Intra-uterine insemination for unexplained subfertility

Comment: The quality of evidence is downgraded by study quality (unclear allocation concealment).

A Cochrane review «Intra‐uterine insemination for unexplained subfertility»1 «Ayeleke RO, Asseler JD, Cohlen BJ et al. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2020;(3):CD001838. »1 included 15 trials involving a total of 2 068 women.

It was uncertain whether treatment with intra-uterine insemination (IUI) in a natural cycle improved live birth rate compared to treatment with expectant management (OR 1.60, 95% CI 0.92 to 2.78; 1 RCT, n=334), or IUI in a stimulated cycle improved live birth rates compared to treatment with timed intercourse (TI) in a stimulated cycle (OR 1.59, 95% CI 0.88 to 2.88; 2 RCTs, n=208). IUI combined with clomiphene citrate or letrozole resulted in a higher live birth rate compared to treatment with expectant management in a natural cycle (OR 4.48, 95% CI 2.00 to 10.01; 1 RCT; n=201). IUI in a natural cycle resulted in a higher cumulative live birth rate compared to treatment with expectant management in a stimulated cycle (OR 1.95, 95% CI 1.10 to 3.44; 1 RCT, n=342). IUI in a stimulated cycle resulted in a higher cumulative live birth rate compared to treatment with IUI in a natural cycle (OR 2.07, 95% CI 1.22 to 3.50; 4 RCTs, n=396).

Another Cacrane review «Interventions for unexplained infertility: a systematic review and network meta‐analysis»2 and a network meta-analysis «Wang R, Danhof NA, Tjon-Kon-Fat RI et al. Interventions for unexplained infertility: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2023;(9):CD012692. »2 included 24 RCTs with 3 983 couples. Ten RCTs including 2 725 couples reported on live birth. For differences between OS, IUI, OS-IUI, or vitro fertilisation with or without intracytoplasmic (IVF/ICSI) versus expectant management see table (table «Expectant management vs other interventions for infertility»1). This suggests that if the chance of live birth following expectant management is assumed to be 17%, the chance following OS, IUI, OS-IUI, and IVF would be 9% to 28%, 11% to 33%, 15% to 37%, and 14% to 47%, respectively. When only including couples with poor prognosis of natural conception (3 trials, 725 couples) OS‐IUI and IVF/ICSI increased LBR compared to expectant management (OR 4.48, 95% CI 2.00 to 10.1; moderate-certainty evidence; OR 4.99, 95 CI 2.07 to 12.04; moderate-certainty evidence), while there was insufficient evidence of a difference between IVF/ICSI and OS-IUI (OR 1.11, 95% CI 0.78 to 1.60; low-certainty evidence). Compared to expectant management, other treatments increased the odds of multiple pregnancy (11 RCTs, 2564 couples).

An open-label, randomised, controlled, two-centre trial «Farquhar CM, Liu E, Armstrong S et al. Intrauterine insemination with ovarian stimulation versus expectant management for unexplained infertility (TUI): a pragmatic, open-label, randomised, controlled»3 included 201 women with unexplained infertility. Women assigned to IUI had a higher cumulative livebirth rate than women assigned to expectant management (31% livebirths vs 9% livebirths; RR 3.41, 95% CI 1.71 to 6.79; p=0.0003).

An individual participant data (IPD) meta-analysis «Lai S, Wang R, van Wely M, et al. IVF versus IUI with ovarian stimulation for unexplained infertility: a collaborative individual participant data meta-analysis. Hum Reprod Update 2024;30(2):174-185. »4 included 4 RCTs (IPD of 934 women, of which 550 were allocated to IVF and 383 to IUI-OS). Considering the time to pregnancy leading to live birth, the cumulative live birth rate was not significantly higher in IVF compared to that in IUI-OS (50.3% versus 43.2%, hazard ratio 1.19, 95% CI 0.81 to 1.74; 4 trials, n=908; I²=42%). For the safety primary outcome, the rate of multiple pregnancy was not significantly lower in IVF than IUI-OS (3.8% versus 5.2% of all couples randomized, odds ratio 0.78, 95% CI 0.41 to 1.50; 3 trials, n=890; I²=0.0%).

A systematic review and individual participant data meta-analysis «Wessel JA, Danhof NA, van Eekelen R, et al. Ovarian stimulation strategies for intrauterine insemination in couples with unexplained infertility: a systematic review and individual participant data me»5 included 7 RCTs with provided IPD of 2495 couples (62.4% of the 3997 couples participating in 22 RCTs), of which 2411 had unexplained infertility and were included. Six RCTs (n=1511) compared gonadotrophins with clomiphene citrate (CC), and one (n=900) compared gonadotrophins, letrozole and CC. Moderate-certainty evidence showed that gonadotrophins increased the live birth rate compared to CC (RR 1.30, 95% CI 1.12 to 1.51; 6 RCTs, n=2058). Low-certainty evidence showed that gonadotrophins may also increase the multiple pregnancy rate compared to CC. Heterogeneity on multiple pregnancy could be explained by differences in gonadotrophin starting dose and choice of cancellation criteria. Moderate certainty evidence showed that gonadotrophins reduced the time to conception leading to a live birth when compared to CC (HR 1.37, 95% CI 1.15 to 1.63; 6 trials, n=2058).

A systematic review and meta-analysis «Nandi A, Raja G, White D, et al. Intrauterine insemination + controlled ovarian hyperstimulation versus in vitro fertilisation in unexplained infertility: a systematic review and meta-analysis. Arch G»6 included 8 RCTs. Compared with IUI, IVF was associated with a statistically significant higher live birth rate with no significant difference in multiple pregnancy rate or OHSS rate. However, sensitivity analysis based on women's age and a history of previous IUI or IVF treatment showed no significant difference in the live birth rates (RR 1.01, 95% CI 0.88 to 1.15, I²=0%, 3 RCTs) in treatment-naïve women younger than 38 years. In women over 38 years, the live birth rates were significantly higher in the IVF group (RR 2.15, 95% CI 1.16 to 4.0, I²=42%, 1 RCT).