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Evidence Report/Technology Assessment Number 167 Effectiveness of Assisted Reproductive Technology Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD 20850 www.ahrq.gov Contract No. 290-02-0025 Prepared by: Duke University Evidence-based Practice Center, Durham, NC Investigators Evan R. Myers, M.D., M.P.H. Douglas C. McCrory, M.D., M.H.S. Alyssa A. Mills, M.D. Thomas M. Price, M.D. Geeta K. Swamy, M.D. Julierut Tantibhedhyangkul, M.D. Jennifer M. Wu, M.D. David B. Matchar, M.D., M.H.S.A. AHRQ Publication No. 08-E012 May 2008 This report is based on research conducted by the Duke University Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-02-0025). The findings and conclusions in this document are those of the author(s), who are responsible for its content, and do not necessarily represent the views of AHRQ. No statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment. This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. ii This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. Suggested Citation: Myers ER, McCrory DC, Mills AA, Price TM, Swamy GK, Tantibhedhyangkul J, Wu JM, Matchar DB. Effectiveness of Assisted Reproductive Technology. Evidence Report/Technology Assessment No. 167 (Prepared by the Duke University Evidence-based Practice Center under Contract No. 290-02-0025.) AHRQ Publication No. 08-E012. Rockville, MD: Agency for Healthcare Research and Quality. May 2008. No investigators have any affiliations or financial involvement (e.g., employment, consultancies, honoraria, stock options, expert testimony, grants or patents received or pending, or royalties) that conflict with material presented in this report. iii Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-Based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. The National Institutes of Health (NIH) Office of Research on Women’s Health (ORWH) requested and provided funding for this report. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments. To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release. AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality. We welcome comments on this evidence report. They may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD 20850, or by e-mail to epc@ahrq.gov. Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality Vivian W. Pinn, M.D. Director, Office of Research on Women's Health National Institutes of Health Jean Slutsky, P.A., M.S.P.H. Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality Beth A. Collins Sharp, R.N., Ph.D. Director, EPC Program Agency for Healthcare Research and Quality iv Acknowledgments The authors gratefully acknowledge R. Julian Irvine for assistance with project management, Rebecca Gray for editorial assistance, and Dr. Michael Handrigan, AHRQ Task Order Officer, for overall assistance. v Structured Abstract Objectives: We reviewed the evidence regarding the outcomes of interventions used in ovulation induction, superovulation, and in vitro fertilization (IVF) for the treatment of infertility. Short-term outcomes included pregnancy, live birth, multiple gestation, and complications. Long-term outcomes included pregnancy and post-pregnancy complications for both mothers and infants. Data Sources: MEDLINE ® and Cochrane Collaboration resources. Review Methods: We included studies published in English from January 2000 through January 2008. For short-term outcomes, we excluded non-randomized studies and studies where a pregnancy or live birth rate per subject could not be calculated. For long-term outcomes, we excluded studies with fewer than 100 subjects and those without a control group. Articles were abstracted for relevant details, and relative risks or odds ratios, with 95 percent confidence intervals, were calculated for outcomes of interest for each study. Results: We identified 5294 abstracts and (for the three questions discussed in this draft report) reviewed 1210 full-text articles and included 478 articles for abstraction. Approximately 80 percent of the included studies were performed outside the United States. The majority of randomized trials were not designed to detect differences in pregnancy and live birth rates; reporting of delivery rates and obstetric outcomes was unusual. Most did not have sufficient power to detect clinically meaningful differences in live birth rates, and had still lower power to detect differences in less frequent outcomes such as multiple births and complications. Interventions for which there was sufficient evidence to demonstrate improved pregnancy or live birth rates included: (a) administration of clomiphene citrate in women with polycystic ovarian syndrome, (b) metformin plus clomiphene in women who fail to respond to clomiphene alone; (c) ultrasound-guided embryo transfer, and transfer on day 5 post-fertilization, in couples with a good prognosis; and (d) assisted hatching in couples with previous IVF failure. There was insufficient evidence