antenatal sentinel event; fetal distress; one min Apgar<3; five min Apgar<5; intubation/ventilation; or severe respiratory distress 21 mths 15/93 (16%) mild handicap 13/93 (14%) moderate handicap 11/93 (12%) severe handicap 20/93 (22%) death Sarnat and Sarnat, Fetal distress, five min Apgar<5, & HIE 12 mths Moderate NE: 3/14 (21%) motor deficits Severe NE: 1/5 (20%) death, & 4/5 (80%) severe handicap Finer et al HIE &: one/five min Apgar < 5; fetal distress; resuscitation; & ventilation>5 min Gray et al., Moderate-severe HIE with two of: fetal distress; five min Apgar<6; ph<7.15; or resuscitation 3 mths-5 yrs 6 died prior to follow-up, & 6 were lost Mild HIE: 6/25 (24%) mild handicap Moderate HIE: 14/39 (36%) moderate-severe handicap, & 1/39 (3%) died Severe HIE:7/12 (58%) moderate-severe handicap, & 5/12 (42%) died 12 mths Moderate HIE: 4/13 (31%) adverse outcome Severe HIE: 7/13 (54%) handicap, & 6/13 (46%) death Thornberg et al., Five min Apgar < 7 >18 mths No HIE: 3/152 (2%) disability Mild HIE: 0/36 (0%) disability Moderate HIE: 8/17 (47%) disability 53 Abnormal FHR, & severe neurological Severe HIE: 12/12 (100%) death/severe disability De Souza and Richards, 2-5 yrs 7/53 (13%) borderline disability abnormality 3/53 (6%) disability without handicap 1/53 (2%) severely disabled & handicapped Adapted from Dilenge et al., Note: CNS: central nervous system: HIE: hypoxic-ischaemic encephalopathy; NE: neonatal encephalopathy.

294 Study N Asphyxia Definition Follow-Up Results Finer et al., HIE with: fetal distress one/five min Apgar<5; resuscitation; or ventilation >5 min 27 mths Mild HIE: 0/7 (0%) handicapped Moderate HIE: 13/41 (41%) mild handicap, & 7/41 (17%) moderate handicap Robertson and Finer, HIE, fetal distress, one/five min <5, & resuscitation Shankaran et al., Three of: fetal distress; MSAF; intubation; or abnormal tone and/or seizures at <24 hrs Severe HIE: 1/1 (100%) handicap 3.5 yrs Mild HIE: 0/66 (0%) handicap/death Moderate HIE: 26/103 (25%) handicap/death Severe HIE: 28/28 (100%) handicap/death 5 yrs 4/28 (14%) neonatal deaths 10/28 (36%) abnormal neurodevelopmental outcome Yudkin et al., One min Apgar 3 5 yr 21/170 (12%) mild-moderate impairment 11/170 (6%) serious impairment/neonatal deaths Robertson et al., HIE, fetal distress, one/five min Apgar <5, & neonatal resuscitation Sato et al., min Apgar score <6 &/or neonatal resuscitation 8 yr Similar scores for mild HIE & controls Significantly lower scores for moderate & severe HIE Moderate HIE: 5% die, 15% neurologically disabled, & 80% intellectual/cognitive deficits Severe HIE: 82% die, & 18% neurologically disabled Discharge 3 (2.1%) EEG neonatal seizures only 3 (2.1%) EEG neonatal seizures & severe neurological abnormalities i.e. coma/hypotonia Low et al., No NE & umbilical arterial 6 yr No difference between cases & controls BB<34mEq/L Korkman et al., Five min Apgar 6, or ph yr No difference between cases & controls Adapted from Dilenge et al., Note: EEG: Electroencephlography; FHR: fetal heart rate; HIE: hypoxic-ischaemic encephalopathy; MSAF: meconium stained amniotic fluid.

295 Appendix B: Incidence/Prevalence of Perinatal Asphyxia Developed Nations * Place Years Incidence (per 1,000) Turku June May 1982 Landspitali University Hospital, Reykjavík Cohort Size Criteria Source Finland ,340 live births Pathological CTG trace ± 1 minute Apgar < 6 ± 15 Piekkala et al., minute Apgar < 8 Iceland ,495 term live births Five minute Apgar score less than six Palsdottir et al., Malaysia Kuala Lumpur 2 months ,018 live births FHR abnormalities, one min Apgar 7, &/or delayed spontaneous respirations Boo and Lye, Sweden Göteborg ,203 live births Five min Apgar<7 & gestation 37 wks Palme-Kilander, 1992; Stockholm 6.9 Five min Apgar<7 5.4 Five min Apgar<7, term & nil other aetiologies Thornberg et al, 1995 and, Milsom et al., ,455, ,648 live births One minute Apgar score 3 or five minute 6 Palme-Kilander, ,969 deliveries Five min Apgar 3 Ergander et al., Note: * Distinction based on the 2006 United Nations Human Development Index with low and medium ranked countries considered developing countries.

296 Developed Nations * Place Years Incidence (per 1,000) Cohort Size Criteria Source United Kingdom Edinburgh, Scotland 3 years ,020 live births Feeding difficulty necessitating tube feeding, apnoeic/cyanotic attacks, apathy, convulsions, hypothermia, cerebral cry ± persistent vomiting Brown et al., California United States of America 5,364,663 live births ICD-9-CM Code 768.6, & Wu et al., United States of ,498 singleton live births Five minute Apgar<7 Nelson and Ellenberg, America 15.7 Five minute Apgar< Ten minute Apgar<4 Pittsburgh ,621 term births > 1 min positive pressure ventilation MacDonald et al., Note: * Distinction based on the 2006 United Nations Human Development Index with low and medium ranked countries considered developing countries.

297 Developing Nations * Place Years Incidence Cohort Size Criteria Source (per 1,000) India New Delhi, India ,371 deliveries excluding lethal & Intrapartum & neonatal evidence of Chandra et al., major malformations asphyxial insult Mumbai, India ,579 deliveries 1,947 deliveries Five minute Apgar<7 Mane and Daga, New Delhi 4 years 7,015 Singh et al., India 85 1,208 singleton deliveries Chaturvedi and Shah, Kuwait Kuwait 9.40 Term deliveries al-alfy et al., Libya Libya 1 year 28 16,365 live births >1 min positive pressure ventilation Mir et al., Nigeria Calabar unorthodox location deliveries Baby not crying soon after delivery Etuk and Etuk, hospital deliveries despite stimulation years Live births Airede, Other 3 months 229 4,267 deliveries Kinoti, East, Central & Southern Africa Papua New Guinea Port Moresby 2.5 years ,700 live births Oswyn et al., Note: * Distinction based on the 2006 United Nations Human Development Index with low and medium ranked countries considered developing countries.

