{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:28:18Z","timestamp":1786699698850,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babes\u201d University of Medicine and Pharmacy"},{"id":[{"id":"https:\/\/ror.org\/00afdp487","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background and Objectives: Maternal psychological vulnerability during pregnancy is associated with adverse obstetric and neonatal outcomes, but the contribution of candidate genetic markers remains insufficiently defined. This exploratory pilot case\u2013control study examined NRG1 rs35753505, NRG1 rs3924999, and OXT rs2740210 together with validated psychological screening and obstetric\u2013neonatal phenotyping in Romanian primiparous women. Methods: Eighty-two primiparous women were enrolled between February 2024 and February 2025 at a tertiary maternity centre in Timi\u0219oara. After genotyping quality control, 79 women with complete data for all three SNPs (50 cases and 29 controls) formed the analytic sample. Fifty women with at least one obstetric complication were compared with 29 women with uncomplicated pregnancies. Participants completed the EPDS, GAD-7, PSS-10, and CD-RISC-25 at 20\u201328 gestational weeks. Genotyping was performed using TaqMan\u00ae allelic discrimination assays, with Hardy\u2013Weinberg equilibrium assessment and exploratory carrier, allele-dosage, correlation, ANOVA, and logistic-regression analyses. Results: The study lot had higher EPDS, GAD-7, and PSS-10 scores and lower CD-RISC-25 scores than controls (all p &lt; 0.001). The three SNPs were in Hardy\u2013Weinberg equilibrium and did not show statistically significant single-locus case\u2013control differences. NRG1 rs3924999 A-carriers showed the strongest exploratory association pattern, including lower neonatal birth weight and higher psychological vulnerability scores. Across exploratory genetic risk score (GRS) tertiles, birth weight, Apgar-5, perceived stress, and resilience differed significantly; however, the formal multiplicative GRS \u00d7 PSS-10 model for low birth weight was not significant. Stratified correlations suggested that the PSS-10-birth weight relationship was stronger in the high-GRS tertile. Conclusions: NRG1 rs3924999 and the composite NRG1\/OXT score may help define future replication hypotheses, but larger genotype-stratified cohorts are required before clinical risk stratification can be proposed. The composite score is an investigator-weighted, internally derived exploratory index rather than a validated genetic risk model, and the formal gene\u2013environment interaction test was null, so the stratified correlations are descriptive only. The findings should be interpreted as hypothesis-generating.<\/jats:p>","DOI":"10.3390\/jcm15166286","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:08:29Z","timestamp":1786694909000},"page":"6286","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating NRG1 and OXT Polymorphisms, Maternal Psychological Vulnerability, and Obstetric\u2013Neonatal Outcomes: A Genotype\u2013Phenotype Pilot Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Ioana Denisa","family":"Socol","sequence":"first","affiliation":[{"name":"Doctoral School, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"},{"name":"Genomic Medicine Centre, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"},{"name":"Discipline of Neonatology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona Sorina","family":"Farca\u0219","sequence":"additional","affiliation":[{"name":"Genomic Medicine Centre, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"},{"name":"Discipline of Genetics, Department of Microscopic Morphology, Faculty of Medicine, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavius George","family":"Socol","sequence":"additional","affiliation":[{"name":"1st Clinic of Obstetrics and Gynecology, \u201cPius Br\u00eenzeu\u201d County Clinical Emergency Hospital, 300723 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogdan-Ionel","family":"Dumitriu","sequence":"additional","affiliation":[{"name":"Doctoral School, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Iacob","sequence":"additional","affiliation":[{"name":"Discipline of Neonatology, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2647-4234","authenticated-orcid":false,"given":"Nicoleta Ioana","family":"Andreescu","sequence":"additional","affiliation":[{"name":"Genomic Medicine Centre, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"},{"name":"Discipline of Genetics, Department of Microscopic Morphology, Faculty of Medicine, \u201cVictor Babe\u0219\u201d University of Medicine and Pharmacy, 300041 Timi\u0219oara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1017\/S0954579420001121","article-title":"Pregnancy as a period of risk, adaptation, and resilience for mothers and infants","volume":"32","author":"Davis","year":"2020","journal-title":"Dev. Psychopathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.jad.2021.03.083","article-title":"The impact of prenatal stressful life events on adverse birth outcomes: A systematic review and meta-analysis","volume":"287","author":"Ding","year":"2021","journal-title":"J. Affect. