Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.
This is a preview of subscription content, access via your institution
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
The code used for this EWAS meta-analysis is available from the corresponding authors upon reasonable request.
Lautarescu A, Craig MC, Glover V. Prenatal stress: effects on fetal and child brain development. Int Rev Neurobiol. 2020;150:17–40.
Coussons-Read ME. Effects of prenatal stress on pregnancy and human development: mechanisms and pathways. Obstet Med. 2013;6:52–7.
Orr ST, James SA, Casper R. Psychosocial stressors and low birth weight. J Dev Behav Pediatr. 1992;13:343–7.
Ruiz R, Fullerton J. The measurement of stress in pregnancy. Nurs Health Sci. 1999;1:19–25.
March of Dimes. Stress and Pregnancy. 2023; at https://www.marchofdimes.org/find-support/topics/pregnancy/stress-and-pregnancy.
Brunst KJ, Zhang L, Zhang X, Baccarelli AA, Bloomquist T, Wright RJ. Associations between maternal lifetime stress and placental mitochondrial DNA mutations in an urban multiethnic cohort. Biol Psychiatry. 2021;89:570–8.
Glover V, O’Donnell KJ, O’Connor TG, Fisher J. Prenatal maternal stress, fetal programming, and mechanisms underlying later psychopathology—A global perspective. Dev Psychopathol. 2018;30:843–54.
Van den Bergh BRH, van den Heuvel MI, Lahti M, Braeken M, de Rooij SR, Entringer S, et al. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neurosci Biobehav Rev. 2017;117:26–64.
Araji S, Griffin A, Dixon L, Spencer S-K, Peavie C, Wallace K. An overview of maternal anxiety during pregnancy and the post-partum period. J Ment Health Clin Psychol. 2020;4:47–56.
Dunkel Schetter C, Tanner L. Anxiety, depression and stress in pregnancy: implications for mothers, children, research, and practice. Curr Opin Psychiatry. 2012;25:141–8.
Dunkel Schetter C, Glynn L. Stress in pregnancy: Empirical evidence and theoretical issues to guide interdisciplinary research. In: Contrada RJ, Baum A, editors. The handbook of stress science: biology, psychology, and health. Springer Publishing; 2011;321–47.
Hobel CJ, Goldstein AMY, Barrett ES. Psychosocial stress and pregnancy outcome. Clin Obstet Gynecol. 2008;51:333–48.
Wadhwa PD, Entringer S, Buss C, Lu MC. The contribution of maternal stress to preterm birth: issues and considerations. Clin Perinatol. 2011;38:351–84.
Rosa MJ, Nentin F, Bosquet Enlow M, Hacker MR, Pollas N, Coull B, et al. Sex-specific associations between prenatal negative life events and birth outcomes. Stress. 2019;22:647–53.
van Meel ER, Saharan G, Jaddoe VWV, de Jongste JC, Reiss IKM, Tiemeier H, et al. Parental psychological distress during pregnancy and the risk of childhood lower lung function and asthma: a population-based prospective cohort study. Thorax. 2020;75:1074–81.
Brunst KJ, Rosa MJ, Jara C, Lipton LR, Lee A, Coull BA, et al. Impact of maternal lifetime interpersonal trauma on childrenʼs asthma. Psychosom Med. 2017;79:91–100.
Lee A, Mathilda Chiu YH, Rosa MJ, Jara C, Wright RO, Coull BA, et al. Prenatal and postnatal stress and asthma in children: temporal- and sex-specific associations. J Allergy Clin Immunol. 2016;138:740–7.
Lee AG, Chiu YM, Rosa MJ, Cohen S, Coull BA, Wright RO, et al. Association of prenatal and early childhood stress with reduced lung function in 7-year-olds. Ann Allergy Asthma Immunol. 2017;119:153–9.
Lahti M, Savolainen K, Tuovinen S, Pesonen A-K, Lahti J, Heinonen K, et al. Maternal depressive symptoms during and after pregnancy and psychiatric problems in children. J Am Acad Child Adolesc Psychiatry. 2017;56:30–9.
Herba CM, Glover V, Ramchandani PG, Rondon MB. Maternal depression and mental health in early childhood: an examination of underlying mechanisms in low-income and middle-income countries. Lancet Psychiatry. 2016;3:983–92.