298 Appendix C: Incidence/Prevalence of Perinatal Asphyxia Related Mortality Developed Countries * Place Years Incidence (per 1,000) Royal Victoria Hospital Montreal Turku Cohort Size Asphyxial Definition Source 29,101 births 31,541 births Canada Fretts et al., Finland 81,620 live births Piekkala et al., Germany Hesse ,930 term vaginal deliveries Obstetrician defined based on ICD-9 Heller et al., Republic of Ireland Dublin ,655 live births >500gm Term/postterm with fetal bradycardia, low five minute Apgar score & HIE with other aetiologies excluded. Halligan et al., Israel Israel ,083 live births Hammerman and Zadka, Note: * Distinction based on the 2006 United Nations Human Development Index with low and medium ranked countries considered developing countries.

299 Developed Countries * Place Years Incidence (per 1,000) Scotland ,012,266 singleton cephalic term deliveries Cohort Size Asphyxial Definition Source United Kingdom Modified Wigglesworth classification Pasupathy et al., Stewart et al., Wales ,206 births Stillborn/death <28 days postpartum, birth weight>1499g, & previous definition. 1708,1710 Oxfordshire January ,682 singleton live births Modified ACOG definition Yudkin et al., September ,110 singleton term live births Royal Maternity Hospital, Belfast ,009 live births Asphyxia pallid, or Asphyxia livida for > 2 minutes Campbell et al., United States of America California ,364,663 live births ICD-9-CM Code 768.5, and/or Wu et al., United States of America ,914,953 live births 3,899,589 live births 3,491,228 live births ICD Guyer et al., Note: *Distinction based on the 2006 United Nations Human Development Index with low and medium ranked countries considered developing countries.

300 Developing Countries * Place Years Incidence Cohort Size Asphyxial Definition Source (per 1,000) Benin Borgon births Tomlinson et al., India New Delhi 4 years 7,109 births Singh et al., Maharashtra August 1977-July ,173 births 3,083 live births Stillbirths Neonatal deaths Shah et al., 1984; and Shah et al., Malaysia Kuala 2 months 1.5 4,018 live births Sarnat Criteria & FHR abnormalities, one min Boo and Lye, Lumpur Apgar 7 ± delayed spontaneous respirations Nepal Kathmandu ,771 term births Ellis et al., Nigeria Lagun live births Lawoyin et al., Calabar births in unorthodox places Baby not responsive to stimulation Etuk and Etuk, South Africa South Africa ,348 births Velaphi and Pattinson, South Africa Jan-Oct ,508 births >1,000 gms Buchmann et al., Vanuatu Vila ,445 births Maouris, Note: * Distinction based on the 2006 United Nations Human Development Index with low and medium ranked countries considered developing countries.

301 Appendix D: Incidence/Prevalence of Neonatal Encephalopathy, and Hypoxic-Ischaemic Encephalopathy Place Years Incidence (per 1,000) Perth, Western Australia Perth, Western Australia Royal Alexandra Hospital, Edmonton North Pas-De- Calais Landspitali University Hospital, Reykjavík June 1993 September ,160 term livebirths w/o chromosomal or neural tube defects Cohort Criteria Source Australia Moderate-severe modified Sarnat et al. NE definition Badawi et al., 1997; Badawi et al., 1998; and Badawi et al., mths in Term live births NE (including dysmorphic syndromes) Adamson et al., Canada September 1974 December ,155 live births Abnormal neurological examination 2 of following: 1. Altered consciousness 2. Global hypo/hypertonia or localised tone disturbance 3. Abnormal primitive reflexes Intrapartum origin 1 of following: 1. Abnormal FHR pattern ± MSAF 2. 1 or 5 min Apgar < 5 3. Need for bag & mask resuscitation/intubation Finer et al., France ,235 term live births Moderate-severe Sarnat et al. NE definition Pierrat et al., ,235 term live births Moderate-severe Sarnat et al. NE definition & intrapartum hypoxic-ischaemic injury evidence Iceland ,495 term live births Palsdottir et al.,

302 Place Years Incidence Cohort Criteria Source (per 1,000) India Mumbai ,579 deliveries Mane and Daga, HIE ,947 deliveries New Delhi 59 Singh, Kuwait Kuwait City ,591 Term Fetal distress/low Apgar & HIE al-alfy et al., Malaysia Kuala 2 months 4.5 4,018 live births FHR abnormalities, one min Apgar 7 ± delayed spontaneous Boo and Lye, Lumpur respirations as well as Sarnat criteria Nepal Kathmandu ,371 term births NE (excluding major dysmorphic syndrome/infection) Ellis et al., Nigeria Nigeria ,261 Fetal distress & HIE Airede, Saudi Arabia Abha, Asir 3 years 4.9 Live Births Term AlShehri and Eid, Madina Al- Munawara June 1995 May ,730 term births Sarnat criteria Itoo et al., Sweden Göteborg ,203 live births Sarnat et al. NE definition, fetal distress & Apgar < 7 Milsom et al., Göteborg ,203 live births 6,440 live births 6,741 live births 6,231 live births 6,152 live births 5,879 live births 5,432 live births 5,328 live births Five min Apgar<7, other aetiologies excluded & Fenichel et al. HIE definition Thornberg et al.,

303 United Kingdom Place Years Incidence Cohort Criteria Source (per 1,000) Derriford Hospital, Plymouth, Devon May 1993-April ,890 births Sarnat grade 2 or 3 HIE with no other attributable cause Allwood et al., Southwest Thames ,159 births Expanded Badawi et al. NE definition Evans et al., Region, England Derby, Derbyshire ,804 live births 24,265 live births 24,824 live births Levene et al. HIE defintion Hull and Dodd, 1992; and, Smith et al., ,443 South West Thames Region, England Trent Region, Devon Trent Region, Devon Leicester, Leicestershire July July ,000 term live births w/o chromosomal or neural tube defects March 1990-? ,000 births 35 weeks gestation w/o congenital anomalies or other reasons for adverse clinical condition April March 1993 Clincal seizures, apnoea & cyanotic spells or any one of: increased muscle tone, decreased muscle tone, abnormal consciousness or feeding problems of central origin in first 4 days grade two NE based on Sarnat & Sarnat criteria & 1 of the following: low Apgars, heavy meconium in labour, midwife diagnosed fetal distress, CTG abnormality, reduced fetal movements ± low cord ph ,435 live births Grade II HIE: history suggestive of asphyxia & convulsions, Grade III HIE: Grade II HIE & need for respiratory support ,975 live births Modified Fenichel et al. HIE definition, and fetal distress Badwai et al., Badwai et al., Bohin et al., Levene et al.,