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.wombi.2015.02.003","article-title":"The effects of maternal depression, anxiety, and perceived stress during pregnancy on preterm birth: A systematic review","volume":"28","author":"Staneva","year":"2015","journal-title":"Women Birth"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1001\/archgenpsychiatry.2010.111","article-title":"A meta-analysis of depression during pregnancy and the risk of preterm birth, low birth weight, and intrauterine growth restriction","volume":"67","author":"Grote","year":"2010","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Matsas, A., Panopoulou, P., Antoniou, N., Bargiota, A., Gryparis, A., Vrachnis, N., Mastorakos, G., Kalantaridou, S.N., Panoskaltsis, T., and Vlahos, N.F. (2023). Chronic stress in pregnancy is associated with low birth weight: A meta-analysis. J. Clin. Med., 12.","DOI":"10.3390\/jcm12247686"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Socol, I.D., Abu-Awwad, A., Socol, F.G., Farcas, S.S., Abu-Awwad, S.-A., Dumitriu, B.-I., Dumitriu, A.-I., Iacob, D., Vasile, D.-V., and Andreescu, N.I. (2025). Psychological vulnerability during pregnancy and its obstetric consequences: A multidimensional approach. Healthcare, 13.","DOI":"10.3390\/healthcare13172211"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.yfrne.2012.11.002","article-title":"Role of the hypothalamic-pituitary-adrenal axis in developmental programming of health and disease","volume":"34","author":"Xiong","year":"2013","journal-title":"Front. Neuroendocrinol."},{"key":"ref_8","unstructured":"Socol, I.D., Socol, F.G., Farca\u0219, S.S., Dumitriu, B.-I., Dumitriu, A.-I., Antal, A., Boarta, A., Iacob, D., and Andreescu, N.I. (2026). Genetic Determinants of Stress Reactivity in Pregnancy: A Systematic Review and Meta-Analysis: Implications for Maternal and Fetal Health. Genes, 17."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/978-1-4939-1372-5_13","article-title":"Prenatal stress and its effects on the fetus and the child: Possible underlying biological mechanisms","volume":"10","author":"Glover","year":"2015","journal-title":"Adv. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0079-6123(01)33010-8","article-title":"The neurobiology of stress in human pregnancy: Implications for prematurity and development of the fetal central nervous system","volume":"133","author":"Wadhwa","year":"2001","journal-title":"Prog. Brain Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrn2392","article-title":"Neuregulin 1 in neural development, synaptic plasticity and schizophrenia","volume":"9","author":"Mei","year":"2008","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1086\/342734","article-title":"Neuregulin 1 and susceptibility to schizophrenia","volume":"71","author":"Stefansson","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.biopsych.2015.08.008","article-title":"Oxytocin pathway genes: Evolutionary ancient system impacting on human affiliation, sociality, and psychopathology","volume":"79","author":"Feldman","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"40","DOI":"10.7150\/ijms.9.40","article-title":"The simplified Edinburgh Postnatal Depression Scale (EPDS) for antenatal depression: Is it a valid measure for pre-screening?","volume":"9","author":"Choi","year":"2012","journal-title":"Int. J. Med. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1038\/sj.mp.4001817","article-title":"Association of the NRG1 gene and schizophrenia: A meta-analysis","volume":"11","author":"Thiselton","year":"2006","journal-title":"Mol. Psychiatry"},{"key":"ref_16","first-page":"9","article-title":"Neuregulin 1 genotype and schizophrenia","volume":"34","author":"Attwood","year":"2008","journal-title":"Schizophr. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Mileva-Seitz, V., Steiner, M., Atkinson, L., Meaney, M.J., Levitan, R., Kennedy, J.L., Sokolowski, M.B., and Fleming, A.S. (2013). Interaction between oxytocin genotypes and early experience predicts quality of mothering and postpartum mood. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061443"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1093\/scan\/nsn004","article-title":"Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting","volume":"3","year":"2008","journal-title":"Soc. Cogn. Affect. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1176\/appi.ajp.2011.11020191","article-title":"A critical review of the first 10 years of candidate gene-by-environment interaction research in psychiatry","volume":"168","author":"Duncan","year":"2011","journal-title":"Am. J. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1176\/appi.ajp.2018.18070881","article-title":"No support for historical candidate gene or candidate gene-by-interaction hypotheses for major depression across multiple large samples","volume":"176","author":"Border","year":"2019","journal-title":"Am. J. