F Health Technology Assessment Report 5 Routine ultrasound scanning before 24 weeks of pregnancy Consultation Assessment Report: 26 August 2003 Authors: Ritchie K, Boynton J, Bradbury I, Foster L, Iqbal K, Kohli H, Love C, Penney G, Quinn S, Reid M, Slattery J, Wright D With significant contributions from the Topic Specific Group and special advisers (see Appendix 1) Consultation comments should be sent by 06 October 2003 to: Miss Susan Quinn, Medical Writer Phone: +44 (0) 141 225 6890 Email: susan.quinn@nhshealthquality.org (See Section 2.4 for further details)
NHS Quality Improvement Scotland was set up to improve the quality of health care in Scotland. Its role is to set standards and monitor performance and provide NHSScotland with advice, guidance and support on effective clinical practice and service improvements. NHSScotland is expected to take account of advice and evidence from NHS Quality Improvement Scotland and to ensure that recommended drugs or treatments are made available to meet clinical need. Established on 01 January 2003, NHS Quality Improvement Scotland is a Special Health Board, built on the expertise developed within the: Health Technology Board for Scotland (HTBS) Clinical Resource and Audit Group Clinical Standards Board for Scotland Nursing and Midwifery Practice Development Unit Scottish Health Advisory Service. NHS Quality Improvement Scotland, 2003 NHS Quality Improvement Scotland consents to the photocopying, electronic reproduction by uploading or downloading from the website, retransmission, or other copying of the findings of this report for the purpose of implementation in NHSScotland and educational and not for profit purposes. No reproduction by or for commercial organisations is permitted without the express written permission of NHS Quality Improvement Scotland.
Contents 1 Executive summary...1-1 2 Introduction and objectives...2-1 2.1 Introduction...2-1 2.2 Objectives...2-1 2.3 Aim and structure of the document...2-1 2.3.1 Rationale for undertaking the HTA...2-1 2.3.2 Structure of the document...2-2 2.4 Current stage of the assessment...2-3 3 Background...3-1 3.1 Description of health issue in Scotland...3-1 3.1.1 Aspects of routine antenatal care relevant to the HTA...3-1 3.1.1.1 Ultrasound scanning for the management of routine pregnancy...3-1 3.1.1.2 Ultrasound scanning for the identification of structural abnormalities...3-2 3.1.1.3 Maternal serum screening...3-4 3.1.1.4 Invasive diagnostic tests...3-5 3.1.1.5 Ethical issues...3-6 3.1.2 Impact of health issue for NHSScotland...3-7 3.1.3 Recent policy and health department initiatives...3-7 3.2 Organisation of health care in Scotland...3-8 3.2.1 Organisation of NHSScotland...3-8 3.2.2 Organisation of routine ultrasound scanning services in Scotland for pregnant women...3-8 3.3 Description of technology...3-8 3.3.1 Scanning equipment...3-8 3.3.2 Storage media...3-9 3.3.3 Doppler ultrasound...3-9 3.4 Focus of HTA...3-10 4 Clinical effectiveness...4-1 4.1 Introduction...4-3 4.2 Methodology...4-3 4.2.1 Evidence sources...4-3 4.2.1.1 Literature search...4-3 4.2.1.2 Other sources of evidence...4-4 4.2.2 Selection criteria...4-4 4.2.3 Methodology for the evaluation of clinical effectiveness...4-5 4.3 Results critical appraisal of literature scanning for fetal viability, gestational age, multiple pregnancies...4-5 4.3.1 Previous HTAs...4-5 4.3.1.1 Gestational age assessment...4-6 4.3.1.2 Identification of multiple pregnancies...4-6 4.3.2 Systematic reviews and meta-analyses...4-6 4.3.3 Other studies or reviews...4-7 4.3.3.1 Ultrasound assessment of gestational age...4-7 4.3.3.2 Ultrasound scanning of multiple pregnancies...4-7
4.3.4 Summary of secondary literature...4-8 4.4 Results critical appraisal of literature scanning for fetal abnormality...4-8 4.4.1 First trimester ultrasound scanning for structural abnormalities...4-8 4.4.2 First trimester ultrasound markers for abnormalities...4-11 4.4.2.1 Nuchal translucency measurement as a screening method for chromosomal abnormalities...4-11 4.4.2.2 Absence of nasal bone...4-14 4.4.2.3 Enlarged nuchal translucency and normal karyotype...4-16 4.5 Results - critical appraisal of literature second trimester scanning for fetal abnormalities...4-18 4.5.1 Previous HTAs...4-18 4.5.1.1 Routine ultrasound examination in pregnancy (Hagenfeldt et al., 1998)...4-18 4.5.1.2 Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost effectiveness and women s views (Bricker et al. 2000)...4-19 4.5.2 Systematic reviews and meta-analyses...4-20 4.5.3 Other studies or reviews...4-20 4.5.3.1 Studies of particular interest...4-20 4.5.3.2 Fetal anomaly scanning in the second trimester...4-23 4.5.3.3 Reporting of specific abnormalities...4-24 4.6 Assessment of safety of ultrasound in clinical practice...4-42 4.6.1 Interaction mechanisms...4-42 4.6.1.1 Thermal effects...4-42 4.6.1.2 Non-thermal effects...4-42 4.6.2 Guidelines on the safe application of ultrasound...4-43 4.6.3 Safety assessment...4-43 4.7 Discussion and conclusions...4-44 4.8 Consultation questions...4-45 5 Issues for pregnant women...5-1 5.1 Introduction...5-2 5.2 Methodology...5-2 5.2.1 Evidence sources...5-2 5.2.1.1 Literature search...5-2 5.2.1.2 Other sources of evidence...5-3 5.2.1.3 Selection criteria...5-3 5.2.2 Methods of analysis...5-4 5.3 Results review of literature...5-4 5.3.1 Positive feelings towards ultrasound scanning...5-5 5.3.1.1 Seeing the baby...5-5 5.3.1.2 Feelings after the scan...5-5 5.3.1.3 Anxiety about the scan...5-6 5.3.1.4 Consent to undergo ultrasound scanning and comprehension of the purpose of the test...5-7 5.3.2 Risk of the procedure...5-8 5.3.3 Problems identified by ultrasound...5-9 5.3.3.1 Putting the pregnancy on hold...5-9 5.3.3.2 Being prepared for bad news...5-10 5.3.3.3 False positive findings...5-11 5.3.4 Partners views and experiences of ultrasound scanning...5-11 5.3.5 The procedure undergoing ultrasound scanning...5-12
