Analysis of Neurodevelopment in Children Born Extremely Preterm Treated With Acid Suppressants Before Age 2 Years

JAMA Netw Open. 2022 Nov 1;5(11):e2241943. doi: 10.1001/jamanetworkopen.2022.41943.


Importance: Children born preterm are at increased risk of adverse neurodevelopmental outcomes and may be particularly vulnerable to the effects of gastric acid suppression during infancy.

Objective: To assess whether early acid suppressant use in infants born extremely preterm is associated with poorer neurodevelopmental outcomes.

Design, setting, and participants: The Extremely Low Gestational Age Newborn study was a multicenter, longitudinal cohort study of infants born before 28 weeks' gestational age between March 22, 2002, and August 31, 2004. The current analyses were performed from September 12, 2020, through September 22, 2022. Of the 1506 infants enrolled, 284 died before discharge and 22 died before 24 months of age. An additional 2 died before age 10 years, leaving 1198 (79.5%) eligible for a visit. Of these, 889 (74%) participated in the visit at age 10. At age 10 years, the association of early-life acid suppressant use with neurocognitive, neurodevelopmental, and psychiatric symptomatology was assessed.

Exposures: Acid suppressant use before 24 months of age was determined from medical records and from questionnaires administered to mothers.

Main outcomes and measures: Neurodevelopmental assessments at age 10 years included the School-Age Differential Ability Scales-II, the Developmental Neuropsychological Assessment-II, the Autism Diagnostic Observation Schedule-2, the Social Responsiveness Scale-2, and the Child Symptom Inventory-4 for attention-deficit/hyperactivity disorder (ADHD), depression, and anxiety.

Results: Of the 889 participants assessed at age 10 years (mean [SD] age, 9.97 [0.67] years; mean [SD] gestational age at birth, 26.1 [1.3] weeks; 455 [51.2%] male), 368 (41.4%) had received acid suppressants by 24 months of age. Associations were observed between acid suppressant use and decreased full-scale IQ z score (adjusted β, -0.29; 95% CI, -0.45 to -0.12), verbal IQ z score (adjusted β, -0.34; 95% CI, -0.52 to -0.15), nonverbal IQ z score (adjusted β, -0.22; 95% CI to -0.39 to -0.05), working memory z score (adjusted β, -0.26; 95% CI to -0.45, -0.08), autism spectrum disorder (adjusted relative risk, 1.84; 95% CI, 1.15-2.95), and epilepsy (adjusted relative risk, 2.07; 95% CI, 1.31 to 3.35). Results were robust to multiple sensitivity analyses. Use of acid suppressants was not associated with inhibitory control, ADHD, anxiety, or depression.

Conclusions and relevance: The results of this cohort study suggest that early-life use of acid suppressants in extremely preterm infants may be associated with poorer neurodevelopmental outcomes and add to evidence indicating caution in use of these agents.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Autism Spectrum Disorder* / drug therapy
  • Autism Spectrum Disorder* / epidemiology
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Gestational Age
  • Humans
  • Infant
  • Infant, Extremely Premature*
  • Infant, Newborn
  • Longitudinal Studies
  • Male