WORKSHEET for Evidence-Based Review of Science for Cord Clamping Worksheet author(s) Date Submitted for review: Feb December 2009

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1 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 1 of 28 WORKSHEET for Evidence-Based Review of Science for Cord Clamping Worksheet author(s) Date Submitted for review: Feb December 2009 Clinical question. In neonates (P), does delayed cord clamping cord (I) versus standard management (C), improve outcome (O) Is this question addressing an intervention/therapy, prognosis or diagnosis? Intervention State if this is a proposed new topic or revision of existing worksheet: Revision Conflict of interest specific to this question Do any of the authors listed above have conflict of interest disclosures relevant to this worksheet? No Search strategy (including electronic databases searched). OVID : Keywords used: Cord clamping, Placental transfusion, Neonatal transition, Umbilical cord, Maternal-fetal exchange. Limit to neonate. EMBASE; Placenta, transfusion, umbilical cord clamping. COCHRANE; Umblical Cord Endnode: Placenta and blood transfusion. State inclusion and exclusion criteria Inclusion-human, neonate, newborn, preterm, term, infant. Systematic reviews. Exclusion-male, cord clamping of cervical cord. animal and milking of the cord, nuchal cord Commentaries and reviews were looked at but excluded from the work sheet. Worksheet was done for 2005 so only reviewing Articles before 2005 are included in the evidence grid. (Total 23). Number of articles/sources meeting criteria for further review: 78 articles from which 6 were non English. 1 Spanish systematic review, 1Portugese study, 1 Dutch review, 1 Danish review, 1 Danish study and 1 Swedish care program. Spanish systematic review translated by coauthor and Danish study not translated Of the remaining 72 after excluding commentaries and reviews 21 articles are reviewed including the Portuguese article. Of these 21 articles, 15 are studies and 6 are systematic reviews. (P=Preterm in the summary evidence)

2 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 2 of 28 Summary of evidence Evidence Supporting Clinical Question Good Fair Poor Chaparro 2006(E) Hutton 2007(E) McDonald 07(E) Rabe(P) 2004(E) Baenziger (P)2007, Aladangady(P)(E) 2006(E) Ceriani 2006(E) Emhamed 2004(E) Mercer(P) 2006(E) Rabe(P)2008(E) vanrheenen04(e) Strauss(P) 2008(E) Ultee (P) 2008(E) Venancio 2008(E) Chaparro 2007(E) Zaramella 2007(E) Level of evidence A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event D = Intact neurological survival Italics = Animal studies P=PRETERM

3 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 3 of 28 Evidence Neutral to Clinical question Good Fair Poor vanrheenen 2007(E) Jahazi 2008(E) Kugelman(P) 2007(E) Mercer(P)2006(E) vanrheenen 2006(E) Wiberg 2008(E) Level of evidence A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event D = Intact neurological survival Italics = Animal studies P=PRETERM Evidence Opposing Clinical Question Good McDonald 2007(E) Fair Poor Level of evidence A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event D = Intact neurological survival Italics = Animal studies

4 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 4 of 28 Evidence Supporting Clinical Question Combined Grid including articles is 2004 worksheet Good Fair Chaparro 2006(E) Hutton 2007(E) McDonald 07(E) Rabe(P) 2004(E) Grajeda 1997(E) Baenziger (P)2007(E), Aladangady(P) 2006(E) Ceriani 2006(E) Emhamed 2004(E) Mercer(P) 2006(E) Rabe(P)2008(E) vanrheenen2004(e) Ibrahim(P)2000(E) Rabe(P)2000(E) Gupta 2002(E) Venancio 2008(E) Oh 1996(E) Oh 1997(E) Chaparro 2007(E) Zaramella 2007(E) Buckles 1965(E) Nelson 1980(E) Poor Strauss(P) 2008(E) Ultee(P) 2008(E) Emman(P)1971(E) Oxford Midwives 1992(E) Kimmond(P)1993(E) Wilson 1941(E) Usher 1963(E) Level of evidence Evidence Neutral to Clinical question Combined Grid including articles is 2004 worksheet Good vanrheenen 2007(E) Fair Poor Jahazi 2008(E) Kugelman(P) 2007(E) Mercer(P)2006(E) vanrheenen 2006(E) Geethanath 1997(E) McDonnell(P)1997(E Linderkamp 1992(E) Nelle1993(E) Nelle1995(E) Nelle1996(E) Colozzi 1954(E) Wu 1960(E) Yao(P) 1969(E) Kilot 1984(E) Wiberg 2008(E) Level of evidence A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint

5 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 5 of 28 REVIEWER S FINAL COMMENTS AND ASSESSMENT OF BENEFIT / RISK: Trials included in this review are since the last worksheet of There are variations between definition of delayed cord clamping (DCC) versus early cord clamping (ECC), location of the infant in relation to the placenta, management of third stage of labor and definition of prematurity. The varied outcomes measured are blood volume, cerebral oxygenation, and hematocrit at 1 hour of age up to hemoglobin at 6 months, bilirubin levels, and iron status up to 6 months, blood pressure, cardiac function, IVH, BPD and late on set sepsis. 9 studies were in term infants and 6 in preterm infants. Table of studies is attached. 3 Reviews are for term infants 2 reviews for preterm infants 1 Review for low birth weight infants. Mercer 2006 and McDonald 2007 appear twice in the tables of evidence because they showed neutral and supporting (Mercer) and supporting and opposing evidence (McDonald). PRETERM Resuscitation can be done before clamping the cord (Aladangady 2006 pg ). There is higher blood volume (Aladangady 2006 pg ), blood pressure (Kugelman 2007 pg ), RBC volume (Strauss 2008 pg ) and hemoglobin (Ultee 2008 pg. F20-3) in the delayed clamping cord (DCC) group. There was a decreased use of pressors. There is indirect evidence that the delayed cord clamping group were likely to have a smother transition as their cardiovascular system was more stable. DCC group had fewer transfusions (Rabe 2004 CD003248, Aladangady 2006 pg , Mercer 2006 pg , Baenziger 2007 pg , Kugelman 2007 pg , Rabe 2008 pg ). Even though the hematocrits were higher (Strauss 2008 pg ) they did not lead to fewer transfusions. Preterms had higher bilirubin levels, polycythemia and some studies received more phototherapy however there was no correlation between phototherapy and polycythemia. There are reports of less IVH (Mercer 2006 pg , Rabe 2008 pg ) in DCC group. There are no reports of increased need for exchange transfusion for polycythemia or hyperbilirubinemia, respiratory distress or poor neurodevelopmental outcome from polcythemia. TERM Major focus of studies has been prevention of iron deficiency anemia. There are reports of higher hemoglobin/hematocrit ranging from soon after birth to 4-6 months following birth (Ceriani 2006 e779-86, Chaparro 2007 pg , Emhamed 2004 pg , vanrheenen 2006 pg ). Higher ferritin levels and breast feeding rates in DCC group. (Venancio 2008 Suppl 2:S323-31). Meta-analysis show benefits in hematological indices (McDonald 2008 CD004074) and more clinical jaundice (vanrheehan 2004 pg. 3-16, McDonald 2008 CD004074). There is increased use of phototherapy (McDonald 2008 CD004074) however the studies used in the meta-analysis did not define indications for phototherapy. There are no correlations between polycythemia, increased levels of bilirubin and use of phototherapy. Neonates at increased risk of iron deficiency anemia benefit from increase in hematocrit, hemoglobin and ferritin. One study documents increased hemoglobin and ferritin levels at 6 months, another reports increase at 4 months and similar levels at 6 months. (Venancio 2008 Suppl 2:S323-31). There is an increase in need for phototherapy. No significant differences in bilirubin levels, even though there are reports of increased bilirubin levels. The study that reports increased need for phototherapy reports similar mean bilirubin levels in the 2 groups. None of the studies report an increased risk of clinically significant polycythemia. Overall the definitions of delayed cord clamping vary from 30 to when the cord stops pulsating. None of the studies report harmful effects of delayed cord clamping. Even though modest all the studies report benefits of delaying cord clamping. There is no study examining the benefits of early cord clamping. Delayed cord clamping used to be the historical norm till the 20 th century. The practice of change to early cord clamping coincides with the establishment of the specialty of obstetrics.