5.3.6 Different technologies...5-12 5.3.6.1 Transvaginal ultrasound scanning...5-12 5.3.6.2 Nuchal translucency screening and soft markers...5-13 5.3.6.3 Accurate identification of fetal sex...5-14 5.3.7 Communication with pregnant women...5-14 5.4 Results other sources of evidence...5-16 5.5 Results communication with pregnant women...5-16 5.6 Discussion and conclusions...5-16 5.7 Consultation questions...5-17 6 Organisational issues...6-1 6.1 Introduction...6-3 6.2 Survey of current practice of routine ultrasound scanning in Scotland...6-3 6.2.1 Methodology...6-3 6.2.2 Results...6-3 6.2.2.1 Booking scan...6-4 6.2.2.2 Routine first trimester scanning...6-6 6.2.2.3 Routine second trimester scanning...6-7 6.2.2.4 Serum screening...6-10 6.2.2.5 Information and consent...6-10 6.2.2.6 Doppler and transvaginal scanning...6-11 6.2.2.7 Fetal anomaly confirmation...6-11 6.2.2.8 Procedure and staffing...6-11 6.2.2.9 Equipment...6-13 6.3 Structure of current service summary of survey...6-13 6.4 Screening issues...6-14 6.5 Information and consent...6-15 6.6 Staff involved in ultrasound scanning and training...6-16 6.7 Equipment...6-17 6.8 Information management of the technology...6-17 6.9 Quality assurance/audit...6-18 6.10 Legal issues...6-19 6.11 Telemedicine and teleultrasound...6-19 6.12 Organisation of the service...6-21 6.13 Discussion and conclusions...6-22 6.14 Consultation questions...6-23 7 Economic evaluation and modelling...7-1 7.1 Introduction...7-3 7.2 Objectives...7-3 7.3 Methodology...7-3 7.3.1 Evidence sources...7-3 7.3.1.1 Literature search...7-3 7.3.1.2 Other sources of evidence...7-4 7.3.2 Exclusion criteria...7-4 7.3.3 Description of model and data inputs...7-5 7.3.3.1 Objectives...7-5 7.3.3.2 Model structure...7-5 7.3.3.3 Identification and measurement of model inputs...7-6 7.4 Results and analysis...7-25 7.4.1 Costs and components of strategies...7-25
7.4.2 Terminations of pregnancy...7-28 7.4.3 Further investigations...7-31 7.4.4 Detection of anomalies...7-33 7.4.5 Summary of results...7-35 7.5 Economic evaluation conclusions...7-35 7.6 Estimated resource implications for NHSScotland...7-36 7.7 Discussion and conclusions...7-36 7.8 Consultation questions...7-39 8 Discussion and conclusions...8-1 8.1 Principal findings...8-1 8.1.1 Scope of the HTA...8-1 8.1.2 Findings from the four HTA components...8-1 8.1.2.1 Clinical effectiveness...8-1 8.1.2.2 Issues for pregnant women...8-2 8.1.2.3 Organisational issues...8-2 8.1.2.4 Economic evaluation and modelling...8-3 8.1.3 Assumptions...8-4 8.1.4 Limitations...8-4 8.1.5 Uncertainties...8-5 8.2 Need for further research...8-5 8.3 Challenges for implementation...8-5 8.4 Summary and conclusions...8-6 8.5 Draft recommendations to NHSScotland...8-7 8.6 Consultation questions...8-8 8.6.1 Clinical effectiveness...8-8 8.6.2 Issues for pregnant women...8-9 8.6.3 Organisational issues...8-9 8.6.4 Economic evaluation and modelling...8-9 9 Acknowledgements...9-1 10 References...10-1
List of tables Table 3-1 Summary of fetal abnormalities...3-4 Table 4-1 Detection of fetal abnormalities by first trimester anomaly scan...4-10 Table 4-2 CUBS study...4-11 Table 4-3 Results of SURUSS study (Wald et al., 2003)...4-13 Table 4-4 Nasal bone as a marker for abnormalities...4-15 Table 4-5 Studies of association between enlarged NT measurement and structural abnormalities in chromosomally normal fetuses...4-17 Table 4-6 Detection of fetal abnormalities suitable for generation of sensitivity and specificities...4-23 Table 4-7 Detection of NTDs using ultrasound scanning...4-25 Table 4-8 Detection rates for CNS defects at second trimester anomaly scan...4-27 Table 4-9 Detection rates for cardiac defects from Bricker et al. (2000)...4-28 Table 4-10 Prospective studies of ultrasound scanning for detection of congenital heart abnormalities...4-29 Table 4-11 Detection rates for gastrointestinal defects...4-30 Table 4-12 Studies of ultrasound scanning for detection of anterior abdominal wall defects...4-32 Table 4-13 Detection rates for urinary tract defects...4-33 Table 4-14 Hanna et al. (1996) primary reasons for referral...4-34 Table 4-15 Kurjak et al. (1999) results of karyotyping...4-35 Table 4-16 DeVore (2001) sensitivity and FPR of real-time ultrasound for anomalies identified...4-37 Table 4-17 DeVore (2001) proportion of fetuses with abnormal ultrasound...4-37 Table 4-18 Results from Winter et al. (2000)...4-40 Table 4-19 Results from Egan et al. (2001)...4-41 Table 6-1 Reason for exclusion of returned questionnaire from analysis...6-3 Table 6-2 Background information...6-4 Table 6-3 Time of booking scan by unit...6-5 Table 6-4 Assessment of abnormalities during first trimester scan (n=34 units)...6-7 Table 6-5 Time of second trimester scan (excluding booking scans) by unit (n=20 units)...6-8 Table 6-6 Assessment of abnormalities during second trimester scan (n=22 units)...6-9 Table 6-7 Criteria for defining high risk...6-10 Table 6-8 Serum screening tests offered (n=36 units)...6-10 Table 6-9 Staff performing ultrasound scanning in pregnancy...6-12 Table 6-10 Key aspects of a screening programme...6-15 Table 6-11 Levels of intrapartum care...6-21 Table 7-1 Strategies for the economic model...7-5 Table 7-2 Total anomaly rates in UK centres and in Eurocat registry...7-6 Table 7-3 Anomaly rates in UK centres based on Eurocat 1995 1999...7-7 Table 7-4 First trimester booking scan a...7-10 Table 7-5 First trimester NT scan (and serum screen) a...7-10 Table 7-6 Second trimester anomaly scan a...7-11 Table 7-7 Second trimester serum screen (AFP and ß-hCG) a...7-12 Table 7-8 Diagnostic follow-up tests a...7-13 Table 7-9 Odds of stillbirth and late fetal deaths combined compared with live births...7-15
Table 7-10 Summary of total cost and resource use...7-17 Table 7-11 Resource use for ultrasound scans (minutes)...7-18 Table 7-12 Total cost for various ultrasound scans...7-18 Table 7-13 Types of maternal serum tests...7-20 Table 7-14 Total costs...7-20 Table 7-15 Cost of genetic tests...7-22 Table 7-16 Cost of terminations and miscarriages...7-22 Table 7-17 Cost of different modes of delivery...7-23 Table 7-18 Summary of cost data...7-24 Table 7-19 Components and costs of strategy for a population of 50 000 pregnancies...7-27 Table 7-20 Number of terminations of pregnancy for trisomy 18 and 21 for a population of 50 000 pregnancies...7-29 Table 7-21 Number of terminations of pregnancy for conditions other than trisomies for a population of 50 000 pregnancies...7-29 Table 7-22 Number of unaffected terminations of pregnancy from false positive screening results for a population of 50 000 pregnancies...7-30 Table 7-23 Number of procedural losses following diagnostic testing for trisomy for a population of 50 000 pregnancies...7-32 Table 7-24 Number of invasive diagnostic tests performed on unaffected pregnancies for a population of 50 000 pregnancies...7-32 Table 7-25 Number of follow-up ultrasound scans performed on unaffected fetuses for a population of 50 000 pregnancies...7-33 Table 7-26 Number of unidentified affected fetuses false negatives for a population of 50 000 pregnancies...7-34 Table 7-27 Number of live born unidentified affected fetuses for a population of 50 000 pregnancies...7-34 Table 7-28 Number of anomalies detected for a population of 50 000 pregnancies...7-34 List of figures Figure 2-1 Development of the HTA report...2-2 Figure 6-1 Timing of booking scan...6-6 Figure 6-2 Timing of second trimester scan (excluding booking scans)...6-8
