The Association Between Foetal Brain and Body Size Mid-Gestation and Neurodevelopmental Disorders in Childhood

Smallness for gestational age and reduced head circumference at birth are consistently associated with later neurodevelopmental disorders (NDD), but it is unclear whether similar associations are present at foetal biometry in mid-gestation.

To investigate associations between second-trimester foetal biometric measurements and later NDD.

We conducted a population-based cohort study using data from routine second-trimester ultrasound scans (gestational weeks 18-21) in Denmark. We included all singleton euploid live births from 2008 to 2015. Foetal biometrics included head circumference, biparietal diameter (BPD), abdominal circumference (AC), femur length, estimated foetal weight (EFW), and the head-abdomen ratio. NDD comprised cerebral palsy (CP), epilepsy, intellectual disability, and autism spectrum disorders (ASD). Children were followed from birth until diagnosis, death, emigration, or 31 December 2022. Associations were examined using multivariable Cox proportional hazards models, and cumulative incidence through age 10 years was estimated accounting for death as a competing risk. Adjusted mean differences in biometric Z-scores were examined using multivariable linear regression.

Among 337,028 children, 13,414 (4.0%; 69.7% males) were diagnosed with at least one NDD. Larger BPD was associated with higher hazards of epilepsy, intellectual disability, and ASD. Larger AC and EFW were associated with lower hazard of intellectual disabilities. Individuals with epilepsy, ASD, and intellectual disabilities had slightly larger mean BPD Z-score at their second-trimester scans, compared to children without NDD. Furthermore, smaller HC was associated with lower hazards and cumulative incidence of epilepsy, whereas shorter FL was associated with higher hazards of CP and epilepsy.

Mid-gestation head size did not follow the expected risk pattern. These findings propose a rethinking of the relationship between restricted brain growth and neurodevelopmental impairment, suggesting that atypical early brain development may be reflected in accelerated rather than reduced growth, or that restricted growth-related causes of NDD act later in pregnancy.