Normative Birth Weight Variation is Associated with White Matter Connectivity in Full-Term Neonates
Authors: Dufford Alexander J. , Dai Wei , Scheinost Dustin 
Published: September 2023

AbstractImportanceVariation in birth weight, an indicator of fetal growth, has been prospectively associated with both alterations in brain development and developmental delays in cognitive and language domains. However, studies examining birth weight variation and white matter development in the brain typically test these associations in infants that are preterm or very low birth weight, leaving potential normative associations in full term infants unclear.ObjectiveHere, we test prospective associations between birth weight variation in the ‘normative’ range (> 2.5 kg and <4.5 kg) and white matter connectivity in full-term neonates. Further, the main objective includes testing associations between normative birth weight variation and cognitive and language developmental scores at 18 months, and if white matter connectivity that is related to birth weight variation is further associated with cognitive language development. We hypothesized, greater normative birth weight would be associated with higher white matter connectivity controlling for gestational age, particularly in thalamic, inferior frontal, and middle temporal connectivity. Further, we predicted greater connectivity for these tracts would be associated with higher scores for cognitive (thalamic) and language development (inferior and middle temporal) at 18 months of age.DesignThe study was an observational longitudinal design of data from the Developing Human Connectome Project (dHCP). Birth weight was measured at the birth of the child, white matter connectivity was measured as neonates (mean=40.07 weeks, SD=1.14), and cognitive/language outcomes were measured at 18 months of age.SettingThe dHCP data was collected at the Evelina Newborn Imaging Centre, Evalina London Children’s Hospital between 2015 and 2019.ParticipantsA sub-sample of the full dHCP was tested. These participants were full-term neonates with birth weight variation in the ‘normative’ range (> 2.5 kg and < 4.5 kg). Participants also had to have usable diffusion-weighted imaging data as neonates and cognitive/language developmental assessments collected at 18 months (n=323).Exposure(s)The study participants were all born at full-term and in the normative birth weight range.Main Outcome(s) and Measure(s)The study had two main outcomes: white matter connectivity at the neonatal timepoint and cognitive/language developmental scores at 18 months. White matter connectivity was calculated from diffusion-weighted data for the whole-brain. Cognitive/language developmental scores were measured using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 18 months.ResultsUsing a Network-Based Statistic (NBS) approach, we found widespread associations between normative birth weight variation and white matter connectivity in full-term neonates, primarily in the positive direction for the right middle occipital gyrus and left supplementary motor area.Conclusions and RelevanceWhile investigations have been focused on the extreme ends of the birth weight spectrum, we find evidence that there is a robust association between birth weight and white matter connectivity even within the normative birth weight range. As normative birth weight variation and regions of white matter associated with birth weight were further associated with language development scores at 18 months, our results suggest the birth weight to white matter pathway may be an underlying pathway between birth weight’s association with language development.Key PointsQuestionAre variations in normative birth weight associated with white matter connectivity and cognitive/language outcomes in infancy?FindingsGreater normative birth weight is associated with greater white matter organization across a widespread network of connections in the neonatal brain. Greater white matter organization in this network for neonates has a positive prospective with expressive language development at 18 months of age.MeaningEven variations within the normative birth weight range have robust associations with early white matter development and can be prospectively linked to language development.