List of appendices Appendix 1 Topic specific group members and special advisers...11-1 Appendix 2 Submission of evidence...11-3 Appendix 3 Description of fetal anomalies...11-4 Appendix 4 Organisation of health care in Scotland...11-7 Appendix 5 Questionnaire...11-8 Appendix 6 Included and excluded congenital abnormalities...11-22 Appendix 7 Strategy for literature searches...11-25 Appendix 8 Detection of fetal abnormalities studies not suitable for data extraction...11-37 Appendix 9 Routine screening for chromosomal abnormalities by NT measurement in unselected or low-risk groups...11-42 Appendix 10 Studies of cohorts of chromosomally normal fetuses with enlarged NT measurement...11-44 Appendix 11 Consultant-led and community maternity units...11-51 Appendix 12 Data extraction forms cost effectiveness...11-52 Appendix 13 Range of costs identified in literature...11-61 Appendix 14 Strategy 1...11-62 Appendix 15 Strategy 2...11-63 Appendix 16 Strategy 3...11-64 Appendix 17 Strategy 4...11-65 Appendix 18 Strategy 5...11-66 Appendix 19 Strategy 6...11-67 Glossary...12-1
1 Executive summary Objectives of the Health Technology Assessment This Health Technology Assessment seeks to determine the most clinically and cost effective programme of routine ultrasound scanning which can be offered to pregnant women in Scotland in the first 24 weeks of pregnancy. In Scotland, current practice varies widely throughout the country. However, ultrasound scanning is generally offered as part of a package of antenatal care which also includes serum screening. Consequently, the assessment considers several strategies. Each strategy combines two or more of the following procedures: first trimester booking scan; second trimester anomaly scan; first trimester nuchal translucency scan; serum screening using the double test (alphafetoprotein and human chorionic gonadotrophin). Methods Systematic literature searching identified evidence published in scientific literature. Evidence was submitted from professional and patient groups, manufacturers, other interested parties and experts. A survey was undertaken by NHS Quality Improvement Scotland in order to assess current practice with regard to ultrasound scanning in Scotland. At this stage in the assessment, clinical effectiveness, issues of importance to the pregnant women and organisational issues have been appraised and costs and inputs have been identified to inform the economic analysis. A decision-tree model has been constructed to estimate the costs and benefits of different screening strategies for trisomy 21 (Down s syndrome), neural tube defects and other congenital abnormalities. The model has been used to determine the optimal strategy or strategies for NHSScotland, however, until a sensitivity analysis has been undertaken to determine the effect of uncertainties in the model, the results are preliminary. Results Scientific evidence shows that ultrasound scanning is an effective method of confirming fetal viability, determining gestational age and identifying multiple pregnancies. Another principle purpose of ultrasound scanning is the identification of fetal abnormalities. Review of the literature on the clinical effectiveness of ultrasound has ascertained that identification of some structural abnormalities is possible during a first trimester scan, with varying sensitivity (between 18 65%). In these studies it has sometimes been necessary to use transvaginal scanning to obtain a satisfactory image. A screening test including ultrasonic measurement of nuchal translucency during the first trimester is a more effective method of screening for chromosomal abnormalities such as trisomy 21 than the double serum test (82% and 66% sensitivity, respectively, at a 5% false positive rate). Analysis of the survey of services indicates that the majority of maternity units in Scotland perform a first trimester scan and note gross fetal abnormality, although only a minority perform transvaginal scanning and only two units (one sizeable, one small) routinely measure nuchal translucency. The literature indicates that early screening is valued by pregnant women. Focus groups and interviews have yet to be carried out, but the literature review has already 1-1
highlighted key issues for women. Women tend to have positive feelings towards ultrasound scanning in pregnancy, although transvaginal scanning may be less acceptable to women than transabdominal scanning. From the literature review it was determined that the sensitivity of ultrasound scanning in the second trimester for detecting structural abnormalities is dependent on the nature of the condition, ranging from 2.3% for cardiac septal defects to 100% for encephalocele in one systematic review. Sensitivity is also dependent on the timing of the scan, the skill of the sonographer and the equipment being used. False positive rates of second trimester scanning for structural abnormalities are reported to be very low, usually 1% or below. This low figure is in part due to the subsequent clinical management of suspected abnormalities, which results in few cases reaching the point of delivery or termination of pregnancy with an incorrect diagnosis of congenital abnormality (only these cases are defined as false positives). Fifty-one percent of the units from which survey responses were received routinely perform second trimester anomaly scanning in addition to first trimester scanning. In each of these units