Tarabulsy GM, Pearson J, Vaillancourt-Morel M-P, Bussières E-L, Madigan S, Lemelin J-P, et al. Meta-analytic findings of the relation between maternal prenatal stress and anxiety and child cognitive outcome. J Dev Behav Pediatr. 2014;35:38–43.
Pearson RM, Bornstein MH, Cordero M, Scerif G, Mahedy L, Evans J, et al. Maternal perinatal mental health and offspring academic achievement at age 16: the mediating role of childhood executive function. J Child Psychol Psychiatry. 2015;57:491–501.
Mennes M, Bergh BVD, Lagae L, Stiers P. Developmental brain alterations in 17 year old boys are related to antenatal maternal anxiety. Clin Neurophysiol. 2009;120:1116–22.
Bergh BRHVD, Mennes M, Oosterlaan J, Stevens V, Stiers P, Marcoen A, et al. High antenatal maternal anxiety is related to impulsivity during performance on cognitive tasks in 14- and 15-year-olds. Neurosci Biobehav Rev. 2005;29:259–69.
Davis EP, Hankin BL, Glynn LM, Head K, Kim DJ, Sandman CA. Prenatal maternal stress, child cortical thickness, and adolescent depressive symptoms. Child Development. 2019;91:e432–50.
Buss C, Davis EP, Muftuler LT, Head K, Sandman CA. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6–9-year-old children. Psychoneuroendocrinology. 2010;35:141–53.
Khashan AS, Abel KM, McNamee R, Pedersen MG, Webb RT, Baker PN, et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry. 2008;65:146.
Cao-Lei L, de Rooij SR, King S, Matthews SG, Metz GAS, Roseboom TJ, et al. Prenatal stress and epigenetics. Neurosci Biobehav Rev. 2020;117:198–210.
Dadds MR, Moul C, Hawes DJ, Mendoza Diaz A, Brennan J. Individual differences in childhood behavior disorders associated with epigenetic modulation of the cortisol receptor gene. Child Dev. 2015;86:1311–20.
Heinrich A, Buchmann AF, Zohsel K, Dukal H, Frank J, Treutlein J, et al. Alterations of glucocorticoid receptor gene methylation in externalizing disorders during childhood and adolescence. Behav Genet. 2015;45:529–36.
Radtke KM, Ruf M, Gunter HM, Dohrmann K, Schauer M, Meyer A, et al. Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl Psychiatry. 2011;1:e21–e21.
Brunst KJ, Tignor N, Just A, Liu Z, Lin X, Hacker MR, et al. Cumulative lifetime maternal stress and epigenome-wide placental DNA methylation in the PRISM cohort. Epigenetics. 2018;13:665–81.
Rijlaarsdam J, Pappa I, Walton E, Bakermans-Kranenburg MJ, Mileva-Seitz VR, Rippe RCA, et al. An epigenome-wide association meta-analysis of prenatal maternal stress in neonates: a model approach for replication. Epigenetics. 2016;11:140–9.
Polinski KJ, Putnick DL, Robinson SL, Schliep KC, Silver RM, Guan W, et al. Periconception and prenatal exposure to maternal perceived stress and cord blood DNA methylation. Epigenet Insights. 2022;15:25168657221082045.
Lund RJ, Kyläniemi M, Pettersson N, Kaukonen R, Konki M, Scheinin NM, et al. Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy. Neurobiol Stress. 2021;15:100374.
Tesfaye M, Chatterjee S, Zeng X, Joseph P, Tekola-Ayele F. Impact of depression and stress on placental DNA methylation in ethnically diverse pregnant women. Epigenomics. 2021;13:1485–96.
Bakulski KM, Halladay A, Hu VW, Mill J, Fallin MD. Epigenetic research in neuropsychiatric disorders: the “tissue issue”. Curr Behav Neurosci Rep. 2016;3:264–74.
Felix JF, Joubert BR, Baccarelli AA, Sharp GC, Almqvist C, Annesi-Maesano I, et al. Cohort profile: pregnancy and childhood epigenetics (PACE) consortium. Int J Epidemiol. 2018;47:22–3u.