304 Appendix E: Incidence/Prevalence of Cerebral Palsy Place Years Incidence Cohort Study (per 1,000) Australia Victoria ,897,290 live births Reid et al., Western Australia ,995 term live births Badawi et al., Western Australia ,420 live births 85,929 live births 83,137 live births Stanley and Watson, Western Australia Five year old neonatal survivors Western Australia Northern Alberta Nova Scotia Canada Stanley and Watson, Neonatal survivors Stanley, 1979; Stanley, 1980; and Stanley, , ,138 live births weeks gestation 672 live births weeks gestation Robertson et al., Vincer et al., Alberta ,359 3 year olds Robertson et al., Adapted from Henderson, 1961 and Pharoah, P a g e

305 Place Years Incidence (per 1,000) Denmark Eastern Denmark Eastern Denmark Cohort Live births Live births Frederiksborg 4.1 4,138 live born 4 y.o. children Funen, Syddanmark Denmark, France, & England Denmark, Eire, France, Italy, Netherlands, Norway, Sweden, & United Kingdom Denmark, France, Eire, Italy, United Kingdom, & Sweden Turku Haute-Garonne, Isère, & Saône et Loire Aquitaine, Lorraine, Picardie, Essonne, Val d'oise & Seine et Marne Hong Kong Study Topp et al., Topp et al., Andersen et al., Thomsen, Europe ,331 live births Rankin et al., Live births with birth Platt et weight < 1500 grams al ,124,962 live births SCPE, Finland ,761 live births followed 2.5 to 5 y.o. France Riikonen et al., ,347 children Rumeau- Rouquette et al., Rumeau- Rouquette et al., Hong Kong Special Administrative Region September , y.o. children Yam et al., June 2004 Adapted from Henderson, 1961 and Pharoah, P a g e

306 Place Years Incidence (per 1,000) Cohort Iceland Iceland ,036 live births ,711 live births ,563 live births ,916 live births ,837 live births ,641 live births ,725 live births ,603 live births ,505 live births ,281 live births ,254 live births Kashmir Padua, & Rovigo 1 st Nov Shiga Prefecture Tottori Prefecture Malta, & Gozo India Italy 63,645 total population 334,589 live births Japan 242,293 6 y.o. school children 74,067 6 y.o. school children 81,765 6 y.o. school children 86,501 6 y.o. school children 14,072 6 y.o. school children 14,408 6 y.o. school children 14,537 6 y.o. school children 15,510 6 y.o. school children 15,500 6 y.o. school children 15,828 6 y.o. school children 16,049 6 y.o. school children 16,603 6 y.o. school children 16,676 6 y.o. school children 16,6096 y.o. school children 16,099 6 y.o. school children 16,714 6 y.o. school children 17,225 6 y.o. school children 17,921 6 y.o. school children 18,542 6 y.o. school children Live births followed to 3 y.o. w/o postnatal causes Malta Adapted from Henderson, 1961 and Pharoah, ,200 live births assessed at 3½ 13½ y.o. Study Gudmundsson, Razdan et al., Bottos et al., Suzuki and Ito, Takeshita et al., Sciberras and Spencer, P a g e

307 Place Years Incidence (per 1,000) Cohort Netherlands Gelderland ,376 neonatal survivors Study Wichers et al., New Zealand Otago 2.50 Births Barclay, Norway Norway Live births Andersen et al., Nordland Birth weight< 1.500g Herder, Vestfold ,976 live births 500g followed to 4 y.o. Meberg and Broch, Ostfold Live births Andersen, People s Republic of China Jiangsu ,192 children<7 yrs Liu et al., Republic of Ireland Galway, Mayo, & Roscommon Dublin, Kildare, & Wicklow ,231 neonatal survivors surveyed at 2-5 y.o Cork & Kerry All births followed to 4 y.o. Live births Slovenia Maribor One year old survivors Slovenia ,585 live births ,639 live births ,884 live births ,704 live births ,909 live births ,089 live births ,839 live births ,058 live births ,031 live births ,001 live births ,431 live births Adapted from Henderson, 1961 and Pharoah, Mongan et al., Dowding and Barry, Cussen et al., Burja et al., Kavcic and Perat, P a g e

308 Place Years Incidence Cohort Study (per 1,000) Sweden Southwest Sweden ,371 live births Himmelmann et al., Southwest Sweden ,724 live births Hagberg et al., Skane, & Blekinge ,514 live births Nordmark et al., Southwest Sweden ,542 live births Hagberg et al., Southwest Sweden ,085 live births Hagberg et al., Southwest Sweden ,666 live births Hagberg et al., Southwest Live births Hagberg et al., Sweden Malmöhus Southwest Sweden ,906 live births 32,668 live births 32,238 live births Live births Lagergren, Hagberg and Olow, Skåne Live births Lagergren, Ostergotland ,100 children aged 2-12 y.o. Turkey Duzce ,000 children aged 1-15 y.o. Herlitz and Redin, Ozturk et al., , y.o. children Serdaroglu et al., Turkey July-October 1996 Gemlik , y.o. children Okan et al., Adapted from Henderson, 1961 and Pharoah, P a g e

309 United Kingdom Place Years Incidence Cohort Study (per 1,000) Merseyside, ,910 CP cases Cheshire, Berkshire, Buckinghamshire, Surman et al., Northamptonshire, Oxfordshire, Northern Ireland & Scotland Northern Ireland ,936 live births Dolk et al., Brimingham, , yrs Coventry, , yrs Winter et Walsall, & , yrs al Stoke-on-Trent, , yrs England Northern Ireland All children born or resident in Northern Ireland Newcastle, Northumberland, & North Tyneside. Northumberland, Newcastle, & North Tyneside ,691 neonatal survivors 48,095 neonatal survivors 48,079 neonatal survivors 45,122 neonatal survivors 54,635 neonatal survivors 64,866 neonatal survivors ,289 neonatal survivors Northern Ireland ,363 live births at 5-9 yrs North East Thames ,666 neonatal Regional Health survivors Authority Merseyside, Cheshire, Berkshire, Buckinghamshire, Northamptonshire, Oxfordshire, & Scotland ,760 neonatal survivors Parkes et al., Colver et al., Jessen et al., Parkes et al., Williams and Alberman, Pharoah et al., Bradford District Health Authority ,564 births Sinha et al., Oxfordshire Jan Sept ,682 singleton live births Yudkin et al., Adapted from Henderson, 1961 and Pharoah, P a g e

