Pregnancy was found to accelerate epigenetic ageing by up to 5.3 years in nulliparous women, suggests a prospective study by American scientists. Additionally, an older first trimester epigenetic age was associated with a composite of pregnancy complications, although chronological age was not.
Nalliparous describes a woman (or female animal) who has never given birth to a live baby, though she may have been pregnant and experienced miscarriages, stillbirths, or abortions.
“Our results suggest that biological ageing may serve as a useful metric to objectively measure how pregnancy can serve as a window to future health, since we know that people who develop gestational diabetes and hypertensive disorders can be at increased risk for these health conditions later in life,” lead author Danielle Panelli, MD, told Medscape Medical News.
Panelli is an instructor in the Department of Obstetrics, Gynaecology and Maternal Foetal Medicine at Stanford University.
One study found a 194% increase in the rate of babies born to older women in the US since 1989. Although older age is a well-established risk factor for pregnancy complications, this latest study, published in Obstetrics & Gynaecology, suggests that chronologic age alone is not a reliable predictor of adverse outcomes.
“Some older women can have uncomplicated pregnancies, and younger women can have unexpected complications,” the authors wrote. “This raises the question of whether biologic, rather than chronologic, age better predicts pregnancy risk.”
“The most interesting part about epigenetic age, or any type of biological age, is that, unlike chronological age, it is modifiable,” said Panelli.
“Ideally, translating this to clinical practice would mean that if you knew someone had accelerated epigenetic age early in pregnancy you could initiate lifestyle interventions earlier, before they potentially go on to develop complications.”
Influenced by environment, diet, stress, and behaviour, these dictate which proteins a cell makes, explaining why identical twins differ and linking epigenetics to development, disease (cancer, addiction, neurological disorders), and even transgenerational traits.
For their research, Panelli and her colleagues screened 305 women, ultimately recruiting a prospective cohort of 75 nulliparous women aged between 18 and 50 who sought obstetric (10-14 weeks’ pregnant) or gynaecologic (non-pregnant) care from 2020 to 2021.
Of the 75 members of the cohort, 45 (60%) were pregnant. Only 61 women total (81.3%) completed the study.
There were 14 participants lost to follow-up; 43 (95.6%) of the pregnant women in the cohort returned for their time 2 evaluation compared with 18 of the non-pregnant participants (60.0%). Sociodemographic factors across the group were similar. White women comprised nearly 46.7% (N = 21) of the pregnant group and 63.3% (N = 19) of the non-pregnant group.
Asian women made up the majority of the non-white groups, with 42.2% (N = 19) in the pregnant group and 26.7% (N = 8) in the non-pregnant group. Most women were in their early 30s.
The investigators took blood samples from participants at enrolment (time 1) and either at postpartum day 1 (pregnant, time 2) or seven months’ post-partum (non-pregnant, time 2).
The women’s respective epigenetic ages were measured with 11 established epigenetic molecular clocks. Within-person changes in epigenetic age were compared with mixed-effects linear regression models adjusted for confounders and interval duration.
“Biologic ageing, driven by cumulative molecular changes that increase disease vulnerability, is strongly linked to morbidity in non-pregnant adults,” Panelli and her co-authors wrote.
Using multivariable logistic regression, they explored associations between first-trimester epigenetic age and a composite of potentially immune-mediated pregnancy complications such as hypertensive disorders, gestational diabetes, preterm birth before 37 weeks of gestation, and small-for-gestational age birth weight.
All were adjusted for age and BMI at enrolment.
Across six of the 11 established epigenetic clocks – Hannum, PhenoAge, GrimAge, GrimAge2, Stem Cell Division, DunedinPACE – pregnant women were found to have significant within-person epigenetic age acceleration compared with non-pregnant women.
Additional epigenetic age acceleration per 200 days in the pregnant cohort spanned 1.58 years (Hannum: 95% CI, 0.45-2.72; P = .01) to 5.28 years (PhenoAge: 95% CI, 2.97-7.61; P < .01). Each additional year of first-trimester ageing measured by GrimAge2 increased odds of the composite of pregnancy complications by 36% (adjusted odds ratio [aOR], 1.36; 95% CI, 1.01-1.84), while chronological age in continuous years showed no association (aOR, 1.00; 95% CI, 0.83-1.21).
