Key Points

Question Is tocolysis associated with an increased risk of neurodevelopmental disabilities in very preterm infants at 5.5 years?

Findings In this cohort study of 1055 mothers of 1320 children who experienced preterm labor and delivered at 24 to 31 weeks of gestation, the risk of overall neurodevelopmental disabilities at 5.5 years did not significantly differ with vs without antenatal exposure to tocolysis. Among infants exposed, there were no differences in outcomes associated with atosiban vs calcium channel blocker exposure.

Meaning In this study, in utero tocolytic exposure was not associated with increased or decreased risk of neurodevelopmental disabilities during early childhood.

Abstract

Importance Neurodevelopmental outcomes of very preterm children exposed to tocolytics are not well described.

Objective To investigate whether tocolysis administered after spontaneous preterm labor is associated with neurodevelopmental outcomes at 5.5 years and to assess whether the type of tocolytic drug is associated with neurodevelopmental outcomes among infants exposed.

Design, Setting, and Participants This prospective, national, population-based cohort study used data from the French Etude Épidémiologique sur les Petits Âges Gestationnels–2 cohort. Children who were alive and participated in an assessment at 5.5 years and whose mothers experienced spontaneous preterm labor without an infectious context and delivered at 24 to 31 weeks were eligible for this study. Recruitment occurred from March to December 2011. Follow-up at age 5.5 years was conducted from September 2016 to December 2017. Data analysis was performed from July 2023 through April 2024.

Exposures The primary analysis examined tocolytics (yes vs no), and the secondary analysis examined the type of tocolytic (atosiban vs calcium channel blockers [CCBs]).

Main Outcome and Measure The composite outcome neurodevelopmental disabilities included cerebral palsy; visual, hearing, and cognitive deficiencies; developmental coordination disorders; or behavioral problems.

Results A total of 1055 mothers (mean [SD] age, 29.2 [5.7] years) had preterm labor without fever and gave birth to 1320 children (704 male [weighted percentage, 53.3%; 95% CI, 50.6%-56.1%]; mean [SD] gestational age, 28.8 [2.0] weeks). Overall, 776 mothers (weighted percentage, 73.5%; 95% CI, 70.8%-76.2%) received tocolytics; 136 mothers (weighted percentage, 17.9%; 95% CI, 15.3%-20.8%) received only a CCB, and 295 mothers (weighted percentage, 37.6%; 95% CI, 34.2%-41.0%) received only atosiban. From modified Poisson regression with propensity score matching, the risk of overall neurodevelopmental disabilities (mild, moderate, or severe) at 5.5 years did not differ between preterm children exposed and not exposed to tocolytics (relative risk [RR], 1.11; 95% CI, 0.85-1.45; P = .44) or in preterm infants exposed to atosiban compared with those exposed to CCBs (RR, 0.94; 95% CI, 0.67-1.32; P = .71).

Conclusions and Relevance In this study, tocolytics were not associated with neurodevelopmental disabilities among very preterm children surviving at 5.5 years.

Introduction

Prematurity, defined as birth before 37 weeks of gestation, is a global public health burden due to its high prevalence, with 15 million premature births per year accounting for 11% of all births worldwide,1,2 and its consequences for morbidity and mortality. Preterm birth is the main cause of mortality in children younger than 5 years.3 Children born preterm may also face a higher risk of developmental challenges, including cerebral palsy, cognitive impairment, deafness, blindness, and autism spectrum disorders, as well as more subtle impairment, such as developmental coordination disorders, neurovisual dysfunctions, specific language and learning disorders, executive function impairment, attention-deficit/hyperactivity disorder, or behavioral problems.4,5 Overall, approximately 30% to 35% of very preterm children have mild disabilities by age 5.5 years.6-8 These findings emphasize the strong need to reduce premature birth incidence to prevent its detrimental consequences.

Tocolytics are used to prevent preterm birth through the induction of smooth muscle relaxation, which helps suppress uterine contractions.9 In delaying birth, these medications provide an opportunity for antenatal optimization. This entails administering corticosteroids for fetal lung maturation, magnesium sulfate for neuroprotection, and antibiotics for group B Streptococcus prevention and allowing time for the expectant individual to be transferred to a facility equipped with adequate neonatal care resources. This therapeutic approach is endorsed by international academic societies for its efficacity in managing cases of preterm labor.10 In France, the 2 main tocolytics drug classes used are calcium channel blockers (CCBs), such as nifedipine or nicardipine, and oxytocin receptor antagonists, such as atosiban.11 The safety of tocolysis for the fetal brain remains uncertain owing to insufficient data. Nifedipine has been associated with a redistribution of the fetal lamb circulation when administered to ewe,12 and fetal death has been reported in humans,13 albeit as a rare adverse effect. In contrast, nifedipine may provide some protection from glutamate toxicity in cortical neurons.14 Atosiban, as an antagonist of oxytocin, could prevent the release of oxytocin, which favors mother-infant interactions after birth and may compensate for potential deleterious effects of stress.15 Using data from the Etude Épidémiologique sur les Petits Âges Gestationnels–2 (EPIPAGE-2) cohort study, our team previously reported that the use of tocolytics was associated with reduced risk of neonatal death and severe intraventricular hemorrhage before hospital discharge for preterm infants born between 24 and 31 weeks of gestation after spontaneous labor.16 A 2022 meta-analysis11 of 122 trials concluded that the association between tocolytic use and neonatal outcomes was uncertain. Furthermore, few studies have evaluated the association between antenatal exposure to tocolytics and long-term neurodevelopment17-20,

We aimed to investigate whether tocolysis administered after spontaneous preterm labor was associated with neurodevelopmental disabilities at 5.5 years in children born very preterm overall. Additionally, we aimed to assess whether the tocolytic type (atosiban vs CCBs) was associated with neurodevelopmental disabilities among infants exposed.

Methods

Data Collection

This cohort study is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cohort analyses. EPIPAGE-2 is a prospective, national, population-based cohort of children born preterm (ie, at 22-34 weeks of gestation) in 2011 in 25 French regions (all French regions except 1).21 Recruitment was conducted over an 8-month period for births at 22 to 26 weeks’ gestation and a 6-month period for births at 27 to 31 weeks’ gestation. Among the 8400 children eligible at birth, 7804 newborns were included at baseline (participation rate: 93.0%). Of those, 5170 children were liveborn with parental consent. A comprehensive neurodevelopmental assessment was proposed to families of all 4441 children surviving at age 5.5 years.6 Parents completed a self-administrated questionnaire, and children had a clinical examination by a physician and a cognitive assessment by a neuropsychologist that were performed in dedicated examination centers. All professionals were trained to ensure homogeneity in data collection. At infant age 5.5 years, at least 1 assessment was performed for 3083 children (69.4%). Full details of the cohort recruitment and data collection were reported elsewhere.21,22