310 United Kingdom Place Years Incidence (per 1,000) Avon Cohort 236,920 births 67,765 births 53,227 births 55,920 births 60,008 births Study MacGillivray and Campbell, Scotland neonatal survivors with birth weight <1750g Anon, Mersey All live births Pharoah et al., England, Scotland, & Wales ,136 neonaal survivors 16,751 neonatal survivors Emond et al., Mersey ,146 live births Pharoah et al., South East ,000 live births Evans et al., Thames Regional Health Authority Ashford, Middlesex Birmingham, England Edinburgh, Scotland Birmingham Coventry, Stokeon-Trent, & Walsal, England ,157 children aged 0-5 y.o. Jenkins et al., ,790 live births ,875 live births ,352 live births ,281 live births ,906 live births ,478 live births Griffiths and ,773 live births Barrett, ,820 live births ,566 live births ,301 live births ,355 live births ,833 live births ,054 live births ,285 births 21,200 births 24,100 births 20,428 births 19,025 births 19,532 births School children aged 5 15 y.o. Adapted from Henderson, 1961 and Pharoah, Ingram, Asher and Schonel, P a g e

311 United States of America Place Years Incidence Cohort Study (per 1,000) California ,145,357 live births Gilbert et al., Atlanta, Georgia ,593 eight year olds 36,749 eight year olds Bhasin et al., Atlanta, Georgia Live births Winter et al., San Francisco, California live singleton <1500g 637 live singleton <1500g 882 live singleton <1500g Grether and Nelson, Northwest Kirby et al., Live births Arkansas United States of Boyle et al., ,110 children 17 years America California ,636 3 y.o. survivors Grether et al., 1992; and Cummins et al Atlanta, Georgia y.o. children Yeargin- Allsopp et al., 1992; and Murphy et al., Copiah County, Mississippi 2.12 Haerer et al., Rochester, Minnesota Neonatal survivors Kudrjavcev et al., New Jersey, & Maryland 4.00 Births Phelps, Adapted from Henderson, 1961 and Pharoah, P a g e

312 Appendix F: Electronic Fetal Monitoring versus Intermittent Auscultation There is considerable debate concerning the best method of intrapartum fetal monitoring particularly focusing on comparing EFM and IA. The latest Cochrane review comparing continuous EFM and IA, included over 33,000 deliveries from 11 RCTs and seven countries (Australia, Denmark, Greece, Ireland, Pakistan, UK, and USA). 751 Amongst neonates monitored with EFM there was a significantly increased caesarean delivery rate, with a difference in risk of caesarean delivery of 5% (95%CI 2%, 8%). The authors concluded that there was an additional caesarean delivery for every 58 deliveries (95%CI 43, 87) monitored using continuous EFM. There was also an increased risk of caesarean delivery for abnormal FHR or fetal acidaemia as well as instrumental delivery amongst those monitored with EFM. Further, FBS was used significantly more often amongst those monitored with EFM. Between studies there was a substantial degree of caesarean delivery rate heterogeneity, although all studies demonstrated either an increase or no significant difference in caesarean delivery rates with continuous EFM. The risk of a caesarean delivery was influenced by RCT quality (interaction test p=0.02). Limiting analysis to the two high quality RCTs, 721,788,917,1067,1770 did not alter heterogeneity, which remained significant (I 2 =54.9%); however, the difference in rates of caesarean delivery between EFM and IA did not remain significant (RR 1.27; 95%CI 0.88, 1.83). Amongst included RCTs there was considerable variance in caesarean rates ranging from 2.3% to 35%. Post-hoc sensitivity analysis evaluating outcomes amongst EFM neonates in trials with low (less than 10%) and high (greater than 10%) caesarean delivery rates, revealed a significant increase in caesarean deliveries with continuous EFM in both cohorts. The magnitude of the increase in caesarean delivery rates was greater in the group with higher caesarean section rates (interaction test: chi-squared 12.7; degrees of freedom 1; p<0.001). An increased operative delivery rate with EFM, primarily caesarean deliveries, has been noted in a number of other meta-analyses. 820, There was a small increase in analgesia utilisation amongst those with EFM; however, there was no difference in pharmacological and epidural analgesia. Alfrirevic et al. postulated that maternal position (supine) during EFM may increase the pain experienced; however, they also noted that during the period most RCTs were conducted those with IA monitoring probably also laboured supine. 751 Further, given that any analgesia encompassed operative anaesthesia and the EFM group had a higher caesarean and instrumental delivery rate this 290 P a g e

313 group would be expected to require more analgesia/anaesthesia. Consequently, it cannot be reasonably concluded that EFM results in a more painful delivery based on analgesia/anaesthesia utilisation. There was no significant difference in perinatal mortality rates between the monitoring types, although the authors noted it would be unrealistic to expect that any intrapartum intervention in modern maternity care will result in a statistically significant improvement in perinatal deaths. 751 Furthermore, despite the meta-analysis size (n=33,000), a much larger cohort (greater than 50,000) would be required to establish whether continuous EFM would be able to prevent one case of perinatal mortality in a thousand deliveries. That being so, other meta-analyses noted that while the overall perinatal mortality rate was not different (4.2 per 1,000 vs. 4.9 per 1,000) between monitoring modalities, the hypoxia associated perinatal mortality rate was significantly reduced with EFM (0.7 per 1,000 vs. 1.8 per 1,000; OR %CI ). 907 A more recent study evaluated the relationship between EFM and perinatal mortality, using 1,732,211 singleton live births derived from the USA National Center for Health Statistics 2004 birth cohort, which comprised 42% of all 2004 deliveries in the USA. 742 Those with EFM had significantly lower early neonatal mortality rates (0.8 vs. 1.7 per 1,000 births; p<0.001) and infant mortality rates (3.0 vs. 4.0 per 1,000 births; p<0.001), but no significant difference in late mortality rates (0.5 vs. 0.6 per 1,000 births; p=0.402) or post-neonatal mortality rates (1.7 vs. 1.8 per 1,000 births; p=0.296). The effect of mortality reduction varied across gestational age range (Table F.1.), with EFM associated with a lower risk of early neonatal mortality, regardless of gestational age. Considering CP there was no difference between EFM and IA, although Alfrienz et al. noted the lower limit of the 95%CI was close to one, implying that while continuous EFM was found to have no impact on CP it may be associated with an increase. 751 That being so, the data regarding CP was drawn from only two studies containing 13,252 participants. The first RCT conducted in Dublin, Ireland found no significant difference in CP between EFM and IA (EFM 0.18% vs. IA 0.15%; RR 1.20; 95%CI 0.52, 2.79; n=13,079). 721,788,917 The authors conducted follow-up on all 30 children who survived neonatal seizures and 125 of the 138 children (91%) with other neonatal neurological abnormalities. 788 Out of this cohort, seven neonates had CP at four years of age, of which the authors postulated that intrapartum asphyxial injury may have contributed to three cases. Fifteen other neonates that developed 291 P a g e

