Vasodilators in women undergoing fertility treatment

Review question: Cochrane review authors investigated the effectiveness and safety of vasodilators (drugs used to widen blood vessels) in women undergoing fertility treatment.

Background: In women undergoing fertility treatment for different causes, interventions aimed at improving the receptivity of the uterus are of utmost importance. Many different drugs have been evaluated, with the aim of increasing rates of implantation and live birth. These include vasodilating agents, which are used to dilate blood vessels to improve endometrial receptivity, thicken the endometrium and favour uterine relaxation, among other effects.

Study characteristics: Ten randomised controlled trials with a total of 797 women were included in this review. Investigators compared the use of vasodilators versus placebo or no treatment in women undergoing fertility treatment. The evidence is current to February 2014.

Key results: Only three of the included studies reported live birth. Overall, no evidence suggests that treatment with vasodilators increased live birth rates compared with placebo or no treatment. Moderate-quality evidence suggests that among women undergoing fertility treatment who have a 24% chance of live birth without the use of vasodilators, between 19% and 40% will achieve live birth with the use of vasodilators. However, low-quality evidence suggests that vasodilators may increase the chance of becoming pregnant. Evidence was insufficient to permit any conclusions regarding adverse effects, as only two studies reported this outcome.

Quality of the evidence: The evidence was of low or moderate quality, and the main limitations were imprecision and lack of clarity about study methods. Risk of publication bias could not be assessed because of the low number of included studies.

Authors' conclusions: 

Evidence was insufficient to show that vasodilators increased the live birth rate in women undergoing fertility treatment. However, low-quality evidence suggests that vasodilators may increase clinical pregnancy rates in comparison with placebo or no treatment. Evidence was insufficient to show whether any particular vasodilator, administered alone or in combination with other active medications, was superior, and evidence was insufficient to allow the review authors to reach any conclusions regarding adverse effects. Adequately powered studies are needed so that each treatment can be evaluated more accurately.

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Background: 

Since 1978, when Patrick Steptoe and Robert Edwards achieved the birth of the first test tube baby, assisted reproductive techniques have been refined and improved. However, the rate of successful pregnancies brought to term has barely increased. Therefore closer evaluation of the interventions is needed along with working towards improving uterus receptivity. Vasodilators have been proposed to increase endometrial receptivity, thicken the endometrium and favour uterine relaxation, all of which could improve uterine receptivity and enhance the chances for successful assisted pregnancies.

Objectives: 

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

Search strategy: 

We searched the following electronic databases, trial registers and websites: the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register of controlled trials, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, Web of Knowledge, the Open System for Information on Grey Literature in Europe (OpenSIGLE), the Latin American and Caribbean Health Science Information Database (LILACS) and ClinicalTrials.gov. The search was conducted in February 2014. No language restrictions were applied.

Selection criteria: 

Randomised controlled trials (RCTs) of vasodilators alone or in combination with other treatments compared with placebo or with other agents in women undergoing fertility treatment.

Data collection and analysis: 

Two review authors independently selected the studies, assessed the risk of bias and extracted data. Risk ratios (RRs) were calculated using the numbers of events in the control and intervention groups of each study. Study data were combined using a random-effects model, and evidence quality was assessed using Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) methods.

Main results: 

Ten studies with a total of 797 women were included in this review. Most of the studies were judged as having an unclear risk of bias. Three studies reported live births, two reported vasodilator-related side effects, 10 reported clinical pregnancies (diagnosed by differing criteria) and four reported other side effects (multiple gestation, miscarriage, ectopic pregnancy).

Overall, no evidence suggested that treatment with vasodilators increased live birth rates compared with placebo or no treatment (RR 1.18, 95% confidence interval (CI) 0.82 to 1.69, P value 0.37, three RCTs, 350 women, I2 = 0%, moderate-quality evidence). This indicates that among women undergoing fertility treatment who have a 24% chance of live birth without the use of vasodilators, between 19% and 40% will achieve live birth with the use of vasodilators.

No evidence was found of a difference between vasodilators and placebo or no treatment in the incidence of treatment side effects (RR 1.63, 95% CI 0.33 to 7.93, P value 0.55, two RCTs, 258 women, I2 = 32%, low-quality evidence). Nor did any evidence show a difference between them in terms of multiple gestation, spontaneous abortion/miscarriage or ectopic pregnancy rates. However few relevant data were available.

Overall, treatment with vasodilators was associated with an increased clinical pregnancy rate compared with placebo or no treatment (RR 1.38, 95% CI 1.00 to 1.92, P value 0.05, eight RCTs, 717 women, I2 = 0%, low-quality evidence). However, confidence intervals do not rule out no effect of the intervention, and when studies of vasodilators combined with another medication (vitamin E or oestrogen) were excluded, the effects of treatment with vasodilators alone on clinical pregnancy rates were more uncertain.

The evidence was of low or moderate quality, and the main limitations were imprecision and lack of clarity about study methods. Risk of publication bias could not be assessed because of the low number of identified studies.

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