Infant subcortical brain volumes associated with maternal obesity and diabetes: a large multicohort human study - UTU Tutkimustietojärjestelmä

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Infant subcortical brain volumes associated with maternal obesity and diabetes: a large multicohort human study

Tekijät: Alex, Ann M.; Rasmussen, Jerod M.; Tuulari, Jetro J.; Sigurdardottir, Julie Nihouarn; Buss, Claudia; Donald, Kirsten A.; Edwards, A. David; Entringer, Sonja; Gilmore, John H.; Groenewold, Nynke A.; Karlsson, Hasse; Karlsson, Linnea; Lawrence, Katherine E.; Mattila, Inka; Stein, Dan J.; Styner, Martin; Thompson, Paul M.; Wadhwa, Pathik D.; Zar, Heather J.; Zhu, Xi; de los Campos, Gustavo; Knickmeyer, Rebecca C.; Luo, Shan; ENIGMA-ORIGINs working group

Julkaisuvuosi: 2026

Lehti: BMC Medicine

eISSN: 1741-7015

DOI: https://doi.org/10.1186/s12916-026-04860-6

Julkaisun avoimuus kirjaamishetkellä: Avoimesti saatavilla

Julkaisukanavan avoimuus : Kokonaan avoin julkaisukanava

Verkko-osoite: https://doi.org/10.1186/s12916-026-04860-6

Tiivistelmä

Background

Maternal diabetes and obesity are established risk factors for adverse offspring health. Emerging evidence suggests that these fetal programming effects vary by sex, yet it remains unclear whether these factors independently or interactively influence early brain development.

Methods

This prospective study included 1,965 infants from six international cohorts. Infant MRI was used to derive subcortical volumes (thalamus, amygdala, hippocampus, pallidum, putamen, caudate). ComBat harmonization was applied. Multiple linear regression tested main and interaction effects of maternal obesity, maternal diabetes, and sex, controlling for covariates with false discovery rate (FDR) corrections.

Results

Of the sample, 46% were female (N = 909), 9% were exposed to maternal diabetes (N = 172), 22% to maternal obesity (N = 386), and 3% to both (N = 61). MRI scans were performed at 25.9 ± 18.8 days. Maternal diabetes was associated with smaller thalamic volume (standardized β = -0.09, 95%CI –0.16 to -0.01, FDR P = 0.020), but this association was attenuated after adjusting for maternal obesity. Maternal obesity was associated with smaller hippocampal (standardized β = -0.13, 95%CI -0.21 to –0.05, FDR P = 0.009) and thalamic volumes (standardized β = -0.09, 95%CI -0.14 to –0.03, FDR P = 0.007).

Sex-specific associations were observed. In females, maternal obesity was associated with smaller hippocampal (standardized β = -0.24, 95%CI -0.36 to -0.13, FDR P < 0.001) and amygdala volumes (standardized β = -0.18, 95% CI = -0.30 to –0.06, FDR P = 0.016). A three-way interaction (diabetes x obesity x sex) was observed for thalamus volume (standardized β = -0.50, 95%CI -0.81 to -0.18, FDR P = 0.017). In males, combined exposure had lower thalamic volume compared to those with one or neither exposure (all Ps < 0.05). In females, maternal obesity (standardized β = -0.12, 95%CI -0.20 to –0.04, FDR P = 0.015) and diabetes (standardized β = -0.16, 95%CI -0.30 to –0.02, FDR P = 0.042) showed independent associations with thalamic volume, without a significant interaction (standardized β = 0.23, 95%CI -0.01 to 0.46, FDR P = 0.092).

Conclusions

Maternal obesity shows stronger associations with infant subcortical volumes than maternal diabetes. It is associated with smaller hippocampal and amygdala volumes in females, while combined exposure to maternal diabetes and obesity is associated with smaller thalamic volumes in males. These findings highlight the role of maternal metabolic health and infant sex in early neurodevelopment.

Julkaisussa olevat rahoitustiedot:
ORIGINs is supported by the National Institute of Mental Health (NIMH; R01MH123716 to RK) and the ENIGMA consortium is supported by the National Institutes of Health (NIH) Big Data to Knowledge (BD2K) award for foundational support and consortium development (Grant No. U54 EB020403 to PMT). This project is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; R01DK137899 to SL). The independent cohorts within this study were supported by the grants and fellowships listed. DCHS - Bill & Melinda Gates Foundation (OPP 1017641), Medical Research Council South Africa: HJZ;Academy of Medical Sciences Newton Advanced Fellowship (NAF002/1001):KAD, the UK Government’s Newton Fund, by NIAAA via (R21AA023887), by the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD) developmental grant (U24 AA014811), US Brain and Behavior Foundation Independent Investigator grant (24467), and the Carnegie Corporation of New York, South African Medical Research Council (SA-MRC) – KAD, DJS, and HZ. EBDS – National Institutes of Health MH070890, HD053000, MH064065: JHG, and P50 HD103573: MS; UCI - R00 HD100593 (PI, Rasmussen); R01 MH091351 (PI, Buss); R01HD060628 (PI, Wadhwa). GMIA – National Institutes of Health R21 MH104330 and R33 MH104330: RCK. dHCP - European Research Council under the European Union Seventh Framework Programme (FP/20072013)/ERC Grant Agreement no. 319456. FinnBrain - Research Council of Finland (#325292); Brain and Behavior Research Foundation; NARSAD YI Grant (#1956); Finnish State Grants for Clinical Research; Signe and Ane Gyllenberg Foundation: LK; Research Council of Finland (#134950, #253270), Finnish State Grants for Clinical Research; Signe and Ane Gyllenberg Foundation, Jane and Aatos Erkko FoundationSigne and Ane Gyllenberg Foundation: HK; Sigrid Jusélius Foundation; Emil Aaltonen Foundation; Finnish Medical Foundation; Hospital District of Southwest Finland; State Grants for Clinical Research (ERVA); Signe and Ane Gyllenberg Foundation: JJT. KL is supported by K01MH135160.