Croft J, Heron J, Teufel C, Cannon M, Wolke D, Thompson A, et al. Association of trauma type, age of exposure, and frequency in childhood and adolescence with psychotic experiences in early adulthood. JAMA Psychiatry. 2019;76:79–86.
Miller-Lewis LR, Searle AK, Sawyer MG, Baghurst PA, Hedley D. Resource factors for mental health resilience in early childhood: an analysis with multiple methodologies. Child Adolesc Psychiatry Ment Health. 2013;7:6.
Cortes Hidalgo AP, Tiemeier H, Metcalf SA, Monninger M, Meyer-Lindenberg A, Aggensteiner PM, et al. No robust evidence for an interaction between early-life adversity and protective factors on global and regional brain volumes. Dev Cogn Neurosci. 2022;58:101166.
Chen YA, Lemire M, Choufani S, Butcher DT, Grafodatskaya D, Zanke BW, et al. Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics. 2013;8:203–9.
McCartney DL, Walker RM, Morris SW, McIntosh AM, Porteous DJ, Evans KL. Identification of polymorphic and off-target probe binding sites on the Illumina Infinium MethylationEPIC BeadChip. Genom Data. 2016;9:22–4.
Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinforma. 2012;13:86.
Gervin K, Salas LA, Bakulski KM, van Zelm MC, Koestler DC, Wiencke JK, et al. Systematic evaluation and validation of reference and library selection methods for deconvolution of cord blood DNA methylation data. Clin Epigenetics. 2019;11:125.
Venables WN, Ripley BD. Modern Applied Statistics with S, 4th ed. Springer: New York; 2002. https://www.stats.ox.ac.uk/pub/MASS4/.
Min JL, Hemani G, Davey Smith G, Relton C, Suderman M. Meffil: efficient normalization and analysis of very large DNA methylation datasets. Bioinformatics. 2018;34:3983–89.
Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58.
Saffari A, Silver MJ, Zavattari P, Moi L, Columbano A, Meaburn EL, et al. Estimation of a significance threshold for epigenome-wide association studies. Genet Epidemiol. 2017;42:20–33.
Peters TJ, Buckley MJ, Statham AL, Pidsley R, Samaras K, V Lord R, et al. De novo identification of differentially methylated regions in the human genome. Epigenetics Chromatin. 2015;8:6.
Sammallahti S, Cortes Hidalgo AP, Tuominen S, Malmberg A, Mulder RH, Brunst KJ. et al. Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation. Mol Psychiatry. 2021;26:1832–45.
Rakyan VK, Down TA, Balding DJ, Beck S. Epigenome-wide association studies for common human diseases. Nat Rev Genet. 2011;12:529–41.
van Dongen J, Nivard MG, Willemsen G, Hottenga J-J, Helmer Q, Dolan CV, et al. Genetic and environmental influences interact with age and sex in shaping the human methylome. Nat Commun. 2016;7:11115.
Hannon E, Knox O, Sugden K, Burrage J, Wong CCY, Belsky DW, et al. Characterizing genetic and environmental influences on variable DNA methylation using monozygotic and dizygotic twins. PLOS Genet. 2018;14:e1007544.
Min JL, Hemani G, Hannon E, Dekkers KF, Castillo-Fernandez J, Luijk R, et al. Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation. Nat Genet. 2021;53:1311–21.
Edgar RD, Jones MJ, Meaney MJ, Turecki G, Kobor MS. BECon: a tool for interpreting DNA methylation findings from blood in the context of brain. Transl Psychiatry. 2017;7:e1187.
Ruiz-Arenas C, Hernandez-Ferrer C, Vives-Usano M, Mari S, Quintela I, Mason D. et al. Identification of autosomal cis expression quantitative trait methylation (cis eQTMs) in children’s blood. eLife. 2022;11:e65310.
Ramesh V, Bayam E, Cernilogar FM, Bonapace IM, Schulze M, Riemenschneider MJ, et al. Loss of Uhrf1 in neural stem cells leads to activation of retroviral elements and delayed neurodegeneration. Genes Dev. 2016;30:2199–212.
Schroeder P, Rivalan M, Zaqout S, Kruger C, Schuler J, Long M, et al. Abnormal brain structure and behavior in MyD88-deficient mice. Brain Behav Immun. 2021;91:181–93.
