A Multi-Center Prospective, Randomized, Double-Blind Trial Studying the Effect of Misoprostol on the Outcome of Intrauterine Insemination

Abstract

Background: Because seminal prostaglandins play a role at natural fertilization, it was hypothesized that vaginal supplementation of prostaglandins at the time of intrauterine insemination (IUI) might enhance chances of conception. We investigated the effect of misoprostol, a prostaglandin analogue, on the success rate of IUI. Methods: A multi-center double-blind randomized controlled trial, using a cross-over design with alternating sequence, was designed. Vaginal tablets of misoprostol or placebo were used in conjunction to intrauterine insemination. In total, 199 women, comprising 466 cycles, were analyzed. Main outcome measures were pregnancy rate and prevalence of vaginal bleeding and uterine cramps. Results: The misoprostol group accounted for 146 cycles with 19 pregnancies, whereas the placebo group cycles totaled 164 cycles with 21 pregnancies (13.0 vs. 12.8%, not significant). There was a statistically significant increase in vaginal bleeding (12.3 vs. 1.8%; OR 7.55; 95% CI 2.31–24.48) and abdominal cramping rates (15.1 vs. 4.3%; OR 3.98; 95% CI 1.68–9.39) after application of misoprostol. Due to these severe adverse events the study was prematurely terminated. Conclusion: Although prostaglandins surely play a role in natural human reproduction, vaginal administration of misoprostol at the time of IUI is associated with a high rate of side effects and does not seem to enhance the outcome.

Uterine peristalsis and fertility: current knowledge and future perspectives: a review and meta-analysis

“…However, other studies did not find a significant difference in pregnancy rates (Billiet et al, 2008;Moslemizadeh et al, 2009). The multicentre randomized controlled trial (RCT) by Billiet et al (2008) was discontinued prematurely because of a high rate of severe adverse events (cramps and cervical bleeding). Despite this, they reached a significant sample size of 466 cycles.…”

“…Prostaglandins: some studies found a significantly higher pregnancy rate in patients undergoing intrauterine insemination with vaginal administration of misoprostol, compared with a control group without misoprostol (Barroso et al, 2001;Brown et al, 2001). However, other studies did not find a significant difference in pregnancy rates (Billiet et al, 2008;Moslemizadeh et al, 2009). The multicentre randomized controlled trial (RCT) by Billiet et al (2008) was discontinued prematurely because of a high rate of severe adverse events (cramps and cervical bleeding).…”

“…Surprisingly, Brown et al (2001), who did find significant effects on pregnancy rates, reported no difference in pain or spotting between the misoprostol group and control group while using the same vaginal application method. Combining the data of all studies mentioned in a meta-analysis, excluding the data of Billiet et al (2008) was unavoidable because of selection bias in the study protocol (continued three-cycle treatment of women in crossover design placebo/ misoprostol). The analysis (Figure 6) shows a RR of 1.68 (1.13-2.50) with no heterogeneity (I 2 : 0%) in favour of the misoprostol group (very low quality of evidence, Table 4).…”

Uterine contractility and elastography as prognostic factors for pregnancy after intrauterine insemination

“…Four randomized trials (19)(20)(21)(22) on the use of uterotonic agents have yielded conflicting results, and a direct pharmacological action on pregnancy occurrence cannot be excluded. Billiet et al found no benefit (13% vs. 12.8%) of vaginal misoprostol on PR when used in 466 IUI of 199 women included in a multicenter study (21). Adverse effects, such as vaginal bleeding and abdominal cramps, were, however, significantly higher with misoprostol.…”

“…The application of tenaculum to the cervix during IUI increased both UC frequency and the PR in one trial (17) but did not affect the PR in another study (18). The administration of uterotonic drugs before IUI has also resulted in conflicting effects: PRs were improved in two trials (19,20) but not in two others (21,22).…”