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/ng749","article-title":"Replication validity of genetic association studies","volume":"29","author":"Ioannidis","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"American College of Obstetricians and Gynecologists (2006). ACOG Committee Opinion No. 348: Umbilical cord blood gas and acid-base analysis. Obstet. Gynecol., 108, 1319\u20131322.","DOI":"10.1097\/00006250-200611000-00058"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"F430","DOI":"10.1136\/adc.2006.099846","article-title":"Use of umbilical cord blood gas analysis in the assessment of the newborn","volume":"92","author":"Armstrong","year":"2007","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1001\/archinte.166.10.1092","article-title":"A brief measure for assessing generalized anxiety disorder: The GAD-7","volume":"166","author":"Spitzer","year":"2006","journal-title":"Arch. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1002\/sim.3697","article-title":"Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples","volume":"28","author":"Austin","year":"2009","journal-title":"Stat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"105243","DOI":"10.1016\/j.earlhumdev.2020.105243","article-title":"Depression during pregnancy and the risk of low birth weight, preterm birth and intrauterine growth restriction: An updated meta-analysis","volume":"152","author":"Ghimire","year":"2021","journal-title":"Early Hum. Dev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8312158","DOI":"10.1155\/2016\/8312158","article-title":"Prenatal maternal anxiety as a risk factor for preterm birth and the effects of heterogeneity on this relationship: A systematic review and meta-analysis","volume":"2016","author":"Rose","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41576-018-0018-x","article-title":"The personal and clinical utility of polygenic risk scores","volume":"19","author":"Torkamani","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.gde.2008.07.006","article-title":"Prediction of individual genetic risk of complex disease","volume":"18","author":"Wray","year":"2008","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1037\/a0017376","article-title":"Beyond diathesis stress: Differential susceptibility to environmental influences","volume":"135","author":"Belsky","year":"2009","journal-title":"Psychol. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1017\/S0954579410000611","article-title":"Differential susceptibility to the environment: An evolutionary\u2013neurodevelopmental theory","volume":"23","author":"Ellis","year":"2011","journal-title":"Dev. Psychopathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1038\/npp.2017.232","article-title":"FKBP5 moderates the association between antenatal maternal depressive symptoms and neonatal brain morphology","volume":"43","author":"Wang","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4161\/epi.3.2.6034","article-title":"Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses","volume":"3","author":"Oberlander","year":"2008","journal-title":"Epigenetics"},{"key":"ref_35","first-page":"1431","article-title":"ErbB receptors in the human placenta: Expression and role in the placentation process","volume":"35","author":"Fantone","year":"2020","journal-title":"Histol. Histopathol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Iwakura, Y., and Nawa, H. (2013). ErbB1\u20134-dependent EGF\/neuregulin signals and their cross talk in the central nervous system: Pathological implications in schizophrenia and Parkinson\u2019s disease. Front. Cell. Neurosci., 7.","DOI":"10.3389\/fncel.2013.00004"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.biopsych.2005.11.002","article-title":"Neuregulin 1 and schizophrenia: Genetics, gene expression, and neurobiology","volume":"60","author":"Harrison","year":"2006","journal-title":"Biol. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/gbb.12069","article-title":"on behalf of the MAVAN Research Team. Genetic variation in oxytocin rs2740210 and early adversity associated with postpartum depression and breastfeeding duration","volume":"12","author":"Jonas","year":"2013","journal-title":"Genes Brain Behav."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.biopsych.2013.09.006","article-title":"Gene \u00d7 environment interaction studies have not properly controlled for potential confounders: The problem and the (simple) solution","volume":"75","author":"Keller","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.psyneuen.2016.04.008","article-title":"Oxytocin receptor DNA methylation in postpartum depression","volume":"69","author":"Kimmel","year":"2016","journal-title":"Psychoneuroendocrinology"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Hogg, K., Blair, J.D., McFadden, D.E., von Dadelszen, P., and Robinson, W.P. (2013). Early onset pre-eclampsia is associated with altered DNA methylation of cortisol-signalling and steroidogenic genes in the placenta. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062969"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"853","DOI":"10.4161\/epi.21180","article-title":"Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight","volume":"7","author":"Mulligan","year":"2012","journal-title":"Epigenetics"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/16\/6286\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:34:10Z","timestamp":1786696450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/16\/6286"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":42,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jcm15166286"],"URL":"https:\/\/doi.org\/10.3390\/jcm15166286","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}