6 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 6 of 28 There is increasing evidence that delayed cord clamping for 60 is likely to be of benefit in both the preterm and term infant. Conclusion DISCLAIMER: Potential possible wording for a Consensus on Science Statement. Final wording will differ due to other input and discussion. CONSENSUS ON SCIENCE: For the uncomplicated birth at term there is evidence of benefit to delaying cord clamping from 60 to when the cord stops pulsating following delivery. Those infants who experience delayed clamping had improved iron status through early infancy and were more likely to receive phototherapy. (LOE 1: Ceriani 2006:e779, Chaparro 2006:506, Emhamed 2004:218, Grajeda 1997:425, Gupta 2002:130, Hutton 2007:1241, McDonald 2008:CD004074, van Rheenen 2004:3). ). For the otherwise uncomplicated preterm birth, there is evidence of a benefit to delaying cord clamping for a minimum time ranging from 30 to 180 following delivery. Those who experienced delayed clamping in this group had higher blood pressures during stabilization, (LOE 1:Rabe 2004:CD003248, Baenziger 2007:455, Mercer 2006:1235, Rabe 2008:138, Kugelman 2007:307)) (LOE 2) a lower incidence of IVH ( LOE 2 Mercer 2006 pg , Rabe 2008 pg ):)and received fewer blood transfusions ( LOE 1: Rabe 2004:CD003248, Rabe 2008:138)but received more phototherapy (LOE 2:Rabe 2004:CD003248).). There are limited data on the hazards or benefits of delayed cord clamping in the non-vigorous infant. (Aladangady 2006;93, Mercer 2006:1235). TREATMENT RECOMMENDATION: Acknowledgements: SUMMARY OF STUDIES Study Aladangady UK 2. Baenziger switzerland 3. Ceriani Argentina. Randomizatio n DCC n ECC n Yes Stratified gest. DCC=23 ECC=23 Yes DCc=15 ECC=24 Yes DCC 3 min.=92 DCC/ECC definition DCC 30-90s? location of infant DCC 60-90secs. Infant at least 15 cm below placenta DCC 60 and 180 Outcome Term/Preterm Comments Blood volume Cerebral oxygenation Venous Hematocrit and clinical Preterm 24 to 326/7 weeks. Preterm completed weeks Term Blood volume greater in vaginal and total group. Not significantly change in C/S. Some babies resuscitated before cord clamped. Part of a larger study. Cerebral blood volume similar at 4 hours. Mean regional tissue oxygenation higher at 4 and 24hrs. Hct. higher 4, 24 and 72 hrs similar at 36 weeks. Hematocrit higher in DCC was not statistically significant.

7 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 7 of Chaparro Mexico 5. Chaparro Mexico 6. Emhamed Libya 7. Jahazi Iran DCC 1 min.=91 ECC=93 Yes DCC=139 ECC=127 Yes DCC=237 Ecc=239 No Continuously randomized?? DCC=57 ECC=45 Yes DCC=34 ECC=30 ECC within 15 DCC 120 ECC 10 DCC 120 ECC 10 DCC cord stopped pulsating ECC 10 DCC 180 ECC 30 Baby held level of introitus Iron and lead status Hematologic and Iron status at 6 months Hematologic effects 24 hours Hematocrit 18 hours Term Term Term Term Less number of babies had anemia in DCC. Breast feeding and Clinical outcomes similar. Part of another trial. Blood lead concentration higher in ECC 25% lost to follow up DCC group higher MCV, ferritin and total body iron DCC mean 215 Higher hemoglobin DCC No difference in need for phototherapy No difference in hematocrit. Even though polycythemia (? Def.) in 20 vs 23.5 % babies at 2 hours, none symptomatic. 8. Kugelman Israel 9. Mercer USA 10. Strauss USA Yes DCC=30 ECC=35 Yes DCC =36 ECC =36 Yes But did not analyse extreme preterm and groups were not equal DCC=45 ECC=60 DCC ECC-5-10 DCC ECC 10 DCC 60 ECC immediately inches below introitus Blood pressure Hematocrit Preterm <35 weeks BPD Preterm <32 weeks No exclusion for resuscitation RBC volume and mass Preterm <36weeks Only reported weeks as < 30weeks too 26/27 DCC were ECC Israel DCC higher BP measured centrally, peripherally. <1500gm tended to have higher BP and needed less mechanical ventilation and surfactant.higher hematocrit in DCC not significant. Higher IVH and Late onset sepsis in ECC. Primary outcome BPD no difference. USA APGARS and SNAP score similar. DCC higher RBC volume at 24 hours, Higher Hct d7,14, 21 and 28.No difference in bilirubin level, more babies in DCC under phototherapy.

8 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 8 of Ultee Netherlands Yes DCC=21 ECC=21 DCC within 180 ECC within 30 Mothers abdomen Neonatal follow up data Preterm weeks Higher Haemoglobin DCC at 1 hour and 10 weeks. No significant difference in ferritin, jaundice, glucose. 12. van Rheenen Zambia Yes DCC=46 ECC=45 DCC Cord stopped pulsation(mean 305s) ECC 20 Hematologic status in malaria infected area. Complication s Term Preterm, C/S need for resuscitation Even though the hemoblobin levels were similar at 4 months more infants in the ECC group were anemic.(p-0.05) At 6 months no difference. No adverse events 13. Venancio Brazil Alternate weeks DCC=164 ECC=161 DCC=60 ECC=Immediat e Anemia 3 months Term Resuscitation excluded 69% follow up data. Higher ferritin levels and more breast feeding trend. 14. Wiberg Sweden 15.Zarmella Italy No N=70 No case control DCC=11 ECC=11 Only DCC Samples taken every 45 DCC- 240 ECC-30 Mothers arms Cord arterial and venous blood gas and lactate. Cardiac function weeks Excluded neonates needing resuscitation Term Only healthy Found a significant decrease in ph and increase in lactate from 0 to 90. Larger left ventricular diameterat end of systole. No change in peripheral perfusion or oxygen metabolism

