Gestational Antidepressant Exposure and Pediatric Disorders of Motility and Gut-Brain Interaction

About This Grant

ABSTRACT Gastrointestinal motility disorders in childhood include rare but life-threatening conditions of Hirschsprung's disease and pediatric intestinal pseudo-obstruction and common conditions termed disorders of gut-brain interaction, including irritable bowel syndrome, functional abdominal pain, constipation, and dyspepsia. These conditions create a substantial burden through chronic health issues and lower quality of life. Hirschsprung and pediatric intestinal pseudo-obstruction are well-understood to be due to abnormalities in the enteric nervous system (ENS), which controls motility, secretion, absorption, and blood flow. Mounting evidence suggests that unrecognized abnormalities in ENS and nervous system development may also predispose to disorders of gut- brain interaction. It follows that disruption of fetal development of the ENS could result in a range of motility disorders and identification of potential disruptors could lead to novel opportunities for prevention. The objective of this proposal is to determine whether antidepressant exposure in pregnancy increases the risk of various pediatric gastrointestinal motility disorders and disorders of gut-brain interaction. We hypothesize that modulation of serotonin, norepinephrine, and dopamine through antidepressant exposure during fetal development, essential for development of the ENS and for maintaining daily functioning of the GI tract, will have long-term effects on ENS function. Animal data has demonstrated this potential, but limited human data exist. To fill this substantial gap in knowledge, we will assess the association between antidepressant use in pregnancy and pediatric motility and disorders of gut-brain interaction using three large healthcare utilization databases in the US and the UK. Specifically, we will estimate the association between in utero exposure to antidepressants and life-threatening GI motility disorders (Aim 1), and common disorders of gut-brain interaction (Aim 2). In both aims, associations of each antidepressant class and individual medications will be explore, as well as gestational timing of exposure. Multiple sources of confounding by indication, familial susceptibility, and environment will be addressed using propensity score methods and through design techniques, including use of various comparator groups, sibling comparisons, and negative control exposures. Acknowledging the complex etiology of disorders of gut-brain interaction, Aims 2.1-2.3 will assess whether various early life stressors (neonatal factors, childhood mental health, and maternal mental health in childhood) are causal mediators or modifiers of the association between antidepressant exposure and disorders of gut- brain interaction. These sub-aims will provide critical insight into causal pathways and interventions. This work will produce generalizable and actionable results that will lead to improvements in preventing these debilitating pediatric GI conditions.