Baris Ata, Ahmed M Abou‐Setta, Ayse Seyhan, William Buckett

The female genital tract is not exposed to seminal plasma during standard assisted reproductive technology (ART) cycles. However, it is thought that the inflammatory reaction triggered by seminal plasma may be beneficial by inducing maternal tolerance to paternal antigens expressed by the products of conception, and may increase the chance of successful implantation and live birth. To assess the effectiveness and safety of application of seminal plasma to the female genital tract prior to embryo transfer in ART cycles. We searched the following databases from inception to October 2017: Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials, Cochrane Central Register of Studies Online (CRSO), MEDLINE, Embase, CINAHL and PsycINFO. We also searched trial registers for ongoing trials, including International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. Other sources searched were; Web of Knowledge, OpenGrey, LILACS, PubMed, Google Scholar and the reference lists of relevant articles. We included randomised controlled trials (RCTs) conducted among women undergoing ART, comparing any procedure that would expose the female genital tract to seminal plasma during the period starting five days before embryo transfer and ending two days after it versus no seminal plasma application. Two review authors independently selected trials, assessed risk of bias, and extracted data. We pooled data to calculate relative risks (RRs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2statistic. We assessed the overall quality of the evidence for the main outcomes using GRADE methods. Our primary outcomes were live birth rate and miscarriage rate. Secondary outcomes were live birth/ongoing pregnancy rate, clinical pregnancy rate, multiple pregnancy rate, ectopic pregnancy rate and the incidence of other adverse events. We included 11 RCTs (3215 women). The quality of the evidence ranged from very low to low. The main limitations were risk of bias (associated with poor reporting of allocation concealment and other methods) and imprecision for the primary outcome of live birth rate.Live birth rates: There was insufficient evidence to determine whether there was a difference between the groups with respect to live birth rates (RR 1.10, 95% CI 0.86 to 1.43; participants = 948; studies = 3; I2= 0%). Low quality evidence suggests that if the live birth rate following standard ART is 19% it will be between 16% and 27% with seminal plasma application.Miscarriage rate: There was insufficient evidence to determine whether there was a difference between the groups (RR 1.01, 95% CI 0.57 to 1.79; participants = 1209; studies = 4; I2= 0%). Low quality evidence suggests that if the miscarriage rate following standard ART is 3.7%, the miscarriage rate following seminal plasma application will be between 2.1% and 6.6%.Live birth or ongoing pregnancy rates: Seminal plasma application makes little or no difference in live birth or ongoing pregnancy rates (RR 1.19, 95% CI 0.95 to 1.49; participants = 1178; studies = 4; I2= 4%, low quality evidence). The evidence suggests that if the live birth or ongoing pregnancy rate following standard ART is 19.5% it will be between 18.5% and 29% with seminal plasma application.Clinical pregnancy rates: Seminal plasma application may increase clinical pregnancy rates (RR 1.15, 95% CI 1.01 to 1.31; participants = 2768; studies = 10; I2= 0%). Very low quality evidence suggests that if the clinical pregnancy rate following standard ART is 22.0% it will be between 22.2% and 28.8% with seminal plasma application. This finding should be regarded with caution, as a post-hoc sensitivity analysis restricted to studies at overall low risk of bias did not find a significant difference between the groups (RR 1.06, 95% CI 0.81 to 1.39; participants = 547; studies = 3; I2= 0%).Multiple pregnancy rate: Seminal plasma application may make little or no difference to multiple pregnancy rates (RR 1.11, 95% CI 0.76 to 1.64; participants = 1642; studies = 5; I2= 9%). Low quality evidence suggests that if the multiple pregnancy rate following standard ART is 7%, the multiple pregnancy rate following seminal plasma application will be between 5% and 11.4%.Ectopic pregnancy: There was insufficient evidence to determine whether seminal plasma application influences the risk of ectopic pregnancy (RR 1.59, 95% CI 0.20 to 12.78, participants =1521; studies = 5; I2= 0%) .Infectious complications or other adverse events: No data were available on these outcomes AUTHORS' CONCLUSIONS: In women undergoing ART, there was insufficient evidence to determine whether there was a difference between the seminal plasma and the standard ART group in rates of live birth (low-quality evidence) or miscarriage (low quality evidence). There was low quality evidence suggesting little or no difference between the groups in rates of live birth or ongoing pregnancy (composite outcome). We found low quality evidence that seminal plasma application may be associated with more clinical pregnancies than standard ART. There was low quality evidence suggesting little or no difference between the groups in rates of multiple pregnancy. There was insufficient evidence to reach any conclusions about the risk of ectopic pregnancy, and no data were available on infectious complications or other adverse events.We conclude that seminal plasma application is worth further investigation, focusing on live birth and miscarriage rates.