9 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 9 of 28 Citation List 1) Aladangady, N., S. McHugh, et al. (2006). "Infants' Blood Volume in a Controlled Trial of Placental Transfusion at Preterm Delivery." Pediatrics 117(1): OBJECTIVE: To investigate whether it was possible to promote placental blood transfer to infants at preterm delivery by (1) delaying cord clamping, (2) holding the infant below the placenta, and (3) administering an oxytocic agent to the mother, we measured the infants' blood volumes. DESIGN: Randomized study. METHODS: Forty-six preterm infants (gestational age: 24[0/7] to 32[6/7] weeks) were assigned randomly to either placental blood transfer promotion (delayed cord clamping [DCC] group, ie, > or =30 from moment of delivery) or early cord clamping (ECC) with conventional management (ECC group). Eleven of 23 and 9 of 23 infants assigned randomly to DCC and ECC, respectively, were delivered through the vaginal route. The study was conducted at a tertiary perinatal center, the Queen Mother's Hospital (Glasgow, United Kingdom). RESULTS: The infants' mean blood volume in the DCC group (74.4 ml/kg) was significantly greater than that in the ECC group (62.7 ml/kg; 95% Confidence interval for advantage: ). The blood volume was significantly increased by DCC for infants delivered vaginally. The infants in the DCC group delivered through cesarean section had greater blood volumes (mean: 70.4 ml/kg; range: ml/kg), compared with the ECC group (mean: 64.0 ml/kg; range: ml/kg), but this was not significant. Additional analyses confirmed the effect of DCC (at least 30 ) to increase average blood volumes across the full range of gestational ages studied. CONCLUSIONS: The blood volume was, on average, increased in the DCC group after at least a 30-second delay for both vaginal and cesarean deliveries. However, on average, euvolemia was not attained with the third stage management methods outlined above. COMMENTS: Randomized, PRETERM end point blood volume. No significant difference in the cesarean section group. Even though a small sample they did not demonstrate a difference in blood volume between 60s and 90s cord clamping. Some infants received ventilation before the cord was clamped. LOE 1, Supportive, fair 2) Baenziger, O., F. Stolkin, et al. (2007). "The Influence of the Timing of Cord Clamping on Postnatal Cerebral Oxygenation in Preterm Neonates: A Randomized, Controlled Trial." Pediatrics 119(3): OBJECTIVE. Our goal was to investigate the effect of placentofetal transfusion on cerebral oxygenation in preterm infants by near-infrared spectroscopy. SUBJECTS. A total of 39 preterm infants with a median gestational age of 30.4 weeks were randomly assigned to an experiment group (n = 15) and a control group (n = 24). INTERVENTIONS. The delivery of the infants in the experiment group was immediately followed by maternal administration of syntocinon, the infant was placed 15 cm below the placenta, and cord clamping was delayed by 60 to 90. The infants in the control group were delivered conventionally. At the ages of 4 and 24 hours, cerebral hemoglobin concentrations, cerebral blood volume, and regional tissue oxygenation were measured by near-infrared spectroscopy. RESULTS. Cerebral blood volume was not different between the 2 groups at the age of 4 hours (6.1 vs 5.8 ml/100 g of tissue) nor at the age of 24 hours (6.2 vs 6.2 ml/100 g of tissue). Mean regional tissue oxygenation of the experiment group was higher at the ages of 4 hours (69.9% vs 65.5%) and of 24 hours (71.3% vs 68.1%). CONCLUSION. Delayed clamping of the umbilical cord improves cerebral oxygenation in preterm infants in the first 24 hours. COMMENTS: Randomized controlled trial PRETERM infants with the neonatologist blinded to the group allocation. End point cerebral oxygenation.part of a larger study on effects of placento fetal

10 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 10 of 28 transfusion.not sure why there are 15 infants in the experimental group and 24 in the control group. Hct higher in the experimental group as was 56 compared to 49 at 24hours. There was no difference at 36 weeks. BP was higher at 4 hours in experimental group no difference at 24 and 72 hours. even though they showed better cerebral oxygenation at 24 hours this effect did not persist. Difficult to extrapolate if this would lead to better neurologic outcomes. LOE 1, Supportive, fair 3) Ceriani Cernadas, J. M., G. Carroli, et al. (2006). "The Effect of Timing of Cord Clamping on Neonatal Venous Hematocrit Values and Clinical Outcome at Term: A Randomized, Controlled Trial." Pediatrics 117(4): e BACKGROUND. The umbilical cord is usually clamped immediately after birth. There is no sound evidence to support this approach, which might deprive the newborn of some benefits such as an increase in iron storage. OBJECTIVES. We sought to determine the effect of timing of cord clamping on neonatal venous hematocrit and clinical outcome in term newborns and maternal postpartum hemorrhage. METHODS. This was a randomized, controlled trial performed in 2 obstetrical units in Argentina on neonates born at term without complications to mothers with uneventful pregnancies. After written parental consents were obtained, newborns were randomly assigned to cord clamping within the first 15 (group 1), at 1 minute (group 2), or at 3 minutes (group 3) after birth. The infants' venous hematocrit value was measured 6 hours after birth. RESULTS. Two hundred seventy-six newborns were recruited. Mean venous hematocrit values at 6 hours of life were 53.5% (group 1), 57.0% (group 2), and 59.4% (group 3). Statistical analyses were performed, and results were equivalent among groups because the hematocrit increase in neonates with late clamping was within the prespecified physiologic range. The prevalence of hematocrit at <45% (anemia) was significantly lower in groups 2 and 3 than in group 1. The prevalence of hematocrit at >65% was similar in groups 1 and 2 (4.4% and 5.9%, respectively) but significantly higher in group 3 (14.1%) versus group 1 (4.4%). There were no significant differences in other neonatal outcomes and in maternal postpartum hemorrhage. CONCLUSIONS. Delayed cord clamping at birth increases neonatal mean venous hematocrit within a physiologic range. Neither significant differences nor harmful effects were observed among groups. Furthermore, this intervention seems to reduce the rate of neonatal anemia. This practice has been shown to be safe and should be implemented to increase neonatal iron storage at birth. COMMENTS: Randomized, TERM not clear if the neonatologist knew the assignment or not. End point hematocrit. All neonates not breathing spontaneously at 10 secs. Were excluded. Primary outcome was Hct at 6 hours. Secondary outomes were Hct at 24 to 48 hours and neonatal morbidity including bilirubin. Polycythemia defined as Hct>65 was significantly in the 3 min. clamping group. Surprisingly they did not find a difference in the bilirubin levels in the 3 groups. No difference in other morbidities, however this was a very low morbidity group. Even though there were no differences in mean Hct between the groups significantly more 8.9% versus 1.15 % and 0 % had anemia defined as Hct <45% at 6 hours. LOE 1, Supportive, fair 4) Chaparro, C. M., R. Fornes, et al. (2007). "Early umbilical cord clamping contributes to elevated blood lead levels among infants with higher lead exposure." J Pediatr 151(5): OBJECTIVE: To investigate whether infant iron status, modified by umbilical cord clamping time and infant feeding mode, affected infant blood lead concentration at 6 months of age. STUDY DESIGN: Participants were a subset of women and their infants randomized to receive