314 CP that were not available for follow-up were identified from local specialist medical services. Consequently, there were 22 CP cases identified out of an original population of 13,079 (0.17%), although some additional cases may have been missed. Table F.1. Comparison of mortality and neonatal morbidity by gestational ages between those monitored with and without EFM Mortality Gestational Age Early Neonatal (0-6 days) Late Neonatal (7-27 days) Post-Neonatal ( days) Infant (0-364 days) All 0.50 (0.44, 0.57) 0.91 (0.74, 1.12) 0.91 (0.81, 1.02) 0.75 (0.69, 0.81) (0.54, 0.72) 0.97 (0.72, 1.31) 1.06 (0.77, 1.45) 0.78 (0.70, 0.87) (0.37, 0.70) 1.25 (0.67, 2.33) 0.98 (0.65, 1.49) 0.75 (0.60, 0.95) (0.21, 0.75) 0.88 (0.31, 2.52) 0.83 (0.47, 1.49) 0.66 (0.44, 0.98) (0.24, 0.71) 1.08 (0.54, 2.15) 1.03 (0.73, 1.44) 0.87 (0.67, 1.13) > (0.47, 0.90) 0.90 (0.63, 1.27) 0.89 (0.78, 1.03) 0.86 (0.76, 0.97) Morbidity Gestational Age Five Minute Apgar Score < 4 Neonatal Seizures Five Minute Apgar Score < 4 or Neonatal Seizures All 0.54 (0.49, 0.59) 0.85 (0.70, 1.03) 0.60 (0.55, 0.65) (0.50, 0.67) 0.61 (0.53, 0.72) (0.41, 0.74) 0.49 (0.16, 1.49) 0.57 (0.43, 0.76) (0.31, 0.78) 0.55 (0.34, 0.86) (0.36, 0.64) 0.80 (0.45, 1.43) 0.54 (0.42, 0.70) > (0.54, 0.71) 0.86 (0.70, 1.07) 0.68 (0.61, 0.77) Adapted from Chen et al., Note: Insufficient number of neonatal seizures The other RCT in USA and Canada, included only very preterm or low birth weight neonates (<32 weeks or <1750 grams) with a CP rate of 19.5% (16/82) in the continuous EFM group and 7.7% (7/91) in the IA group (RR 2.54; 95%CI 1.10, 5.86; n=173) The study also noted significantly higher proportions of neonates with low mental and psychomotor developmental scores at 18 months and a lower mean adjusted mental developmental index at four months amongst those with EFM It can be seen this second study despite its small size heavily influenced the meta-analysis due to its high CP incidence. Given this study only included preterm neonates and excluded neonates with a birth weight greater than 1750 grams; amounting to 34% of the initial randomised cohort there may be some bias. Furthermore, use of 99% CI rather than 95% CI caused the difference to disappear. The management protocol for those with EFM was considerably different to those monitored with IA. If there was an EFM FHR abnormality, protocol dictated FBS should occur and delivery could only occur based on abnormal ph values or a FHR abnormality greater than 30 minutes. In contrast, amongst those monitored with IA, delivery was expedited based on presence of FHR abnormalities alone. Consequently there was a significant difference in median FHR abnormality to delivery interval between the groups (104 vs. 60 minutes). 292 P a g e

315 In preterm neonates that are less likely to be able to endure hypoxic-ischaemic insults such a significant delay does not reflect clinical practice or account for the potential lack of reserve. So profound were the contrasts in management that some authors expressed concern over the ethical nature of these differences. 818 Consequently, there is a possibility that the difference between monitoring methods may have been a chance or confounded finding, especially given that there were no significant differences in any other evaluated outcomes. Consequently, both studies have significant methodological and statistical issues, which means that the relationship between CP, EFM and IA cannot be stated with any direct certainty. The most profound difference in the Cochrane Review was regarding neonatal seizures with continuous EFM associated with a halving of the risk of seizures. Despite considerable variation in neonatal seizure incidence (0.03%-5.69%), the reduction was consistent across all of the RCTs and subgroups. In terms of numbers needed to treat, 661 deliveries (95%CI 384, 2002) would have to be monitored with continuous EFM to prevent one neonatal seizure. The findings of reduced neonatal seizures with continuous EFM concurs with a number of other meta-analyses and studies. 742,820, For other forms of perinatal morbidity, e.g. five minute Apgar scores, umbilical cord blood gas values, NICU admission and HIE, there was no significant difference between EFM and IA. These findings should be cautiously interpreted as despite the large overall sample size the number of reported cases with these adverse findings that could be considered avoidable by intrapartum monitoring is low. Additionally, other meta-analyses and studies have noted with continuous EFM significant improvements in perinatal status markers, such as one minute, 820, and five minute Apgar scores. 820, Consequently, Alfirevic et al. concluded that without additional data the difference in perinatal morbidity between IA and EFM can only be assessed using neonatal seizures and CP, although even these parameters are complicated by low sample sizes. Amongst low risk pregnancies (three RCTs) the reported outcomes were consistent with the overall cohort, although there was a significant increase in NICU admissions amongst those with EFM and no significant difference between groups for caesarean delivery (Table F.2.). In high risk pregnancies the results were also generally consistent with the overall findings (Table F.3.); however, there was no significant difference in neonatal seizures, or instrumental vaginal deliveries between monitoring modalities. Any differences between subgroups and 293 P a g e

