Placental histopathology and early childhood neurodevelopment in the Environmental influences on Child Health Outcomes cohort

Abstract

Background: Prenatal exposures influence childhood neurodevelopment. Placental histopathology has been associated with abnormal early childhood neurodevelopment, albeit often confounded by prematurity and/or fetal growth restriction. Most pregnant people, however, have term births, and some of these children have abnormal neurodevelopment despite the absence of adverse birth outcomes. Leveraging placental histopathology may help distinguish infants at a higher risk of subsequent neurodevelopmental impairment following a term birth.

Objective: To investigate the association of placental histopathology with a high-risk screen for abnormal early childhood neurodevelopment following a term birth.

Study design: The sample included singleton births at ≥37 weeks 0 days between 2020 and 2023 in the prospective, longitudinal multisite Environmental Influences on Child Health Outcomes cohort. Children with available placental histopathologic data and whose birthing parent had completed at least one Ages & Stages Questionnaire-Third Edition between 2 and 18 months of life were eligible for inclusion. Children diagnosed with hypoxic-ischemic encephalopathy after birth were excluded. Exposures were chronic placental inflammation, maternal or fetal acute inflammatory response, and maternal or fetal vascular perfusion. The primary outcome was a high-risk composite Ages & Stages Questionnaire-Third Edition screen, defined as a high-risk score (≥2 standard deviations below the mean) on at least one of the 5 individual domains (communication, gross motor, fine motor, personal-social, and problem-solving) on any Ages & Stages Questionnaire-Third Edition questionnaire performed between 2 and 18 months of life. Individual Ages & Stages Questionnaire-Third Edition domains were secondarily assessed. Generalized estimating equation models were used to calculate the odds of a high-risk screen for each outcome in children exposed vs unexposed to each placental histopathologic finding, adjusted for maternal age, education, insurance, depression, parity, child sex, and birthweight.

Results: At Environmental Influences on Child Health Outcomes sites performing placental collection and histopathologic evaluation, assessment of at least one Ages & Stages Questionnaire-Third Edition domain was performed in 7353 children aged 2 to 18 months during the study period. Of these, 486 (13%) were born at term and met additional eligibility criteria. Pregnant participants self-identified predominately as non-Hispanic White (57%), exceeded a high school education (78%), and were multiparous (70%). The frequency of each placental histopathologic exposure ranged from 16.5% to 59.5%, and the primary outcome of a high-risk composite Ages & Stages Questionnaire-Third Edition screen was present in 26% of children. In multivariable analyses, none of the placental exposures were associated with a high-risk composite Ages & Stages Questionnaire-Third Edition screen (adjusted odds ratio, 1.43; 95% confidence interval, 0.95-2.15) at 2 to 18 months. However, chronic placental inflammation was associated with high-risk communication (adjusted odds ratio, 2.84; 95% confidence interval, 1.09-7.40) and fine motor (adjusted odds ratio, 2.26; 95% confidence interval, 1.02-5.04) domain scores at 2 to 18 months and with a high-risk screen for the composite Ages & Stages Questionnaire-Third Edition score (adjusted odds ratio, 2.07; 95% confidence interval, 1.05-4.07) and gross motor domains (adjusted odds ratio, 3.89; 95% confidence interval, 1.25-12.10) at 12 to 18 months. In post-hoc sensitivity analyses, associations between chronic placental inflammation and high-risk Ages & Stages Questionnaire-Third Edition screens varied by child sex and were not present in individuals without obesity (body mass index <30 kg/m²).

Conclusion: After a term birth, placental histopathology was not associated with a high-risk composite Ages & Stages Questionnaire-Third Edition screen in children assessed at 2 to 18 months. However, chronic placental inflammation was positively associated with a high-risk composite score in children aged 12 to 18 months. This population may warrant enhanced surveillance, screening, and diagnostic follow-up for neurodevelopmental impairment in early childhood.

Keywords: histopathology; maternal-fetal interface; neurodevelopment; perinatal pathology; placenta.