Neurodevelopmental outcomes at five years in children born very preterm (24-31 weeks) exposed to opioids with or without midazolam: results from the French nationwide EPIPAGE-2 cohort study

Elizabeth Walter-Nicolet; Laetitia Marchand-Martin; Andrei S Morgan; Monique Kaminski; Valérie Benhammou; Pierre-Yves Ancel; Pierre Tourneux; Véronique Pierrat; Xavier Durrmeyer

doi:10.1016/j.lanepe.2025.101242

Neurodevelopmental outcomes at five years in children born very preterm (24-31 weeks) exposed to opioids with or without midazolam: results from the French nationwide EPIPAGE-2 cohort study

Lancet Reg Health Eur. 2025 Feb 18:52:101242. doi: 10.1016/j.lanepe.2025.101242. eCollection 2025 May.

Authors

Elizabeth Walter-Nicolet^{1

2

3}, Laetitia Marchand-Martin¹, Andrei S Morgan^{1

4

5}, Monique Kaminski¹, Valérie Benhammou¹, Pierre-Yves Ancel¹, Pierre Tourneux^{6

7}, Véronique Pierrat^{1

8}, Xavier Durrmeyer^{1

8

9}

Affiliations

¹ University Paris-Cité, CRESS, Obstétrical Perinatal and Pediatric Epidemiology Research Team, EPOPé, INSERM, INRAE, Paris, France.
² Neonatal Intensive Care Unit, Saint Joseph Hospital, 185 rue Raymond Losserand, Paris 75014, France.
³ Gynecology-Obstetric Department, Max Fourestier Hospital, 403 Avenue de la république, Nanterre 92014, France.
⁴ Elizabeth Garrett Anderson Institute for Women's Health London, University College London, London, UK.
⁵ Department of Neonatology, National Maternity Hospital, Holles Street, Dublin, Ireland.
⁶ Neonatal and Paediatric Intensive Care Unit, University Hospital, Amiens, France.
⁷ PériTox - UMI 01, Medicine University, Picardie Jules Verne University, Amiens, France.
⁸ Neonatal Intensive Care Unit, Centre Hospitalier Intercommunal de Créteil, Créteil, France.
⁹ Université Paris Est Créteil, Faculté de Santé de Créteil, IMRB, GRC CARMAS, Créteil, France.

Abstract

Background: Data on preschool neurodevelopment of preterm infants according to the duration of their neonatal exposure to opioids with/without midazolam is limited. We aimed to assess neurodevelopment outcome in children aged five years, born very preterm (24-31 weeks), according to exposure to these drugs.

Methods: Secondary analysis from the French prospective cohort study EPIPAGE-2 (Etude Epidémiologique sur les Petits Ages Gestationnels, 2011). Exposure to opioids with/without midazolam was classified as none, ≤7 or >7 days. Percentages were weighted to account for the study design. The primary outcome was moderate/severe neurodevelopmental disabilities (NDD). Analyses were conducted using logistic regression and adjusted for perinatal confounders.

Findings: Among 3117 survivors, 1165 (35.9%) were exposed (762/1165 (68.0%) ≤7 days, 403/1165 (32.0%) >7 days). Of these 49.5% received opioids only, 41.4% opioids and midazolam, and 9.1% midazolam only. Moderate/severe NDD occurred in 17.8%, 18.9%, and 31.7% in the unexposed, exposed ≤7 days, and exposed >7 days groups, respectively. After adjustment for baseline confounders, only exposure >7 days was associated with increased rates of moderate/severe NDD (adjusted odds ratio 2.07; 95% CI 1.32-3.26). After additional adjustment for severe neonatal morbidities no significant association was found between any duration of exposure and NDD.

Interpretation: Exposure to opioids with/without midazolam >7 days might be associated with a higher prevalence of moderate/severe NDD at five years in very preterm born children but severe neonatal morbidities are a major modulator of this association.

Funding: French Institute of Public Health Research, National Institute of Health and Medical Research, National Institute of Cancer, National Solidarity Fund for Autonomy, PremUp, APICIL Foundations.

Keywords: Cumulative exposure; Five years neurodevelopment; Midazolam; Nationwide cohort study; Opioids; Very preterm neonates.