11 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 11 of 28 early (10 ) or delayed (2 minutes) umbilical cord clamping and were monitored to 6 months postpartum in Mexico City. Iron and lead status was analyzed in maternal, placental, and 6-month infant blood samples. Baseline maternal lead exposure data and infant feeding data at 2, 4, and 6 months were collected. RESULTS: In the total sample, maternal blood lead concentration, infant ferritin, and breast-feeding practices predicted infant blood lead concentration. Among infants with higher placental blood lead concentration and breast-fed infants not receiving any iron-fortified formula or milk at 6 months, early clamping increased infant blood lead concentration, an effect mediated in part via decreased infant iron status. CONCLUSIONS: Early cord clamping, by decreasing infant iron status, contributes to higher blood lead concentrations at 6 months of age among infants at high risk. COMMENTS: A retrospective analysis of a prospective randomized trial. TERM infants. Inclusion criteria were availability of blood sample to carry out the blood lead and Iron outcome measure. Demographic data on the mother infant dyad not included, it is said to be the same. Looking at the previous study numbers the infants not included in this study were equally distributed in the. ECC and DCC groups. They did multiple regressions controlling for maternal exposure to lead, placental lead levels and breast feeding. Overall they did demonstrate that ECC lead to higher lead levels at 6 months of age. Multiple analyses were done controlling for few things at a time. However they did analysis showing 23% of total effect of DCC on the infant lead status could be explained by increase in iron stores. LOE 2, Supportive, fair 5) Chaparro, C. M., L. M. Neufeld, et al. (2006). "Effect of timing of umbilical cord clamping on iron status in Mexican infants: a randomised controlled trial." Lancet 367(9527): BACKGROUND. Delayed clamping of the umbilical cord increases the infant's iron endowment at birth and haemoglobin concentration at 2 months of age. We aimed to assess whether a 2-minute delay in the clamping of the umbilical cord of normal-weight, full-term infants improved iron and haematological status up to 6 months of age. METHODS. 476 mother-infant pairs were recruited at a large obstetrics hospital in Mexico City, Mexico, randomly assigned to delayed clamping (2 min after delivery of the infant's shoulders) or early clamping (around 10 s after delivery), and followed up until 6 months postpartum. Primary outcomes were infant haematological status and iron status at 6 months of age, and analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT FINDINGS. 358 (75%) mother-infant pairs completed the trial. At 6 months of age, infants who had delayed clamping had significantly higher mean corpuscular volume (81 0 fl vs 79 5 fl 95% CI -2 5 to -0 6, p=0.001), ferritin (50 7 μg/L vs 34 4 μg/L 95% CI -30 7 to - 1 9, p=0â 0002), and total body iron. The effect of delayed clamping was significantly greater for infants born to mothers with low ferritin at delivery, breastfed infants not receiving ironfortified milk or formula, and infants born with birthweight between 2500 g and 3000 g. A cord clamping delay of 2 minutes increased 6-month iron stores by about mg. INTERPRETATION. Delay in cord clamping of 2 minutes could help prevent iron deficiency from developing before 6 months of age, when iron-fortified complementary foods could be introduced. COMMENTS: Randomized study with end point iron status at 6 months in TERM neonates. Retrospectively obtained history of maternal intake of iron during pregnancy. Randomization was done at the time of admission for delivery. Large study. Very little difference in the Hct. ECC.595 and DCC.620. Do not provide information on the number infants with Hct.>65. No difference in the 2 groups in bilirubin levels. ECC group consumed iron fortified foods at 2 months and DCC group received more

12 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 12 of 28 iron supplements at 4 months. Their conclusions regarding prevention of iron deficiency before 6 months with DCC for 2 minutes is reasonable. LOE 1, Supportive, Good 6) Emhamed, M. O., P. van Rheenen, et al. (2004). "The early effects of delayed cord clamping in term infants born to Libyan mothers." Trop Doct 34(4): This study was conducted to evaluate the haematological effects of the timing of umbilical cord clamping in term infants 24 h after birth in Libya. Mother-infant pairs were randomly assigned to early cord clamping (within 10s after delivery) or delayed clamping (after the cord stopped pulsating). Maternal haematological status was assessed on admission in the delivery room. Infant haematological status was evaluated in cord blood and 24 h after birth. Bilirubin concentration was assessed at 24 h. 104 mother-infant pairs were randomized to delayed (n=58) or early cord clamping (n=46). At baseline the groups had similar demographic and biomedical characteristics, except for a difference in maternal haemoglobin, which was significantly higher in the early clamping group (11.7 g/dl, SD 1.3 g/dl versus 10.9 g/dl, SD 1.6 g/dl; P=0.0035). Twenty-four hours after delivery the mean infant haemoglobin level was significantly higher in the delayed clamping group (18.5 g/dl versus 17.1 g/dl; P=0.0005). No significant differences were found in clinical jaundice or plethora. Surprisingly, blood analysis showed that two babies in the early clamping group had total serum bilirubin levels (> 15 mg/dl) that necessitated phototherapy. There were no babies in the late clamping group who required phototherapy. Three infants in the delayed clamping group had polycythaemia without symptoms, for which no partial exchange transfusion was necessary. Delaying cord clamping until the pulsations stop increases the red cell mass in term infants. It is a safe, simple and low cost delivery procedure that should be incorporated in integrated programmes aimed at reducing iron deficiency anaemia in infants in developing countries. COMMENTS: Randomized, TERM infants, end point Hct. at 24 hours. DCC group was till cord stopped pulsating mean 214 second. Infants were placed on the mothers abdomen.5.3% infants in DCC had polycythemia Hct.>65 however there was no difference in bilirubin in the 2 groups. All the infants needing resuscitation were excluded from the analysis. No follow up information is provided. LOE 1, Supportive, fair 7) Hutton, E. K. and E. S. Hassan (2007). "Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials." JAMA 297(11): CONTEXT: With few exceptions, the umbilical cord of every newborn is clamped and cut at birth, yet the optimal timing for this intervention remains controversial. OBJECTIVE: To compare the potential benefits and harms of late vs early cord clamping in term infants. DATA SOURCES: Search of 6 electronic databases (on November 15, 2006, starting from the beginning of each): the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Neonatal Group trials register, the Cochrane library, MEDLINE, EMBASE, and CINHAL; hand search of secondary references in relevant studies; and contact of investigators about relevant published research. STUDY SELECTION: Controlled trials comparing late vs early cord clamping following birth in infants born at 37 or more weeks' gestation. DATA EXTRACTION: Two reviewers independently assessed eligibility and quality of trials and extracted data for outcomes of interest: infant hematologic status; iron status; and risk of adverse events such as jaundice, polycythemia, and respiratory distress. DATA SYNTHESIS: The meta-analysis included 15 controlled trials (1912 newborns). Late cord clamping was delayed for at least 2 minutes (n = 1001 newborns), while early clamping in most trials (n = 911 newborns) was performed immediately after birth. Benefits over ages 2 to 6 months associated

