Key messages
1. Vasodilators (medicines that widen blood vessels) compared with dummy treatment or no treatment probably help women become pregnant, but probably have side effects. In addition, vasodilators compared with dummy treatment or no treatment, and compared with oestrogens (female sex hormones), may have little or no effect on the chance of women carrying the pregnancy to term and having the baby.
2. To draw more solid conclusions, we need larger, well-designed studies on this treatment.
Background
For women undergoing fertility treatment, it is important to ensure the blastocyst (the rapidly dividing ball of cells that will become the fetus) can implant normally in the endometrium (womb lining). There are many medicines that could increase rates of implantation and live births. These include vasodilators, which dilate blood vessels to thicken the endometrium and help the womb relax, among other effects that could make the womb more receptive to the blastocyst.
What did we want to find out?
We wanted to know whether vasodilators could help improve rates of live births, rates of pregnancy, and endometrial thickness. We also wanted to know whether vasodilators had any effect on rates of multiple pregnancy (twins, triplets, etc.), miscarriage, and ectopic pregnancy (when the fertilised egg implants outside the womb), and whether they had any side effects.
What did we do?
We looked for studies comparing vasodilators with placebo (dummy treatment) or no treatment, or compared with a different medicine, in women of any age undergoing fertility treatment. We compared and summarised the results of the studies and rated our confidence in the evidence based on factors such as study size and methods.
Study characteristics
We found 45 studies that compared vasodilators with placebo or no treatment or with oestrogens (one of the main female sex hormones) in a total of 4404 women undergoing fertility treatment. The studies were carried out in different countries: 20 in Egypt, 12 in Iran, four in Iraq, three in India, one in Australia, one in France, one in the UK, one in Russia, one in Belgium, and one in Korea. Only 21 of 45 studies declared the funding sources. Two of these studies declared financing was from pharmaceutical companies. Researchers or independent institutions funded the other 19 studies.
Main results
Vasodilators compared with placebo or no treatment
Only six studies reported live birth or ongoing pregnancy rates in this comparison. Vasodilators compared with placebo or no treatment may have little or no effect on rates of live birth or ongoing pregnancy, but probably increase the chance of women becoming pregnant. Vasodilators probably have side effects, including headache and tachycardia (faster than normal heartbeat), but probably make little or no difference to rates of other unwanted events (multiple pregnancy, miscarriage, and ectopic pregnancy). We are unsure about the effect of vasodilators compared with placebo or no treatment on endometrial thickness.
Vasodilators compared with oestrogens
Only one study reported live birth or ongoing pregnancy rates in this comparison. Vasodilators compared with oestrogens may have little or no effect on rates of live birth or ongoing pregnancy, and we are unsure if they can help women become pregnant or improve endometrial thickness. The evidence on miscarriage is very uncertain.
What are the limitations of the evidence?
For the first comparison (vasodilators compared with placebo or no treatment), we are moderately confident in most of the evidence, but have less confidence in the results for live birth and endometrial thickness. For the second comparison (vasodilators compared with oestrogens), we are not confident in most of the evidence, and we have little confidence in the results for live birth. The main limitations of the evidence are that some studies were very small, many women knew which treatment they were receiving, and the results sometimes varied considerably from study to study.
More research is needed to draw more solid conclusions (13 studies are ongoing and will be incorporated into this review in a future update).
How up to date is this evidence?
This review updates our previous review published in 2018. The evidence is current to April 2024.
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.
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.
To evaluate the effectiveness and safety of vasodilators in women undergoing fertility treatment.
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.
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.
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.
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)