The effects of nifedipine and atosiban on perinatal brain injury: a secondary analysis of the APOSTEL III trial

Brain injury in prematurely born neonates is strongly associated with poor neurodevelopmental outcome. The aim of our study is to evaluate if nifedipine reduces overall brain injury compared to atosiban in women with threatened preterm birth. We performed a secondary analysis of the APOSTEL III-trial (Dutch Clinical Trial Registry, number NTR2947). This was a randomized clinical trial that allocated women with threatened preterm labor between 25-34 weeks of gestation to nifedipine or atosiban. For this secondary analysis, we included women delivering at ≤ 32 weeks of gestational age in the two main contributing centers. The primary outcome was the presence of brain injury. Brain injury was defined as the existence of abnormalities on ultrasound investigation, it was divided into mild and severe brain injury. To evaluate type and severity of brain injury, all neonatal ultrasounds made during neonatal intensive care admission and medium care admission were analyzed. A sensitivity analysis assessing differences in baseline or known risk factors for brain injury, was performed to test the robustness of our results. We studied 117 neonates, born from 102 women, of which 51 neonates had been exposed to nifedipine and 66 to atosiban. Brain injury was observed in 22 neonates (43.1%) in the nifedipine group and in 37 (56.1%) neonates in the atosiban (OR 0.60; 95% CI: 0.29-1.24). Mild brain injury was comparable between nifedipine (33.3%) and atosiban (48.5%, OR 0.53; 95% CI 0.25-1.13). Severe brain injury was also comparable between the groups, 9.8% for nifedipine and 7.6% for atosiban (OR 1.33; 95% CI 0.36-4.85). Intraventricular hemorrhage (≥ grade I) was most frequently seen; 18 neonates (35.3%) in the nifedipine group versus 25 neonates (37.9%) in the atosiban group (OR 0.90; 95% CI 0.42-1.91). The sensitivity analysis, with adjustment for maternal age and gestational age at randomization, showed no statistical difference of brain injury (OR 0.58; 95% CI 0.27-1.27). In children born before 32 weeks after the use of tocolytics, the prevalence of brain injury was high. No significant differences were found between nifedipine and atosiban in terms of overall brain injury. However, as this study was a secondary analysis of the APOSTEL III trial, it was underpowered for brain injury, as the latter was not the primary outcome of APOSTEL III