13 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 13 of 28 with late cord clamping include improved hematologic status measured as hematocrit (weighted mean difference [WMD], 3.70%; 95% confidence interval [CI], 2.00%-5.40%); iron status as measured by ferritin concentration (WMD, 17.89; 95% CI, ) and stored iron (WMD, 19.90; 95% CI, ); and a clinically important reduction in the risk of anemia (relative risk (RR), 0.53; 95% CI, ). Neonates with late clamping were at increased risk of experiencing asymptomatic polycythemia (7 studies [403 neonates]: RR, 3.82; 95% CI, ; 2 high-quality studies only [281 infants]: RR, 3.91; 95% CI, ). CONCLUSIONS: Delaying clamping of the umbilical cord in full-term neonates for a minimum of 2 minutes following birth is beneficial to the newborn, extending into infancy. Although there was an increase in polycythemia among infants in who cord clamping was delayed, this condition appeared to be benign. COMMENTS: A well done systematic review of randomized and non randomized controlled studies till 2006 in TERM infants. End point was not predefined. Exclusive preterm and LBW studies were excluded. Even though the relative risk of Hct.>65 was (3.44) higher in the DCC group none of these infants were symptomatic and did not have increased levels of bilirubin. LOE 1, Supportive, Good 8) Jahazi, A., M. Kordi, et al. (2008). "The effect of early and late umbilical cord clamping on neonatal hematocrit." J Perinatol 28(8): OBJECTIVE: To compare the effect of early and late cord clamping (LCC) on neonatal hematocrit at 2 and 18 h of life. STUDY DESIGN: In this double-blind randomized trial, 64 healthy full-term vaginally born neonates were randomly allocated to either early (30 s) or late (3 min) umbilical cord clamping. During the interval between delivery and cord clamping, the attendant held the neonate supine at the level of the introitus. Neonatal venous hematocrit was measured at 2 and 18 h of life. RESULT: Neonatal hematocrit at 2 h of life (61+/-4.9 vs 61.6+/- 4.5%) and 18 h of life (56.9+/-4.1 vs 56.2+/-3.9%) was not significantly different between the two groups. This was also true for neonatal polycythemia (20 vs 23.5%). In the LCC group, placental residual blood volume (PRBV) was 39.5% lower and estimated neonatal blood volume (ENBV) was 7.1% higher than that in the early cord clamping (ECC) group (P<0.001). CONCLUSION: Late cord clamping does not lead to a significant difference in the hematocrit level of the neonate or neonatal polycythemia, but is associated with a significant increase in ENBV and a significant decrease in PRBV. Further trials should examine the effect of delaying cord clamping for a longer period of time or changing the position that the neonate is held in to determine whether these variations result in more clinically significant results. COMMENTS: Randomized, TERM infants, end point hematocrit at 18 hours. Early group had the cord clamped at 30s and late at 3 minutes. Neonate held at the level of the introitus. No difference in the Hct. in the 2 groups. No difference in polycythemia. LOE 1, Neutral, fair 9) Kugelman, A., L. Borenstein-Levin, et al. (2007). "Immediate versus delayed umbilical cord clamping in premature neonates born < 35 weeks: a prospective, randomized, controlled study." Am J Perinatol 24(5): The purpose of this study was to test whether delayed versus immediate cord clamping would result in higher blood pressure (BP) and hematocrit (Hct), and to assess its clinical effects on the neonatal course in premature neonates (< 35 weeks). This was a prospective, masked, randomized, controlled study. Prior to delivery, 35 neonates were randomly assigned to

14 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 14 of 28 immediate cord clamping (ICC) at 5 to 10, and a comparable group of 30 neonates were randomly assigned to delayed cord clamping (DCC) at 30 to 45. Intention-to-treat analyses revealed that the DCC group tended to have higher initial diastolic BP and higher Hct (especially in vaginally delivered neonates). Infants weighing < 1500 g with DCC tended to have higher mean BP, and needed less mechanical ventilation and surfactant compared with ICC neonates. Infants with DCC did not experience more polycythemia (Hct > 60%), but had a trend toward higher bilirubin levels with no differences in the phototherapy needs. DCC seems to be safe and may be beneficial when compared with ICC in premature neonates. However, the differences between the two methods were modest and the clinical relevance needs to be assessed further by larger studies and additional meta-analysis of randomized trials. COMMENTS: Prospective, masked, randomized, PRETERM neonates, end point initial blood pressure cuff or central and initial hematocrit. DCC was 30 to 45. There was a difference in the mean BP in infants <1500gm 36 mm Hg versus 43 mmhg. This was a subset analysis. No significant difference in the whole group. Hct. was initially similar but was higher in the DCC at 24 hours. LOE 1, Neutral, fair 10) McDonald, S. J. and P. Middleton (2008). "Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes." Cochrane Database Syst Rev(2): CD BACKGROUND: Policies for timing of cord clamping vary, with early cord clamping generally carried out in the first 60 after birth, whereas later cord clamping usually involves clamping the umbilical cord greater than one minute after the birth or when cord pulsation has ceased. OBJECTIVES: To determine the effects of different policies of timing of cord clamping at delivery of the placenta on maternal and neonatal outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (December 2007). SELECTION CRITERIA: Randomised controlled trials comparing early and late cord clamping. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality and extracted data. MAIN RESULTS: We included 11 trials of 2989 mothers and their babies. No significant differences between early and late cord clamping were seen for postpartum haemorrhage or severe postpartum haemorrhage in any of the five trials (2236 women) which measured this outcome (relative risk (RR) for postpartum haemorrhage 500 mls or more 1.22, 95% confidence interval (CI) 0.96 to 1.55). For neonatal outcomes, our review showed both benefits and harms for late cord clamping. Following birth, there was a significant increase in infants needing phototherapy for jaundice (RR 0.59, 95% CI 0.38 to 0.92; five trials of 1762 infants) in the late compared with early clamping group. This was accompanied by significant increases in newborn haemoglobin levels in the late cord clamping group compared with early cord clamping (weighted mean difference 2.17 g/dl; 95% CI 0.28 to 4.06; three trials of 671 infants), although this effect did not persist past six months. Infant ferritin levels remained higher in the late clamping group than the early clamping group at six months. AUTHORS' CONCLUSIONS: One definition of active management includes directions to administer an uterotonic with birth of the anterior shoulder of the baby and to clamp the umbilical cord within of birth of the baby (which is not always feasible in practice). In this review delaying clamping of the cord for at least two to three minutes seems not to increase the risk of postpartum haemorrhage. In addition, late cord clamping can be advantageous for the infant by improving iron status which may be of clinical value particularly in infants where access to good nutrition is poor, although delaying clamping increases the risk of jaundice requiring phototherapy. COMMENTS: Studies included TERM neonates till Early cord clamping defined as within 60 and delayed as 2 minutes. Clinical jaundice was more likely to occur in DCC group. LOE 1, Opposing, Good

