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

Rationale: 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. Miscarriage is an early pregnancy loss. For women who have recurrent miscarriage, it has been suggested that a causative factor may be inadequate secretion of progesterone. Therefore, clinicians sometimes use progestogens (drugs that interact with the progesterone receptors), beginning in the first trimester of pregnancy, in an attempt to prevent spontaneous miscarriage. It is important to understand if this is beneficial or harmful. This is an update of the review, last published in 2019. Previous versions included two trials that have since been retracted. This update included an updated trial search and evaluation of all trials using the Cochrane Trustworthiness Screening Tool.

Objectives: To assess the benefits and harms of progestogens as a preventative therapy against recurrent miscarriage.

Search methods: For this update, we searched CENTRAL, MEDLINE, Embase, CINAHL, Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (July 2024). We also searched reference lists from relevant articles, attempted to contact trial authors where necessary, and contacted experts in the field for unpublished works.

Eligibility criteria: We included randomized or quasi-randomized controlled trials in pregnant participants comparing progestogens with placebo or no treatment, given in an effort to prevent miscarriage. We included trials of participants who were diagnosed with recurrent miscarriage (usually of unknown origin) and who began treatment with progestogens in the first trimester of pregnancy. We excluded trials treating participants with threatened miscarriage or who had conceived by in-vitro fertilization.

Outcomes: The critical outcome was miscarriage. The main important outcomes were live birth rate and preterm birth (< 37 weeks' gestation). Other important outcomes were neonatal death, fetal genital abnormalities, stillbirth, low birthweight (< 2500 g), maternal adverse events and neonatal intensive care unit admission. Other maternal outcomes of interest were severity of 'morning sickness', thromboembolic events, depression, admission to special care unit and subsequent fertility.

Risk of bias: Two review authors assessed the studies using the RoB 1 tool for selection, performance, detection, attrition, incomplete outcome data, selective reporting and other bias.

Synthesis methods: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two reviewers assessed the certainty of the evidence using the GRADE approach. We utilized a random-effects model to synthesize the results.

Included studies: Nine trials with 1426 randomized participants met the inclusion criteria. Eight trials included analyzable data for 1276 participants. Overall, the risk of bias was low for six trials, while three had areas of concern. Because few studies reported on important outcomes, imprecision was high for those outcomes, limiting the certainty of those analyses.

Synthesis of results: Seven of the included trials compared treatment with placebo and the other two compared progestogen administration with no treatment. The trials were a mix of multicenter and single-center trials, conducted in Jordan, the UK, the Netherlands, and the USA. In three trials, participants had three or more consecutive miscarriages and in six trials, participants had two or more consecutive miscarriages. Route, dosage and duration of progestogen treatment varied across the trials. The majority of trials were at low risk of bias for most domains. Eight trials with 1276 participants contributed data to the analyses. Meta-analysis suggests that there is probably little to no difference in the miscarriage rate for women given progestogen supplementation compared to placebo or no treatment (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.76 to 1.07; I² = 0%; 8 studies, 1276 participants; moderate-certainty evidence). Subgroup analyses comparing placebo-controlled versus non-placebo-controlled trials, trials of participants with three or more prior miscarriages compared to women with two or more miscarriages, and different routes of administration showed no clear differences between subgroups for miscarriage. For women with recurrent miscarriage of unclear etiology receiving progestogen, there was probably little to no difference in live birth rate compared to placebo (RR 1.04, 95% CI 0.96 to 1.12; 5 trials, 1063 participants; moderate-certainty evidence). We are uncertain about the effect on the rate of preterm birth; there was probably little to no difference (RR 1.15, 95% CI 0.55 to 2.41; 3 trials, 256 participants; very low-certainty evidence). No clear differences were seen for women receiving progestogen for the other important outcomes, including neonatal death, fetal genital abnormalities, or stillbirth. There was little or no data on other important outcomes of low birth weight, maternal adverse events, teratogenic effects, or admission to a special care unit. None of the trials reported on any other important maternal outcomes, including severity of morning sickness, thromboembolic events, depression, admission to a special care unit, or subsequent fertility.

Authors' conclusions: For women with unexplained recurrent miscarriage, progestogen supplementation therapy probably results in little to no effect on outcomes in subsequent pregnancies.

Funding: This Cochrane review had no dedicated funding.

Registration: Previous versions of this review were published in the Cochrane Library, available at doi.org/10.1002/14651858.CD003511.pub5.