Pregnancy was found to accelerate epigenetic aging by up to 5.3 years in nulliparous women, a prospective study has found. Further, an older first trimester epigenetic age was associated with a composite of pregnancy complications, although chronological age was not.

“Our results suggest that biological aging 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, Gynecology and Maternal Fetal Medicine at Stanford University in Palo Alto, California.

Maternal mortality rates in the US outstrip those in other high-income countries, a fact that is exacerbated by a sharp spike in pregnancies in women older than 40 years. 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 new study, published in Obstetrics & Gynecology, suggests that chronologic age alone is not a reliable predictor of adverse outcomes.

“[S]ome 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.”

Panelli told Medscape Medical News, “The most interesting part about epigenetic age, or any type of biological age, is that, unlike chronological age, it is modifiable. 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.”

Panelli and her colleagues screened 305 women, ultimately recruiting a prospective cohort of 75 nulliparous women aged between 18 and 50 years who sought obstetric (10-14 weeks’ pregnant) or gynecologic (nonpregnant) care in 2020 through 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 nonpregnant 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 nonpregnant 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 nonpregnant group. Most women were in their early thirties.

The investigators took blood samples from participants at enrollment (time 1) and either at postpartum day 1 (pregnant, time 2) or 7 months postpartum (nonpregnant, time 2). The women’s respective epigenetic ages were measured with eleven 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 aging, driven by cumulative molecular changes that increase disease vulnerability, is strongly linked to morbidity in nonpregnant adults,” Panelli and her coauthors wrote.

Using multivariable logistic regression, Panelli and colleagues 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 enrollment.

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 nonpregnant 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 aging 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 nonpregnant 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 Gynecology at Columbia University, Irving Medical Center, New York City, wrote that the finding that there is an association between elevated GrimAge2-measured aging in early pregnancy and subsequent complications is “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 nonpregnant populations,” Williams and Suh 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 counseling to enhanced surveillance.”

For family medicine physician, Cynthia Chen-Joea, MD, who was not involved with study, the results signal what women’s medicine could be, rather than what it currently is.

“The big take-away of this study is the fact that there are so many modifiable risk factors that we maybe have not focused on as much in maternal care,” Chen-Joea said in an interview with Medscape Medical News. She is the medical director of both inpatient medicine at the Charles R. Drew University of Medicine and Science, in Los Angeles, and the Copa de Oro Medical Group in Norwalk, California.

“I think this study is actually revolutionary and suggests how we’re going to be providing maternal care in the future, by focusing on the individual person and the molecular levels of their risk factors,” said Chen-Joea.

The authors had no relevant financial disclosures. Williams, Suh, and Chen-Joea had no relevant financial disclosures.