316 the overall results have to be cautiously interpreted due to the relatively small number of RCTs and participants. That being so, Alfirevic et al. concluded that there was no evidence that the impact of continuous CTG monitoring on important clinical outcomes vary significantly across risk classification. 751 Table F.2. Comparison of intermittent auscultation and continuous electronic fetal monitoring associated outcomes Outcome Population Size Relative Risk (95%CI) Caesarean delivery 18, (1.30, 2.13) Caesarean delivery for abnormal FHR &/or acidaemia 33, (1.88, 3.00) Instrumental vaginal delivery 18, (1.01, 1.32) Instrumental vaginal delivery for abnormal FHR 12, (1.95, 3.31) &/or acidaemia Need for any analgesia 2, (1.01, 1.18) Epidural analgesia 17, (0.90, 1.12) Pharmacological analgesia 1, (0.93, 1.08) Fetal blood sampling 13, (1.03, 1.49) Oxytocin during first two stages 3, (0.87, 1.35) Five minute Apgar score < 7 4, (0.72, 1.31) Five minute Apgar score < 4 1, (0.61, 3.34) Umbilical cord acidaemia 2, (0.27, 3.11) NICU admission 33, (0.93, 1.10) Length of NICU stay (-1.17, 1.57) Hypoxic-ischaemic encephalopathy 1, (0.04, 5.03) Neonatal seizures 32, (0.31, 0.80) Perinatal death 33, (0.59, 1.23) Neurodevelopmental disability at one years old (0.83, 18.17) Cerebral palsy 13, (0.97, 3.11) FSE or FBS damage (0.31, 28.61) Adapted from Alfirevic et al., Note: Weighted Mean Difference (95%CI) Alfirevic and colleagues noted that translation of this evidence into clinical practice is associated with a number of significant challenges. Improvements in technology, interpretation, and training have occurred since the studies were conducted, in the 1970s, 1980s and early 1990s, with the resulting influence on external validity. Furthermore, clinical practice has changed considerably since many of the studies were conducted. In a number of RCTs, particularly the Dublin trial, 721,788,917 intact fetal membranes were ruptured at the earliest opportunity to look for MSAF with the presence of MSAF being considered exclusion criteria in some studies. Additionally, in the Dublin RCT approximately 4% of those in the IA arm had FBS. These practices differ significantly from those found in modern labour and birth suites, especially homebirth or midwifery led settings, where there is 294 P a g e

317 a tendency to avoid artificial rupture of membranes, the absence of equipment and expertise necessary for FBS, and rigid adherence to IA schedule may not be a priority. Similarly, while most deliveries particularly in the Dublin RCT had one-to-one midwifery care throughout the intrapartum period, this may not be always freely available. Additionally, there was considerable divergence in the manner in which IA was utilised in the various RCTs in the Cochrane Review. 237 Consequently, the meta-analysis requires the results to be interpreted within their study context and not solely on a statistical basis. Table F.3. Comparison of intermittent auscultation and continuous electronic fetal monitoring associated outcomes in high and low risk populations Outcome Population Size Relative Risk (95%CI) Low Risk Caesarean delivery (0.91, 4.18) Caesarean delivery for abnormal FHR &/or acidaemia 15, (1.49, 3.59) Instrumental vaginal delivery (1.02, 1.62) NICU admission 15, (1.01, 1.87) Neonatal seizures 24, (0.16, 0.81) Perinatal death 15, (0.31, 3.31) High Risk Caesarean delivery 1, (1.58, 2.57) Caesarean delivery for abnormal FHR &/or acidaemia 1, (1.69, 3.59) Instrumental vaginal delivery 1, (0.85, 1.26) Need for any analgesia (1.00, 1.12) Epidural analgesia 1, (0.82, 1.12) Pharmacological analgesia (0.85, 1.03) Oxytocin during first two stages 1, (0.87, 1.13) Five minute Apgar score < (0.33, 1.70) Five minute Apgar score < (0.67, 4.07) NICU admission 1, (0.48, 1.33) Neonatal seizures 4, (0.36, 1.22) Perinatal death 1, (0.61, 1.71) Neurodevelopmental disability at one years old (0.83, 18.17) Cerebral palsy (1.10, 5.86) FSE or FBS damage (0.31, 28.61) Adapted from Alfirevic et al., Note: Absence or presence of identifiable risk factors associated with increased perinatal mortality and morbidity as defined by each study s authors The authors concluded that deliveries monitored with continuous EFM experience a reduction in neonatal seizures, no obvious difference in CP or perinatal mortality, but an associated increase in caesarean and instrumental delivery. A combination of numbers needed to treat calculations, for neonatal seizures and caesarean deliveries, suggests that for 628 deliveries with continuous EFM, there would be one less case of neonatal seizures and 295 P a g e

318 11 more caesarean deliveries than if the same cohort was monitored with IA. The associated adverse outcomes of operative deliveries have been well described; however, similar data concerning the long-term neurodevelopmental outcome associated with neonatal seizures is relatively lacking. The restrictions in mobility and use of H 2 O therapy with older EFM forms must also be taken into account if ambulatory H 2 O proof technology is not available. Rotunda Hospital Randomised Controlled Trial The largest study and the one contributing the greatest number of participants to the Cochrane Review was conducted at the Rotunda Hospital in Dublin, Ireland on a cohort of 12,904 women. 820,906,917 This study is of particular importance, due to its central role in literature surrounding intrapartum fetal monitoring and deserves further independent discussion. The authors found no difference in intrapartum fetal mortality, low Apgar scores, need for resuscitation, SCN admissions, or long-term outcome between the groups. Interestingly, no significant difference was noted in caesarean deliveries between study arms (2.4% vs. 2.2%; p>0.05), although instrumental delivery was significantly more common amongst those monitored electronically (8.2% vs. 6.3%; p<0.001). Neonatal seizures (RR %CI 0.22, 0.91; p=0.025) were significantly less common amongst those monitored with continuous EFM than their counterparts monitored with IA. Further, persistent adverse neurological symptoms lasting for greater than a week were significantly more common amongst those monitored by IA. The authors noted that the effect of EFM in preventing neonatal seizures appeared to be greater amongst low-risk pregnancies. 917 MacDonald and colleagues postulated that this difference in neonatal seizures may have been related to the longer labour duration amongst those monitored with IA, which they found to be independent of oxytocin use. The lack of significant difference in intrapartum mortality and long-term adverse neurodevelopmental outcome; should be viewed in context, as the institution had a low intrapartum mortality and CP rate, which some suggest was unlikely to be further reduced. 13,1774 This finding could be due to inadequate power as a result of the rarity of preventable intrapartum deaths and CP in the study institution. Additionally, Steer identified that the early electronic fetal monitor used, the Sonicaid FM 2 (Sonicaid Ltd., Bognor Regis, UK), is noticeably inferior to currently available devices, particularly in FHR trace quality and acquisition. 13,1775 This observation is consistent with other authors evaluations of first and later generation EFM technology Further, internal fetal monitoring as conducted in the Dublin EFM trial is longer extensively utilised. Similarly, all staff members involved in the RCT were unlikely to have been very familiar with EFM, 818,1775 with staff members unlikely to 296 P a g e

