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Evaluate the comparative effectiveness and safety of treatments for common causes of infertility.
Objective. Previous studies have demonstrated varying success for treatment of infertility. Much of this literature, however, does not focus on treatment of women with specific diagnoses. This systematic review evaluated the comparative effectiveness and safety of fertility treatment strategies for (a) women of reproductive age (18–44) who are infertile due to polycystic ovary syndrome (PCOS), endometriosis, unknown reasons, or tubal or peritoneal factors or (b) couples with male factor infertility, and evaluated short- and long-term health outcomes of gamete donors in infertility.
Data sources. We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for English-language studies published from January 1, 2007, to October 3, 2018, that reported live birth rates, pregnancy and neonatal outcomes, time to pregnancy, and short-term and long-term adverse outcomes for mothers and children born after infertility treatment. For male and female donors, we searched for studies reporting short- and long-term adverse effects and quality-of-life outcomes.
Review methods. Two investigators screened each abstract and full-text article for inclusion; abstracted data; and performed quality ratings, applicability ratings, and evidence grading. Where appropriate, random-effects models were used to compute summary estimates of effects.
Results. We identified a total of 151 studies/primary articles that met our inclusion criteria: 56 for PCOS, 7 for endometriosis, 50 for infertility secondary to unknown causes, 8 for tubal/peritoneal factor infertility, 23 for male factor infertility, and 5 for outcomes in male and female gamete donors. There were also 21 studies that adjusted for cause of infertility but whose findings were relevant across all infertility diagnoses. For women with infertility associated with PCOS, there was moderate strength of evidence (SOE) that letrozole results in higher live birth rates than clomiphene while reducing multiple births and with no difference in ectopic pregnancies (moderate SOE). No differences were seen in low birthweight or time to pregnancy (low SOE). There was moderate SOE that there is no difference between clomiphene and metformin as primary therapy. Comparing laparoscopic ovarian drilling with oral agents, live birth rates were not different (moderate SOE). For couples with unexplained infertility, there is no difference between the oral agents of letrozole and anastrozole for the outcome of ectopic pregnancy (low SOE), but evidence is insufficient for other outcomes of interest. There was also no difference between differing adjunct treatments used in combination with oral agents and intrauterine insemination (IUI) for the outcomes of live birth, miscarriage, and ovarian hyperstimulation syndrome (OHSS) (low SOE for all outcomes). Time to pregnancy was shorter with immediate in vitro fertilization (IVF) compared with strategies that started with clomiphene and IUI or gonadotropins and IUI, followed by IVF if necessary (moderate SOE). For couples with male factor infertility, live birth rate (moderate SOE) and miscarriage (low SOE) did not differ between intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphological sperm injection. (The latter is not used in the United States.) For oocyte donors, studies suggested a lower incidence of OHSS with gonadotropin-releasing hormone (GnRH) agonist trigger than with human chorionic gonadotropin (hCG) trigger (low SOE). However, there was a lack of evidence on any long-term outcomes. Evidence concerning specific comparisons was insufficient for couples with tubal factor or endometriosis infertility. Findings applicable across all indications for infertility for couples undergoing assisted reproductive technology (ART) included lower live birth rates for African-Americans compared with other racial/ethnic groups (low SOE); lower live birth rates but significant reductions in multiple birth rates with elective single-embryo transfer compared with multiple embryo transfer (low SOE); no increase in most maternal cancers after ART treatment after adjustment for infertility in general or specific causes (low SOE); and, for children born after ART, a possible increased risk of neurodevelopmental disorders after ICSI compared with IVF (low SOE).
Conclusions. Although there is evidence supporting some strategies for treatment of infertility, both for specific diagnoses and for couples with any diagnosis, consensus on which outcomes to collect and report, and which areas of uncertainty are most important to resolve, is needed in order to design future studies that will improve the ability of patients and clinicians to make optimal decisions.
Suggested citation: Myers ER, Eaton JL, McElligott KA, Moorman PG, Chatterjee R, Zakama AK, Goldstein K, Strauss J, Coeytaux RR, Goode A, Borre E, Swamy GK, McBroom AJ, Lallinger K, Schmidt R, Davis JK, Hasselblad V, Sanders GD. Management of Infertility. Comparative Effectiveness Review No. 217. (Prepared by the Duke Evidence-based Practice Center under Contract No. 290-2015-00004-I.) AHRQ Publication No. 19-EHC014-EF. Rockville, MD: Agency for Healthcare Research and Quality; May 2019. Posted final reports are located on the Effective Health Care Program search page. DOI: https://doi.org/10.23970/AHRQEPCCER217
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Purpose of Review
Evaluate the comparative effectiveness and safety of treatments for common causes of infertility.
Key Messages
- The ability to compare the effectiveness of treatments would be enhanced by greater consistency in reporting of outcomes, particularly live birth rates, as well as reporting of diagnosis-specific outcomes for treatments, such as assisted reproductive technology, that are used for multiple diagnoses.
- Letrozole most likely results in more live births with lower multiple births than clomiphene alone in women with polycystic ovary syndrome.
