Prenatal stress and gestational epigenetic age: no evidence of associations based on a large prospective multi-cohort study

Psychological stress during pregnancy is known to have a range of long-lasting negative consequences on the development and health of offspring. Here, we tested whether a measure of prenatal early-life stress was associated with a biomarker of physiological development at birth, namely gestational epigenetic age acceleration (GEAA), using foetal cord-blood DNA-methylation data from three population-based cohorts. Longitudinal cohorts from the Netherlands (Generation R Study [Generation R] n = 1396), the UK (British Avon Longitudinal Study of Parents and Children [ALSPAC] n = 642), and Norway (Mother, Father and Child Cohort Study [MoBa] n1 = 1212 and n2 = 678) provided data on prenatal maternal stress and genome-wide DNA methylation from cord blood and were meta-analysed (pooled n = 3928).

Measures of GEAA were calculated using three different gestational epigenetic clocks: Bohlin, EPIC overlap and Knight. Prenatal stress exposure, examined as an overall cumulative score, was not significantly associated with GEAA in any of the clocks, based on the pooled meta-analysis results or the individual cohorts. No significant associations were identified with specific domains of prenatal stress exposure, including negative life events, contextual (socio-economic) stressors, parental risks (e.g., maternal psychopathology) and interpersonal risks (e.g., family conflict).

Further, no significant associations were identified when stratifying analyses by sex. Overall, we find little support that prenatal psychosocial stress is associated with variation in epigenetic age at birth within the general paediatric population. The MoBa Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research.

We are grateful to all the participating families in Norway who take part in this ongoing cohort study. We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting, and the whole team including interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The Generation R Study is conducted by Erasmus MC, University Medical Center Rotterdam in close collaboration with the School of Law and Faculty of Social Sciences of the Erasmus University Rotterdam, the Municipal Health Service Rotterdam area, the Rotterdam Homecare Foundation, and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC).

This research was conducted while CC was a Hevolution/AFAR New Investigator Awardee in Aging Biology and Geroscience Research. We gratefully acknowledge the contribution of children and parents, general practitioners, hospitals, midwives and pharmacies in Rotterdam. The generation and management of the EWAS data for the Generation R Study was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC.

We thank Mr Michael Verbiest, Ms Mila Jhamai, Ms Sarah Higgins, Mr Marijn Verkerk and Dr Lisette Stolk for their help in creating the EWAS database. Teumer for his work on the quality control and normalization scripts. This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme through the European Research Council EarlyCause project (grant agreement No. 848158; EW and CC); UK Research and Innovation (UKRI) under the UK government’s Horizon Europe / ERC Frontier Research Guarantee (BrainHealth, grant number EP/Y015037/1, EW); the European Union’s Horizon Europe Research and Innovation Programme through the FAMILY (grant agreement No. 101057529; CC) and HappyMums (grant agreement No. 101057390; CC) projects; the European Research Council through the TEMPO project (grant agreement No. 101039672; CC); the Research Council of Norway (grant Nos. 288083 and 301004; MB).