Gestational Age and Cognitive Development in Childhood

Abstract

Importance: Preterm and early-term births are known risk factors for cognitive impairment, but studies that comprehensively include genetics, prenatal risk, and child-specific factors in high-risk populations are lacking.

Objective: To investigate the long-term cognitive outcomes of children born at various gestational ages, including very preterm (28-31 weeks), moderately preterm (32-33 weeks), late preterm (34-36 weeks), and early term (37-38 weeks), compared with full-term (≥39 weeks), accounting for genetics and other risk factors.

Design, setting, and participants: In this prospective, multicenter, longitudinal cross-sectional study, children aged 9 to 10 years were recruited from the Adolescent Brain and Cognitive Development Study between January 1, 2016, and December 31, 2018. Children underwent cognitive assessments using the National Institutes of Health Toolbox, Little Man Task, and Rey Auditory Verbal Learning Test. Polygenic scores for cognitive performance (cogPGS) were generated using results of a genome-wide association study from the genetic variants related to cognitive performance, educational attainment, and mathematical ability. Data analysis was performed from March to June 2024.

Exposure: Preterm (very preterm, moderately preterm, late preterm) and early-term birth status, with full-term birth status as the reference group.

Main outcomes and measures: The primary outcome of interest was the composite cognitive score, while secondary outcomes included individual cognitive domain scores. Hierarchical regression models were used to examine associations between gestational age and cognitive outcomes, adjusting for socioeconomic status (SES), cogPGS, prenatal risks, and child-specific factors.

Results: Among 5946 children included in the study (mean [SD] age, 9.9 [0.6] years; 3083 [51.8%] male), 55 (0.9%) were born very preterm, 110 (1.8%) were born moderately preterm, 454 (7.6%) were born late preterm, 261 (4.4%) were born early term, and 5066 (85.2%) were born full term. The cogPGS was positively associated with the composite cognitive score (β = 0.14; 95% CI, 0.12-0.17; P < .001) in the overall cohort. Compared with full-term children, those born moderately preterm had lower composite cognitive scores (β = -0.39; 95% CI, -0.55 to -0.22; P < .001) and lower scores in vocabulary (β = -0.36; 95% CI, -0.53 to -0.19; P < .001), working memory (β = -0.27; 95% CI, -0.45 to -0.09; P = .003), episodic memory (β = -0.32; 95% CI, -0.50 to -0.14; P < .001), and both short-delay recall (β = -0.36; 95% CI, -0.54 to -0.18; P < .001) and long-delay recall (β = -0.29; 95% CI, -0.48 to -0.11; P = .002). These associations were independent of SES, cogPGS, and other risk factors. Importantly, the lowest cognitive scores appeared among children born at 32 weeks or less. In contrast, late-preterm and early-term children performed similarly to full-term peers.

Conclusions and relevance: In this cross-sectional study of children aged 9 to 10 years, moderately preterm birth was associated with long-term cognitive problems independent of SES, genetics, and other risk factors. These findings underscore the need for continued follow-up of all preterm children, with particular focus on those born before 34 weeks' gestational age, because they may face greater developmental challenges over time.

Figure 1.. Principal Component Analysis

A, The scree plot represents the proportion of variance accounted for by each principal component. B, The heat map displays the loadings for the first 10 principal components identified from the cognitive measures of 5946 children. In this context, red indicates a positive loading, meaning that higher values in the cognitive measures contribute positively to that principal component, whereas blue indicates a negative loading, suggesting that higher values in the cognitive measures are associated with lower contributions to that component.

Figure 2.. Correlation Analysis

A, Correlation matrix showing associations between each independent and dependent variable of interest. B, Association between preterm birth and early-term (ET) birth on composite cognitive scores at 9 to 10 years of age. C, Effect estimates of MPT birth and composite cognitive scores, adjusted for all covariates (model 3). D, Comparative box plot of adjusted composite cognitive scores by weeks of gestational age at 9 to 10 years of age. The model was adjusted for age, sex, socioeconomic status (SES), and polygenic scores for cognitive performance (cogPGS). Maternal dimension 1 and maternal dimension 2 represent the first 2 dimensions derived from the multiple correspondence analysis of maternal characteristics. The ends of the boxes represent the 25th and 75th percentiles; horizontal lines inside the boxes, medians; whiskers, the upper and lower adjacent values; and dots, points that fall beyond the whiskers. Error bars indicate 95% CIs. LPT indicates late preterm; MPT, moderately preterm; VPT, very preterm. ^aP < .001. ^bP < .05.