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Placentas of fetuses with CHD have abnormalities, including unbalanced fetal\/placental weight ratios (F\/P). Although DNA methylation profiles have revealed insights into the maternal-fetal environment (MFE), it is unknown if DNA methylation correlates to normalized F\/P weight ratio groups and how these differences relate to ND outcomes.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We prospectively recruited a cohort of pregnant women carrying a fetus with CHD. A subset of the cohort had DNA methylation performed on either umbilical cord blood or postnatal blood (45 full-term neonates). We calculated normalized F\/P weight ratios, focusing on three normalized F\/P ratio groups for analysis. We calculated differential methylation signals in eight ND disabilities-associated gene sets. Normalized F\/P ratios were compared to 18-month Bayley Scales of Infant Development-III scores (BSID-III).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Unbiased gene ontology enrichment analysis of differentially methylated regions revealed enrichment for brain development-related pathways. Although there were no significant differences between normalized F\/P weight ratio groups and BSID-III, disease-associated gene set pathway analysis revealed significant methylation differences between the most severely unbalanced F\/P weight ratio and normal F\/P weight ratio groups.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Gene ontology enrichment analysis of differential methylation regions revealed significant differences between normalized F\/P weight ratio groups in neurogenesis genes. Furthermore, our data identified methylation differences between unbalanced and balanced normalized F\/P weight ratio groups in gene pathways associated with ND dysfunction common in the aging CHD population suggesting converging pathways for ND disorders that should be investigated further.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0317944","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T17:32:50Z","timestamp":1754501570000},"page":"e0317944","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA methylation differences stratified by normalized fetal\/placental weight ratios suggest neurodevelopmental deficits in neonates with congenital heart disease"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9489-6594","authenticated-orcid":true,"given":"Marin","family":"Jacobwitz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Xie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7822-590X","authenticated-orcid":true,"given":"Jamie","family":"Catalano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingo","family":"Helbig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-5604","authenticated-orcid":true,"given":"J. William","family":"Gaynor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy","family":"Burnham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca L.","family":"Linn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juliana","family":"Gebb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark W.","family":"Russell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hakon","family":"Hakonarson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara H.","family":"Chaiyachati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana 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