regarding other interventions. Infertility itself is associated with most of the adverse longer-term outcomes. Consistently, infants born after infertility treatments are at risk for complications associated with abnormal implantation or placentation; the degree to which this is due to the underlying infertility, treatment, or both is unclear. Infertility, but not infertility treatment, is associated with an increased risk of breast and ovarian cancer. Conclusions: Despite the large emotional and economic burden resulting from infertility, there is relatively little high-quality evidence to support the choice of specific interventions. Removing barriers to conducting appropriately designed studies should be a major policy goal. vii Contents Executive Summary 1 Evidence Report 7 Chapter 1. Introduction 9 Normal Reproduction 9 Infertility 9 Assisted Reproductive Technologies 10 Prevalence and Burden of Disease 10 Evidence and Practice 12 Uses of This Report 12 Chapter 2. Methods 15 Topic Assessment and Refinement 15 Analytic Framework 18 Literature Search and Review 18 I. Sources 18 II. Search Strategies 19 III. Screening of Abstracts 19 IV. Screening of Full Texts 20 Data Abstraction and Development of Evidence Tables 24 Quality Assessment Criteria 24 Peer Review Process 26 Chapter 3. Results 27 Ovulation Induction without Assisted Conception (Question 2) 27 I. Research Question 27 II. Approach 27 III. Search Results 28 IV. Induction of Ovulation in Anovulatory Women 29 V. Superovulation in Ovulatory Women 42 Assisted Conception: IVF and ICSI (Question 3) 48 I. Research Question 48 II. Approach 48 III. Search Results 50 IV. The Female Partner 51 V. The Embryo 86 Longer-Term Outcomes (Question 4) 99 I. Research Question 99 II. Approach 99 III. Search Results 100 IV. Fetal/Neonatal Outcomes 101 V. Maternal Outcomes during Pregnancy 110 viii VI. Infant Outcomes from Birth to 1 Year 114 VII. Childhood Outcomes at 1 Year and Beyond 118 VIII. Maternal Outcomes: Long-Term 119 Chapter 4. Discussion 129 Chapter 5. Future Research 131 Study Design and Data Collection 131 Barriers to High-Quality Research 132 Areas for Prioritizing Research 133 I. Clinical Research 133 II. Epidemiologic Research 134 III. Health Services Research 134 Chapter 6. Conclusions 135 Ovulation Induction without Assisted Conception (Question 2) 135 I. General Issues 135 II. Ovulation Induction in Anovulatory Women 136 III. Superovulation in Ovulatory Women 136 Assisted Conception: IVF and ICSI (Question 3) 137 I. General Issues 137 II. The Female Partner 138 III. The Embryo 139 Longer-Term Outcomes (Question 4) 140 I. General Issues 140 II. Short-term Fetal Outcomes 141 III. Maternal Pregnancy Outcomes 142 IV. Infant Outcomes – Birth to 1 Year 142 V. Child Outcomes – Beyond 1 Year 143 VI. Maternal Long-Term Outcomes 143 References and Included Studies 145 Acronyms and Abbreviations 195 Figures Figure 1. Growth in numbers of ART cycles, deliveries, and infants in the United States, 1996-2005 11 Figure 2. Analytic framework for evidence report 18 Figure 3. Literature flow diagram – Question 2 29 Figure 4. Literature flow diagram – Question 3 51 Figure 5. Literature flow diagram – Question 4 101 ix Tables Table 1. Full-text screening criteria by question 20 Table 2. Results of abstract and full-text screening 23 Table 3. Included full-text articles by question 24 Table 4. Estrogen inhibitors alone in anovulation 30 Table 5. Cochrane review, estrogen inhibitors alone in anovulation 31 Table 6. Insulin sensitizers in anovulation 33 Table 7. Gonadotropins alone in PCOS 35 Table 8. Combination therapy as first-line-treatment in anovulation 37 Table 9. Combination therapy in women who fail initial treatment with clomiphene 38 Table 10. Cochrane review, combination therapies in clomiphene-resistant women 40 Table 11. Surgical interventions for anovulatory infertility 41 Table 12. Estrogen inhibitors, alone and in combination, for superovulation 43 Table 13. Gonadotropin protocols for superovulation 45 Table 14. Cochrane review, gonadotropins for superovulation 47 Table 15. Methods for pituitary down-regulation – GnRH agonists alone 52 Table 16. Methods for pituitary down-regulation – GnRH agonists versus antagonists 53 Table 17. Methods for pituitary down-regulation – GnRH antagonist regimens 55 Table 18. Down-regulation protocols in patients at risk of poor response 57 Table 19. Cochrane reviews, pituitary down-regulation 58 Table 20. Ovarian stimulation – different gonadotropin preparations 59 Table 21. Ovarian stimulation – rFSH alone versus rFSH + rLH 61 Table 22. Ovarian stimulation – gonadotropin dosing regimens 62 Table 23. Ovarian stimulation – methods of administering gonadotropins 63 Table 24. Protocols for stimulation in poor responders 63 Table 25. Cochrane reviews, ovarian stimulation 64 Table 26. Methods for inducing final follicular maturation 65 Table 27. Cochrane review, methods for follicular maturation 67 Table 28. Methods for oocyte