Prenatal Nifedipine Exposure Linked to Poorer School Performance at 12 years of age: APOSTEL 2 Trial

A commonly used first-line tocolytic agent is nifedipine, a calcium channel blocker. Nifedipine is prescribed off-label in pregnancy. During the design of the APOSTEL 2 trial (Assessment of Perinatal Outcome with Sustained Tocolysis in Early Labour) in 2010, maintenance tocolysis beyond 48 h was still widely practised under the assumption that further prolonging pregnancy improved neonatal outcomes. In the APOSTEL 2 trial, women with threatened preterm birth between 26+0 and 32+2 weeks of gestation who remained pregnant after initial 48-h tocolysis were randomised to maintenance tocolysis with nifedipine or placebo for up to 12 days. No benefit was observed on perinatal outcomes. Also, in an individual participant data meta-analysis including six randomised controlled trials, maintenance tocolysis was not associated with improved perinatal outcomes. In the 2- year follow-up study of the APOSTEL 2 trial, children in the nifedipine group showed more fine motor problems compared to placebo, but fewer poor problem-solving skills. Among those with ruptured membranes, gross motor issues and developmental delays were more frequent in the nifedipine group. These findings stress the importance of evaluating long-term outcomes. However, only 34% of children participated, and their mothers more often had higher levels of education. Therefore, findings may be subject to selection bias.

Therefore, the aim of the current study is to assess school performance at 12 years of age in children from the APOSTEL 2 study, comparing those exposed to maintenance tocolysis with nifedipine to those exposed only to initial tocolysis and placebo.

Of 492 eligible children, 357 were included (follow-up rate 73%). In the nifedipine group, significantly fewer children received a high track recommendation for secondary school, 67/189 (35.4%), compared to 74/168 (44.0%) in the placebo group (adjusted risk ratio (aRR) 0.76; 95% confidence interval (CI) 0.61–0.95). Outcomes were significantly poorer in children with the longest nifedipine exposure (9–14days) compared to those not exposed (aRR 0.58; 95% CI 0.41–0.83).

In this registry-based long-term follow-up study of the randomised controlled APOSTEL 2 trial, authors found that children's school performance at 12 years of age was significantly poorer following maintenance tocolysis with nifedipine compared to placebo, as significantly fewer children in the nifedipine group received a high track recommendation for secondary school. Results were consistent when track recommendation was based solely on the teachers' assessment or on the standardised school performance test result. They accounted for important factors known to influence a child's educational outcomes, including a low SES, maternal education and a child's biological sex. When correcting for other confounding factors (e.g., maternal age, ethnicity), outcomes were similar. Study findings suggest that maintenance tocolysis with nifedipine for threatened preterm birth between 26+0 and 32+2 weeks of gestation negatively affects a child's development, as reflected by poorer school performance at 12 years of age.

Although maintenance tocolysis is not supported by the majority of guidelines, international surveys demonstrate considerable discrepancies regarding clinical practice on tocolytic treatmentand evidence-based guidelines recommendations. Both the initial results of the APOSTEL 2 study and those of the current 12 year follow-up study do not support the use of nifedipine for maintenance tocolysis. Unexpected long-term neurodevelopmental effects may be present, and further follow-up is needed to evaluate child outcomes after maintenance tocolysis with nifedipine. In conclusion, authors observed that children prenatally exposed to maintenance tocolysis with nifedipine had significantly poorer school performance at 12 years of age compared to placebo.

Source: Larissa I. van der Windt, Jim A. L. Meliezer, Eva Pajkrt;

BJOG: An International Journal of Obstetrics & Gynaecology, 2025; 0:1–11 https://doi.org/10.1111/1471-0528.70030