the primary purpose of the second trimester scan is the detection of abnormalities, although there is some variation in the abnormalities assessed. For several conditions, the detection rates, false positive rates and prevalence reported in the literature were used as clinical inputs to the economic model, the results of which are summarised in the following table: Strategy Number of abnormalities detected per 50 000 pregnancies a Number of abnormalities missed per 50 000 pregnancies a Number of iatrogenic losses per 50 000 pregnancies a Dating scan, 2 nd trimester serum 159.2 339.6 19.9 screen Dating scan, 2 nd trimester serum 362.5 132.8 50.6 screen, anomaly scan 2nd trimester serum screen, 328.2 135.8 51.6 anomaly scan Nuchal translucency scan, 1 st 383.8 142.0 51.2 trimester serum screen, anomaly scan Nuchal translucency scan, 1 st 182.9 272.3 32.0 trimester serum screen, 2 nd trimester serum screen Nuchal translucency scan, 1 st 347.6 105.5 57.9 trimester serum screen, 2 nd trimester serum screen, anomaly scan Nuchal translucency scan, 1 st trimester serum screen, anomaly scan with no assessment for trisomy 21 or trisomy 18 376.5 151.6 19.4 a Only those abnormalities detected and missed in the proportion of women screened are presented. The assumption that women who do not accept one test do not accept any of the further tests in the programme of screening, results in those strategies with many tests finding fewer abnormalities than other strategies with fewer screening episodes. 1-2
Conclusions From these results it has been concluded that, to maximise the identification of fetal abnormalities, women should be offered a nuchal translucency scan and serum screen in the first trimester and an anomaly scan in the second trimester. However, second trimester anomaly scanning which includes the use of ultrasound or soft markers in the assessment of risk of trisomy 21 and 18 greatly increases the rates of iatrogenic and unaffected fetal loss. Therefore, unless amniocentesis is already planned on the basis of other risk assessments (e.g. following a high risk serum result) assessment of trisomy risk using these markers should not be included in the anomaly scan. During an anomaly scan soft markers may be incidental findings. However, these should be viewed from the perspective that women have already been screened for trisomy 21 and should not prompt clinical action. An estimate of the resource impact for NHSScotland will be calculated once a sensitivity analysis has been performed to determine the effect of uncertainties in the model. It is clear that many women do not understand the purpose of ultrasound scanning in pregnancy and are unprepared for a result which requires further investigation. Many women do not feel well informed and do not consider that they explicitly consent to undergo scanning. As already noted, only a minority of maternity units in Scotland currently perform an assessment of nuchal translucency and almost 50% of units do not routinely perform a second trimester scan. Therefore, considerable re-organisation will be required if all maternity services are routinely to offer pregnant women a nuchal translucency scan with first trimester serum screen and second trimester anomaly scan. Routine ultrasound scanning should be performed by formally trained staff in appropriate surroundings with suitable scanning equipment. There should be consistent record keeping and information technology systems in maternity services throughout Scotland to facilitate internal and external quality assurance and audit. 1-3
Draft recommendations The following draft recommendations are based on this version of the Assessment Report and may change in subsequent drafts. A first trimester test should be offered to women who present before 14 completed weeks of gestation. The test should comprise an ultrasound scan for determination of gestational age, confirmation of fetal viability and nuchal translucency measurement, and a serum screen as this gives greater benefit for detection of trisomy 21 and 18 compared with that achieved by second trimester serum screening. An anomaly scan should be offered to women in the second trimester between 18 20 weeks gestation. Second trimester anomaly scanning should not include the use of soft markers alone to assess risk of trisomy 21 and trisomy 18 following a previous screening for these conditions, unless amniocentesis is already planned on the basis of other risk assessments. Ultrasound scanning should be offered to women for the purposes of screening or clinical investigation and not for any other indication e.g. to provide a visual record of the pregnancy. Screening involving nuchal translucency measurement should always employ an estimation of risk of abnormality which includes the gestational age of the fetus at the time of scanning and maternal age. The National Services Division s national guidelines/protocols for trisomy 21 and neural tube defects should be extended to cover second trimester anomaly scanning to ensure that routine ultrasound scanning advice is consistent with this Health Technology Assessment and the Standards for Pregnancy and Newborn Screening. Ultrasound scanning equipment must meet the European Council Directive, enforced by the Medicines and Healthcare products Regulatory Agency, to ensure that it is safe and effective to use. Equipment should, ideally, be no more than five years old with appropriate, up-to-date software. The repair and maintenance of scanners should be undertaken in a consistent way throughout Scotland to ensure quality control. The safety of ultrasound scanning should be continuously monitored and guidelines of good practice, including Royal College of Obstetricians and Gynaecologists and British Medical Ultrasound Society guidelines, should be implemented. Screening using nuchal translucency measurement should be subject to the same level of quality control as other methods of screening for chromosomal abnormalities in pregnancy. 1-4
