Title: Should IUI replace IVF as first-line treatment for unexplained infertility? A Literature
Review.
Version: 2 Date: 19 Jul 2023
Reviewer:  Anupa Nandi
Reviewer's report:
Should IUI replace IVF as a first-line treatment for unexplained infertility? A Literature Review.
This is a literature review evaluating the available evidence on the first-line management options
for unexplained infertility.
Authors have included studies including IUI with or without stimulation and IVF, from 2010
till January 2022, with the primary outcome being live birth rate and the secondary outcome
being CPR, OP.
The authors have concluded that the overall evidence comparing IUI and IVF as the first line
of management for unexplained infertility remains inconclusive and suggested that large RCTs
are needed and proposed that, in the interim clinics should continue to offer both IUI and IVF
for unexplained infertility.
Although the evidence is nicely summarised, I fail to understand what new information this
paper is adding to existing knowledge in this field.
Similar outcomes have been reported in previous opinion papers (1) and systematic reviews and
meta-analyses (2,3).
As per the Cochrane Systematic Review and Network meta-analysis in 2019(2), there is
insufficient evidence of differences in live birth between expectant management and the other
four interventions (OS, IUI, OS-IUI, and IVF/ICSI).
According to another systematic review and meta-analysis(3), sensitivity analysis based on
women's age and a history of previous IUI or IVF treatment, there was no significant difference
in the live birth rates (RR 1.01, 95% CI 0.88-1.15) in treatment-naïve women younger than 38
years between IUI and IVF.
The quality of evidence has been considered as low to moderate quality.
Multiple pregnancy rates remain one of the challenges with IUI + ovarian stimulation. This
can be potentially avoided by adopting IVF and a single embryo transfer policy. I find it quite
surprising that the multiple pregnancy rate has not been included in the secondary outcome in
this review.
There remain fewer studies for women >40 years of age. A recent systematic review and
meta-analysis for women >38 years, presented at the ESHRE this year, failed to come to any
conclusion due to insufficient evidence (4). They compared one RCT and 5 cohort studies. Meta-
regression on data from IUI studies suggested that IUI for women >43 years of age resulted in
a pregnancy rate <5%, while that for IVF showed livebirth rates of 20% at 38 years to 5% at 43
years and zero above 44 years and a high miscarriage rate of >50% at 43 years and above.
The conclusion of the Literature review seems very generic and recommends offering IUI
and also IVF to all patients with unexplained subfertility. The age of the women, duration of
subfertility, and previous treatments should be taken into consideration while discussing IUI and
IVF for couples with unexplained infertility.
It seems logical to start with IUI for a woman <38 years, with no previous treatment and trying
for <2 years, IVF could be offered first to those>38 years.
Reference:
1. R Homburg. IUI is a better alternative than IVF as the first-line treatment of unexplained
infertility. RBMonline. Decemeber 2021, https://doi.org/10.1016/j.rbmo.2021.12.015
2.  Wang R, Danhof NA, Tjon-Kon-Fat RI, Eijkemans MJ, Bossuyt PM, Mochtar MH,
van der Veen F, Bhattacharya S, Mol BWJ, van Wely M. Interventions for unexplained
infertility: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2019
Sep 5;9(9):CD012692. doi: 10.1002/14651858.CD012692.pub2. PMID: 31486548; PMCID:
PMC6727181.
3. Nandi A, Raja G, White D, Tarek ET. Intrauterine insemination + controlled ovarian
hyperstimulation versus in vitro fertilisation in unexplained infertility: a systematic
review and meta-analysis. Arch Gynecol Obstet. 2022 Apr;305(4):805-824. doi: 10.1007/
s00404-021-06277-3. Epub 2021 Oct 12. PMID: 34636983.
4 . J Rake and others, P-789 Unexplained subfertility in women aged 38 years and above:
could intrauterine insemination be an alternative for in vitro fertilization? A systematic
review and meta-analysis, Human Reproduction, Volume 38, Issue Supplement_1, June 2023,
dead093.144, https://doi.org/10.1093/humrep/dead093.144