Edward G. Hughes

The routine use of gonadotropin-releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled trials*

OBJECTIVE To assess the efficacy of gonadotropin-releasing hormone agonists (GnRH-a) used in ovulation induction for in vitro fertilization and embryo transfer (IVF-ET) and gamete intrafallopian transfer (GIFT). DESIGN Meta-analysis of 10 trials comparing treatment cycle outcomes after GnRH-a (n = 914) with other ovulation induction protocols (n = 722) and 7 trials comparing outcomes after short flare-up (n = 368) with longer suppression (n = 476) GnRH-a protocols. MAIN OUTCOME MEASURES The outcome of primary interest was clinical pregnancy rate (PR) per treatment cycle commenced. Data describing the amount of gonadotropin used, cycle cancellation rate, clinical pregnancy per ET, and multiple pregnancy and abortion rates were also analyzed. RESULTS Clinical PR per cycle commenced was significantly improved after GnRH-a use for IVF (common odds ratio [OR] 1.80, 95% confidence interval [CI] 1.33 to 2.44) and GIFT (common OR 2.37, 95% CI 1.24 to 4.51). Clinical PR per embryo transfer was also significantly improved with GnRH-a use (common OR 1.40, 95% CI 1.01 to 1.95). Cycle cancellation was decreased (common OR 0.33, 95% CI 0.25 to 0.44), whereas spontaneous abortion rate was similar with and without GnRH-a use. Cycle cancellation and PRs after short flare-up and longer suppression protocols were similar between groups. CONCLUSIONS This meta-analysis supports the routine use of GnRH-a for IVF and GIFT. Further research is needed, however, to assess the potential for increased rates of multiple pregnancy and ovarian hyperstimulation syndrome, which may be associated with this treatment.

The role of luteal phase support in infertility treatment: a meta-analysis of randomized trials

OBJECTIVE To determine whether the use of luteal phase support improves pregnancy rate (PR) in infertility. DESIGN A meta-analysis of randomized trials of luteal phase support. Search of the National Library of Medicine MEDLINE data base from 1971 using the words luteal, pregnancy, human, and comparative. Bibliography of relevant articles, reviews, and abstracts of scientific meetings were hand searched. All randomized controlled trials of luteal phase support in infertility were included. Luteal phase support for recurrent abortion and nonrandomized trials were excluded. The common odds ratio was calculated for each intervention using the Mantel-Haentzel test. Homogeneity of treatment effect was evaluated using the Breslow-Day test. MAIN OUTCOME MEASURES Pregnancy per cycle, rate of spontaneous abortion, and ovarian hyperstimulation syndrome rate. RESULTS Eighteen trials met the above criteria. Human chorionic gonadotropin improved PRs in IVF when GnRH agonist (GnRH-a) was used (n = 151) and was superior to P (n = 352). Its benefit in all IVF cycles, however, was not established because of significant heterogeneity of treatment effect. Progesterone improved the PR in all IVF cycles (n = 457). No significant reduction in spontaneous abortion was noted with luteal support (n = 200). Ovarian hyperstimulation syndrome occurred in 5% of patients with hCG. Combination of data from trials of luteal support with other infertility therapies was not possible because of the differences in patient populations. CONCLUSIONS The meta-analysis supports the routine use of hCG in IVF cycles using a GnRH-a. Progesterone was also beneficial for luteal phase support in IVF. For other infertility therapy, however, further research is needed to evaluate the role of luteal phase support.

A quantitative overview of controlled trials in endometriosis-associated infertility*

OBJECTIVE To undertake quantitative overviews of the following commonly used treatments for endometriosis-associated infertility: ovulation suppression, laparoscopic ablation, and conservative laparotomy. DESIGN A protocol was prospectively defined detailing the research question, mode of study identification, inclusion and exclusion, data extraction, and pooling methods. Studies were assessed for relevance and validity by independent reviewers and their findings compared. Data were extracted in a similar fashion. PATIENTS Women with visually diagnosed endometriosis, complaining of infertility. MAIN OUTCOME MEASURE Pregnancy as defined by positive pregnancy test. RESULTS Twenty-five relevant randomized controlled trials and cohort studies were identified with a total of 37 treatment comparisons. The common odds ratio (OR) from seven studies comparing ovulation suppression (danazol, medroxyprogesterone acetate [MPA], or gestrinone) versus placebo or no treatment was 0.85, suggesting no treatment benefit. The common OR for pregnancy after ovulation suppression (MPA, gestrinone, or GnRH agonist) versus danazol was also nonsignificant: 1.07. Although pooled data from trials of laparoscopic surgery suggested a treatment benefit, significant heterogeneity between studies undermines this conclusion. Laparoscopic data were similar to those from conservative laparotomy studies. Studies assessing conservative surgery plus danazol versus danazol alone showed no significant benefit from this adjunct. CONCLUSION Ovulation suppression is an ineffective treatment for endometriosis-associated infertility. Well-designed trials of laparoscopic ablation deserve a high priority.

