Evidence-based treatments for couples with unexplained infertility

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Evidence-based treatments for couples with unexplained infertility: a guideline


Objective: To provide evidence-based recommendations to practicing physicians and others regarding the effectiveness and safety of therapies for unexplained infertility.

Methods: ASRM conducted a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1968 through 2019. The ASRM Practice Committee and a task force of experts used available evidence and informal consensus to develop evidence-based guideline recommendations.

Main Outcome Measure(s): Outcomes of interest included: live-birth rate, clinical pregnancy rate, implantation rate, fertilization rate, multiple pregnancy rate, dose of treatment, rate of ovarian hyperstimulation, abortion rate, and ectopic pregnancy rate.

Result(s): The literature search identified 88 relevant studies to inform the evidence base for this guideline.

Recommendation(s): Evidence-based recommendations were developed for the following treatments for couples with unexplained infertility: natural cycle with intrauterine insemination (IUI); clomiphene citrate with intercourse; aromatase inhibitors with intercourse; gonadotropins with intercourse; clomiphene citrate with IUI; aromatase inhibitors with IUI; combination of clomiphene citrate or letrozole and gonadotropins (low dose and conventional dose) with IUI; low-dose gonadotropins with IUI; conventional-dose gonadotropins with IUI; timing of IUI; and in vitro fertilization and treatment paradigms.

Conclusion(s): The treatment of unexplained infertility is by necessity empiric. For most couples, the best initial therapy is a course (typically 3 or 4 cycles) of ovarian stimulation with oral medications and intrauterine insemination (OS-IUI) followed by in vitro fertilization for those unsuccessful with OS-IUI treatments.




INTRAUTERINE INSEMINATION (IUI), NATURAL CYCLE

Summary Statement
*There is strong evidence that IUI in unstimulated cycles is less effective than OS with IUI and it is not significantly more effective than expectant management.

Recommendation
*It is not recommended to perform IUI in natural cycles for the treatment of unexplained infertility. It is less effective than OS with IUI and likely no more effective than expectant management. (Strength of Evidence: A; Strength of recommendation: Strong)


CLOMIPHENE CITRATE WITH INTERCOURSE

Summary Statement
*There is good evidence that clomiphene citrate with timed intercourse is no more effective than expectant management.

Recommendation
*It is not recommended to use clomiphene citrate with timed intercourse as a treatment for unexplained infertility, as it is no more effective than expectant management. (Strength of Evidence: B; Strength of Recommendation: Moderate)


AROMATASE INHIBITORS WITH INTERCOURSE

Summary Statement
*There is good evidence that letrozole with timed intercourse is no more effective than clomiphene citrate with timed intercourse or expectant management in the treatment of unexplained infertility.

Recommendation
*It is not recommended to use letrozole with timed intercourse as a treatment for unexplained infertility, as it is no more effective than expectant management. (Strength of Evidence: B; Strength of Recommendation: Moderate)


GONADOTROPINS WITH INTERCOURSE

Summary Statement
*There is insufficient evidence that gonadotropins with timed intercourse is superior to expectant management in the treatment of unexplained infertility, and there is moderate evidence that treatment outcomes with gonadotropins are similar to oral medications in timed-intercourse cycles. Most studies report no difference in pregnancy outcomes comparing gonadotropins to OS with oral agents or higher pregnancy rates at the expense of increased risk of multiple-gestation pregnancy. Differences in outcomes between investigations are likely due to different patient populations, dosing, and cancellation criteria.

Recommendation
*It is not recommended to use gonadotropins with timed intercourse in the treatment of unexplained infertility. Studies report either no difference in pregnancy outcomes compared to OS with oral agents or higher pregnancy rates associated with a higher risk of multiple-gestation pregnancy. (Strength of Evidence: B; Strength of Recommendation: Moderate)


CLOMIPHENE CITRATE WITH INTRAUTERINE INSEMINATION (IUI)

Summary Statement
*There is strong evidence that clomiphene citrate with IUI is superior to expectant management and natural-cycle IUI for the outcome of live-birth rate in couples with unexplained infertility. Multiple gestation pregnancy rates with clomiphene citrate with IUI treatment range from 0 to 12.5%. Differences in multiple gestation outcomes between investigations are likely due to different patient populations, dosing, and cancellation criteria.

