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

Abstract Study question Considering current available evidence, how do intrauterine insemination and IVF compare in terms of pregnancy outcomes in women aged > 38 years with unexplained subfertility? Summary answer In women > 38 years both IUI and IVF lead to pregnancies and live births, there is insufficient evidence to determine the relative effectiveness What is known already Solid evidence has shown that intrauterine insemination (IUI) with ovarian stimulation (OS) is the preferred treatment option for women with unexplained subfertility below the age of 38. In women who are 38 or older IVF is the first choice of treatment, according to the Dutch guideline in order to "not waste any more time” Evidence of IVF being more effective compared to IUI-OS is lacking while IVF compared to IUI-OS is an invasive, costly and burdensome procedure. Study design, size, duration We have conducted a systematic review and meta-analysis after a comprehensive literature search which includes articles on IVF, IUI, and both, from May 1985 to May 2022. We have included randomized controlled trials and cohort studies regarding IUI and/or IVF treatment in women aged 38 and above with unexplained subfertility and/or mild subfertility factors. Participants/materials, setting, methods The primary outcome was live birth rate and primary safety outcome was miscarriage rate. Data of the comparative IUI versus IVF studies were pooled in a forest plot and expressed in risk ratio with a 95% CI using a random effect model. We calculated prevalence estimates and performed meta-regression to study the effect of age on live birth and miscarriage Main results and the role of chance We included 17 studies in our meta-analysis. One RCT compared two IUI cycles with two IVF cycles and found a halving of live birth (RR 0.46, 95% CI 0.25-0.86. n = 154), very low-quality evidence especially in view of the unfair comparison in treatment time. Pooling the data of five cohort studies that compared IU with IVF resulted in a comparable risk estimate, though the difference between IUI and IVF was not significantly different (RR 0.56, 95% CI 0.30-1.05, I2=73%, n = 7288), low quality evidence in view of the unequal distribution of female age over the groups and the heterogeneity. Meta-regression on data from IUI studies suggested that IUI above 43 years old resulted in pregnancy chances below 5% (3 studies n = 397, only women older than 40). Meta-regression on data from IVF studies (8 studies, n = 22 708) suggested that following IVF, live birth rates declined from about 20% at 38 years to 5% at 43 year and zero above 44 years. At the same time miscarriage rates increased from an estimate of 25% at 38 years old to more than 50% above a female age of 43 years. Limitations, reasons for caution Female age, a likely effect modifier, was not equally distributed in the cohort studies, especially in the small IUI cohort studies. The available evidence lacked information on duration of treatment. For a fair comparison the treatment time horizon should be equal. Wider implications of the findings It is expected that the average age of women trying to conceive will only further increase within the coming years. Findings of this systematic review underline the importance of a randomized controlled trial to provide more evidence on which treatment should be recommended for women > 38 with unexplained subfertility. Trial registration number Not applicable