Appropriate written patient information on antenatal screening should be available, with time for the pregnant woman to consider and discuss this information with a health professional, prior to attending for ultrasound examination. This information should include clearly described details of the conditions which can and cannot be detected by ultrasound and the chance of successful detection of these conditions together with the risks associated with follow-up procedures. Informed written consent should be received from all women prior to screening or scanning procedures in line with the NSD guidelines and protocols. Staff undertaking routine ultrasound scanning must have appropriate training and continuing professional development to ensure effective practice. This includes undertaking and interpreting scans, providing information and counselling to women, confirming written informed consent is given by women, ensuring consistent record keeping, and participating in internal/external quality assurance and audit. Images of ultrasound scans whether hard copies or electronic files should be retained by maternity units for 25 years in accordance with the advice given in MEL(1993)152. Routine scanning should be transabdominal. A prospective assessment of the benefits of transvaginal scanning should be carried out in Scotland prior to this being used as a component of routine ultrasound scanning. Further studies should explore the effectiveness of nuchal translucency measurement for detecting structural abnormalities or chromosomal abnormalities other than trisomy 21. Appropriately designed studies should be considered to evaluate how soft markers and other markers which may be associated with aneuploidy (e.g. nasal bone) can be used in conjunction with results of other screening tests to assess the risk of chromosomal abnormalities. These studies should be designed to estimate the overall impact of such investigations on routine screening programmes. Routine ultrasound scanning should be audited against the national standards. Audits must also complement the Standards for Pregnancy and Newborn Screening to inform the standards review process. 1-5
2 Introduction and objectives 2.1 Introduction NHS Quality Improvement Scotland (NHS QIS) uses the internationally recognised definition of Health Technology Assessment (HTA) as a multidisciplinary field of policy analysis that considers the medical, social, ethical and economic implications of the development, diffusion and use of health technology (INAHTA, 2000). This form of HTA takes account of four components: clinical effectiveness, patient issues, organisational issues and economic evaluation. National and international evidence is critically appraised, taking account of Scottish circumstances, so that clear and practicable recommendations can be made to NHSScotland. The aim is to influence decision-making based on critically appraised evidence and shared best practice. This HTA follows the process published by the Health Technology Board for Scotland (HTBS) in June 2002 (Health Technology Board for Scotland, 2002b) involving submission and collection of evidence from a wide variety of sources, robust analyses undertaken by expert staff, use of a multidisciplinary Topic Specific Group (TSG) to critique evidence and analyses, expert external review and wide-ranging open consultation. Figure 2-1 presents the development of an HTA report. 2.2 Objectives The key objective of this HTA is to answer the following question: What is the most clinically and cost effective routine ultrasound scanning policy which can be offered to pregnant women in Scotland before 24 weeks of pregnancy: first trimester scan only second trimester scan only first trimester scan plus second trimester scan? In this HTA, each of these options is considered with and without additional maternal serum screening (see Section 3.4). 2.3 Aim and structure of the document 2.3.1 Rationale for undertaking the HTA Ultrasound scanning has become an integral part of antenatal care and each year in Scotland over 50 000 women are offered ultrasound in pregnancy. This has a major impact on National Health Service (NHS) resources. In the first 24 weeks of pregnancy the main use of ultrasound is the first trimester booking scan and the second trimester anomaly scan. Various programmes of ultrasound scanning are offered in Scotland: some maternity units offer a booking scan only, others offer an anomaly scan only and the remainder offer both scans routinely to all women (see Chapter 6). 2-1
Figure 2-1 Development of the HTA report Definition of the policy question(s) & HTA objective Determination of background information Protocol development Assessment Reports Working with evidence Economic evaluation Organisational issues Clinical effectiveness Patient issues Epidemiology Scottish interpretation with Topic Specific Group External review including open consultation Conclusions & recommendations HTA Report Dissemination of Report, Advice, Understanding Implementation of HTA by NHS Boards This HTA therefore seeks to establish the most clinically and cost-effective policy for routine ultrasound scanning in Scotland before 24 weeks gestation in order to rationalise scanning policies, thus contributing to more equitable and cost-effective care for women in Scotland. 2.3.2 Structure of the document This Assessment Report presents a critical appraisal and detailed presentation of the analysis of evidence gathered to date to inform the four components of the HTA: 2-2
clinical effectiveness (Chapter 4), issues for pregnant women (Chapter 5), organisational issues (Chapter 6) and economic evaluation and modelling (Chapter 7). A final discussion and recommendations bring together the key aspects from each section. The evidence used to compile this report was obtained from systematic literature searching, from submissions from interested parties, patient organisations, manufacturers, professional organisations and by the collection of primary data. Details of the literature searching carried out are provided in the relevant sections of this Assessment Report. The list of submitted evidence is given in Appendix 2. It is intended that the final Health Technology Assessment Report should be used by those involved in the planning and running of routine ultrasound scanning in pregnancy in NHSScotland, informing decision-making and policy. The Assessment Report was produced by a multidisciplinary team of NHS QIS and external staff, guided by the TSG, an external consultant and a member of the NHS QIS Board. 