Recommendation
*It is recommended to use clomiphene citrate with IUI in the treatment of couples with unexplained infertility. (Strength of Evidence: A; Strength of Recommendation: Strong)


AROMATASE INHIBITORS WITH INTRAUTERINE INSEMINATION (IUI)

Summary Statement
*There is strong evidence that there is no significant difference in pregnancy rates or multiple-gestation pregnancy rate following letrozole with IUI as compared to clomiphene citrate with IUI. Both are superior to expectant management and natural-cycle IUI.

Recommendation
*It is recommended that letrozole with IUI treatments be considered as an alternative regimen for couples with unexplained infertility, as studies to date suggest similar efficacy. Of note, letrozole is not FDA approved for treatment of unexplained infertility, but is considered an effective and well tolerated option. (Strength of Evidence: A; Strength of Recommendation: Strong)


INTRAUTERINE INSEMINATION (IUI) WITH COMBINATION OF CLOMIPHENE CITRATE OR LETROZOLE AND GONADOTROPINS (LOW DOSE AND CONVENTIONAL DOSE)

Summary Statement
*There is fair evidence that clomiphene citrate and conventional-dose gonadotropins with IUI treatments are associated with higher pregnancy rates than expectant management.

*There is good evidence that clomiphene citrate with conventional-dose gonadotropins with IUI treatments are associated with an increased risk of multiple-gestation pregnancy.

*There is good evidence that clinical pregnancy and livebirth rate are similar when comparing letrozole and low dose gonadotropins with IUI vs. clomiphene citrate and low-dose gonadotropins with IUI.

Recommendation
*It is not recommended to use letrozole or clomiphene citrate plus conventional-dose gonadotropins with IUI, as most studies associated with improved pregnancy rate over OS-IUI with oral medications are also associated with an increased risk of multiple-gestation pregnancy. (Strength of Evidence: B; Strength of Recommendation: Moderate)


INTRAUTERINE INSEMINATION (IUI) WITH LOW-DOSE GONADOTROPINS

Summary Statement
*There is insufficient evidence that treatment with low-dose gonadotropins with IUI is associated with a higher pregnancy rate than clomiphene citrate or letrozole with IUI. Differences in the outcomes of these trials may be due to different dosing protocols, patient populations, and cancellation criteria.

*In couples with unexplained infertility who have a good or intermediate prognosis for unassisted conception, there is fair evidence that treatment with low-dose gonadotropins with IUI is no more effective than 6 months of expectant management.

*There is no difference in multiple-pregnancy rates between clomiphene citrate or letrozole with IUI treatments compared to low-dose gonadotropins with IUI.

Recommendation
*It is not recommended to use low-dose gonadotropins with IUI in the treatment of unexplained infertility, as it is more complex and expensive, and likely no more effective than OS with oral medications with IUI. (Strength of Evidence: B; Strength of Recommendation: Moderate)


INTRAUTERINE INSEMINATION (IUI) WITH CONVENTIONAL-DOSE GONADOTROPINS

Summary Statement
*There is insufficient evidence that treatment with conventional-dose gonadotropins with IUI is associated with a higher pregnancy rate than clomiphene citrate or letrozole with IUI based on mixed findings from well designed studies. Treatment with conventional-dose gonadotropins with IUI demonstrates either no difference in pregnancy outcomes with similar multiple-gestation pregnancy rates compared to OS with clomiphene citrate or letrozole with IUI, or higher pregnancy rates associated with a higher rate of multiple-gestation pregnancy. Differences in both outcomes between investigations are likely due to different patient populations, dosing, and cancellation criteria.