15 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 15 of 28 11) Mercer, J. S., B. R. Vohr, et al. (2006). "Delayed Cord Clamping in Very Preterm Infants Reduces the Incidence of Intraventricular Hemorrhage and Late-Onset Sepsis: A Randomized, Controlled Trial." Pediatrics 117(4): OBJECTIVE. This study compared the effects of immediate (ICC) and delayed (DCC) cord clamping on very low birth weight (VLBW) infants on 2 primary variables: bronchopulmonary dysplasia (BPD) and suspected necrotizing enterocolitis (SNEC). Other outcome variables were late-onset sepsis (LOS) and intraventricular hemorrhage (IVH). STUDY DESIGN. This was a randomized, controlled unmasked trial in which women in labor with singleton fetuses <32 weeks' gestation were randomly assigned to ICC (cord clamped at 5-10 ) or DCC (30-45 ) groups. Women were excluded for the following reasons: their obstetrician refused to participate, major congenital anomalies, multiple gestations, intent to withhold care, severe maternal illnesses, placenta abruption or previa, or rapid delivery after admission. RESULTS. Seventy-two mother/infant pairs were randomized. Infants in the ICC and DCC groups weighed 1151 and 1175 g, and mean gestational ages were 28.2 and 28.3 weeks, respectively. Analyses revealed no difference in maternal and infant demographic, clinical, and safety variables. There were no differences in the incidence of our primary outcomes (BPD and suspected NEC). However, significant differences were found between the ICC and DCC groups in the rates of IVH and LOS. Two of the 23 male infants in the DCC group had IVH versus 8 of the 19 in the ICC group. No cases of sepsis occurred in the 23 boys in the DCC group, whereas 6 of the 19 boys in the ICC group had confirmed sepsis. There was a trend toward higher initial hematocrit in the infants in the DCC group. CONCLUSIONS. Delayed cord clamping seems to protect VLBW infants from IVH and LOS, especially for male infants. COMMENTS: Randomized, PRETERM, end point BPD. DCC was 30 to 45. No comment on the resuscitation of these infants. Authors did not demonstrate a difference in BPD, however their secondary analysis showed a difference in IVH and late onset sepsis. LOE 1, Neutral, fair 12) Rabe, H., G. Reynolds, et al. (2004). "Early versus delayed umbilical cord clamping in preterm infants." Cochrane Database Syst Rev(4): CD BACKGROUND: Optimal timing for clamping of the umbilical cord at birth is unclear. Early clamping allows for immediate resuscitation of the newborn. Delaying clamping may facilitate transfusion of blood between the placenta and the baby. OBJECTIVES: To delineate the shortand long-term effects for infants born at less than 37 completed weeks' gestation, and their mothers, of early compared to delayed clamping of the umbilical cord at birth. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (2 February 2004), the Cochrane Neonatal Group trials register (2 February 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2004), PubMed (1966 to 2 February 2004) and EMBASE (1974 to 2 February 2004). SELECTION CRITERIA: Randomized controlled trials comparing early with delayed (30 or more) clamping of the umbilical cord for infants born before 37 completed weeks' gestation. DATA COLLECTION AND ANALYSIS: Three reviewers assessed eligibility and trial quality. MAIN RESULTS: Seven studies (297 infants) were eligible for inclusion. The maximum delay in cord clamping was 120. Delayed cord clamping was associated with a higher hematocrit four hours after birth (four trials, 134 infants; weighted mean difference 5.31, 95% confidence interval (CI) 3.42 to 7.19), fewer transfusions for anaemia (three trials, 111 infants; relative risk (RR) 2.01, 95% CI 1.24 to 3.27) or low blood pressure (two trials, 58 infants; RR 2.58, 95% CI 1.17 to 5.67) and less intraventricular haemorrhage (five trials, 225 infants; RR 1.74, 95% CI 1.08 to 2.81) than early clamping. REVIEWERS' CONCLUSIONS: Delaying cord clamping by

16 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 16 of to 120, rather than early clamping, seems to be associated with less need for transfusion and less intraventricular haemorrhage. There are no clear differences in other outcomes. COMMENTS: Systematic meta analysis PRETERM trials till Overall there is less need for transfusions and decrease in IVH. No difference in jaundice. LOE 1, Supportive, Good 13) Rabe, H., G. Reynolds, et al. (2008). "A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants." Neonatology 93(2): BACKGROUND: The optimal timing of clamping the umbilical cord in preterm infants at birth is the subject of continuing debate. Objective: To investigate the effects of a brief delay in cord clamping on the outcome of babies born prematurely. METHODS: A retrospective metaanalysis of randomised trials in preterm infants was conducted. Data were collected from published studies identified by a structured literature search in EMBASE, PubMed, CINAHL and the Cochrane Library. All infants born below 37 weeks gestation and enrolled into a randomised study of delayed cord clamping (30 s or more) versus immediate cord clamping (less than 20 s) after birth were included. Systematic search and analysis of the data were done according to the methodology of the Cochrane collaboration. RESULTS: Ten studies describing a total of 454 preterm infants were identified which met the inclusion and assessment criteria. Major benefits of the intervention were higher circulating blood volume during the first 24 h of life, less need for blood transfusions (p = 0.004) and less incidence of intraventricular hemorrhage (p = 0.002). CONCLUSIONS: The procedure of a delayed cord clamping time of at least 30 s is safe to use and does not compromise the preterm infant in the initial post-partum adaptation phase. COMMENTS: Authors repeated the Cochrane review. Included 3 more studies in the analysis 2 that were reported before their initial analysis and one before Conclusions were no different. LOE 1, Supportive, fair 14) Strauss, R. G., D. M. Mock, et al. (2008). "A randomized clinical trial comparing immediate versus delayed clamping of the umbilical cord in preterm infants: short-term clinical and laboratory endpoints." Transfusion 48(4): BACKGROUND: Most neonates less than 1.0 kg birth weight need red blood cell (RBC) transfusions. Delayed clamping of the umbilical cord 1 minute after delivery transfuses the neonate with autologous placental blood to expand blood volume and provide 60 percent more RBCs than after immediate clamping. This study compared hematologic and clinical effects of delayed versus immediate cord clamping. STUDY DESIGN AND METHODS: After parental consent, neonates not more than 36 weeks' gestation were randomly assigned to cord clamping immediately or at 1 minute after delivery. The primary endpoint was an increase in RBC volume/mass, per biotin labeling, after delayed clamping. Secondary endpoints were multiple clinical and laboratory comparisons over the first 28 days including Score for Neonatal Acute Physiology (SNAP). RESULTS: Problems with delayed clamping techniques prevented study of neonates of less than 30 weeks' gestation, and 105 neonates 30 to 36 weeks are reported. Circulating RBC volume/mass increased (p = 0.04) and weekly hematocrit (Hct) values were higher (p < 0.005) after delayed clamping. Higher Hct values did not lead to fewer RBC transfusions (p > or = 0.70). Apgar scores after birth and daily SNAP scores were not significantly different (p > or = 0.22). Requirements for mechanical ventilation with oxygen were similar. More (p = 0.03) neonates needed phototherapy after delayed clamping, but initial bilirubin levels and extent of phototherapy did not differ. CONCLUSIONS: Although a 1-

