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

Abstract

ImportanceChildren born preterm are at increased risk of adverse neurodevelopmental outcomes and may be particularly vulnerable to the effects of gastric acid suppression during infancy.ObjectiveTo assess whether early acid suppressant use in infants born extremely preterm is associated with poorer neurodevelopmental outcomes.Design, Setting, and ParticipantsThe 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.ExposuresAcid suppressant use before 24 months of age was determined from medical records and from questionnaires administered to mothers.Main Outcomes and MeasuresNeurodevelopmental 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.ResultsOf 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 RelevanceThe 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.

Microbiome and its impact on fetal and neonatal brain development: current opinion in pediatrics

“…In an observational study – with inherent limitations and therefore not proving causation – we observed that prolonged empirical antibiotic treatment in preterm infants was associated with below-average gross-motor development at 24 MCA [ 46 ]. The avoidance of acid suppressants, known to alter gut microbiota, could therefore be beneficial for preserving neurocognitive outcomes, as a recent study showed the use of acid suppressants to be associated with adverse neurocognitive outcomes [ 47 ]. However, it was not confirmed that this effect was mediated by changes in gut microbiota.…”

Proton pump inhibitor therapy may alter the sensory motor characteristics of pharyngoesophageal motility in infants with suspected GERD

“…4 Potential consequences of PPI therapy include vitamin B12 deficiencies, hypomagnesemia, susceptibility to obesity and bone fractures in early childhood, asthma, rhinitis, infections (i.e., necrotizing enterocolitis, gastroenteritis, bacterial pneumonia), sepsis, rebound hyperacidity, and impaired neurodevelopment. [5][6][7][8][9][10][11] Regardless of guidelines, empiric PPI therapy or esophageal pH-metry are common approaches used in the management of GERD. The acid reflux index (ARI) or percent of time that the esophagus is exposed to acid is a common metric.…”

“…Currently, the absence of a gold standard test to diagnose GERD in infants leads to widely variable management strategies and over prescription of proton pump inhibitors (PPIs) with 56% of those treated remaining on acid suppressive therapy at discharge 4 . Potential consequences of PPI therapy include vitamin B12 deficiencies, hypomagnesemia, susceptibility to obesity and bone fractures in early childhood, asthma, rhinitis, infections (i.e., necrotizing enterocolitis, gastroenteritis, bacterial pneumonia), sepsis, rebound hyperacidity, and impaired neurodevelopment 5–11 . Regardless of guidelines, empiric PPI therapy or esophageal pH‐metry are common approaches used in the management of GERD.…”