Ovarian Stimulation Strategies for Intrauterine Insemination in Couples with Unexplained Infertility - A Systematic Review and Individual Participant Data Meta-analysis

Wessel JA; Danhof NA; van Eekelen R; Diamond MP; Legro RS; Peeraer K; Erdem M; Dankert T; Ecochard R; Mol BW; van Wely M; Mochtar MH; Wang R

doi:10.1142/s2661318222740772

Assisted Reproduction · Outcomes and Effectiveness

Ovarian Stimulation Strategies for Intrauterine Insemination in Couples with Unexplained Infertility - A Systematic Review and Individual Participant Data Meta-analysis

Wessel JA, Danhof NA, van Eekelen R, Diamond MP, Legro RS, Peeraer K, Erdem M, Dankert T, Ecochard R, Mol BW, van Wely M, Mochtar MH, Wang R

Published September 2022 Fertility & Reproduction

DOI 10.1142/s2661318222740772

RRM Academy Synopsis

IUI gonadotropins raise live birth, multiple pregnancy vs clomiphene

Gonadotropins raised the chance of a live birth compared with clomiphene citrate. They also raised the risk of multiple pregnancy compared with clomiphene citrate. Six pooled trials of insemination in couples with unexplained infertility showed both.

Key Findings

Six randomized trials with 2299 participants shared individual participant data.
Live birth with gonadotropins versus clomiphene citrate: 5 trials, 1946 women, moderate-quality evidence, RR 1.28, 95% CI 1.10 to 1.49, I2 = 25%.
Live birth with letrozole versus clomiphene citrate: 1 trial, 599 women, insufficient evidence of a difference, RR 0.77, 95% CI 0.58 to 1.03.
Multiple pregnancy with gonadotropins versus clomiphene citrate: 4 trials, 1696 women, low-quality evidence, RR 2.17, 95% CI 1.33 to 3.55, I2 = 69%.
Multiple pregnancy with letrozole versus clomiphene citrate: 1 trial, 599 women, insufficient evidence of a difference, RR 0.71, 95% CI 0.33 to 1.56.

Interpretation

The source is a congress abstract. It reports an individual participant data meta-analysis, which pools each woman's original trial records. The authors rated the live birth evidence for gonadotropins as moderate quality and the multiple pregnancy evidence as low quality. The letrozole comparisons rest on one trial of 599 women, and the intervals include no difference. The authors found no strong evidence that female age, BMI or primary versus secondary infertility changed the effects. The conclusion also compares gonadotropins with letrozole. The abstract prints no figure for that comparison.

RRM Context

Unexplained infertility means no cause has been found. Restorative reproductive medicine treats it as undiagnosed. The first question is why conception has not happened, and both partners are evaluated along with the ovulatory cycle. The trials measured live birth and multiple pregnancy after stimulation drugs with insemination. Comparing one stimulation drug with another leaves the cause undiagnosed.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

Intrauterine insemination with ovarian stimulation (IUI-OS) is a first-line treatment for couples with unexplained infertility. Individual participant data meta-analysis (IPD-MA) is the gold standard for evidence synthesis.

Aim

To compare the effectiveness and safety of ovarian stimulation with gonadotrophin, Letrozole and clomiphene citrate (CC) and to explore treatment-covariate interactions for important baseline characteristics in women undergoing IUI.

Method

We searched electronic databases including PubMed, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL). We included randomised controlled trials (RCTs) comparing IUI-OS with gonadotropins, Letrozole or CC among couples with unexplained infertility. We excluded dose comparing studies of the same drug. We contacted the authors of eligible RCTs to share the IPD and established the IUI IPD-MA collaboration. The primary effectiveness outcome was live birth and the primary safety outcome was multiple pregnancy. We used a one-stage approach using a random effects model.

Results

Six RCTs (n= 2299) provided IPD. Gonadotropins increased the chance of a live birth compared to both CC (5 RCTs, 1946 women, RR 1.28, 95%CI 1.10 to 1.49, I2 = 25%, moderate-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.77 95%CI 0.58 to 1.03). Gonadotropins increased the risk of a multiple pregnancy compared to both CC (4 RCTs, 1696 women, RR 2.17, 95%CI 1.33 to 3.55, I2 = 69%, low-quality evidence) whereas there was insufficient evidence of a difference between Letrozole and CC (1 RCT, 599 women, RR 0.71, 95%CI 0.33 to 1.56). No strong evidence on the treatment-covariate interactions (female age, BMI or primary versus secondary infertility) was found.

Conclusion

Gonadotropins increased the chance of a live birth compared to both CC and Letrozole but also increased the chance of a multiple pregnancy. Further RCTs comparing Letrozole and other interventions in couples with unexplained infertility are needed.

Topics

Assisted Reproduction › Outcomes and Effectiveness › Live Birth Rates · Therapeutics › Ovulation Agents › Selective Estrogen Receptor Modulators · Research Methods › Evidence Synthesis › Meta-Analysis

Jennifer A. Wessel, Richard S Legro, Karen Peeraer, René Ecochard, Ben W Mol, Madelon van Wely

Jen Wessel, Jenny Wessel, J Wessel, Rick Legro, Dick Legro, Rich Legro, R Legro, K Peeraer, R Ecochard, Benjamin Mol, B Mol, M Wely

DOI 10.1142/s2661318222740772 10.1142/s2661318222740772 Wessel et al. 2022, Wessel 2022

Ovarian Stimulation Strategies for Intrauterine Insemination in Couples with Unexplained Infertility - A Systematic Review and Individual Participant Data Meta-analysis

IUI gonadotropins raise live birth, multiple pregnancy vs clomiphene

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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