17 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 17 of 28 minute delay in cord clamping significantly increased RBC volume/mass and Hct, clinical benefits were modest. Clinically significant adverse effects were not detected. Consider a 1- minute delay in cord clamping to increase RBC volume/mass and RBC iron, for neonates 30 to 36 weeks' gestation, who do not need immediate resuscitation. COMMENTS: Randomized. PRETERM. DCC was 1 minute. End point RBC volumes. Secondary end points hemodynamic status, clinical condition, need for RBC transfusion. Randomization was stratified into weeks GA and < 30 weeks GA. Was powered to detect a 50% decrease in RBC transfusions. Uniform transfusion guidelines are said to be followed. They lost 26 of the 27 infants < 30 weeks GA due to unsatisfactory collection of placental blood (18) and insufficient volume for transfusion (7). They report the weeks infants. 8% in the ECC and 4 % of infants in the DCC received blood transfusion. This was not statistically significant. More infants in DCC (73%) versus (53%) p=0.03 required phototherapy. Hematocrits were higher in the DCC till day 28. They report no difference in IVH but not all the babies in the weeks had cranial ultrasounds so that comment cannot be interpreted. LOE 1, Supportive, Poor 15) Ultee, C. A., J. van der Deure, et al. (2008). "Delayed cord clamping in preterm infants delivered at weeks' gestation: a randomized controlled trial." Arch Dis Child Fetal Neonatal Ed 93(1): F20-3. BACKGROUND: Even mild iron deficiency and anemia in infancy may be associated with cognitive deficits. A delay in clamping the cord improves haematocrit levels and results in greater vascular stability and less need for packed cell transfusions for anaemia in the first period after birth. Follow-up data on haemoglobin levels after the neonatal period were not available. OBJECTIVE: To provide neonatal and follow-up data for the effects of early or delayed clamping of the cord. METHODS: 37 premature infants (gestational age 34 weeks, 0 days-36 weeks, 6 days) were randomly assigned to one of two groups in the first hour after birth, and at 10 weeks of age. In one group the umbilical cord was clamped within 30 (mean (SD) 13.4 (5.6)) and in the other, it was clamped at 3 minutes after delivery. In the neonatal period blood glucose and haemoglobin levels were determined. At 10 weeks of age haemoglobin and ferritin levels were determined. RESULTS: The late cord-clamped group showed consistently higher haemoglobin levels than the early cord-clamped group, both at the age of 1 hour (mean (SD) 13.4 (1.9) mmol/l vs 11.1 (1.7) mmol/l), and at 10 weeks (6.7 (0.75) mmol/l vs 6.0 (0.65) mmol/l). No relationship between delayed clamping of the umbilical cord and pathological jaundice or polycythaemia was found. CONCLUSION: Immediate clamping of the umbilical cord should be discouraged. COMMENTS: Randomized. PRETERM. End point hemoglobin and ferritin levels. There was no difference in the ferritin levels. Hb./Hct were significantly higher at 1 hour and 10 weeks of age. No difference in bilirubin levels and no increase in polycythemia. Very small numbers. LOE 1, Supportive, Poor 16) van Rheenen, P. and B. J. Brabin (2004). "Late umbilical cord-clamping as an intervention for reducing iron deficiency anaemia in term infants in developing and industrialised countries: a systematic review." Annals Of Tropical Paediatrics 24(1): This review evaluates the potential of delayed cord-clamping for improving iron status and reducing anaemia in term infants and for increasing the risk of polycythaemia and hyperbilirubinaemia. We applied a strict search protocol to identify controlled trials of early vs late cord-clamping. Four trials from developing and four from industrialised countries were finally assessed. Two of the four studies from developing countries found a significant difference in infant haemoglobin levels at 2-3 months of age in favour of delayed cordclamping. This difference was more marked when mothers were anaemic. Three of four studies

18 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 18 of 28 from industrialised countries showed a significant difference in haematocrit levels in favour of delayed clamping. Although meta-analysis showed an increased risk for hyperbilirubinaemia of 12%, no studies reported the need to apply phototherapy or perform exchange transfusion. We conclude that delayed cord-clamping in term infants, especially those with anaemic mothers, increases haemoglobin concentration in infants at 2-3 months of age and reduces the risk of anaemia, without an associated increased risk of perinatal complications. In developing countries where fetal anaemia is common, the advantages of delayed cord-clamping might be especially beneficial. COMMENTS: Reasonable systematic review. TERM. However there were only 2 studies with a total of 46 babies in the ECC group and 73 in DCC group for inclusion for anemia in developing countries. These had different timings of cord clamping stopping of cord pulsations and after placenta in the vagina. In the developed countries analysis they just report the hematocrit. They report increase in bilirubin but no increase in use of phototherapy. LOE 1, Supportive, Fair 17) van Rheenen, P., L. de Moor, et al. (2007). "Delayed cord clamping and haemoglobin levels in infancy: a randomised controlled trial in term babies." Trop Med Int Health 12(5): OBJECTIVES: This study was carried out to assess whether delaying umbilical cord clamping is effective in improving the haematological status of term infants living in a malaria-endemic area, and whether this is associated with complications in infants and mothers. METHODS: We randomly assigned women delivering term babies in Mpongwe Mission Hospital, Zambia, to delayed cord clamping (DCC, n = 46) or immediate cord clamping (controls, n = 45) and followed their infants on a bi-monthly basis until the age of 6 months. We compared the haemoglobin (Hb) change from cord values and the proportion of anaemic infants. Secondary outcomes related to infant and maternal safety. RESULTS: Throughout the observation period infant Hb levels in both groups declined, but more rapidly in controls than in the DCC group [difference in Hb change from baseline at 4 months 1.1 g/dl, 95% confidence interval (CI) 0.2; 2.1]. By 6 months, this difference had disappeared (0.0 g/dl, 95% CI -0.9; 0.8). The odds ratio for iron deficiency anaemia in the DCC group at 4 months was 0.3 (95% CI 0.1; 1.0), but no differences were found between the groups at 6 months. No adverse events were seen in infants and mothers. CONCLUSION: Our findings indicate that DCC could help improve the haematological status of term infants living in a malaria-endemic region at 4 months of age. However, the beneficial haematological effect disappeared by 6 months. This simple, free and safe delivery procedure might offer a strategy to reduce early infant anaemia risk, when other interventions are not yet feasible. COMMENTS: Randomized. TERM. End point 6 months hemoglobin levels. Spefically state they did the trial in malaria zone. Even though the hemoglobin levels were similar in the 2 groups at 4 months the number of infats with Hb<10.3 their cut off for anemia were 21% DCC and 41% ECC group. At 6 months there were no differences. However the there is evidence in the literature that early iron deficiency anemia may have an impact on neurodevelopmental outcome. LOE 1, Neutral, Good 18) van Rheenen, P. F., S. Gruschke, et al. (2006). "Delayed umbilical cord clamping for reducing anaemia in low birthweight infants: implications for developing countries." Annals Of Tropical Paediatrics 26(3): BACKGROUND: Cheap and effective interventions are needed to reduce the risk of infant anaemia in developing countries. Delayed cord clamping (DCC) has been shown to be a simple, safe and cost-free delivery procedure that augments red cell mass in appropriate-for-gestationalage term and preterm infants. It is not known, however, whether DCC is similarly safe and effective in small-for-gestational-age (SGA) infants. We analysed the available evidence to