Li G, Forero MG, Wentzell JS, Durmus I, Wolf R, Anthoney NC. et al. A Toll-receptor map underlies structural brain plasticity. eLife. 2020;9:e52743.
Harrison JS, Cornett EM, Goldfarb D, DaRosa PA, Li ZM, Yan F. et al. Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. eLife. 2016;5:e17101.
Watanabe K, Stringer S, Frei O, Umicevic Mirkov M, de Leeuw C, Polderman TJC, et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat Genet. 2019;51:1339–48.
Hoffman GE, Ma Y, Montgomery KS, Bendl J, Jaiswal MK, Kozlenkov A, et al. Sex differences in the human brain transcriptome of cases with schizophrenia. Biol Psychiatry. 2022;91:92–101.
Flynn M, Whitton L, Donohoe G, Morrison CG, Morris DW. Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function. Hum Mol Genet. 2020;29:407–17.
Hamshere ML, Walters JT, Smith R, Richards AL, Green E, Grozeva D, et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the schizophrenia PGC. Mol Psychiatry. 2013;18:708–12.
Monk C, Lugo-Candelas C, Trumpff C. Prenatal developmental origins of future psychopathology: mechanisms and pathways. Ann Rev Clin Psychol. 2019;15:317–44.
Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84.
Lee Y, Choi I, Kim J, Kim K. DNA damage to human genetic disorders with neurodevelopmental defects. J Genet Med. 2016;13:1–13.
Qi T, Wu Y, Zeng J, Zhang F, Xue A, Jiang L. et al. Identifying gene targets for brain-related traits using transcriptomic and methylomic data from blood. Nat Commun. 2018;9:2282.
Joseph RM. Neuronatin gene: Imprinted and misfolded: Studies in Lafora disease, diabetes and cancer may implicate NNAT-aggregates as a common downstream participant in neuronal loss. Genomics. 2014;103:183–8.
Dunn EC, Soare TW, Zhu Y, Simpkin AJ, Suderman MJ, Klengel T, et al. Sensitive periods for the effect of childhood adversity on DNA methylation: results from a prospective, longitudinal study. Biol Psychiatry. 2019;85:838–49.
Liu J, Cerutti J, Lussier AA, Zhu Y, Smith BJ, Smith A et al. Socioeconomic changes predict genome-wide DNA methylation in childhood. Hum Mol Genet. 2022;32:709–19.
Lussier AA, Zhu Y, Smith BJ, Simpkin AJ, Smith A, Suderman MJ, et al. Updates to data versions and analytic methods influence the reproducibility of results from epigenome-wide association studies. Epigenetics. 2022;17:1373–88.
Merid SK, Novoloaca A, Sharp GC, Kupers LK, Kho AT, Roy R, et al. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age. Genome Med. 2020;12:25.
Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, et al. Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J Allergy Clin Immunol. 2019;143:2062–74.
Maccani JZJ, Koestler DC, Lester B, Houseman EA, Armstrong DA, Kelsey KT, et al. Placental DNA methylation related to both infant toenail mercury and adverse neurobehavioral outcomes. Environ Health Perspect. 2015;123:723–9.
Lee KWK, Richmond R, Hu P, French L, Shin J, Bourdon C, et al. Prenatal exposure to maternal cigarette smoking and dna methylation: epigenome-wide association in a discovery sample of adolescents and replication in an independent cohort at birth through 17 years of age. Environ Health Perspect. 2015;123:193–9.
Ghazi T, Naidoo P, Naidoo RN, Chuturgoon AA. Prenatal air pollution exposure and placental dna methylation changes: implications on fetal development and future disease susceptibility. Cells. 2021;10:3025.
Alves AC, Cecatti JG, Souza RT. Resilience and stress during pregnancy: a comprehensive multidimensional approach in maternal and perinatal health. Sci World J. 2021;2021:9512854.
Acknowledgements and funding for each of the participating studies are listed in the Supplementary Methods sections.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kotsakis Ruehlmann, A., Sammallahti, S., Cortés Hidalgo, A.P. et al. Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation. Mol Psychiatry (2023). https://doi.org/10.1038/s41380-023-02010-5