319 have the same degree of detailed and extensive training that is currently available to allow accurate FHR interpretation. That being so, staff members were likely to have had some experience, contrary to Steer s assumption, as EFM had been used occasionally on high risk cases prior to the RCT. Almost 25% of the enrolled subjects delivered with an hour of randomisation, and approximately 50% within two hours, raising the potential that there was insufficient time to alter fetal outcome, 1775 with a greater proportion of those with EFM having a shorter randomisation to delivery interval (p<0.001). Electronic fetal monitoring versus intermittent auscultation summary The major problem with IA and EFM comparisons is that analysis of neonatal condition is complicated by markers of neonatal condition, such as Apgar score, SCN admission and neonatal resuscitation, having a wide range of confounding factors. Further, the subjective nature of these outcomes is a major limitation. Measurement of fetal acidaemia at birth using umbilical cord blood gases is considered the most objective indicator of neonatal and fetal status. Vintzileos et al. found that EFM had a higher sensitivity, PPV and NPV than IA for detecting fetal acidaemia at delivery. 907 In contrast, the specificity was significantly higher for IA. Of particular interest was the tendency for IA sensitivity to vary based on acidaemia type, with the greatest sensitivity for respiratory acidaemia while the least was for metabolic acidaemia, with mixed respiratory and metabolic acidaemia falling in-between. In contrast, EFM sensitivity for respiratory acidaemia was 100% and 95% for metabolic and mixed acidaemia. Therefore, there might be some role for continuous EFM to predict adverse outcome in low-risk women; however, testing on larger and more diverse cohorts than that included in Vintzileos et al. study is required in order to confirm these findings It appears that the debate about intrapartum monitoring will continue for the foreseeable future, with the debate focusing on the caesarean delivery and neonatal seizure aspects. The perceived conflict between maternal risk (increased caesarean and instrumental vaginal delivery rate) and neonatal benefit (decreased incidence of neonatal seizures), makes it exceptionally difficult to make quality judgments as to which effect and the resultant issues is more important. 297 P a g e

320 Appendix G: Prognosis and Aetiological Background of Vigorous Neonates with Acidaemia Prognosis of vigorous neonates with acidaemia One of the most important factors concerning vigorous neonates with a concomitant acidaemia is neonatal prognosis and the likelihood of suffering from adverse outcomes particularly those persisting into childhood and adulthood. Unfortunately, there is a relative paucity of studies evaluating this and those which are available are limited typically in terms of cohort size. King et al. evaluated neonates delivered at or near term with a five minute Apgar score greater than six, birth weight of greater than 2099 grams and no serious cardiopulmonary abnormalities that were subsequently admitted to a newborn nursery Thirty five neonates with an umbilical artery ph less than or equal to seven were paired with 35 non-acidaemic neonates matched for gestational age and delivery method. Neurological evaluation revealed no differences between cases and controls in muscle tone, reflexes and cranial nerve function. There were a greater number of neonates with acidaemia that had an abnormal serum creatinine level (greater than one milligram per decilitre) on the second day (28% vs. 3%, p=0.022). The change in serum creatinine level between the first and second day was greater in control infants compared with acidaemic infants (-0.15±0.16 vs ±0.21; p=0.014). That being so, all acidaemic neonates with abnormal creatinine levels, that were able to be retested levels had normal levels within one to eight weeks. Finally, there were significantly more neonates with haemoglobin positive urine dip stick results amongst acidaemic neonates (p=0.005). Hepatic function as assessed by alanine transaminase, aspartate transaminase, and alkaline phosphatase was similar amongst cases and controls except for gamma-glutamyl transferase which was significantly greater amongst those without acidaemia on day one (p=0.030). In terms of GIT function, all abdominal examinations and stool guaic tests were negative and no neonate in either group had intolerance to feeding. King et al. concluded that overall acidaemic neonates had similar levels of neurologic dysfunction, hearing deficits, feeding intolerance, and liver function abnormalities within the 48 hours following delivery as neonates without acidaemia. The only parameters in which there was a significant difference between acidaemic and non-acidaemic groups were serum creatinine levels and haem-positive dip-stick urine. The increased serum creatinine levels appear to be pre-renal in origin as there was no difference in other adverse renal function indicators, such as time to first void, urine specific gravity, and microscopic haematuria. 298 P a g e

321 King et al. postulated that this was due to increased tissue catabolism with resulting myoglobinuria and haemoglobinuria, as a result of the underlying processes mediating fetal acidaemia. The elevated creatinine levels amongst acidaemic neonates whilst relatively benign do illustrate the potential for additional adverse events amongst acidaemic but vigorous neonates i.e. transient renal clearance impairment. Consequently, King et al. concluded that for neonates with acidaemia, clinical condition is an excellent discriminating variable to assess subsequent risk of morbidity and mortality risk. They did note that it is not a completely infallible discriminating mechanism as two neonates amongst those with acidaemia (n=37) were transferred to the NICU due to hypoglycaemia. It is possible in these neonates and potentially others, disturbances in glucose homeostasis might have influenced acid-base balance and produced acidaemia. That being so, King et al. still concluded that for clinically well neonates with an umbilical artery ph less than 7.00, neonatal management should be similar to non-acidaemic counterparts. These findings are replicated in one of the longest follow-up studies to evaluate neonatal outcomes in acidaemic neonates. Hafstrom et al. identified 78 neonates with an umbilical artery ph less than 7.05 and a base excess less than mmol/l from a population of 14,687 term deliveries Of the 78 neonates, 43 (55%) were sent to the neonatal nursery while the remaining 35 (45%) went to the maternity ward with their mothers. Controls were the subsequent two deliveries sent to the maternity ward with the same intrapartum monitoring (CTG or CTG and STAN), gestational age and gender, as well as an arterial ph greater than At six and a half years of age, neonates with metabolic acidaemia but no nursery admission did not exhibit any definitive adverse neurodevelopmental outcomes, although eight (N=33; 24%) had speech, language, behaviour, or motor deficits requring referral or specific educational arrangements. Control comparison revealed no significant difference in neurodevelopmental or behavioural problems requiring referral or definitive neurodevelopmental issues. Furthermore, there was no significant difference in 18 month head circumference and weight and height at six and a half years of age between controls and acidaemia neonates admitted to the maternity ward. The authors concluded that metabolic acidaemia in neonates well enough to not require nursery admission, do not have an increased risk of neurodevelopmental or behavioural problems requiring specialised review or care in later life. 299 P a g e

