Background: Selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed antidepressants in pregnancy. Most clinical studies to date have examined brain and behavioral outcomes of SSRI exposures, despite animal studies showing that gestational SSRI exposure also increases risk for abnormalities in enteric nervous system development and dysfunction in GI motility. Whether SSRI exposure may increase the risk of Disorders of Gut-Brain Interaction (DGBIs) through childhood and adolescence is not clearly understood.
Objectives: To investigate the association between prenatal exposure to SSRIs and the risk of childhood DGBIs
Methods: Using Danish nationwide registers, we included 1,135,556 liveborn singletons from 1997-2015, with follow-up until age 18 years, migration, death, date of outcome or December 31, 2018, whichever came first. Our primary exposure was maternal SSRI use during pregnancy. Main outcomes were a first diagnosis of DGBI, categorized into any DGBI, functional nausea and vomiting disorders, functional abdominal pain disorders, and functional defecation disorders. Hazard ratios (HR) were estimated using Cox regression with propensity score weighting to adjust for potential confounders. We further applied multiple sensitivity analyses to test robustness of results including SSRI discontinuer comparison, exposure restriction to mothers who redeemed ≥2 SSRI prescriptions during pregnancy and inclusion of paternal SSRI use as a negative control exposure.
Results: In total, 21,969 children were exposed to SSRIs during pregnancy (1.9%) After adjustment for potential confounders, prenatal exposure to SSRIs was associated with an increased risk of any childhood DGBI (HR 1.19, [95% CI 1.10-1.29]) compared to non-exposure. The association was driven by functional defecation disorders (1.31, [1.18-1.44]), while no association was seen for functional nausea and vomiting disorders (1.08, [0.86-1.35]) or functional abdominal pain disorders (0.96, [0.83-1.11]). Restricting exposure to mothers with at least two prescriptions for an SSRI during pregnancy enhanced associations (HR 1.26, [1.17-1.36] for any DGBI), while using mothers who discontinued use of SSRIs prior to pregnancy as the control group, diminished HRs to 1.09 (1.02-1.16) for any DGBI. Paternal SSRI use in the absence of maternal use during pregnancy was, however, also associated with an increased HR for any DGBI of 1.14 (1.08-1.25).
Conclusions: In this population-based cohort study, we found prenatal SSRI exposure to be associated with an increased risk of childhood DGBIs, specifically functional defecation disorders. Associations seem mainly driven by family factors, however, the association warrants further research.