2.4 Current stage of the assessment This HTA is currently at the stage of open consultation. This Consultation Report is issued to interested parties across the United Kingdom (UK) and is available on the NHS QIS website (www.nhshealthquality.org) for comment. There is a six-week period of public consultation on this Consultation Report. The open consultation period begins on 26 August 2003. During the consultation period, a public meeting, to include workshops, is being held on 24 September 2003 to present evidence on the clinical and cost effectiveness of routine ultrasound scanning in the first 24 weeks of pregnancy, to address organisational issues and issues for pregnant women, and to discuss key issues arising from the Consultation Report. Comments should be submitted by 06 October 2003 to Miss Susan Quinn. It would be appreciated if you could indicate why you are interested in this topic. Electronic files in plain text or in MS Office packages are preferred, but paper copies will be accepted. Comments may be sent via email to susan.quinn@nhshealthquality.org or posted to NHS Quality Improvement Scotland, Delta House, 50 West Nile Street, Glasgow G1 2NP, fax +44 (0) 141 248 3778. In the month following consultation, all comments will be posted on the NHS QIS website (www.nhshealthquality.org). Please indicate if you do not wish your comments to be posted on this website. Also, please mark any confidential information, so that this can be removed before your comment is published on the web. Consultation comments will be incorporated into the Health Technology Assessment Report, as considered appropriate by NHS QIS. Individual replies will not be made unless specifically requested. The final Health Technology Assessment Report will be accompanied by Health Technology Assessment Advice that outlines the HTA recommendations issued to 2-3
NHSScotland and an Understanding Advice document, which is suitable for, among others, the general public, patients and carers. 2-4
3 Background 3.1 Description of health issue in Scotland 3.1.1 Aspects of routine antenatal care relevant to the HTA Ultrasound scanning and serum screening tests are offered to pregnant women as part of routine antenatal care in Scotland. This HTA considers only the aspects of scanning and screening that are applicable to the first 24 weeks of pregnancy in routine situations. Sections 3.1.1.1 to 3.1.1.3 provide a summary of the nature and purpose of these procedures and Section 3.1.1.4 summarises subsequent invasive diagnostic tests. Antenatal screening can indicate a multitude of fetal abnormalities and the most prevalent conditions which are serious and detectable are considered in this HTA. A brief description of the more common conditions and their incidence in Scotland is given in Table 3-1. In the majority of pregnancies there is no significant fetal disorder present. 3.1.1.1 Ultrasound scanning for the management of routine pregnancy The use of ultrasound in obstetrics and gynaecology was pioneered in Glasgow during the mid to late 1950s (www.ob-ultrasound.net). It is now a well established method of determining fetal viability, gestational age and identifying multiple pregnancies, and this HTA will consider the evidence which supports this. For these purposes, a booking scan is generally carried out at around 10 14 weeks of pregnancy, although some units conduct a booking scan early in the second trimester at around 15 16 weeks gestation. This scan will identify some fetuses with gross abnormalities, but this is not the primary purpose of a scan at this stage in pregnancy. There are various levels of scanning in obstetric ultrasound, each of which has a different purpose. For example a level 1 scan, of which a booking scan would be an example, is performed when there is no clinical suspicion of fetal abnormality. This is a basic evaluation of pregnancy site, fetal number, fetal life, fetal lie, fetal size, placental site and amniotic fluid volume. A level 2 scan includes the same components as a level 1 scan plus anatomical assessment. A level 1 scan requires less time and a lesser degree of operator skill than a level 2 scan (Warsof et al., 1983). 3.1.1.1.1 Fetal viability and measurement of gestational age Ultrasound can be used transvaginally and transabdominally to confirm intrauterine pregnancy. From seven weeks after last menstrual period, the viability of the fetus can be established by ultrasound detection of fetal heart pulsations (Neilson J & Grant A, 1989). Gestational age can be estimated by measurement of crown rump length (CRL) from 6 14 weeks gestation and can also be determined by ultrasonic measurement of biparietal diameter and femur length (Wald & Leck, 2000). First trimester assessment of gestational age is advantageous as this can be included in the algorithm for assessment of abnormalities using serum screening in the second trimester. 3-1
3.1.1.1.2 Multiple pregnancies Multiple pregnancies can be detected by abdominal ultrasound as early as singleton pregnancies by the presence of multiple gestation sacs. Not all viable multiple pregnancies confirmed in the first trimester will subsequently deliver multiple infants. 3.1.1.1.3 Other purposes In addition to providing information about the fetus and placenta, ultrasound scanning in pregnancy can also enable the detection of uterine abnormalities and indicate the presence of maternal adnexal masses. Ultrasound can also be used in the first 24 weeks of pregnancy to provide a qualitative assessment of amniotic fluid volume. It is well established that an abnormal volume of amniotic fluid (oligohydramnios and polyhydramnios) is associated with increased perinatal morbidity and mortality (Magann et al., 1995); (Magann et al., 2000). Accurate estimation of amniotic fluid volume therefore has important implications for obstetric care, particularly late in the second trimester when abnormalities of amniotic fluid volume are suggestive of poor pregnancy outcomes (Magann et al., 1995); (Magann et al., 2000). Ultrasound is also used for guiding invasive procedures such as amniocentesis and for progressive evaluation of fetal disorders. 