Vasodilators for women undergoing fertility treatment.

Background: The rate of successful pregnancies brought to term has barely increased since the first assisted reproductive technology (ART) technique became available. Research suggests that vasodilators may increase endometrial receptivity, thicken the endometrium, and favour uterine relaxation, all of which could improve the chances of successful assisted pregnancy.

Objectives: To evaluate the effectiveness and safety of vasodilators in women undergoing fertility treatment.

Search methods: We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, CENTRAL, MEDLINE, Embase, three other databases, and two clinical trial registries in April 2024, with no language or date restrictions. We also searched grey literature sources and checked the reference lists of relevant articles.

Selection criteria: We included randomised controlled trials (RCTs) comparing vasodilators (alone or combined with other treatments) versus placebo or no treatment or versus other agents in women undergoing fertility treatment.

Data collection and analysis: Two review authors independently selected studies, assessed risk of bias, extracted data, and calculated risk ratios (RRs). We combined study data using a fixed-effect model and assessed evidence certainty using the GRADE approach. Our primary outcomes were live birth or ongoing pregnancy and vasodilator side effects. Our secondary outcomes were clinical pregnancy, endometrial thickness, multiple gestation, miscarriage, and ectopic pregnancy.

Main results: We included 45 studies with a total of 4404 women. The included studies compared a vasodilator versus a placebo or no treatment (40 RCTs), vasodilators plus another agent versus placebo or no treatment (3 RCTs) or versus oestrogens (3 RCTs). The mean length of follow-up was 15.45 weeks. Overall, the certainty of evidence was very low to moderate. The main limitations were imprecision (low number of events and participants) and risk of bias (lack of blinding in studies that reported subjective outcomes). Vasodilators versus placebo or no treatment Vasodilators may result in little to no difference in rates of live birth or ongoing pregnancy compared with placebo or no treatment (RR 1.21, 95% CI 0.93 to 1.58; I² = 0%; 6 RCTs, 740 women; low-certainty evidence), but probably increase overall rates of side effects (RR 2.14, 95% CI 1.55 to 2.98; I² = 0%; 7 RCTs, 668 women; moderate-certainty evidence). The evidence suggests that 246 per 1000 women achieve live birth or ongoing pregnancy with a placebo or no treatment, and 229 to 389 per 1000 will do so using vasodilators. Vasodilators compared with placebo or no treatment likely increase rates of clinical pregnancy (RR 1.45, 95% CI 1.28 to 1.64; I² = 22%; 25 RCTs, 2506 women; moderate-certainty evidence). Vasodilators compared with placebo or no treatment probably have little or no effect on rates of multiple gestation or birth (RR 1.37, 95% CI 0.73 to 2.55; I² = 0%; 7 RCTs, 763 women; moderate-certainty evidence), miscarriage (RR 1.01, 95% CI 0.59 to 1.74; I² = 0%; 8 RCTs; 829 women; moderate-certainty evidence), and ectopic pregnancy (RR 1.25, 95% CI 0.34 to 4.59; I² = 0%; 4 RCTs, 543 women; moderate-certainty evidence). Most studies found a beneficial effect of vasodilators for endometrial thickness, but the reported effect estimates varied (I² = 93%), from a mean difference of 0.47 mm higher (95% CI 0.90 mm lower to 1. 84 mm higher) to 1.94 mm higher (95% CI 1.37 higher to 2.51 mm higher), and the evidence was very uncertain. Hence, we are unsure how to interpret these results. Vasodilators versus oestrogens Vasodilators compared with oestrogens may have little or no effect on rates of live birth or ongoing pregnancy (RR 0.83, 95% CI 0.30 to 1.33; 1 RCT, 44 women, low-certainty evidence). The evidence is very uncertain regarding the effect of sildenafil compared with oestrogens on clinical pregnancy rates (RR 0.99, 95% CI 0.71 to 1.38; I² = 59%; 3 RCTs, 262 women; very low-certainty evidence), endometrial thickness (RR 1.90, 95 CI 1.15 to 3.13; 1 RCT, 120 women; very low-certainty evidence) and miscarriage rates (RR 0.50, 95% CI 0.05 to 5.12; 1 RCT, 44 women; very low-certainty evidence) AUTHORS' CONCLUSIONS: Among women undergoing fertility treatment, there may be little or no difference in the rate of live birth or ongoing pregnancy in those who receive vasodilators compared with those who receive a placebo or no treatment, and compared with those who receive oestrogens. Compared with placebo or no treatment, vasodilators likely increase rates of clinical pregnancy, but probably also increase overall rates of side effects. The evidence on clinical pregnancy with vasodilators versus oestrogens is very uncertain, and we found no evidence on overall side effects for the comparison of vasodilators versus oestrogens. We are unsure about the effect of vasodilators versus placebo or no treatment and versus oestrogens on endometrial thickness. Vasodilators versus placebo or no treatment probably have little or no effect on multiple gestation or birth, miscarriage, and ectopic pregnancy. Future studies should be adequately randomised and powered to ensure a more accurate evaluation of each treatment, with live births as a primary outcome.