Background There is a need for non-invasive prenatal markers of the brain to assess fetuses at risk for poor postnatal neurodevelopmental outcome. Periconceptional maternal conditions and pregnancy complications impact prenatal brain development.

Aims To investigate associations between growth trajectories of fetal brain structures and neurodevelopmental outcome in children in the early life course.

Study design Periconceptional prospective observational cohort.

Subjects Singleton pregnancies were included in the Rotterdam periconception cohort. Two- and three-dimensional ultrasound scans at 22, 26 and 32 weeks gestational age were analysed.

Outcome measures Head circumference (HC), cerebellum, corpus callosum (CC), Sylvian fissure, insula and parieto-occipital fissure (POF) were measured. Neurodevelopment was evaluated using the Age-and-Stages-questionnaire-3 (ASQ-3) and the Child-Behaviour-Checklist (CBCL) at 2 years of age. Linear mixed models, used to estimate the prenatal brain growth trajectories, and linear regression models, used to evaluate the associations between prenatal brain structures and neurodevelopmental outcomes, were applied in the total study population, and in subgroups: fetal growth restriction (FGR), preterm birth (PTB), fetal congenital heart disease (CHD), and uncomplicated controls.

Results Consent for participation was received from parents on behalf of their child 138/203 (68%). ASQ-3 was completed in 128/203 children (63%) and CBCL in 93/203 children (46%). Significant smaller subject-specific growth trajectories (growth rate of CC, HC, left insula, left POF and right POF and the baseline size of CC, HC, left POF and right POF) were found in the FGR subgroup, compared to the other subgroups (all p-values <0.05). In the total group (n = 138), the growth rate of the left insula was associated with poorer ASQ-3 score (β = −869.51; p < 0.05). Healthy controls (n = 106) showed a comparable association (β = −1209.87; p < 0.01). FGR (n = 10) showed a larger baseline size of the right Sylvian fissure in association with poorer CBCL-score (β = 4.13; p < 0.01). In CHD (n = 12) the baseline size of the left Sylvian fissure and its growth rate were associated with respectively poorer and better CBCL-scores (β = 3.11; p < 0.01); (β = −171.99; p < 0.01). In PTB (n = 10) no associations were found.

Conclusions This explorative study suggests associations between ultrasound measurements of fetal brain growth and neurodevelopmental outcome at 2 years of age. In future, this non-invasive technique may improve early identification of fetuses at risk for neurodevelopmental outcome and follow-up postnatal clinical care.

Fetal brain trajectories, Cortical folding, Fetal programming, Neurodevelopment, Children,
Early Human Development
Department of Gynaecology & Obstetrics

Welling, M.S., Husen, S.C., Go, A.T.J.I, Groenenberg, I.A.L, Willemsen, S.P, Bijma, H.H, & Steegers-Theunissen, R.P.M. (2020). Growth trajectories of the human fetal brain in healthy and complicated pregnancies and associations with neurodevelopmental outcome in the early life course. Early Human Development, 151. doi:10.1016/j.earlhumdev.2020.105224