Maintenance Tocolysis With Oral Micronized Progesterone for Prevention of Preterm Birth After Arrested Preterm Labor

Abstract

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. The accepted treatment of preterm labor is acute tocolysis, but whether maintenance tocolysis is appropriate after initial tocolysis for spontaneous preterm labor is uncertain. Progesterone has not been thoroughly investigated for use to maintain tocolysis. This double-blind, randomized, placebo-controlled trial was undertaken to evaluate the efficacy of maintenance therapy with oral micronized progesterone (OMP) for prolongation of pregnancy in parturients with arrested preterm labor. Women at 24 to 34 weeks’ gestation with a singleton pregnancy were recruited after successful tocolysis with nifedipine therapy. Preterm labor was defined as 4 contractions per 20 minutes or 8 contractions per 60 minutes associated with progressive cervical changes or dilation of greater than 1 cm or cervical effacement of 80% or greater. All women with threatened preterm labor received lactated Ringer solution, betamethasone, and tocolysis with nifedipine, which were continued until uterine contractions subsided for 12 hours or longer. After the arrest of preterm labor, patients were recruited within 48 hours and allocated to the OMP or the placebo group. At each weekly visit, the patients received envelopes containing a 7-day supply of capsules with 200 mg of OMP or placebo. They took the drug/placebo from recruitment to 37 weeks or delivery, whichever was earlier. The primary outcome was prolongation of pregnancy/latency period. Secondary outcomes were number of preterm births, birth weight, gestational age at delivery, readmission for preterm labor, neonatal intensive care unit admission and length of stay, as well as neonatal morbidity. Statistical analyses were performed with SPSS version 20; P < 0.05 indicated statistical significance. Each group had 45 women and was matched for age, parity, and presence of risk factors of preterm birth. The mean gestational ages at recruitment were 31.91 and 32.42 weeks in the OMP and placebo groups, respectively (P = 0.20). The mean (SD) latency period in the OMP group was 33.29 (22.16) days compared with 23.07 (15.42) days in the placebo group (P = 0.013). The group treated with OMP had significantly more undelivered women at each specific time point until delivery (P = 0.014; log-rank χ2 = 6.06). In the OMP group, 28 women (62%) delivered at 37 weeks or later, whereas a large proportion of women in the placebo group delivered at 34 to 36 weeks (17 [38%]; P = 0.01). The preterm birth rates in the OMP and placebo groups were 33% and 58%, respectively (P = 0.03). The mean (SD) birth weight was 2.44 (0.58) kg in the OMP group and 2.14 (0.47) kg in the placebo group neonates (P = 0.009). Most neonates in both groups were appropriate for gestational age, and no significant differences were seen in Apgar scores at birth or 5 minutes. Sixteen neonates (37%) in the OMP group had low birth weight compared with 27 (64%) in the placebo group (P = 0.017). No significant differences were found between the groups in neonatal intensive care unit admission or length of stay, respiratory distress syndrome, sepsis, or neonatal mortality. One neonate in the OMP group died of severe prematurity with respiratory distress syndrome; 1 neonate in the placebo group died of sepsis and pulmonary hemorrhage. Most parturients did not report any adverse effects. Symptoms of preterm labor recurred in 46 patients, who continued on the same medication. Maintenance tocolysis with OMP significantly prolonged pregnancy and decreased the number of preterm births, supporting its use as a maintenance tocolytic for prolongation of pregnancy in parturients with arrested preterm labor.