Recommendation
*It is not recommended to use conventional-dose gonadotropins with IUI, as most studies associated with improved pregnancy rate over OS-IUI with oral medications are also associated with a high multiple-gestation pregnancy rate. (Strength of Evidence: A; Strength of Recommendation: Strong)


TIMING OF INTRAUTERINE INSEMINATION (IUI)

Summary Statement
*There is fair evidence that the timing of IUI relative to hCG injection between 0 and 36 hours does not impact pregnancy rates in OS with IUI treatments.

*There is fair evidence that live-birth rate following single IUI is not significantly different than double IUI in treatment cycles with clomiphene citrate.

*There is insufficient evidence that ultrasound monitoring for timing of IUI improves pregnancy outcomes compared to urinary LH monitoring in clomiphene citrate-IUI treatments.

Recommendation
*It is recommended that a single IUI be performed between 0 and 36 hours relative to hCG injection in OS with IUI treatments. (Strength of Evidence: B; Strength of Recommendation: Moderate)


IN VITRO FERTILIZATION (IVF) AND TREATMENT PARADIGMS

Summary Statement
*Current evidence does not support IVF as a first-line therapy for unexplained infertility over expectant management for 6 months or a limited course of treatment of OS with IUI in women <38 years of age. However, it is important to note that many of the included studies were conducted in an era of lower IVF success rates than those currently observed.

*There is good evidence that immediate IVF in women R38 years of age may be associated with a higher pregnancy rate and shorter time to pregnancy as compared to a strategy consisting of OS with IUI treatments with either oral medications or gonadotropins prior to IVF.

*There is good evidence that in couples who fail to achieve a pregnancy following a course of clomiphene citrate with IUI treatment, immediate IVF results in a shorter time to pregnancy and lower cost per pregnancy than a strategy that incorporates gonadotropins with IUI treatments in women %40 years.

*There is good evidence that there is no reported difference in clinical pregnancy and live-birth rates when comparing IVF with conventional fertilization to IVF with ICSI in the setting of unexplained infertility. However, ICSI has been associated with higher fertilization rates and a reduced risk of complete fertilization failure as compared to conventional fertilization.

Recommendation
*It is recommended that couples with unexplained infertility initially undergo a course (typically 3 or 4 cycles) of OS and IUI with oral agents. For those unsuccessful with OS and IUI treatments with oral agents, IVF is recommended rather than OS and IUI with gonadotropins. (Strength of Evidence: B; Strength of Recommendation: Moderate)



CONCLUSIONS
For most couples with unexplained infertility there is no role for OS with gonadotropins, with or without IUI. Pregnancy rates associated with these treatments are dose dependent, and meaningful improvements over outcomes seen with OS-IUI with oral medications are only achieved at doses associated with a high risk for multiple-gestation pregnancy. Together with compelling evidence that a strategy of 3 cycles of clomiphene citrate-IUI followed immediately by IVF results in a shorter time to pregnancy at lower cost than a strategy that includes an intervening gonadotropin-IUI course, gonadotropin-IUI cycles should be rare. While IVF is an effective treatment for unexplained infertility, it is also associated with risks of multiple-gestation pregnancy, preterm delivery, and low birth weight. Furthermore, it is cost prohibitive for many couples. There is a pressing need for investigations to evaluate treatments to bridge the gap between the effectiveness of IVF and the low (and unchanging) success rates associated with OS-IUI treatments with oral medications. Additionally, further research is needed regarding barriers to the access of treatments such as ART, including social, cultural, and economic factors.



SUMMARY RECOMMENDATIONS AND FUTURE DIRECTIONS

*For most couples with unexplained infertility, the best initial therapy is a course (typically 3 or 4 cycles) of OS and IUI, either with clomiphene or letrozole, followed by IVF for those couples unsuccessful in achieving a pregnancy with OS and IUI.

*There is a pressing need for additional therapies to bridge the wide gap in effectiveness between OS and IUI with oral medications and IVF.

*Further research is needed into methods to improve access to care, including ART treatments.
 

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