The causal association between maternal mental illness and infection in pregnancy and neurodevelopmental disorders among 410,461 children- a population study using quasi-negative control cohorts and sibling analysis

Background To address if the long-standing association between maternal infection, depression/anxiety in pregnancy and offspring neurodevelopmental disorder (NDD) is causal we conducted two negative-control studies.

Methods Four primary care cohorts of UK children (pregnancy, 1 and 2 years prior to pregnancy and siblings) born between 1st January 1990 to 31st December 2017 were constructed.

NDD included autism/autism spectrum disorder, attention deficit/hyperactivity disorder, intellectual disability, cerebral palsy, and epilepsy. Maternal exposures included depression/anxiety and/or infection. Maternal (age, smoking status, comorbidities, BMI (Body Mass Index), NDD); child (gender, ethnicity, birth year); and area-level (region and level of deprivation) confounders were captured.

The NDD incidence rate among 1) children exposed during or outside of pregnancy and 2) siblings discordant for exposure in pregnancy was compared using Cox-regression models, unadjusted and adjusted for confounders.

Results The analysis included 410,461 children of 297,426 mothers and 2,793,018 person-years of follow-up with 8900 NDD cases (incidence rate=3.2 per 1000 person years). After adjustments, depression and anxiety consistently associated with NDD (pregnancy adjusted HR=1.58, 95%CI 1.46-1.72; 1-year adj.HR=1.49, 95%CI 1.39-1.60; 2-year adj.HR=1.62, 95%CI 1.50-1.74); and to a lesser extent, of infection (pregnancy adj. HR=1.16, 95%CI 1.10-1.22; 1-year adj.HR=1.20, 95%CI 1.14-1.27; 2-year adj.HR=1.19 95%CI 1.12-1.25). NDD risk did not differ among siblings discordant for pregnancy exposure to mental illness HR=0.97, 95%CI 0.77-1.21 or infection HR=0.99, 95%CI 0.90-1.08.

Conclusions Triangulation of results from two negative control studies provided no evidence of a specific, and therefore causal, link between in-utero exposure to infection, common mental illness, and later development of NDD.