Progestogen for preventing miscarriage in women with recurrent miscarriage of unclear etiology

Cochrane Database of Systematic Reviews Cochrane Systematic Review - Intervention Version published: 08 October 2018 see what's new New search View article information David M HaasTaylor J HathawayPatrick S RamseyView authors' declarations of interest Abstract available in English Español Français Background Progesterone, a female sex hormone, is known to induce secretory changes in the lining of the uterus essential for successful implantation of a fertilized egg. It has been suggested that a causative factor in many cases of miscarriage may be inadequate secretion of progesterone. Therefore, clinicians use progestogens (drugs that interact with the progesterone receptors), beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. This is an update of a review, last published in 2013. Objectives To assess the efficacy and safety of progestogens as a preventative therapy against recurrent miscarriage. Search methods For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (6 July 2017) and reference lists from relevant articles, attempting to contact trial authors where necessary, and contacted experts in the field for unpublished works. Selection criteria Randomized or quasi‐randomized controlled trials comparing progestogens with placebo or no treatment given in an effort to prevent miscarriage. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two reviewers assessed the quality of the evidence using the GRADE approach. Main results Thirteen trials (2556 women) met the inclusion criteria. Nine of the included trials compared treatment with placebo and the remaining four trials compared progestogen administration with no treatment. The trials were a mix of multicenter and single‐center trials, conducted in Egypt, India, Jordan, UK and USA. In six trials women had had three or more consecutive miscarriages and in seven trials women had suffered two or more consecutive miscarriages. Routes, dosage and duration of progestogen treatment varied across the trials. The majority of trials were at low risk of bias for most domains. Eleven trials (2359 women) contributed data to the analyses. The meta‐analysis of all women, suggests that there is probably a reduction in the number of miscarriages for women given progestogen supplementation compared to placebo/controls (average risk ratio (RR) 0.69, 95% confidence interval (CI) 0.51 to 0.92, 11 trials, 2359 women, moderate‐quality evidence). A subgroup analysis comparing placebo‐controlled versus non‐placebo‐controlled trials and different routes of administration showed no differences between subgroups for miscarriage. However, there appears to be a subgroup difference for miscarriage between women with three or more prior miscarriages compared to women with two or more miscarriages, with a more pronounced effect in women with three or more prior miscarriages. However, it should be noted that there was high heterogeneity in the subgroup of women with three or more prior miscarriages. None of the trials reported on any secondary maternal outcomes, including severity of morning sickness, thromboembolic events, depression, admission to a special care unit, or subsequent fertility. There was probably a slight benefit for women receiving progestogen seen in the outcome of live birth rate (RR 1.11, 95% CI 1.00 to 1.24, 7 trials, 2086 women, moderate‐quality evidence). While the rate of preterm birth is probably reduced for women receiving progestogen, this outcome was mainly driven by one trial and thus should be interpreted with great caution (RR 0.59, 95% CI 0.39 to 0.89, 5 trials, 811 women, moderate‐quality evidence). No clear differences were seen for women receiving progestogen for the other secondary outcomes of neonatal death or fetal genital abnormalities. A possible reduction in stillbirth was seen, but again this outcome was driven mainly by one trial and should be interpreted with caution (RR 0.38, 95% CI 0.24 to 0.58, 3 trials, 1199 women). There may be little or no difference in the rate of low birthweight and trials did not report on the secondary child outcomes of teratogenic effects or admission to a special care unit. Authors' conclusions For women with unexplained recurrent miscarriages, supplementation with progestogen therapy probably reduces the rate of miscarriage in subsequent pregnancies. Plain language summary available in English Español Français 日本語 Русский Progestogen for preventing miscarriage What is the issue? Early pregnancy loss, also known as miscarriage, generally occurs in the first trimester. For some women and their partners, miscarriages can happen several times, also known as recurrent miscarriages. While there are sometimes causes for miscarriages that are found, often no clear reasons can be found. The hormone called progesterone prepares the womb (uterus) to receive and support the newly fertilized egg during the early part of pregnancy. It has been suggested that some women who miscarry may not make enough progesterone in the early part of pregnancy. Supplementing these women with medications that act like progesterone (these are called progestogens) has been suggested as a possible way to prevent recurrent miscarriage. Why is this important? Having miscarriages can be both physically and emotionally difficult for women and their partners. Finding a therapy to help reduce recurrent miscarriages could help them avoid a miscarriage and have a live baby. What evidence did we find? We searched for evidence on 6 July 2017 and identified a total of 13 trials that enrolled a total of 2556 women with a history of recurrent miscarriages. These trials found that giving progestogen medication to women with recurrent miscarriages early in their pregnancy may help lower the rates of miscarriage in that pregnancy from 26.3% to 19.4%. We believe that these findings are based on evidence of only moderate quality, so we cannot be certain about the results. We found that progestogen treatment may be most helpful for women who had had at least three miscarriages before they started the study. We did not find that giving the progestogen medication by mouth, as a shot (injection), or in the vagina was any better than any of the other ways. We also found that the trials showed that giving progestogen to women with prior recurrent miscarriages made the chances of having a live baby in the current pregnancy slightly higher. While we found evidence that giving progestogens to women in these groups might lower the rate of having a baby too early or having a stillbirth, this evidence was not very strong and should be backed up with more studies. We did not find evidence of improvement in other outcomes such as newborn death, low birthweight, or newborn birth defects for women given progestogens. What does this mean? We found evidence from randomized controlled trials that giving progestogen medication can probably prevent miscarriage for women with recurrent previous miscarriages.