Review question: Cochrane authors reviewed the evidence about the effect of double intrauterine insemination (IUI) versus single IUI in subfertile couples (couples who have tried to conceive for at least one year).
Background: for couples who have tried to conceive for at least one year a common way to induce pregnancy is placement of the sperm directly into the uterus and therefore close to any eggs. This is combined with fertility medicines to stimulate the release of eggs (IUI with ovarian stimulation). The insemination is less stressful, invasive and expensive compared to in vitro fertilisation (where an egg is combined with sperm outside the body) and similar procedures. It is often used when a male partner is subfertile, or when the reason for not becoming pregnant is unknown. Generally, IUI is carried out once in a menstrual cycle, but it is sometimes attempted twice (double IUI). Different clinical trials reached differing conclusions whether double IUI resulted in more pregnancies than single IUI.
Study characteristics: we found nine randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) comparing double IUI with single IUI with 2751 woman. The evidence is current to July 2020.
Key results : our main analysis, of which the evidence is rated as low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. The evidence suggests that if the chance of live birth following single IUI is 16%, then the chance following double IUI would be between 12% and 27%. The evidence suggests that if chance of miscarriage following single IUI is 1.5%, the chance following double IUI would be between 1.5% and 5%. Performing analysis with the highest quality trials showed similar results for both outcomes. Pregnancy rate may increase with double IUI. This result should be interpreted with caution due to low quality of the evidence. The evidence suggests that chance of pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%. However, when we analysed only with the high quality studies, the positive effect of double IUI was lost and we no longer saw the improvement anymore.
We are uncertain whether double IUI reduces multiple- (two or more fetuses) and ectopic pregnancy rate (where a fertilised egg implants itself outside of the womb, usually in one of the tubes connecting the ovary and womb) compared to single IUI. The evidence suggests that if the chance of multiple pregnancy following single IUI is 0.7%, then the chance following double IUI would be between 0.7% and 3.2%. The evidence suggests that if the chance of ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%.
Quality of the evidence: the evidence was of low quality. The main limitations in the evidence were unclear risk of bias and small trials with imprecise results.
Our main analysis, of which the evidence is low quality, shows that we are uncertain if double IUI improves live birth and reduces miscarriage compared to single IUI. Our sensitivity analysis restricted to studies of low risk of selection bias for both outcomes is consistent with the main analysis. Clinical pregnancy rate may increase in the double IUI group, but this should be interpreted with caution due to the low quality evidence. We are uncertain whether double IUI has an effect on multiple pregnancy rate and ectopic pregnancy rate compared to single IUI.
In subfertile couples, couples who have tried to conceive for at least one year, intrauterine insemination (IUI) with ovarian hyperstimulation (OH) is one of the treatment modalities that can be offered. When IUI is performed a second IUI in the same cycle might add to the chances of conceiving. In a previous update of this review in 2010 it was shown that double IUI increases pregnancy rates when compared to single IUI. Since 2010, different clinical trials have been published with differing conclusions about whether double IUI increases pregnancy rates compared to single IUI.
To determine the effectiveness and safety of double intrauterine insemination (IUI) compared to single IUI in stimulated cycles for subfertile couples.
We searched the Cochrane Gynaecology and Fertility (CGF) Group trials register, CENTRAL, MEDLINE, Embase and CINAHL in July 2020 and LILACS, Google scholar and Epistemonikos in February 2021, together with reference checking and contact with study authors and experts in the field to identify additional studies.
We included randomised controlled, parallel trials of double versus single IUIs in stimulated cycles in subfertile couples.
Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information.
We identified in nine studies involving subfertile women. The evidence was of low quality; the main limitations were unclear risk of bias, inconsistent results for some outcomes and imprecision, due to small trials with imprecise results.
We are uncertain whether double IUI improves live birth rate compared to single IUI (odds ratio (OR) 1.15, 95% confidence interval (CI) 0.71 to 1.88; I2 = 29%; studies = 3, participants = 468; low quality evidence). The evidence suggests that if the chance of live birth following single IUI is 16%, the chance of live birth following double IUI would be between 12% and 27%. Performing a sensitivity analysis restricted to only randomised controlled trials (RCTs) with low risk of selection bias showed similar results.
We are uncertain whether double IUI reduces miscarriage rate compared to single IUI (OR 1.78, 95% CI 0.98 to 3.24; I2 = 0%; studies = 6, participants = 2363; low quality evidence). The evidence suggests that chance of miscarriage following single IUI is 1.5% and the chance following double IUI would be between 1.5% and 5%.
The reported clinical pregnancy rate per woman randomised may increase with double IUI group (OR 1.51, 95% CI 1.23 to 1.86; I2 = 34%; studies = 9, participants = 2716; low quality evidence). This result should be interpreted with caution due to the low quality of the evidence and the moderate inconsistency. The evidence suggests that the chance of a pregnancy following single IUI is 14% and the chance following double IUI would be between 16% and 23%.
We are uncertain whether double IUI affects multiple pregnancy rate compared to single IUI (OR 2.04, 95% CI 0.91 to 4.56; I2 = 8%; studies = 5; participants = 2203; low quality evidence). The evidence suggests that chance of multiple pregnancy following single IUI is 0.7% and the chance following double IUI would be between 0.85% and 3.7%.
We are uncertain whether double IUI has an effect on ectopic pregnancy rate compared to single IUI (OR 1.22, 95% CI 0.35 to 4.28; I2 = 0%; studies = 4, participants = 1048; low quality evidence). The evidence suggests that the chance of an ectopic pregnancy following single IUI is 0.8% and the chance following double IUI would be between 0.3% and 3.2%.