3.1.1.2 Ultrasound scanning for the identification of structural abnormalities Ultrasound scanning is used as both a screening and diagnostic test (Wald & Leck, 2000). For example, in experienced centres, spina bifida can be diagnosed by directly visualising the spinal lesion. Otherwise, ultrasound can contribute to screening assessments for spina bifida by identification of cranial signs (see Appendix 3). The tendency for the fetus to lie on its back in utero, and the slackness of the skin in the neck area results in the collection of fluid observed as nuchal translucency (NT). Down s syndrome (hereafter referred to as trisomy 21) fetuses have greater elasticity of their connective tissue which may result in an increase in observed fluid accumulation in the nuchal area. Similarly, if the fetus has a congenital cardiac abnormality this might also result in detectable oedema (Berger, 1999). Visualisation by ultrasound of NT (known as an NT scan ) is possible between 11 14 weeks gestation approximately, prior to the complete development of the fetal lymphatic system. These observations have resulted in measurement of NT being considered as a possible method for screening for a number of congenital conditions including chromosomal and cardiac abnormalities. NT is one of several sonographic markers that may be assessed as the major organs develop in the first trimester. Other such sonographic markers include fetal heart rate, a smaller than expected CRL, exomphalos, major skeletal defects and other gross fetal abnormalities. It is important to note that while these signs may be detectable by highly experienced health professionals under optimal conditions, it might not be possible to do so in many services providing routine maternity care. As the pregnancy progresses visualisation of much of the fetal anatomy becomes easier, therefore the gestational age at which ultrasound scanning is performed is a limiting factor in the detection of fetal abnormalities. For this reason, an anomaly scan (performed with the specific objective of identifying fetal structural 3-2
abnormalities) is usually carried out at around 20 weeks gestation. In addition to the diagnosis of structural abnormalities, markers for chromosomal abnormalities have been reported to be identified at this stage in pregnancy. Some sonographic abnormalities (e.g. hydrocephalus) may not appear until the late second trimester or third trimester and for other abnormalities (e.g. tracheoesophageal fistula) there is often no associated sonographic sign (Rodeck & Whittle, 2000). It is conventional to divide anomalous findings on antenatal ultrasound into those which are considered to be direct visualisations of pathological abnormalities which might be considered to be diseases in their own right and those which only sometimes accompany disease states which are not directly observable on ultrasound. Examples of this latter group, known as soft markers, are choroid plexus cysts (CPC), nuchal pad, echogenic foci in the heart, dilated renal pelvis, echogenic gut and short femur/humerus. Soft markers may be associated with several different diseases and may also be associated with poor clinical prognosis even when no identifiable disease is present. This makes evaluation of the clinical importance of these signs very difficult. A brief summary of the more common of the fetal abnormalities that are included in this HTA is provided in Table 3-1. More comprehensive details, including a description of each condition, are presented in Appendix 3. The prevalence figures quoted are the aggregate rates from Glasgow between 1995 1999 (Eurocat Working Group, 2002). 3-3
Table 3-1 Summary of fetal abnormalities Nature of condition Anomaly Ultrasound tests a Prevalence in Glasgow (late 1990s) Chromosomal Trisomy 21 Screening: first 16.9/10000 Trisomy 18 trimester NT scan and 3.2/10000 Trisomy 13 other ultrasonic 1.3/10000 markers Neural tube defects Spina bifida Second trimester scan 8.8/10000 for screening or diagnostic purposes Anencephaly First trimester 8.1/10000 diagnostic scan Encephalocele Second trimester diagnostic scan 2.6/10000 Holoprosencephaly Second trimester 1.9/10000 diagnostic scan Musculoskeletal and Congenital diaphragmatic Second trimester 4.0/10000 connective tissue abnormalities hernia Gastroschisis diagnostic scan First or second 3.2/10000 trimester diagnostic scan Exomphalos First or second 2.6/10000 trimester diagnostic scan Cardiac defects Aortic stenosis 13.5/10000 Coarctation of the aorta 5.6/10000 Tetralogy of fallot 3.8/10000 Transposition of the great 1.5/10000 Second trimester arteries diagnostic scan Hypoplastic left heart 1.1/10000 Pulmonary atresia <1/10000 Atrioventricular septal <1/10000 defects Internal urogenital and Bilateral renal agenesis 2.82/10000 Second trimester renal anomalies Congenital hydronephrosis diagnostic scan <1/10000 Megacystis <1/10000 a Alternative methods of screening/diagnosis of these conditions are provided in Appendix 3. 3.1.1.3 Maternal serum screening Serum screening has been possible for more than 20 years, when maternal serum alphafetoprotein (AFP) was first used to screen for neural tube defects (NTDs). It has since become apparent that AFP is also of use for the screening of pregnancies at high risk of other conditions, particularly anterior abdominal wall defects. Serum screening for trisomy 21 has been theoretically possible since 1984, when Merkatz established that AFP is approximately 25% lower in pregnancies with fetal chromosomal abnormalities compared with normal pregnancies. This fact, coupled with the subsequent discoveries that maternal serum human chorionic gonadotrophin (hcg) is increased and unconjugated oestriol (ue 3 ) is decreased in Down s pregnancies, led to the development of the double test (AFP and hcg ) and triple test (AFP, hcg and ue 3 ) (Wald & Leck, 2000). In the 1990s, biochemical screening tests for Trisomy 21 were refined as further markers were found. The more sensitive quadruple test was developed, adding a 3-4