322 Aetiological background of vigorous neonates with acidaemia A number of different aetiologies have been postulated for acidaemia in otherwise vigorous neonates, with the aetiology most likely varying on a case by case basis. 132,1187,1778 Initially it was assumed fetal acidosis originated in the mother, in whom acidosis occurs at least partly due to increased metabolic demands during delivery. 993, Biological plausibility of maternal infusion acidosis entering fetal circulation has been demonstrated in an experimental model following maternal administration of ammonium chloride That being so, later studies postulated that while maternal acidosis could be a significant factor in fetal acidosis the majority of fetal acidosis is fetal in origin; 993,998,1058,1390, however, it was not until the late 1980s and early 1990s that there were concrete attempts to quantify exact contributions to fetal acidosis. Suidan and Young evaluated the contribution of maternal acid-base status to the fetus using simultaneous measurements of maternal arterial and umbilical cord ph, pco 2 and BD values The authors found significant correlations between maternal and umbilical blood gas values (p<0.001) with the correlation being stronger amongst vigorous neonates. This would indicate reduced influence of maternal acid-base balance on the non-vigorous fetus. Given that maternal ph values were lower and BD values higher amongst mothers with vigorous yet acidaemic neonates (p<0.001), there is some evidence for maternogenic fetal acidosis amongst vigorous neonates. That being so, if fetal acidosis was entirely due to maternal acidosis then the maternal-fetal differences in blood gas values should be similar amongst acidaemic and non-acidaemic neonates, which was not the case. The maternal-fetal differences in ph, pco 2 and BD values amongst vigorous acidaemic neonates was significantly greater (p<0.001) than those noted amongst vigorous yet non-acidotic neonates. This would be further indication of a partial contribution of maternal acidosis to that of the fetus. An alternative or additional mechanism is a late second stage acidosis of insufficient duration to cause fetal injury. There were significant differences between maternal arterial and umbilical venous ph (0.15±0.06 vs. 0.08±0.04; p<0.001), pco 2 (-15±7 vs. -11±5; p<0.001) and BD (-1.5±2.7 vs. 0.7±1.7; p<0.001) values in vigorous acidaemic and non-acidaemic neonates. This is consistent with an acidotic change at placental level with a falling ph during the late second stage of labour due to decreased intervillous perfusion. There were also significant differences between maternal arterial and umbilical arterial ph (0.23±0.06 vs. 0.13±0.05; p<0.001), pco 2 (-28±12 vs. -18±8; p<0.001) and BD (-1.1±3.1 vs. 1.3±2.2; p<0.001) in vigorous acidaemic and non-acidaemic neonates. Given these differences were 300 P a g e

323 greater than that between maternal artery and umbilical vein there is the possibility of fetal insult response resulting in acidaemia occurring with the neonate being delivered before compensation occurs. Other studies looking at continuous intrapartum fetal scalp ph measurements have identified similar occurrences. 730, Whilst fetal ph levels might fluctuate during the intrapartum period, poor neonatal condition at delivery is typically only seen in relation to birth asphyxia when fetal acidaemia remains uncompensated at delivery Suidan and Young noted no difference in maternal arterial blood gas values between mothers delivering acidotic vigorous or non-vigorous neonates That being so, the difference between maternal artery and umbilical vein ph and pco 2 as well as maternal and umbilical artery ph was greater amongst non-vigorous acidaemic neonates. That is indicative of a more severe acidaemia in non-vigorous acidaemic neonates, which is reflected in some neonatal umbilical cord blood gas results (Table G.1.). The fact that arterial ph is normal suggests fetal compensation is occurring despite placental acidosis as indicated by venous ph. This is further supported by continuous tissue ph monitoring, with fetal compensation producing a lower ph value than was present prior to the acidosis inducing insult. 730, Table G.1 Umbilical cord blood gas values amongst vigorous and non-vigorous acidaemic neonates Vigorous Acidaemia Non-Vigorous Acidaemia (n = 21) (n = 8) P-Value Umbilical Artery ph 7.13 ± ± 0.15 > 0.05 pco ± ±13.0 > 0.05 Base Deficit 9.8 ± ±4.5 <0.05 Umbilical Vein ph 7.21 ± ± 0.07 <0.001 pco ± ± 9.0 > 0.05 Base 10.2 ± ± 2.8 > 0.05 Deficit Adapted from Suidan and Young, Note: One minute Apgar score 7 and umbilical artery ph < 7.20; One minute Apgar score < 7 and umbilical artery ph < Consequently, Suidan and Young attribute vigorous acidaemia to one or a combination of three distinct mechanisms Firstly, there is maternal-fetal H + transfer across the placenta. Secondly, late second stage acidosis occurs with delivery of the fetus before sufficient adverse effects necessary to alter the neonatal Apgar score can occur, and finally the fetus might be in 301 P a g e

324 the process of compensation for the acidosis invoking insult and be delivered having reversed the clinical effects but still in the process of correcting the umbilical acidaemia. Piquard et al. found that fetal metabolic acidosis primarily originates from the fetus for a number of reasons Firstly the difference in umbilical arteriovenous lactate concentrations was positive and large in steady-state conditions as well as in non-vigorous neonates. Secondly, the conditions necessary for a net maternal-fetal lactate transfer, a positive maternal-fetal ph and lactate gradient, rarely occur. Finally, statistical analysis of the relationship between fetal, neonatal, and maternal lactate concentrations noted only a weak correlation. Given the regression coefficient was lower in neonates with a history of acute stress it is likely that lactate concentration changes in the mother and fetus/neonatal occur independently. That being so, existence of a correlation means that there is the possibility that increased intrapartum maternal lactate production may alter maternal-fetal transfer in approximately six percent of fetuses. Another potential cause was postulated by King et al. based on 10 of the neonates with acidaemia being delivered via a repeat, scheduled caesarean delivery Post-hoc analysis identified increased ephedrine utilisation after spinal anaesthesia (p=0.017) and longer anaesthesia to delivery intervals amongst the acidaemic cohort. Thus the authors suggested that maternal hypotension resulting from such differences might have produced uterine hypoperfusion and resulting acidaemia. This theory is supported by other studies noting maternal hypotension is a frequent spinal anaesthesia complication and is associated with fetal acidaemia. 84,1789 Crawford et al. also noted that the interval between induction of anaesthesia and delivery is inversely proportional to umbilical artery ph values; 1790 however, other authors have not concurred with this finding. 84,1791 Interestingly, two studies have noted that fetal acidaemia produced after spinal anaesthesia hasn t been associated with low Apgar scores. 84,1789 That being so, it is unlikely that anaesthesia is the sole mechanism responsible for clinically well neonates developing acidaemia as the profound acidaemia observed in the King et al. study is a relatively rare occurrence following spinal anaesthesia. 84,87,1789 Consequently, it appears that a single aetiological factor is unlikely to be responsible for a vigorous neonate also having a concomitant acidaemia. Rather it is likely to be a combination of factors, such as anaesthesia, compensation, and late insults, acting together to produce an acidaemia in a otherwise clinically vigorous neonate. 302 P a g e

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