Does cigarette smoking impair natural or assisted fecundity

OBJECTIVES To assess the effects of female and male smoking on natural and assisted fecundity. DESIGN A systematic review of published studies was conducted, identifying reports using on-line and hand search techniques. INCLUDED STUDIES Potentially relevant articles were screened for inclusion based on the following criteria: comparative study (cohort or case control) with clinical pregnancy or live birth reported among smokers and nonsmokers. EXPOSURE Cigarette smoking. MAIN OUTCOME MEASURES Time to conceive; conceptions per subject or per cycle; spontaneous abortion rate. RESULTS Thirteen relevant studies of natural conception were identified. All but one demonstrated a negative association between smoking and fecundity (odds ratio [OR] for conception or live birth 0.33 to 1.0). Seven studies of IVF-GIFT yielded a common odds ratio for conception of 0.57 (95% confidence interval 0.42 to 0.78). Seven studies evaluating spontaneous abortion suggested a small increased risk among female smokers (OR 0.83 to 1.8). Twenty-one studies assessing smoking in men demonstrated no consistent effect on sperm quality. None of the four studies evaluating fertility in male smokers demonstrated significant impairment. CONCLUSION This body of literature suggests a small but clinically significant detrimental effect of female smoking on both time to conception and spontaneous abortion risk. Variability between studies, particularly in terms of adjustment for confounding factors, undermines the strength of these conclusions. However, the consistent dose-response effect in both the spontaneous conception and abortion literature and a return to normal fecundity among exsmokers suggest a causal association. The effect of male smoking on fecundity is probably far less significant.

Follicle-stimulating hormone versus human menopausal gonadotropin for in vitro fertilization cycles: a meta-analysis

OBJECTIVE To conduct a systematic overview of available data comparing FSH with hMG in IVF treatment cycles. DESIGN A meta-analysis of randomized trials of FSH versus hMG use in ovarian stimulation protocols, with or without GnRH agonists, in IVF treatment cycles. Search strategies included on-line searching of the National Library of Medicine MEDLINE data base from 1975 to 1993 and hand searching of bibliographies of relevant publications and reviews and abstracts of scientific meetings. Common odds ratio (OR) and overall absolute treatment effect were calculated after demonstrating homogeneity of treatment effect across all trials. MAIN OUTCOME MEASURES Clinical pregnancy rates per cycle start, per cycle reaching oocyte retrieval, and per cycle reaching ET. RESULTS Eight trials met the inclusion criteria. The overall OR in favor of FSH for cycle start, oocyte retrieval, and ET were 1.71, 1.69 and 1.70, respectively, and represented an overall absolute treatment effect of 8.5%, 8.0% and 8.3%, respectively. CONCLUSIONS This meta-analysis demonstrates that in IVF cycles the use of FSH is associated with a significantly higher clinical pregnancy rate than hMG.

Cigarette smoking and the outcomes of in vitro fertilization: measurement of effect size and levels of action

OBJECTIVE To assess whether cigarette smoking in women or men affects the outcomes of IVF-ET and at what functional levels smoking is active. INTERVENTIONS Demographic and smoking data were collected by questionnaire at the onset of consecutive treatment cycles (n = 462) and at the time of ET. In addition to routine endocrine and clinical data, circulating immunoreactive inhibin, follicular fluid E2 endometrial thickness, and morphology were assessed. Reported exposure to cigarettes was validated using a serum cotinine assay. RESULTS Serum cotinine level at the onset of treatment correlated strongly with the number of cigarettes reported (r = 0.68). The duration and dose of gonadotropin treatment was greater among active smokers than never smokers: 10.2 versus 9.2 days and 24.7 versus 19.8 ampules, respectively. Fertilization, pregnancy, and abortion rates were similar between groups. Multivariate analyses demonstrated negative correlation between female age, but no such effect was seen with female or male smoking. Sperm concentration was significantly reduced in male smokers (prewash: 108 versus 130 x 10(6); postwash: 17.1 versus 21.6 x 10(6)), although fertilization rate was unaffected (66% versus 62%). Follicular function, assessed using serum inhibin and E2, as well as follicular fluid E2 levels showed no significant difference between active smokers and never smokers. Endometrial thickness and morphology also were similar between groups. CONCLUSIONS These data suggest that among couples undergoing IVF neither female nor male smoking has a measurable deleterious effect on conception rate. Female age remains a far more potent prognostic factor in the current study. However, when all the published data are combined, a significant deleterious effect of smoking on conception is suggested, with a common odds ratio of 0.540 (95% confidence interval 0.385 to 0.757).

