Integrated Analysis of Preterm Birth and Socioeconomic Status with Neonatal Brain Structure

Importance Preterm birth and socioeconomic status (SES) are associated with brain structure in childhood, but the relative contributions of each during the neonatal period are unknown. Objective To investigate associations of gestational age (GA) and SES with neonatal brain morphology, by testing 3 hypotheses: GA and SES are associated with brain morphology; associations between SES and brain morphology vary across the GA range, and; associations between SES and brain structure/morphology depend on how SES is operationalized. Design Cohort study, recruited 2016-2021. Setting Single center, UK. Participants 170 preterm infants and 91 term infants with median (range) birth GA 30+0 (22+1-32+6) and 39+4 (36+3-42+1) weeks, respectively. Exclusion criteria: major congenital malformation, chromosomal abnormality, congenital infection, cystic periventricular leukomalacia, hemorrhagic parenchymal infarction, post-hemorrhagic ventricular dilatation. Exposures Using linear ridge regression models, we investigated associations of GA and SES, operationalized at the neighborhood-level (Scottish Index of Multiple Deprivation), family-level (parental education and occupation) and subjectively (WHO Quality of Life), with regional brain volumes and cortical morphology. Main outcomes/measures Brain volume (85 parcels) and 5 whole-brain cortical morphology measures (gyrification index, thickness, sulcal depth, curvature, surface area) at term-equivalent age. Results In fully adjusted models, GA associated with a higher proportion of brain volumes (22/85 [26%], β range |-0.13| to |0.22|) than neighborhood SES (1/85 [1%], β=0.17). GA associated with cortical surface area (β=0.10 [95% confidence interval (CI) 0.02-0.18]) and gyrification index (β=0.16 [95% CI 0.07-0.25]); neighborhood SES did not. Family-level SES associated with the volumes of more parcels than neighborhood SES, but it did not have as extensive associations with brain structure as GA. There were interactions between GA and both family- and subjective-level SES measures on brain structure. Conclusions/relevance In a UK cohort, GA and SES impact neonatal brain morphology, but low GA has more widely distributed effects on neonatal brain structure than neighborhood-level, family-level and subjective measures of SES. Further work is warranted to elucidate the mechanisms embedding GA and level-specific SES in early brain development. Question What are the impacts of preterm birth and socioeconomic status (SES), operationalized at neighborhood, family, and subjective levels, on neonatal brain structure? Finding After mutual adjustment, both low gestational age (GA) and SES associate with brain structure. The nature of SES-brain structure associations varies depending how SES is operationalized; there are interactions between GA and measures of family- and subjective-level SES on brain structure. Meaning Low GA, and to a lesser extent SES, are associated with neonatal brain structure. Further work is required to elucidate the mechanisms that embed preterm birth and level-specific SES in the developing brain. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Protocols ### Funding Statement This work was supported by Theirworld (www.theirworld.org) and was carried out in the Medical Research Council Centre for Reproductive Health, which was funded by Medical Research Council Centre Grant (MRC G1002033). Participants were scanned in the University of Edinburgh Imaging Research MRI Facility at the Royal Infirmary of Edinburgh, which was established with funding from The Wellcome Trust, Dunhill Medical Trust, Edinburgh and Lothians Research Foundation, Theirworld, The Muir Maxwell Trust and other sources. KV and LJ-S are funded by the Wellcome Translational Neuroscience PhD Programme at the University of Edinburgh (108890/Z/15/Z). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the UK National Research Ethics Service (South East Scotland Research Ethic Committee 16/SS/0154). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes A copy of the dataset will be placed in the University of Edinburgh DataVault (https://datavault.ed.ac.uk/). Requests for access should be made to the TEBC Chief Investigator (Professor J Boardman).