Faculty Bibliography

Preclinical data suggest that gestational exposure to selective serotonin reuptake inhibitors (SSRI) alter gut innervation, and delays colonic motility. In this study we investigated associations between gestational SSRI exposure and offspring disorders of gut-brain interaction (DGBI). Using population-based registries, we included all single-birth Danish children born 1997-2015 with follow-up until outcome occurrence, age 15 years, death, emigration, or December 2018. Children to mothers who continued SSRIs during pregnancy and children to mothers who discontinued SSRI use before pregnancy were compared using Cox regression. Main outcomes were the first diagnosis of a childhood DGBI (functional nausea and vomiting, functional abdominal pain disorders, functional diarrhea, and functional constipation), or a physician-prescribed laxative. Among 1,158,560 children, 21,969 children (1.9%) were exposed to SSRIs prenatally and 30,174 children (2.6%) were born to mothers who discontinued SSRIs before pregnancy. Overall, the estimated 15-year cumulative incidence of any DGBI was 15.5% (95% CI, 14.9-16.2) in the SSRI-exposed group and 14.7% (14.0-15.3) in the unexposed group. SSRI-exposed children had an overall increased risk of DGBIs (HR 1.08, [1.02-1.14]), which was driven by functional constipation (HR 1.19, [1.10-1.28]) rather than functional nausea and vomiting (HR 0.97, [0.83-1.13]) or functional abdominal pain disorders (HR 0.90, [0.81-1.00]). These data suggest that prenatal SSRI exposure is associated with an increased risk of developing functional constipation. These findings are also consistent with extensive preclinical data supporting key roles for serotonin in gut development and function. Together findings support the need for further investigation of the long-term impact of maternal depression and SSRI exposure on development of common gastrointestinal disorders.

BACKGROUND & AIMS/OBJECTIVE:Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although SSRIs are first line pharmacological treatments for these disorders, they may impart adverse effects including anxiety, anhedonia, dysmotility and, in children exposed in utero, an increased risk of cognitive, mood and gastrointestinal disorders. SSRIs act systemically to block SERT and enhance serotonergic signaling in the brain, intestinal epithelium and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development. METHODS:We utilized transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial SERT or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development. RESULTS:SERT ablation targeted to the intestinal epithelium promoted anxiolytic and anti-depressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms. CONCLUSION/CONCLUSIONS:These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation and suggest a new link in humans between in utero SSRI exposure and DGBI development.

OBJECTIVES/OBJECTIVE:Individuals with neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), often experience a higher prevalence of gastrointestinal (GI) symptoms but have complex medical and behavioral comorbidities that make diagnosis and treatment difficult. A multi-stakeholder conference was convened to (a) determine patient and family experiences related to GI symptoms in NDDs, (b) review the clinicians' and researchers' perspectives, and (c) determine actionable steps for future research. METHODS:The Consortium for Autism, Neurodevelopmental Disorders and Digestive Diseases (CANDID; www.candidgi.com) virtually over 2 days in 2022 and consisted of four key activities: (1) an electronic family survey to assess underlying NDDs and GI symptoms, (2) a session focused on family perspectives, (3) review current clinical care and research, and (4) discussion to identify key next steps. Survey results were obtained electronically via the REDCap platform, and descriptive statistics were generated. The sessions were recorded, and themes were identified. RESULTS:The pre-conference survey ran for ~2 months and 739 families provided responses, with 634 completing all items. 83% had a child with an NDD under age 18, and most patients were White (85%) and non-Hispanic (87%). Constipation (80%), gastrointestinal reflux disease (51%), and bloating (49%) were the most frequently reported symptoms. Families gave unstructured feedback that the measures used in the surveys were often difficult to answer for patients with NDDs or who were nonspeaking. Family and clinical/scientific sessions identified several common themes, including (1) the need for less invasive diagnostic modalities, (2) the need to validate or adapt existing diagnostic measures (e.g., the Rome IV criteria) and outcome assessments, and (3) the need for enhanced attention to parent and caregiver input in treatment plans. CONCLUSIONS:Those providing care to children with NDDs, especially those with communication and cognitive challenges, should be aware of the differing needs in this community and consider family perspectives in managing, treating, and measuring GI issues. Future research should focus on adapting or creating diagnostic and research measures for those with NDDs, developing new diagnostic methods to account for diversity in neurodevelopment and communication, and improving methods for family and caregiver engagement in the care of GI disorders.