Abstract
BackgroundPreterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. International guidelines recommend expectant management, along with antenatal steroids before 34 weeks and antibiotics. Up-to-date evidence about the risks and benefits of administering tocolysis after PPROM, however, is lacking. In theory, reducing uterine contractility could delay delivery and reduce the risks of prematurity and its adverse short- and long-term consequences, but it might also prolong fetal exposure to inflammation, infection, and acute obstetric complications, potentially associated with neonatal death or long-term sequelae. The primary objective of this study is to assess whether short-term (48 h) tocolysis reduces perinatal mortality/morbidity in PPROM at 22 to 33 completed weeks of gestation.MethodsA randomized, double-blind, placebo-controlled, superiority trial will be performed in 29 French maternity units. Women with PPROM between 220/7 and 336/7 weeks of gestation, a singleton pregnancy, and no condition contraindicating expectant management will be randomized to receive a 48-hour oral treatment by either nifedipine or placebo (1:1 ratio). The primary outcome will be the occurrence of perinatal mortality/morbidity, a composite outcome including fetal death, neonatal death, or severe neonatal morbidity before discharge. If we assume an alpha-risk of 0.05 and beta-risk of 0.20 (i.e., a statistical power of 80%), 702 women (351 per arm) are required to show a reduction of the primary endpoint from 35% (placebo group) to 25% (nifedipine group). We plan to increase the required number of subjects by 20%, to replace any patients who leave the study early. The total number of subjects required is thus 850. Data will be analyzed by the intention-to-treat principle.DiscussionThis trial will inform practices and policies worldwide. Optimized prenatal management to improve the prognosis of infants born preterm could benefit about 50,000 women in the European Union and 40,000 in the United States each year.Trial registrationClinicalTrials.gov identifier: NCT03976063 (registration date June 5, 2019).
Highlights
Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births
Rationale Epidemiology of PPROM and neonatal consequences Preterm prelabor rupture of membranes (PPROM) is defined as spontaneous rupture of the fetal membranes occurring before the onset of labor and before 37 weeks of gestation [1, 2]
Despite the rupture of membranes, pregnancy can be prolonged by a latency period ranging from a few hours to several weeks
Summary
Preterm prelabor rupture of membranes (PPROM) before 34 weeks of gestation complicates 1% of pregnancies and accounts for one-third of preterm births. PPROM is a complex and multifactorial pathology, resulting from the progressive weakening of the membranes under the effect of chemical, mechanical, and/or infectious factors [3]. The infant’s prognosis depends mainly on gestational age at birth [13,14,15], fetal exposure to inflammation, infection, and acute obstetric complications (placental abruption, umbilical cord compression or prolapse) can increase short- and long-term mortality/morbidity [16,17,18]. In cases of PPROM, medical teams must weigh the benefits of prolonging pregnancy to reduce prematurity-related adverse consequences against those of inducing delivery to shorten exposure to intrauterine inflammation, infection, and acute obstetric complications
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