The greatest increase in within-person epigenetic age acceleration was measured by PhenoAge and GrimAge2, with the pregnant group gaining 5.28 (P < .01) and 4.56 (P < .01) additional epigenetic years, respectively, over a 200-day interval compared with the non-pregnant group.
A sensitivity analysis adjusted for cell proportions found similarly robust results for GrimAge, GrimAge2, and DunedinPACE.
“This suggests a vulnerability that may reflect a shift in maternal immune tolerance or other early pathophysiologic changes,” the authors wrote.
In an accompanying editorial, Zev Williams, MD, PhD, and Yousin Suh, PhD, both from the Department of Obstetrics and Gynaecology at Columbia University, Irving Medical Centre, New York City, wrote that the finding that there is an association between elevated GrimAge2-measured ageing in early pregnancy and subsequent complications was “promising”.
“GrimAge2, a second-generation epigenetic clock incorporating DNA methylation surrogates for plasma proteins, chronologic age, and smoking history, predicts mortality and morbidity risks in non-pregnant populations,” they wrote. “Its early elevation in pregnancy suggests a potential future in which a simple first-trimester blood test might identify women at higher risk for complications, enabling timely interventions – from low-dose aspirin to nutritional counselling to enhanced surveillance.”
Study details
Longitudinal epigenetic ageing in pregnancy and associations with adverse outcomes
Panelli, Danielle; Gladish, Nicole; Perlman, Nicola, et al.
Published in Obstetrics & Gynaecology in December 2025
Objective
To understand the relationship between pregnancy and epigenetic ageing estimated by DNA methylation “clocks,” which offers a molecular measure of biologic ageing.
Methods
This was a prospective cohort study of nulliparous women (age 18–50 years) seeking obstetric (pregnant 10–14 weeks) or gynaecologic (non-pregnant) care in 2020–2021. Blood was collected at enrolment (time 1) and postpartum day 1 (pregnant, time 2) or 7 months later (non-pregnant, time 2). Epigenetic age was measured with 11 established clocks from Illumina EPIC 2 arrays. Within-person changes in epigenetic age were compared with mixed-effects linear regression models adjusted for confounders and interval duration (days). Results were scaled per 200-day interval. P values were corrected for multiple testing. Multivariable logistic regression explored associations between first-trimester epigenetic age and a composite of potentially immune-mediated complications (hypertensive disorders, gestational diabetes mellitus, preterm birth before 37 weeks of gestation, and small-for-gestational-age birth weight) adjusted for age and body mass index (BMI) higher than 30 at time 1.
Results
In total, 75 women enrolled; 45 (60.0%) were pregnant, and 61 (81.3%) completed the study. Pregnant women exhibited significant within-person epigenetic age acceleration compared with nonpregnant women in six clocks (Hannum, PhenoAge, GrimAge, GrimAge2, Stem Cell Division, DunedinPACE). Additional epigenetic age acceleration per 200 days in the pregnant cohort ranged from 1.58 years (Hannum, 95% CI, 0.45–2.72, P=.01) to 5.28 years (PhenoAge, 95% CI, 2.97–7.61, P<.01). Each additional year of first-trimester GrimAge2 increased odds of the composite of pregnancy complications by 36% (adjusted odds ratio [aOR] 1.36, 95% CI, 1.01–1.84), while chronologic age (in continuous years) showed no association (aOR 1.00, 95% CI, 0.83–1.21).
Conclusion
Pregnancy accelerated within-person epigenetic aging by up to 5.3 years. Older first-trimester GrimAge2, but not chronologic age, was associated with a composite of pregnancy complications. These findings suggest that gestation may influence biologic ageing and support further investigation into epigenetic age as a potential marker of pregnancy health.
Medscape article – Epigenetic Analyses Show Women Age 5 Years During Pregnancy (Open access)
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