19 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 19 of 28 generate a balanced inference on the use of DCC in developing countries. OBJECTIVES: To examine the short- and long-term effects in SGA infants of DCC compared with immediate clamping, and to assess the relationship between time of clamping and the potential postnatal haematological complications of DCC in SGA infants. SEARCH STRATEGY: PubMed (1966 to January 2006), EMBASE (1988 to January 2006) and The Cochrane Library (Issue 1, 2006) were searched. Reference lists of published trials were examined and major journals of perinatal and tropical medicine were hand-searched. SELECTION CRITERIA: Randomised and quasirandomised trials comparing delayed with immediate cord clamping in infants born between 30 and 42 completed weeks of gestation and which included a proportion of SGA infants. DATA COLLECTION AND ANALYSIS: Three reviewers assessed eligibility and trial quality. MAIN RESULTS: To date, no trials have specifically reported the effects of DCC in SGA infants. Three trials were included, of 190 term and 40 preterm infants, a proportion of whom were SGA. DCC was associated with higher haemoglobin levels in term infants at follow-up [two trials, 127 infants, weighted mean difference (WMD) 9.17 g/l, 95% confidence interval (CI) ]. In preterm infants, the proportion who required a blood transfusion in the 1st 6 weeks after birth was lower after DCC (one trial, 38 infants, RR 0.56, 95% CI ). It was not possible to infer from the available data whether SGA infants were at greater risk of adverse effects in the early neonatal period. CONCLUSIONS: DCC in a group that contains both AGA and SGA infants was associated with higher haemoglobin levels at 2-3 months of age in term infants and a reduction in the number of blood transfusions needed in the 1st 4-6 weeks of life in preterm infants. No reliable conclusions could be drawn about the potential adverse effects of DCC. The paucity of information on DCC in SGA infants justifies further research, especially in developing countries where the baseline risk for polycythaemia-hyperviscosity syndrome is likely to be lower than in industrialised countries. COMMENTS: An attempt at a systematic review of the effect of DCC in low birth weight infants. Authors use appropriate methods however they did not find any articles other than indirect evidence and reporting on SGA infants in 3 studies. 2 of these studies they assumed had SGA infants and 1 study reported 36% SGA infants. No specific conclusions can be made about this subset of SGA infants that may be increased risk of polycythemia. LOE 1, Neutral, Poor 19) Venancio, S. I., R. B. Levy, et al. (2008). "Effects of delayed cord clamping on hemoglobin and ferritin levels in infants at three months of age." Cad Saude Publica 24 Suppl 2: S This study assessed the effect of delayed (1 minute after delivery) clamping of the umbilical cord on hemoglobin and ferritin levels in infants at three months of age. Mothers and their infants born through vaginal delivery, at term, and without congenital anomalies (325 pairs) were recruited at a hospital in Sao Paulo, Brazil, in 2006 (164 in the delayed clamping subgroup and 161 in the early clamping subgroup). Maternal hemoglobin at delivery, umbilical cord hemoglobin, and ferritin were recorded. At three months follow-up, venous blood samples were drawn from 224 (69%) infants for hemoglobin and ferritin measurement. Socioeconomic, maternal reproductive, anthropometric, and infant feeding variables were studied. Multiple linear regression models were used to analyze the data. The effect of delayed clamping at birth, measured at three months, was only significant for ferritin (p = 0.040), and the concentration was higher (23.29ng/mL) in this subgroup as compared to the early clamping subgroup. Delayed umbilical cord clamping can serve as a strategy to improve infant iron status and prevent iron deficiency. Methods: Late clamping was defined as clamping at one minute, with the infant maintained at the level of the placenta. The study was not strictly randomized, because for operational reasons the timing of cord clamping

20 C2010 Worksheet:NRP-030B 23-Feb-2010 Atkins.doc Page 20 of 28 was alternated by weeks. Mother-infant pairs were studied after term, normal vaginal births. Criteria for exclusion were eclampsia, pre-eclampsia, diabetes, Rh isoimmunization, and neonatal anoxia. Sample size was calculated in EpiInfo to be 280, which was increased to 322 with the expectation of 13% loss to follow-up. The study required somewhat longer to complete than expected, due to failure to perform the procedures required to include mothers/infants in the study (e.g. cord blood collection), especially when no study personnel where present (night). Information was obtained on mothers through interviews and record reviews. Mail and phone reminders were sent regarding the 3-month follow-up appointment. Re-appointments were made, and even home visits conducted to obtain 3-month samples. Venous blood specimens were collected (3mL). Research personnel were trained in interview techniques and anthropometry, and follow-up personnel were masked to the intervention group. Duplicate data entry was performed in EpiInfo and statistical analysis used Stata 8.0 with linear regression modeling. Three cases (all in the late-clamped group) were excluded because of ferritin values more than 3SD above the mean. Multiple linear regression was perform with stepwise backward selection, using late/early clamping as the primary explanatory variable, and cord ferritin, maternal hemoglobin (prenatal), birth weight, sex of infant, age of baby at follow-up, administration of vitamins/fe to baby, and fever < 15d. before follow-up as covariates. Results: Of the 325 mother-infant pairs enrolled, 224 were followed (68.9%). Approximately 21% were lost to follow-up and another 10.5% were excluded because of loss of specimens. There were no statistical differences between the late and early clamping groups on the basis of maternal variables. Mean time of follow-up for the infants was 3.22 months, due to the need to reappoint many infants. Chi-square showed a significant difference in the proportion of infants breastfed at 3 months (76% in the early group and 88% in the late group) and trend toward less cough in the last 2 weeks for infants in the late clamping group. T-tests showed a trend toward higher ferritin at 3 months in the late clamping group. Multiple regression confirmed ferritin at 3 months was on average 23.3 ng/ml higher in the late-clamping group as compared to immediate clamping when all other covariates were held constant. Discussion: There were no significant differences in the occurrence of jaundice in the 2 groups, though data are not presented. Limitations include inability to measure CRP as an indicator of inflammation, which can elevate ferritin; for this reason fever was included as a covariate. The number lost to follow-up impacted the ability of the study to detect a difference between groups, but there was no evidence that the subjects lost to follow-up differed systematically from those followed. No difference was found in hemoglobin at 3 months. The authors speculate that this is likely due to the very high rates of breast feeding (highly bioavailable iron) and high prevalence of iron supplementation among both the early and late-clamping groups. Late clamping is concluded to be a beneficial practice for Brazilian infants. COMMENTS: This prospective cohort study examined the effect of delayed (> 1 min) vs. immediate cord clamping on hemoglobin and ferritin levels in infants at 3 months of age. Article published in Portugese, Above is a translated abstract. Uncomplicated vaginal deliveries at term (325 mother-infant pairs, 164 delayed clamping and 161 early clamping) were studies in Sao Paulo, Brazil between April 2006 and March Early clamping was routine in the Municipal Hospital of Campo Limpo. LOE 2, Supportive, Good 20) Wiberg, N., K. Kallen, et al. (2008). "Delayed umbilical cord clamping at birth has effects on arterial and venous blood gases and lactate concentrations." BJOG 115(6): OBJECTIVE: To estimate the influence of delayed umbilical cord clamping at birth on arterial and venous umbilical cord blood gases, bicarbonate (HCO3-), base excess (BE) and lactate in