The contraction inhibitor atosiban (Tractocile) was no better than placebo for neonatal outcomes in the context of threatened preterm birth, the investigators in the multicenter, randomized, placebo-controlled assessment of perinatal outcome after specific tocolysis in early labor (APOSTEL) 8 superiority trial reported in The Lancet.

“The most important result of our study, that tocolytic drugs do not improve neonatal outcome when administered above 30 weeks of gestation, was unexpected,” the study coauthor Larissa I. van der Windt, MD, an obstetrician and PhD candidate at Amsterdam University Medical Center in Amsterdam, the Netherlands, told Medscape Medical News. “The primary goal of tocolysis should not be prolongation of pregnancy but improvement of neonatal outcomes.” 

Study Details

Between December 2017 and July 2023, a total of 755 adult women at 26 Dutch, English, and Irish hospitals were randomized; 752 were included in the intention-to-treat analysis. The primary endpoint was a composite of adverse neonatal outcomes. These included perinatal mortality up to 28 days postpartum, which included bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotizing enterocolitis > Bell’s stage 1, retinopathy of prematurity > grade 2 or needing laser therapy, and culture-proven sepsis. 

The primary outcome occurred in 37/449 (8.2%) infants in the atosiban group and 40/435 (9.2%) in the placebo group (relative risk [RR] 0.90; 95% CI, 0.58-1.40). Three (0.7%) and four (0.9%) infants died in the two groups, respectively (RR, 0.73; 95% CI, 0.16- 3.23). All deaths were deemed unlikely to be related to the study drug, and maternal adverse events did not differ between groups. 

In the atosiban group, significantly more pregnancies were prolonged beyond 48 hours than in the placebo group (292/375, 78% vs 261/377, 69%; RR, 1.13; 95% CI, 1.03-1.23). There were 15 (4%) planned cesarean sections in the atosiban group vs 29 (8%) in the placebo group (RR, 0.52, 95% CI, 0.28-0.95). The overall cesarean section rate, however, was similar in both groups (RR, 0.90; 95% CI, 0.69-1.16). 

Other secondary neonatal and maternal outcomes did not significantly differ between groups. There were 17 serious adverse events in the atosiban group and 12 in the placebo group, again, not considered treatment related.

Although atosiban itself is not approved in the United States, tocolytic drugs have long been part of standard care, primarily based on studies investigating surrogate outcomes such as increasing gestational age and are often used off-label to prevent premature labor.

In the APOSTEL 3 trial, the tocolytics nifedipine and atosiban were equally effective in prolonging pregnancy, but nifedipine showed a nonsignificant twofold increase in neonatal mortality. 

“When we looked into the evidence for whether these drugs are actually associated with better neonatal outcomes, we found no study demonstrated a positive effect of tocolytic therapy,” van der Windt said. “We felt it was time to investigate these drugs with the proper primary outcome because tocolytic drugs should be given with the purpose of improving neonatal outcomes.” 

Van der Windt questioned the advisability of inhibiting contractions in the setting of preterm labor since most women affected go into preterm labor for reasons such as infection or placental problems. “In this setting, it might not be the best option to try to inhibit contractions.” In her opinion, further research should primarily focus on preventive therapies/interventions for preterm birth.

“We expect that it will take time for practitioners to adjust to this new perspective,” van der Windt said, adding that OB/GYN guideline committees should review their current recommendations on preterm labor and incorporate this new evidence into their guidelines.

She cautioned, however, that this trial only studied pregnancies with a gestational age > 30 weeks, and outcomes might be different earlier in pregnancy. “To investigate tocolytic drugs at lower gestational ages from 24 to 30 weeks would be a next logical step for research,” van der Windt said.

Commenting on the study but not involved in it, Perinatologist Cynthia Gyamfi-Bannerman, MD, MS, chair of Department of Obstetrics, Gynecology, and Reproductive Sciences at UC San Diego called the findings “very provocative” since they suggest no role for tocolysis with atosiban or similar oxytocin antagonists in the tertiary prevention of preterm birth.

“For the US audience, both because the drug is not available and because the FDA [US Food and drug Administration] did not approve it for this indication, the study results will not affect practice,” she told Medscape Medical News. “We have no available oxytocin antagonists in our armamentarium, but we do use two classes of drugs for tocolysis, which have been shown to be better than placebo in prolonging pregnancy, namely calcium-channel blockers such as nifedipine and cyclooxygenase inhibitors such as indomethacin.”

Gyamfi-Bannerman agreed that the study “leaves the window open for tocolysis with atosiban for pregnancies at earlier gestational ages not studied, namely < 30 weeks gestation…and for studies of tocolytics that focus on neonatal outcomes rather than the proxy of pregnancy prolongation.”

She questioned, however, whether researchers would be willing to randomize members of this vulnerable group to a placebo knowing that pregnancy is prolonged with current regimens.

This study was funded by ZonMw, the Dutch Organization for Health Research and Development. The authors declared no financial relationships that could be construed as conflicts of interest. Several authors reported unrelated ties to private-sector companies, and professional and research-funding bodies. Gyamfi-Bannerman had no competing interests to disclose. 

Diana Swift is an independent medical journalist based in Toronto, Ontario, Canada.