A Prospective Study Examining the Role of Gestational SSRI Exposure in the Development of Functional Gastrointestinal Disorders

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Abstract Functional gastrointestinal disorders (FGIDs) are common, costly, and cause significant impairment that can begin in infancy. FGIDs remain poorly understood, and treatment are often ineffective, prompting a recent NIDDK workshop to conclude an urgent need for improved understanding and management paradigms. In this proposal, we test the hypothesis that serotonin reuptake inhibitor (SSRI) antidepressant exposure in pregnancy is a major contributor to FGIDs in children. This is based on the premise that SSRIs, when used by women in pregnancy, alter the fetal availability of serotonin (5-HT), which is critical for healthy nervous system development in both the brain and the gut. There are significant public health implications, as SSRI use in pregnancy is continually increasing and it is estimated that upwards of 350,000 newborns per year were exposed to an SSRI during gestation. Most of the studies to date on the long-term effects of SSRI exposures have focused on offspring brain development. In contrast, studies on the effects of maternal SSRI exposure on gut development are lacking. However, our group has compelling evidence, through both published studies and new preliminary data, suggesting associations between SSRI exposure and FGID risk, which are independent of exposure to maternal depression. We have also identified a specific microbiome profile (enterotype) that is highly linked to FGIDs, and which our preliminary results suggest, may be transferred from mother to infant where it continues to drive elevated 5-HT signaling. Thus, SSRI exposure could increase offspring FGID risk, and this risk could be mediated by microbiome changes in the mother and child. We will investigate these questions by building on an ongoing birth cohort study of 375 mother-infant dyads (“The MYRNA Study”; controls, maternal depression +/- SSRI exposure) being followed through pregnancy and the first two years of life. Our new study, which we term, “Gestational SSRI Exposures in the DevelopmenT of Functional GAStrointestinal Disorders (GETGAS)”, will leverage MYRNA infrastructure and population, while adding extensive characterization of FGID diagnoses and symptoms, and analyzing stool samples (mother in pregnancy, and infant at birth, 1 yr and 2 yr) to test the role of microbiota-driven 5-HT signaling pathways. We will do this through three specific aims: Aim 1: Confirm effects of gestational SSRI exposure on infant FGID development trajectories in the first two years. Aim 2: Test whether maternal SSRI use during pregnancy promotes a 5-HT producing microbiome that is vertically transferred to the offspring where it increases FGID risk. Aim 3: Use data driven methods to identify clusters of maternal and infant factors most predictive of FGIDs in early life. Findings from this innovative and cost-effective proposal will help disambiguate the effects of PMD, SSRI exposure, and transmission of maternal microbiota on the development of FGIDs in early life, inform clinical management of FGIDs, and provide a foundation for biomarker and therapeutic target discovery.