- For women with unexplained infertility, there is most likely shorter time to pregnancy for women with immediate in vitro fertilization (IVF) than for those who undergo other treatments prior to IVF. For the outcomes of live birth, multiple births, ectopic pregnancy, miscarriage, low birthweight, and ovarian hyperstimulation syndrome. However, there may be no difference between the two groups.
- Across all diagnoses, elective single-embryo transfer results in slightly lower live birthrates but substantially lower reductions in multiple birth rates than multiple-embryo transfer
Structured Abstract
Objective. Previous studies have demonstrated varying success for treatment of infertility. Much of this literature, however, does not focus on treatment of women with specific diagnoses. This systematic review evaluated the comparative effectiveness and safety of fertility treatment strategies for (a) women of reproductive age (18–44) who are infertile due to polycystic ovary syndrome (PCOS), endometriosis, unknown reasons, or tubal or peritoneal factors or (b) couples with male factor infertility, and evaluated short- and long-term health outcomes of gamete donors in infertility.
Data sources. We searched PubMed®, Embase®, and the Cochrane Database of Systematic Reviews for English-language studies published from January 1, 2007, to October 3, 2018, that reported live birth rates, pregnancy and neonatal outcomes, time to pregnancy, and short-term and long-term adverse outcomes for mothers and children born after infertility treatment. For male and female donors, we searched for studies reporting short- and long-term adverse effects and quality-of-life outcomes.
Review methods. Two investigators screened each abstract and full-text article for inclusion; abstracted data; and performed quality ratings, applicability ratings, and evidence grading. Where appropriate, random-effects models were used to compute summary estimates of effects.
Results. We identified a total of 151 studies/primary articles that met our inclusion criteria: 56 for PCOS, 7 for endometriosis, 50 for infertility secondary to unknown causes, 8 for tubal/peritoneal factor infertility, 23 for male factor infertility, and 5 for outcomes in male and female gamete donors. There were also 21 studies that adjusted for cause of infertility but whose findings were relevant across all infertility diagnoses. For women with infertility associated with PCOS, there was moderate strength of evidence (SOE) that letrozole results in higher live birth rates than clomiphene while reducing multiple births and with no difference in ectopic pregnancies (moderate SOE). No differences were seen in low birthweight or time to pregnancy (low SOE). There was moderate SOE that there is no difference between clomiphene and metformin as primary therapy. Comparing laparoscopic ovarian drilling with oral agents, live birth rates were not different (moderate SOE). For couples with unexplained infertility, there is no difference between the oral agents of letrozole and anastrozole for the outcome of ectopic pregnancy (low SOE), but evidence is insufficient for other outcomes of interest. There was also no difference between differing adjunct treatments used in combination with oral agents and intrauterine insemination (IUI) for the outcomes of live birth, miscarriage, and ovarian hyperstimulation syndrome (OHSS) (low SOE for all outcomes). Time to pregnancy was shorter with immediate in vitro fertilization (IVF) compared with strategies that started with clomiphene and IUI or gonadotropins and IUI, followed by IVF if necessary (moderate SOE). For couples with male factor infertility, live birth rate (moderate SOE) and miscarriage (low SOE) did not differ between intracytoplasmic sperm injection (ICSI) and intracytoplasmic morphological sperm injection. (The latter is not used in the United States.) For oocyte donors, studies suggested a lower incidence of OHSS with gonadotropin-releasing hormone (GnRH) agonist trigger than with human chorionic gonadotropin (hCG) trigger (low SOE). However, there was a lack of evidence on any long-term outcomes. Evidence concerning specific comparisons was insufficient for couples with tubal factor or endometriosis infertility. Findings applicable across all indications for infertility for couples undergoing assisted reproductive technology (ART) included lower live birth rates for African-Americans compared with other racial/ethnic groups (low SOE); lower live birth rates but significant reductions in multiple birth rates with elective single-embryo transfer compared with multiple embryo transfer (low SOE); no increase in most maternal cancers after ART treatment after adjustment for infertility in general or specific causes (low SOE); and, for children born after ART, a possible increased risk of neurodevelopmental disorders after ICSI compared with IVF (low SOE).
Conclusions. Although there is evidence supporting some strategies for treatment of infertility, both for specific diagnoses and for couples with any diagnosis, consensus on which outcomes to collect and report, and which areas of uncertainty are most important to resolve, is needed in order to design future studies that will improve the ability of patients and clinicians to make optimal decisions.
Citation
Suggested citation: Myers ER, Eaton JL, McElligott KA, Moorman PG, Chatterjee R, Zakama AK, Goldstein K, Strauss J, Coeytaux RR, Goode A, Borre E, Swamy GK, McBroom AJ, Lallinger K, Schmidt R, Davis JK, Hasselblad V, Sanders GD. Management of Infertility. Comparative Effectiveness Review No. 217. (Prepared by the Duke Evidence-based Practice Center under Contract No. 290-2015-00004-I.) AHRQ Publication No. 19-EHC014-EF. Rockville, MD: Agency for Healthcare Research and Quality; May 2019. Posted final reports are located on the Effective Health Care Program search page. DOI: https://doi.org/10.23970/AHRQEPCCER217
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