Screening of pregnant women for preterm birth, based on their obstetric history and sonographic measurement of the cervical length, can identify greater than 50% of those at risk. Administration of progesterone to at-risk women with a singleton pregnancy can significantly reduce rates of preterm birth. However, effects of this agent on the actual perinatal and long-term consequences of prematurity are difficult to assess. Existing randomized controlled trials (RCTs) and systematic reviews have focused mainly on the primary outcome of reduction of preterm birth rates. The aim of this meta-analysis was to systematically review published evidence and pool data on the perinatal outcome in women treated with progesterone for the prevention of preterm birth.
MEDLINE and SCOPUS databases were searched for clinical trials in which progesterone was given to prevent preterm birth in pregnant women at risk compared with placebo. Randomized controlled trials that compared progesterone versus placebo in women with singleton or multiple pregnancies at risk for preterm birth based on previous history or short cervix were selected. The CONSORT statement was used to address the reporting quality of the RCTs. The risk of bias in the RCTs was assessed with the “risk-of-bias” tool from the Cochrane Collaboration. The primary outcomes were the rates of neonatal and perinatal mortality. Secondary outcomes were the rates of perinatal complications, including respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH) grade 3–4, sepsis, necrotizing enterocolitis (NEC), sepsis, retinopathy, and admission to the neonatal intensive care unit (NICU); a composite adverse outcome was also determined and defined as the presence of any perinatal morbidity or mortality.
Of 628 retrieved items, 16 RCTs reporting on the use of progesterone in asymptomatic women to prevent preterm birth were included in the meta-analysis. Pooled data indicated that progesterone administration in these women significantly decreased the risk for composite adverse outcome (RR, 0.576; 95% confidence interval [CI], 0.373–0.891), neonatal death (relative risk, 0.487; 95% CI, 0.290–0.818), RDS (RR, 0.677; 95% CI, 0.490–0.935), and admission to the NICU (RR, 0.410; 95% CI, 0.204–0.823). No significant differences were found in rates of perinatal death, grade 3–4 IVH, NEC, retinopathy, or sepsis. Pooled data from 3 studies that used vaginal progesterone in women with a short cervix showed that progesterone significantly decreased the rate of composite adverse outcome (RR, 0.576; 95% CI, 0.373–0.891) and RDS (RR, 0.464; 95% CI, 0.275–0.786), but results did not reach statistical significance for rates of neonatal death, perinatal death, grade 3–4 IVH, NEC, sepsis, or admission to the NICU. Three studies tested systemic progesterone in women with a singleton pregnancy and a history of preterm birth; pooled results found that progesterone significantly decreased rates of neonatal death (RR, 0.412; 95% CI, 0.201–0.842) and NICU admission (RR, 0.277; 95% CI, 0.160–0.479). In 7 RCTs reporting on women with twin pregnancies, progesterone administration did not significantly affect the rates of neonatal death, grade 3–4 IVH, NEC, retinopathy, sepsis, or NICU admission. Progesterone significantly increased the rates of composite adverse outcome (RR, 1.211; 95% CI, 1.029–1.425), perinatal death (RR, 1.551; 95% CI, 1.014–2.372), and RDS (RR, 1.218; 95% CI, 1.038–1.428). The pooled data from 2 RCTs on women with triplets did not show significant differences in the rates of composite adverse outcome, neonatal death, RDS, grade 3–4 IVH, NEC, or sepsis.
Preterm birth is a major cause of perinatal mortality and morbidity with long-term consequences. Results of this meta-analysis indicate that prophylactic progesterone administration in singleton pregnancies at risk can lower the rates of neonatal mortality, RDS, admission to the NICU, and a composite adverse outcome. Data, however, also indicate that use of progesterone in multiple pregnancies may lead to increased rates of perinatal death, RDS, and a composite adverse outcome.
Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki (A.S.); and Department of Obstetrics and Gynecology, Ioannina University Hospital, Ioannina (S.P., G.M.), Greece