Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix: a meta-analysis of individual patient data

Abstract

Background: The efficacy of vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in singleton gestations with a short cervix has been questioned after publication of the OPPTIMUM study.

Objective: To determine whether vaginal progesterone prevents preterm birth and improves perinatal outcomes in asymptomatic women with a singleton gestation and a midtrimester sonographic short cervix.

Study design: We searched MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to September 2017); Cochrane databases; bibliographies; and conference proceedings for randomized controlled trials comparing vaginal progesterone vs placebo/no treatment in women with a singleton gestation and a midtrimester sonographic cervical length ≤25 mm. This was a systematic review and meta-analysis of individual patient data. The primary outcome was preterm birth <33 weeks of gestation. Secondary outcomes included adverse perinatal outcomes and neurodevelopmental and health outcomes at 2 years of age. Individual patient data were analyzed using a 2-stage approach. Pooled relative risks with 95% confidence intervals were calculated. Quality of evidence was assessed using the GRADE methodology.

Results: Data were available from 974 women (498 allocated to vaginal progesterone, 476 allocated to placebo) with a cervical length ≤25 mm participating in 5 high-quality trials. Vaginal progesterone was associated with a significant reduction in the risk of preterm birth <33 weeks of gestation (relative risk, 0.62; 95% confidence interval, 0.47-0.81; P = .0006; high-quality evidence). Moreover, vaginal progesterone significantly decreased the risk of preterm birth <36, <35, <34, <32, <30, and <28 weeks of gestation; spontaneous preterm birth <33 and <34 weeks of gestation; respiratory distress syndrome; composite neonatal morbidity and mortality; birthweight <1500 and <2500 g; and admission to the neonatal intensive care unit (relative risks from 0.47-0.82; high-quality evidence for all). There were 7 (1.4%) neonatal deaths in the vaginal progesterone group and 15 (3.2%) in the placebo group (relative risk, 0.44; 95% confidence interval, 0.18-1.07; P = .07; low-quality evidence). Maternal adverse events, congenital anomalies, and adverse neurodevelopmental and health outcomes at 2 years of age did not differ between groups.

Conclusion: Vaginal progesterone decreases the risk of preterm birth and improves perinatal outcomes in singleton gestations with a midtrimester sonographic short cervix, without any demonstrable deleterious effects on childhood neurodevelopment.

Keywords: cervical length; prematurity; preterm delivery; progestins; progestogens; transvaginal ultrasound.

Conflict of interest statement

Disclosure: RR, AC-A, EDF, EC, SSH, and KHN declare no conflict of interest. JMO’B was involved in studies of progesterone gel treatment for preterm birth prevention sponsored by a maker of progesterone gel. He served on advisory boards and as a consultant for Watson Pharmaceuticals, a company with a financial interest in marketing vaginal progesterone gel for preterm birth prevention; he and others are listed in a patent on the use of progesterone compounds to prevent preterm birth (USA Patent Number 7884093: progesterone for the treatment and prevention of spontaneous preterm birth). He has received no royalty payments. GWC was an Employee of Columbia Laboratories, Inc. when the previous meta-analysis of individual patient data was conducted in 2011.

Professor Jane Norman has no conflict of interest in relation with our meta-analysis of individual patient data.

Published by Elsevier Inc.

Figures

Figure 1. Summary of evidence search and selection

CL, cervical length; IPD, individual patient data

Figure 2. Risk of bias in each included study

*Low risk of bias for obstetric and neonatal primary outcomes; high risk of bias for childhood primary outcome

Figure 3. Effect of vaginal progesterone on preterm birth

Figure 4. Subgroup analyses of the effect of vaginal progesterone on preterm birth

SPB, spontaneous preterm birth