Prenatal exposure to maternal depression and antidepressants and neurodevelopmental outcomes: A population cohort study

Background The long-term effects of antidepressant use in pregnancy on child neurodevelopment are unclear; meanwhile antidepressant use in pregnancy is increasing. We aimed to clarify associations between prenatal maternal depression and/or antidepressant exposure and neurodevelopmental outcomes in school-age children. Methods and findings This population-wide cohort study included 167,447 children born in Wales, UK between 2009 and 2016, followed until 2022 (mean age 5.68 years) using linked primary care, maternity and education records. Exposures were one or more antidepressant prescriptions during pregnancy or up to one month before conception, and/or maternal depression diagnosis recorded in the two years before delivery. Outcomes were all-cause and cause-specific special educational need (SEN), including autism spectrum disorder (ASD), sensory impairment, communication difficulties, learning difficulties, physical and medical difficulties, and behavioral-emotional-social difficulties, as well as attention deficit hyperactivity disorder (ADHD). Generalized estimating equation models with an interaction term between maternal depression and antidepressant exposure were used to investigate SEN and causes of SEN. Predicted probabilities and marginal effects were derived to quantify absolute risk. Separate models were fitted for individual antidepressant classes and combinations. Cox proportional hazards regression and flexible parametric survival models were used for time to ADHD diagnosis. Covariates included child sex, area-level deprivation quintile, ethnicity, age, maternal age, smoking, parity, multiple birth and epilepsy. In total, 12,630 children (7.6%) were exposed to untreated depression during pregnancy; 7,005 (4.2%) to treated depression; and 5,996 (3.6%) to antidepressant medication without a recorded depression diagnosis. SEN was associated with both maternal depression (adjusted odds ratio (aOR) 1.25 (95% CI [1.20,1.31])) and antidepressant medication exposure (aOR 1.46 (95% CI [1.38,1.56])). Predicted probabilities of all-cause SEN were highest among children exposed to both maternal depression and antidepressants (26.5 per 100 children (95% CI [25.5,27.5])) and lowest among unexposed children (20.0 per 100 (95% CI [19.8,20.2])). Depression alone was associated with an increase to 23.6 per 100 children (95% CI [22.9,24.3]), while antidepressant exposure without depression was associated with an increase to 26.3 per 100 (95% CI [25.3,27.4]). Antidepressant exposure was associated with a 6.3% absolute increase in SEN risk (95% CI [5.2,7.4]) among children of mothers without depression and 2.9% absolute increase (95% CI [1.7,4.1]) among children of mothers with depression. Associations with antidepressant exposure were observed across multiple outcomes including ASD (aOR 1.59 (95% CI [1.31,1.92])) and ADHD (adjusted hazard ratio (aHR) 1.89 (95% CI [1.57,2.27])). No antidepressant class showed a markedly different association with SEN risk, although tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) had significant differences in absolute risk of SEN when comparing treated and untreated depression (TCAs 8.8% (95% CI [3.2,14.4]); SNRIs 8.8% (95% CI [2.6,15.0])). Key limitations include potential confounding by indication and depression severity, as women prescribed antidepressants likely represent a more severely depressed group. Conclusions Offspring of mothers with depression have a higher risk of SEN that cannot be attributed solely to antidepressant exposure. Prenatal exposure to antidepressants may confer a small additional absolute risk, but findings may partly represent confounding by depression severity. Further research is needed.