Guidelines for the Number of Embryos toTransfer Following In Vitro Fertilization

OBJECTIVE To review the effect of the number of embryos transferred on the outcome of in vitro fertilization (IVF), to provide guidelines on the number of embryos to transfer in IVF-embryo transfer (ET) in order to optimize healthy live births and minimize multiple pregnancies. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy or birth by number of embryos transferred are compared. OUTCOMES Clinical pregnancy, multiple pregnancy, and live birth rates. EVIDENCE The Cochrane Library and MEDLINE were searched for English language articles from 1990 to April 2006. Search terms included embryo transfer (ET), assisted reproduction, in vitro fertilization (IVF), ntracytoplasmic sperm injection (ICSI), multiple pregnancy, and multiple gestation. Additional references were identified through hand searches of bibliographies of identified articles. VALUES Available evidence was reviewed by the Reproductive Endocrinology and Infertility Committee and the Maternal-Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada and the Board of the Canadian Fertility and Andrology Society, and was qualified using the Evaluation of Evidence Guidelines developed by the Canadian Task Force on the Periodic Health Exam. BENEFITS, HARMS, AND COSTS This guideline is intended to minimize the occurrence of multifetal gestation, particularly high-order multiples (HOM), while maintaining acceptable overall pregnancy and live birth rates following IVF-ET.

Funding in vitro fertilization treatment for persistent subfertility: the pain and the politics

OBJECTIVE To consider the arguments for and against funding for in vitro fertilization (IVF) and to explore potential avenues for policy change. DESIGN Narrative literature review, policy analysis. SETTING University Department of Obstetrics and Gynecology. PATIENT(S) Sub-fertile women and men. INTERVENTION(S) Fertility treatments, in particular IVF. RESULT(S) The two main arguments used against funding for IVF are that [1] subfertility is a social, not a medical problem, and therefore its treatment is not medically indicated or necessary, and [2] the clinical effectiveness of IVF is unproven. These and other major arguments are critiqued. CONCLUSION(S) Dismissing IVF as medically unnecessary seems premature because medical necessity has not been operationally defined. Demonstrating IVF effectiveness through a randomized trial has not been done but is feasible: a multicenter trial is currently underway in Canada. Dealing with the concern that subfertility treatment challenges the role of women in society, as well as with questions of cost-effectiveness, are more difficult challenges that deserve further debate. The potential for unethical uses and broader social implications of IVF add to its dubious status and provide a convenient rationale for refusing to pay. However, none of these concerns is unique to IVF: many currently covered health services are susceptible to the same criticisms. For all services, judgments of eligibility for coverage should be consistent and transparent and should explicitly separate the issues of cost from other factors.

