Developmental Origins of Health and Disease

Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are evaluated predominantly in adult, steady-state systems. This disconnect may contribute to unexplained variability in drug response and toxicity later in life. Pregnancy is accompanied by dynamic remodeling of the maternal gut microbiota and its metabolic output, generating bioactive microbial metabolites that regulate immune tone, metabolic homeostasis and the expression of drug-metabolizing enzymes and transporters. These microbial signals intersect with pharmacological interventions across gestation, shaping maternal pharmacokinetics, placental regulation and fetal drug exposure during developmentally sensitive windows. Importantly, microbiota-drug interactions initiated during pregnancy do not terminate at birth. Instead, they extend into infancy through vertical microbial transmission, breast milk-mediated metabolic signaling, and the immaturity of neonatal drug-handling systems, collectively contributing to developmental programming of drug responsiveness beyond early life. In this review, we propose a microbiota-informed framework that reframes perinatal drug exposure as a developmentally embedded signal operating across a maternal-placental-infant continuum. This perspective introduces a missing developmental dimension into drug discovery and highlights new opportunities to improve translational predictability and precision pharmacotherapy across the life course.

Decades of research on the developmental origins of health and disease highlight how prenatal and perinatal conditions are associated with long-term neurocognitive development. Exposures such as maternal stress, substance use, metabolic disorders, obstetric complications, low birthweight, and preterm birth have been linked to differences in brain, cognition, and mental health. Yet, most prior studies have been limited by small sample sizes, narrow exposure measures, or isolated outcomes. The Adolescent Brain Cognitive Development (ABCD) Study provides an unparalleled opportunity to overcome these limitations with nearly 12,000 children recruited at ages 9-10 across the United States, followed longitudinally with harmonized multimodal MRI, cognitive and behavioral testing, biospecimens, genetic data, and rich environmental measures in a diverse cohort. Retrospective caregiver reports provide key prenatal and perinatal information, which can be prospectively related to neurodevelopmental outcomes across adolescence. This review synthesizes findings from 111 ABCD-based studies published from 2017 to 2026. Results implicate maternal health conditions, substance use, birth outcomes, and cumulative adversity as being associated with variation in brain, cognitive, and behavioral development. Leveraging its size and diversity, ABCD has fostered advanced analytic approaches, such as multimodal integration of imaging and behavioral data, and longitudinal tracking of developmental trajectories, rarely possible elsewhere. While methodological challenges remain, including retrospective reporting and imaging site variability, ABCD offers unique opportunities to clarify pathways of vulnerability and resilience within an observational framework. Insights from this work can inform public health strategies and guide policies to reduce prenatal risks and strengthening early-life environments to optimize developmental outcomes.

ImportanceDevelopmental delay affects daily living, social functioning, and mental health. Maternal cardiovascular health (CVH) during pregnancy may indicate an adverse intrauterine environment, but its association with developmental delay is unclear.ObjectiveTo examine the association between maternal CVH during pregnancy and developmental delay in offspring at 4 years of age.Design, setting, and participantsThis cohort study enrolled patients between July 19, 2013, and March 31, 2017, with 5 years of follow-up, at obstetric hospitals and clinics in Miyagi Prefecture, Japan. Participants included eligible mother and offspring pairs enrolled in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Offspring were followed up until age 4 years. Data analyses were conducted from November 12, 2024, to March 24, 2026.ExposureMaternal CVH during pregnancy, which was assessed using Life's Essential 8 metrics (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure). Each metric was scored on a scale of 0 (least favorable) to 100 (most favorable), and these scores were used to categorize mothers as having high (80-100), moderate (50-79), or low (0-49) CVH.Main outcomes and measuresDevelopmental delay at age 4 years, which was evaluated by the mother using the validated Japanese version of Ages and Stages Questionnaire, Third Edition. This instrument has 5 domains: communication, gross motor, fine motor, problem solving, and personal-social skills. Domain-specific delay was defined as 2 or more SDs below the mean score, and developmental delay in total was defined as delay in 1 or more of the 5 domains.ResultsAmong 19 160 eligible mother and offspring pairs, 8238 (43.0%) were analyzed. Offspring were assessed at a mean (SD) age of 4.1 (0.2) years and included 4299 males (52.2%). Among mothers with high, moderate, and low CVH, 154 (8.8%), 763 (12.1%), and 33 (16.8%), respectively, had offspring with developmental delay in total. Compared with high CVH, moderate (risk ratio [RR], 1.30; 95% CI, 1.09-1.54) and low (RR, 1.62; 95% CI, 1.11-2.36) CVH during pregnancy were associated with developmental delay in total. Low CVH was associated with higher prevalence of developmental delay across all 5 domains, with personal-social domain having the largest effect size (RR, 2.23; 95% CI, 1.23-4.07; P for trend = .002) and communication domain having the smallest effect size (RR, 1.40; 95% CI, 0.69-2.85; P for trend = .03).Conclusions and relevanceIn this cohort study of mother and offspring pairs in Japan, better maternal CVH during pregnancy was associated with a lower risk of offspring developmental delay at age 4 years.