ABSTRACT: Preterm birth is the most common cause of neonatal morbidity and mortality worldwide and is associated with long-term burdens. The effectiveness of maintenance tocolysis on pregnancy and perinatal outcomes has not been demonstrated. This multicenter, double-blind, placebo-controlled trial was designed to evaluate the effectiveness of maintenance tocolysis with nifedipine on perinatal outcome.
Eligible women had threatened preterm labor at 26 to 32 weeks’ gestation and had not delivered after a 48-hour course of tocolytics and corticosteroids. Study medication was 20 mg nifedipine slow-release tablets every 6 hours, for a total daily dose of 80 mg nifedipine, or placebo. The medication was given 48 to 72 h after the start of initial tocolysis and was phased out from day 10 until day 12 and discontinued on day 13. The primary outcome was a composite of adverse perinatal outcomes due to premature birth. Secondary outcomes were gestational age at delivery, birth weight, days using ventilation support, length of stay in neonatal intensive care unit, and total days in hospital until 3-month corrected age. Exploratory analyses examined prolongation of pregnancy, maternal mortality, maternal blood loss, and infant respiratory distress syndrome.
Of 636 eligible women, 406 agreed to participate; 201 received nifedipine, and 205 received placebo. Mean gestational age at randomization was 29.2 weeks for both groups. Adverse perinatal outcomes occurred in 24 cases (11.9%) in the nifedipine group and 28 (13.7%) in the placebo group; perinatal death occurred in 5 (2.5%) and 4 cases (2.0%), respectively. Rates of chronic lung disease, proven neonatal sepsis, intraventricular hemorrhage greater than grade 2, periventricular leukomalacia greater than grade 1, and necrotizing enterocolitis were comparable in the 2 groups. Mean gestational ages at delivery were 34.1 and 34.2 weeks for the nifedipine and placebo groups, respectively. Birth weights did not differ significantly between the 2 groups. Neonatal intensive care unit admission occurred in 100 (40.8%) of 245 neonates in the nifedipine group and in 102 of 257 (39.7%) in the placebo group; neonatal intensive care unit and hospital stays were 10 and 23 days for both groups. The nifedipine and placebo infants required ventilation support for 2 and 3 days, respectively. Women in the 2 groups randomized at different gestational ages had no differences in perinatal mortality, composite adverse perinatal outcome, gestational age at delivery, or birth weight. Delivery before 32 weeks’ gestation occurred in 66 women (32.8%) given nifedipine and 71 women (34.6%) receiving placebo. Infant respiratory distress syndrome treated with surfactant occurred in 12 pregnancies (6.0%) in the nifedipine group and 14 (6.8%) in the placebo group. No mother in either group died. Cesarean deliveries were performed in 26.4% of women given nifedipine and 27.3% of those given placebo. Severe blood loss of more than 1000 mL occurred 11.1% and 7.3% in the nifedipine and placebo groups, respectively.
Compared with placebo, nifedipine maintenance tocolysis for 12 days did not significantly reduce adverse perinatal outcomes. The etiology of preterm labor is multifaceted such that future research should investigate therapies targeted to the specific underlying causes of preterm labor.
Department of Obstetrics and Gynecology (C.R., M.E.A.S., F.K.L.), Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands; Department of Epidemiology (E.S.), Julius Center for Health Sciences and Primary Care, Utrecht, the Netherlands; Department of Obstetrics and Gynecology (A.K., M.A.O.), University Medical Center Utrecht, Utrecht, the Netherlands; Department of Obstetrics and Gynecology (K.W.M.B., S.A.S.), Leiden University Medical Center, Leiden, the Netherlands; Department of Obstetrics and Gynecology (A.C.B., C.J.d.G.), VU University Medical Center, Amsterdam, the Netherlands; Department of Obstetrics and Gynecology (J.C., J.J.J.D.), Erasmus Medical Center, Rotterdam, the Netherlands; Department of Obstetrics and Gynecology (J.v.E., B.N.B.), Isala Clinics, Zwolle, the Netherlands; Department of Obstetrics and Gynecology (M.T.M.F., M.G.v.P., K.M.S.), University Medical Center, Groningen, the Netherlands; Departments of Neonatology (J.H.K.), Obstetrics and Gynecology (S.M.C.V., B.W.J.M., J.A.M.v.d.P.), and Clinical Research Unit (B.C.O.), Academic Medical Center, Amsterdam, the Netherlands; Department of Obstetrics and Gynecology (A.M., M.M.P.), Maxima Medical Center, Veldhoven, the Netherlands; Department of Obstetrics and Gynecology (D.N.M.P.), Amphia Hospital, Breda, the Netherlands; and Department of Obstetrics and Gynecology (H.C.J.S., C.W.), Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, Maastricht, the Netherlands