Elective Single Embryo Transfer Following In Vitro Fertilization

OBJECTIVE To review the effect of elective single embryo transfer (eSET) compared with double embryo transfer (DET) following in vitro fertilization (IVF), and to provide guidelines on the use of eSET in order to optimize live birth rates and minimize twin pregnancies. OPTIONS Rates of live birth, clinical pregnancy, and multiple pregnancy following eSET and DET are compared. OUTCOMES Live birth, clinical pregnancy, and multiple pregnancy rates, and cost-effectiveness. EVIDENCE Published literature was retrieved through searches of PubMed, Medline, and The Cochrane Library in 2009, using appropriate controlled vocabulary (e.g., elective single embryo transfer) and key words (e.g., embryo transfer, in vitro fertilization, intracytoplasmic sperm injection, assisted reproductive technologies, blastocyst, and multiple pregnancy). Results were restricted to English language systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. There were no date restrictions. Searches were updated on a regular basis and incorporated in the guideline to November 2009. Additional references were identified through searches of bibliographies of identified articles and international medical specialty societies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES Available evidence was reviewed by the Joint Society of Obstetricians and Gynaecologist of Canada-Canadian Fertility and Andrology Society Clinical Practice Guidelines Committee and the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada, and was qualified using the evaluation of evidence criteria outlined in the report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS This guideline is intended to minimize the occurrence of twin gestations while maintaining acceptable overall live birth rates following IVF-ET. SUMMARY STATEMENTS 1. Indiscriminate application of eSET in populations with less than optimal prognosis for live birth will result in a significant reduction in effectiveness compared with DET. (I) 2. In women aged 38 years and over, eSET may result in a significant reduction in live birth rate compared with DET. (II-2) 3. Selective application of eSET in a small group of good-prognosis patients may be effective in reducing the overall multiple rate of an entire IVF population. (II-3) 4. Given the high costs of treatment, uptake of eSET would be enhanced by public funding of IVF treatment. (II-2) Recommendations 1. Patients should be informed of the reductions in both multiple pregnancy rate and overall live birth rate after a single fresh eSET when compared with DET in good-prognosis patients. (I-A) 2. Because the cumulative live birth rate after fresh eSET followed by transfer of a single frozen-thawed embryo is similar but not equivalent to the rate after fresh DET in good-prognosis patients, the eSET strategy should be used in order to avoid multiple pregnancy. (I-A) 3. Women aged 35 years or less, in their first or second IVF attempt, with at least 2 good quality embryos available for transfer should be considered good-prognosis patients. (I-A) 4. In order to maximize cumulative live birth rates following eSET, effective cryopreservation programs should be in place. (I-A) 5. In order to maintain the reduction in the rate of multiples achieved by fresh eSET, eSET should be performed in subsequent frozen-thawed embryo transfer cycles. (II-2A) 6. Because blastocyst stage embryo transfer generally increases the chance of implantation and live birth compared with cleavage stage embryo transfer, eSET should be performed in good-prognosis patients who have good quality blastocysts available. (I-A) 7. In women aged 36 to 37 years, eSET should be considered in good-prognosis patients with good quality embryos, particularly when blastocysts are available for transfer. (II-2A) 8. In oocyte donor-recipient cycles when the donor has good prognosis and when good quality embryos are available, eSET should be performed. (II-2B) 9. In women with medical or obstetrical contraindications to twin pregnancy, eSET should be performed. (III-B) 10. In order to achieve successful uptake of eSET, it is essential to provide patient and physician education regarding the risks of twin pregnancy and regarding the similar cumulative live birth rate following an eSET strategy and DET. (III-C) 11. When considering both direct health care and societal costs, it should be noted that live birth following eSET is significantly less expensive than DET in good-prognosis patients. (I-A) Therefore, from a cost-effectiveness perspective, eSET is indicated in good-prognosis patients. (III-A).

Dinoprostone vaginal insert for cervical ripening and labor induction: a meta-analysis.

Objective To compare dinoprostone 10 mg controlled-release vaginal insert with other forms of vaginal or cervical prostaglandin for cervical ripening. Data Sources Literature search strategy included review of the Cochrane database of randomized trials, on-line searching of MEDLINE, hand searching of bibliographies, and contact with authors of relevant reports. Methods of Study Selection Randomized trials were included if they compared a dinoprostone slow-release vaginal insert with an alternative vaginal or cervical prostaglandin for cervical ripening and labor induction in women at term with singleton gestations. Primary end points were delivery by 24 hours postinsertion, uterine hypertonus with fetal heart change, and cesarean delivery rate. Study inclusion, validity assessment, and data extraction were carried out independently by two reviewers, and cross-checked for consistency. Data were combined when appropriate, using the Mantel–Haenszel fixed-effects method. Statistical heterogeneity was assessed using chi-square statistics. Tabulation, Integration, and Results Nine relevant trials were identified, seven comparing the dinoprostone 10 mg vaginal insert with dinoprostone gel and two with misoprostol. Five trials reported adequate methods for randomization concealment. None were double blind. The likelihood of delivery by 24 hours was similar with the vaginal insert and alternatives: common odds ratio (OR) 0.80 (95% confidence interval [CI] 0.56, 1.15). Uterine hypertonus with change in fetal heart and cesarean delivery rate were also similar: common OR 1.19 (95% CI 0.56, 2.54) and 0.78 (95% CI 0.56, 1.08), respectively. The secondary end points of mean time to delivery and delivery by 12 hours appeared to favor misoprostol-dinoprostone gel. However, data for these end points were heterogeneous and their combination is therefore of limited value and potentially misleading. Conclusion No clinically significant differences were identified between the vaginal insert and alternatives used for cervical ripening at term.