Abstract
Gestational diabetes mellitus (GDM) affects 14% of pregnancies worldwide with adverse maternal and offspring outcomes. Fetal sex is known to influence pregnancy outcomes and shape placental function. Although the placenta plays a central role in regulating maternal glucose levels, the molecular mechanisms driving GDM pathophysiology—and how they vary by fetal sex—are incompletely understood. We examined fetal sex impact on placental gene programs in GDM using two independent cohorts. In a case-control study (N = 101, 42 with GDM), we assessed expression of eight glycemic/immune regulation genes via qPCR in GDM placentas versus sex-matched controls. In a second prospective cohort of 433 individuals (N = 35 with GDM), we performed sex-stratified transcriptomic analyses of placental RNA-Seq data. Placental expression of genes implicated in glucose metabolism (IGFBP1, RBP4, EPYC, and PRL) was sexually dimorphic in GDM versus sex-matched controls. Transcriptomic analyses revealed enrichment in proinflammatory/glycolytic pathways and dysregulated retinoic acid signaling in male GDM placentas, while female GDM placentas showed enrichment in cell growth and immunoregulatory pathways. GDM elicits sex-specific differences in placental gene programs, highlighting the importance of incorporating fetal sex in pregnancy studies. These findings may inform future sex-tailored strategies for offspring risk prediction and intervention in GDM.
Data availability
The Gen3G placental RNA-seq data are available on dbGAP ( https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs003151.v1.p1). The R code supporting the conclusions of the manuscript is available on GitHub (https://github.com/labjacquespe/diff-exp and https://github.com/labjacquespe/GO-analysis).
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Funding
NIH/NICHD: 5K12HD103096 (to L.L.S.), 5R01HD100022 (to A.G.E.), R01HD094150 (to M.F.H.). Gen3G was initially supported by a Fonds de recherche du Québec – Santé (FRQS) operating grant (to M-FH, grant #20697); Canadian Institute of Health Research (CIHR) operating grants (to M-FH grant #MOP 115071 and to LB #PJT-152989); and a Diabète Québec grant. LB and PEJ are senior research scholars from the FRQS. MFH was a recipient of an American Diabetes Association (ADA) Pathways To Stop Diabetes Accelerator Award (#1-15-ACE-26).
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L.L.S. performed data analysis, interpreted results, and drafted the manuscript. F.W. performed bioinformatic analysis of RNA-seq data and contributed to data interpretation. S.T.B., L.I.P., D.H., and K.A. performed laboratory experiments and data analysis of the MGH cohort. F.A., K.G.A. and P.-E.J. performed RNA sequencing and contributed to bioinformatics pipeline development of the Gen3G cohort. L.B. co-led the Gen3G cohort, oversaw biospecimen processing and data interpretation. C.E.P. designed the SPRING study, provided clinical expertise, and critically revised the manuscript. S.A.K. and J.C.F critically revised the manuscript. M.-F.H. conceptualized the study, obtained funding, supervised the Gen3G cohort analysis, and critically revised the manuscript. A.G.E. conceptualized the study, obtained funding, led enrollment in the MGH cohort, supervised MGH cohort laboratory experiments and analyses, and critically revised the manuscript. All authors reviewed and approved the final version of the manuscript.
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C.E.P. has received fees and royalties from Mediflix and UpToDate (Wolters Kluwer), respectively, for presentations and articles related to diabetes over which she had full control of content. C.E.P. and L.L.S. have received research support from Dexcom, outside the submitted work. A.G.E. reports serving as a consultant for Mirvie, Inc and Merck Sharp and Dohme, Inc outside the submitted work. The remaining authors declare no competing interests.
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Shook, L.L., White, F., Acharya, K.D. et al. Fetal sex-specific differences in the placental transcriptome of gestational diabetes. Sci Rep (2026). https://doi.org/10.1038/s41598-026-39975-6
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DOI: https://doi.org/10.1038/s41598-026-39975-6
