Sensitive periods for prenatal alcohol exposure shape internalizing symptoms across development

Importance Prenatal alcohol exposure (PAE) is associated with lasting cognitive and neurodevelopmental deficits and can quadruple risk for depression later in life. However, it remains unknown whether there are specific trimesters when PAE is more strongly associated with longitudinal trajectories of internalizing symptoms - an indicator of depression risk - across childhood and adolescence. Objective To investigate how PAE timing and dosage are associated with internalizing symptom trajectories from ages 4 to 16.5 years. Design, Setting and Participants We analyzed prospective data from the Avon Longitudinal Study of Parents and Children (ALSPAC), an ongoing longitudinal birth cohort from the United Kingdom. Internalizing symptom trajectories were estimated for 6,409 participants. Primary analyses were conducted on 2,254 participants with complete data on PAE in all three trimesters, covariates, and trajectories. Main Outcomes and Measures We used growth mixture modelling to identify latent trajectories of depressive symptoms measured using the internalizing symptom scale from the Strengths and Difficulties Questionnaire (SDQ) at seven occasions between ages 4 to 16.5 years. Prospective alcohol consumption during each trimester were categorized into three PAE dosages: unexposed (0 drinks/week), low (1-7 drinks/week) and high (7+ drinks/week). Results We identified five distinct depressive symptom trajectories: stable low (75.9% of participants), moderate childhood peak (11.2%), progressive increase (5.57%), high early childhood (4.73%), and early adolescent peak (2.61%). PAE in the second (relative risk [RR]=2.08, 95% CI=1.15-3.76) and third trimesters (RR=1.83, 95% CI=1.05-3.21), as well as total PAE burden across pregnancy (RR=1.33, 95% CI=1.06-1.68) increased risk for the progressive increase trajectory, versus the stable low trajectory. High PAE in the second (RR=2.71, 95% CI=1.41-5.21) and third (RR=2.27, 95% CI=1.27-4.05) trimesters drove elevated risk for this trajectory. PAE in the first trimester or at low dosages showed no associations with depressive symptom trajectories. Negative control analyses of paternal drinking also found no associations. Conclusions and Relevance Our results highlight the second and third trimesters as potential sensitive periods for the impact of PAE on rising depressive symptoms from childhood to adolescence. Ultimately, these findings could inform the design of prevention programs, and facilitate targeted interventions to youth at elevated risk for depression.