fourth maker, inhibin A (which is elevated in Down s pregnancies compared with normal pregnancies), to the markers used in the triple test (Wald & Leck, 2000). An alternative approach is the combined test which considers maternal age together with measurement of NT, pregnancy associated plasma protein A (PAPP-A) which is depressed in women with fetal trisomy 21 during the first trimester, and free ß-hCG which is raised in trisomy 21 pregnancies (Wald & Leck, 2000). In 1999, the integrated test, a single screening procedure comprising the quadruple test plus the combined test, was developed (Wald & Leck, 2000). In clinical practice, various combinations of the five biochemical markers discussed previously and another biochemical marker, a-hcg, are used in screening programmes for trisomy 21 (Wald et al., 1998). 3.1.1.4 Invasive diagnostic tests Following ultrasound or serum screening, invasive diagnostic testing will be offered to those women considered to be at increased risk of having a fetus with a chromosomal abnormality. Chorionic villus sampling (CVS) in the first trimester and amniocentesis in the second trimester are methods of determining the chromosomal status of the fetus without removing any tissue from the fetus itself. The subsequent karyotyping (laboratory analysis of the structure and number of chromosomes) of the cells obtained (or more effectively of cultures from the cells obtained) enables diagnoses of many disorders including chromosomal abnormalities and Mendelian genetic disorders. Both procedures are invasive and increase the risk of miscarriage, but they are not identical tests: there are differences in applications, availability, expertise necessary, laboratory resources required, reliability and risks. During amniocentesis, amniotic fluid is extracted from the amniotic sac which surrounds the fetus by the insertion of a thin needle via the abdomen. The fetal material used for karyotyping in amniocentesis is taken from the amniotic fluid cells, which have been shed from the surface of the fetus and membranes (Advisory Committee on Genetic Testing, 2000). The cell content of amniotic fluid increases as the pregnancy progresses and the proportion of viable cells obtained from the sample decreases with gestation. Amniocentesis is usually performed in the second trimester and the timing of the procedure is crucial, not least considering the increased physical and emotional distress associated with late terminations. The small volume of amniotic fluid before 15 weeks gestation necessitates the removal of a greater proportion of fluid at amniocentesis (thus further increasing the risk of miscarriage), and this coupled with the low cell content during this period means that early amniocentesis is generally considered to be contraindicated (Wald & Leck, 2000). CVS is performed from 10 weeks gestation onwards in the first trimester and therefore offers the advantage of earlier diagnoses (and consequently earlier termination of pregnancy [TOP] if relevant) that amniocentesis does not. Genetic material is obtained by extraction of a sample of the chorionic villi, folds of the embryonic membrane from which the fetal part of the placenta is formed. Extraction can be either transabdominal or transvaginal: both methods are aided by ultrasound 3-5
visualisation. To avoid contamination by maternal tissues and thus misdiagnosis if maternal cells are karyotyped, all maternal tissue must be removed under a dissecting microscope. Therefore, more specialist expertise is required for CVS compared with amniocentesis (Wald & Leck, 2000). A direct preparation of the tissue obtained by amniocentesis or CVS can be used for chromosomal analysis, or alternatively the cells can be cultured for approximately two weeks and the cell cultures used. CVS material is usually the tissue of choice (Wald et al., 1998) and is often the only suitable material, e.g. for diagnosis of single gene disorders such as cystic fibrosis. Amniocentesis is occasionally indicated for other metabolic and fetal disorders. Chromosomal analysis can be performed by karyotyping, or more recently by fluorescence in situ hybridisation or polymerise chain reaction (PCR) (Grimshaw et al., 2003). Results are available with minimal delay following FISH and PCR, as this technique uses freshly sampled cells. FISH and PCR however do not provide a full karyotype and are only specific for some disorders (e.g. trisomy 21). 3.1.1.5 Ethical issues Given that antenatal screening is routinely offered in Scotland, the ethical considerations discussed in Chapter 5 are confined to the way in which parents are informed about antenatal screening so that they can make decisions about participation according to their own principles. It has been hypothesised that when the State (and therefore by extension the NHS) funds a screening programme that selects for fetal anomalies there is a risk that this may be viewed as eugenics, or that the social acceptance of people with disabilities is diminished leading to substandard health care of affected children (Robins, 2002). The HTA can only acknowledge this broader ethical issue. The purpose of an antenatal screening programme should be to allow parents an element of choice and not to decrease the birth rate of babies with anomalies. Yet, in opting to participate in antenatal screening, parents may have to make difficult decisions and judgements about certain conditions. TOP can never be an easy decision to make, nor can deciding to proceed with a pregnancy in which the fetus has an anomaly that may greatly reduce its quality of life and that of the parents and other family members. While antenatal screening tests may be perceived to be of some benefit to parents, there are inherent risks. Screening and diagnostic procedures may decrease the risk of delivering a baby with a serious condition, however the probability of miscarriage of a healthy fetus is increased by amniocentesis and CVS. There is also the risk of decisions being made based on results which are falsely positive or falsely negative. From the decision as to whether or not to participate in antenatal screening, to the decision as to how to proceed in the event of a positive result, all may have consequences which can evoke feelings of guilt and blame. It is, partly for this reason, that there should be voluntary informed consent for antenatal screening. This is difficult to ensure for a variety of reasons: it is mandatory to offer antenatal screening tests, but acceptance of such an offer may be construed as compulsory; pregnancy can be a vulnerable time and parents may be susceptible to influence from third parties; 3-6