retrieval 68 Table 29. Methods for pituitary down-regulation – endometrial preparation for frozen- thawed embryo transfer 70 Table 30. Cochrane review, endometrial preparation for frozen-thawed embryo transfer 70 Table 31. Methods for embryo transfer 72 Table 32. Methods for embryo transfer – ultrasound guidance 73 Table 33. Methods for luteal support – progesterone formulations 74 Table 34. Methods for luteal support – hCG 75 Table 35. Methods for luteal support – timing of beginning or ending progesterone supplementation 76 Table 36. Methods for luteal support – adjuncts to progesterone 77 Table 37. Cochrane review, methods for luteal support 78 Table 38. Medical therapy 80 Table 39. “Non-medical” adjuncts 81 Table 40. Adjuncts in patients with poor prognosis 82 Table 41. Cochrane reviews, adjunct therapies for IVF 85 [...]... Fertility Care and Department of Obstetrics and Gynecology; University of Pennsylvania Health System; Philadelphia, PA • Lisa Begg, Dr.P.H., R.N.; NIH Office of Research on Women’s Health; Bethesda, MD • David A Grainger, M.D.; Center for Reproductive Medicine, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology; University of Kansas School of Medicine; Wichita, KS (representing... Johnson, M.D.; Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology; University of Vermont and Fletcher Allen Health Care; Burlington, VT • Richard E Leach, M.D.; Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology; University of Illinois at Chicago; Chicago, IL • Richard S Legro, M.D.; Division of Reproductive Endocrinology,... procedures Topic Assessment and Refinement The National Institutes of Health (NIH) Office of Research on Women’s Health (ORWH) and the Agency for Healthcare Research and Quality (AHRQ), sponsors of this report, and the other partners, the American College of Obstetrics and Gynecology (ACOG) and the Society for Assisted Reproductive Technology (SART), originally identified four key questions to be addressed... questions are: • Question 1: Among women of reproductive age (12-44), what factors identify couples with a low probability of spontaneously conceiving? Factors to be considered could include: age of mother, age of father, presence of endometriosis, prior conception history, body size, alcohol use, smoking, history of previous sexually transmitted infection, and results of infertility testing (hysterosalpingogram,... Adequacy of randomization concealment For cohort studies: • Unbiased selection of the cohort (prospective recruitment of subjects) • Large sample size • Adequate description of the cohort • Use of validated method for ascertaining exposure • Use of validated method for ascertaining clinical outcomes • Adequate followup period • Completeness of followup • Analysis (multivariate adjustments) and reporting of. .. evidence for the effectiveness and efficiency of assisted reproductive technology (ART) The Duke research team clarified and refined the overall research objectives and key questions by first consulting with AHRQ and the study partners, and then convening a national panel of technical experts to serve as advisors to the project These experts were selected to represent relevant specialties Members of the technical... months,4 a finding borne out in clinical trials, where four to five percent of subjects may conceive spontaneously between enrollment and the beginning of treatment.6,7 Because a large number of couples meeting the definition of infertility are actually 9 capable of conceiving and simply represent one end of the distribution of fecundity, many, particularly in Europe, prefer the term “subfertility.”5,8... Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology 2005 Assisted Reproductive Technology Success Rates: National Summary and Fertility Clinic Reports, Atlanta: Centers for Disease Control and Prevention; 2007.14 Over this time, the proportion of deliveries in the United States resulting from ART has increased from 0.37 percent in... consistent criticism of the methodological quality of much of the clinical literature, for both immediate outcomes of treatment (such as pregnancy, live birth, and complication rates) and especially for longer term outcomes (such as neonatal and childhood outcomes in children conceived after infertility treatment.36,37 Uses of This Report This report summarizes the results of our review of the evidence... prevent OHSS 86 Table 43 Methods of fertilization 88 Table 44 Selection of embryos for transfer 90 Table 45 Assisted hatching 91 Table 46 Timing of transfer 94 Table 47 Cochrane reviews, timing of transfer 96 Table 48 Number of embryos transferred 98 Table 49 Cochrane reviews, number of embryos transferred 99 Table 50 Maternal . Evidence Report /Technology Assessment Number 167 Effectiveness of Assisted Reproductive Technology Prepared for: Agency. studies of effectiveness and long-term outcomes in male partners, and prevention of preterm birth. One area of great potential is further investigation of