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Effective Health Care Program

Management of Infertility

Systematic Review Draft

Open for comment through May 1, 2018

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Key Messages

Purpose of Review

Evaluate the comparative effectiveness and safety of treatments for common causes of infertility.

Key Messages

  • 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 with immediate in vitro fertilization (IVF). There may be however no differences between immediate IVF versus other treatments prior to IVF for the outcomes of live birth, multiple births, ectopic pregnancy, miscarriage, low birthweight, and ovarian hyperstimulation syndrome.
  • Although the risk of some cancers is increased in women with some infertility diagnoses, infertility treatments do not appear to increase overall cancer risk.
  • The ability to compare the effectiveness of treatments would be enhanced by greater consistency in reporting of outcomes, particularly live birth rates.

Structured Abstract

Objective: Previous studies have demonstrated varying success for treatment of infertility. Much of this literature however does not focus on women with specific diagnoses. Our objective was to evaluate 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 evaluate 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 September 17, 2015, 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 86 studies/primary articles that met our inclusion criteria: 31 for PCOS, 8 for endometriosis, 34 for infertility secondary to unknown causes, 11 relevant to tubal/peritoneal factor infertility, 18 relevant to male factor infertility, and 5 relevant to outcomes in male and female gamete donors. For women with infertility associated with PCOS, there was moderate strength of evidence (SOE) that letrozole compared to clomiphene results in higher live birth rates while reducing multiple births (moderate SOE). No differences were seen in other outcomes (low SOE). There was low SOE that there is no difference between clomiphene and metformin as primary therapy.  Live birth rates are not different comparing laparoscopic ovarian drilling (LOD) with oral agents (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 is also no difference between differing adjunct treatments used in combination with oral agents and 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 to strategies starting 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 (IMSI). For oocyte donors, studies suggest a lower incidence of OHSS with GnRH agonist trigger than with hCG trigger (low SOE). However, there was a lack of evidence on any long-term outcomes. For couples with tubal factor or endometriosis infertility, SOE was rated insufficient for all specific comparisons.  Findings applicable across all indications for infertility for couples undergoing ART included: lower live birth rates for African-Americans compared to other racial/ethnic groups (low SOE); slightly lower live birth rates but significant reductions in multiple birth rates with elective single-embryo transfer compared to 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 to IVF (low SOE).

Conclusions: There is evidence supporting strategies for treatment of infertility in women with PCOS and with unexplained infertility. 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.