Comparative Effectiveness Review Number 217 R Management of Infertility Evidence Summary Background Purpose of Review Condition and Therapeutic Strategies Evaluate the comparative effectiveness and safety of “Infertility” has traditionally been defined treatments for common causes of infertility. as failure to achieve pregnancy after 12 Key Messages months of regular unprotected intercourse with the same partner (or after 6 months • The ability to compare the effectiveness of for women greater than 35 years of age). treatments would be enhanced by greater However, as many as half of such couples consistency in reporting of outcomes, particularly will conceive without intervention over the live birth rates, as well as reporting of diagnosis- next 12-24 months. Because of this, the term specific outcomes for treatments, such as assisted “subfertility” is preferred by many.1 From a reproductive technology, that are used for population perspective, couples who meet the multiple diagnoses. dichotomous criteria for “infertility” include • Letrozole most likely results in more live births couples who are “normal” but who are in with lower multiple births than clomiphene alone the upper end of the population distribution in women with polycystic ovary syndrome. for “time to pregnancy,” and couples who have a physiological or anatomical cause for • For women with unexplained infertility, there is a prolonged time to pregnancy. However, to most likely shorter time to pregnancy for women be concise, we will use the term “infertility” with immediate in vitro fertilization (IVF) throughout this report. than for those who undergo other treatments prior to IVF. For the outcomes of live birth, Self-reported infertility in the United States, multiple births, ectopic pregnancy, miscarriage, using the 12-month definition, affected low birthweight, and ovarian hyperstimulation approximately 6 percent of married women syndrome however, there may be no difference aged 15-44 in the 2006-2010 National Survey between the two groups. of Family Growth (the most recent available Across all diagnoses, elective single-embryo 2 • data). In one population-based study, transfer results in slightly lower live birth rates but approximately 10 percent of pregnant women substantially lower reductions in multiple birth reported receiving infertility treatment, with rates than multiple-embryo transfer. 29 percent of these women using fertility- enhancing medications; 21 percent using assisted reproductive technology (ART), including in vitro fertilization (IVF); 15 percent some diagnoses (e.g., ovulation induction in PCOS using artificial insemination with fertility- or unexplained infertility) may not be appropriate enhancing drugs; and 23 percent using other for others (e.g., women with documented tubal treatments, including surgery.3 Other estimates of occlusion). In other cases, the appropriate the prevalence of infertility treatment are similar.4-8 comparisons may involve sequencing or Particularly in the United States, where availability combinations of treatment options—for example, of infertility services is variable depending on one strategy might consist of several cycles of a number of factors, particularly insurance ovulation induction, followed by ART only if coverage, utilization of infertility treatments may pregnancy does not occur, compared to proceeding underestimate the overall burden of infertility. directly to ART. Note that throughout this report, we use the term “adjunct treatments” to refer to The most common demographic factor associated interventions performed within a major treatment with female infertility is “advanced reproductive category (for example, comparison of metformin age,” although the probability of pregnancy begins to placebo as pretreatment in women with PCOS to decline by the mid-20’s, the slope of decline undergoing IVF). sharply increases by age 35.9 Other common causes of female infertility include polycystic Although there has been ongoing debate about ovary syndrome (PCOS), endometriosis, occlusion the most appropriate outcome for evaluation of the fallopian tubes from prior infectious of infertility treatments, there is a growing disease,6 and infertility secondary to cancer consensus that live birth is the most important treatment.10-12 Isolated male factor infertility affects patient-centered outcome.17,18 Trade-offs between approximately 17 percent of couples seeking outcomes (particularly multiple gestations), time treatment, with 34.6 percent of couples having to pregnancy, and out-of-pocket costs might be both male and female diagnoses.13 different between the various treatment strategies even if cumulative live birth rates were identical. Treatment options are usually dependent on the underlying etiology of infertility. For female causes, Different treatments also carry different safety options include surgical management of tubal risks. There are known short-term risks such as occlusion, surgical treatment of endometriosis, ovarian hyperstimulation syndrome (OHSS) or ovarian “drilling” for treatment of PCOS, use acute risks associated with any surgery. Surgery of ovulation-induction agents including oral may have additional longer-term risks which may (clomiphene citrate or letrozole) and injected affect subsequent fertility (such as scarring or drugs (gonadotropins), artificial insemination decreased ovarian reserve with procedures such as with either partner or donor sperm (depending on laparoscopic ovarian drilling (LOD). The literature partner fertility status), and ART, which includes suggests that observed associations between both traditional IVF (fertilization of the egg by the infertility treatment and female reproductive sperm occurs without direct manipulation) and cancers, particularly ovarian cancer, are likely IVF with intra-cytoplasmic sperm injection (ICSI) the result of the underlying infertility rather (fertilization occurs via direct injection of sperm than treatment itself. There is, however, some into the egg).14,15 Treatment options for male factor uncertainty surrounding some cancer outcomes in infertility include medical treatment of a diagnosed subgroups of patients.19-21 endocrinopathy or other conditions affecting sperm production, empiric treatments with Some adverse pregnancy outcomes, such as hormonal or other agents, surgical management preterm birth, are associated with infertility of varicocele, intrauterine insemination, IVF, ICSI, treatment; however, many of the conditions or use of donor sperm.16 Options appropriate for associated with infertility are also associated with 2 these adverse outcomes, complicating assessment The specific Key Questions (KQs) addressed in this of comparative effectiveness.22-25 There may also be review are listed below, and Figure A displays the direct effects of some treatments that have unclear analytic framework that guided our work. implications for long-term health in children born after these treatments.26,27 Finally, infertility clearly • KQ 1. What are the comparative safety and has an emotional impact,12,28,29 and the comparative effectiveness of available treatment strategies for effects of infertility treatments on quality of life are women with polycystic ovary syndrome who an important consideration for both women and are infertile and who wish to become pregnant? men. – KQ 1a. Does the optimal treatment strategy vary by patient characteristics such as age, There may be significant variation in outcomes of ovarian reserve, race, body mass index different treatments in specific subpopulations. For (BMI), presence of other potential causes of example, age affects the likelihood of conception, female infertility, or presence of male factor and the risk of many pregnancy complications infertility? associated with infertility treatments, such as preterm birth or low birthweight, are also • KQ 2. What are the comparative safety and increased with higher maternal age. Obesity is effectiveness of available treatment strategies common in women with PCOS, and, like older for women with endometriosis who are infertile maternal age, is also associated with adverse and who wish to become pregnant? pregnancy outcomes independent of its association with infertility. The utilization and outcomes – KQ 2a. Does the optimal treatment strategy of infertility treatment differ among different vary by patient characteristics such as racial and ethnic groups, even after adjusting for age, ovarian reserve, race, BMI, stage of insurance coverage.30-33 endometriosis, presence of other potential causes of female infertility, or presence of Finally, a unique subpopulation is women who male factor infertility? donate oocytes for use by other couples in ART. There are almost no data on the long-term safety • KQ 3. What are the comparative safety and of multiple courses of ovulation induction for the effectiveness of available treatment strategies for purposes of oocyte donation.34 In addition, there women who are infertile for unknown reasons are complex ethical and legal considerations, and who wish to become pregnant? including the balance between fair compensation – KQ 3a. Does the optimal treatment strategy 35 and inducement, and sharing information about vary by patient characteristics such as age, 36 donors with recipients. ovarian reserve, race, BMI, presence of other Scope and Key Questions potential causes of female infertility, or presence of male factor infertility? This systematic review evaluates the comparative KQ 4. What are the comparative