Analysis of Pregnancy Complications and Epigenetic Gestational Age of Newborns

Abstract

Importance: Preeclampsia, gestational hypertension, and gestational diabetes, the most common pregnancy complications, are associated with substantial morbidity and mortality in mothers and children. Little is known about the biological processes that link the occurrence of these pregnancy complications with adverse child outcomes; altered biological aging of the growing fetus up to birth is one molecular pathway of increasing interest.

Objective: To evaluate whether exposure to each of these 3 pregnancy complications (gestational diabetes, gestational hypertension, and preeclampsia) is associated with accelerated or decelerated gestational biological age in children at birth.

Design, setting, and participants: Children included in these analyses were born between 1998 and 2018 and spanned multiple geographic areas of the US. Pregnancy complication information was obtained from maternal self-report and/or medical record data. DNA methylation measures were obtained from blood biospecimens collected from offspring at birth. The study used data from the national Environmental Influences on Child Health Outcomes (ECHO) multisite cohort study collected and recorded as of the August 31, 2021, data lock date. Data analysis was performed from September 2021 to December 2022.

Exposures: Three pregnancy conditions were examined: gestational hypertension, preeclampsia, and gestational diabetes.

Main outcomes and measures: Accelerated or decelerated biological gestational age at birth, estimated using existing epigenetic gestational age clock algorithms.

Results: A total of 1801 child participants (880 male [48.9%]; median [range] chronological gestational age at birth, 39 [30-43] weeks) from 12 ECHO cohorts met the analytic inclusion criteria. Reported races included Asian (49 participants [2.7%]), Black (390 participants [21.7%]), White (1026 participants [57.0%]), and other races (92 participants [5.1%]) (ie, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple races, and other race not specified). In total, 524 participants (29.0%) reported Hispanic ethnicity. Maternal ages ranged from 16 to 45 years of age with a median of 29 in the analytic sample. A range of maternal education levels, from less than high school (260 participants [14.4%]) to Bachelor's degree and above (629 participants [34.9%]), were reported. In adjusted regression models, prenatal exposure to maternal gestational diabetes (β, -0.423; 95% CI, -0.709 to -0.138) and preeclampsia (β, -0.513; 95% CI, -0.857 to -0.170), but not gestational hypertension (β, 0.003; 95% CI, -0.338 to 0.344), were associated with decelerated epigenetic aging among exposed neonates vs those who were unexposed. Modification of these associations, by sex, was observed with exposure to preeclampsia (β, -0.700; 95% CI, -1.189 to -0.210) and gestational diabetes (β, -0.636; 95% CI, -1.070 to -0.200), with associations observed among female but not male participants.

Conclusions and relevance: This US cohort study of neonate biological changes related to exposure to maternal pregnancy conditions found evidence that preeclampsia and gestational diabetes delay biological maturity, especially in female offspring.

Figure 1.. Association of Prenatal Exposure to Gestational Diabetes With Decelerated Epigenetic Gestational Age in Neonates

A, Graph shows correlation between estimated epigenetic age and reported chronological age. Each data point represents a participant’s gestational age at birth according to exposure to gestational diabetes during development. Lines represent the average residual values among a group of participants with or without exposure and in the overall sample (dark blue line). B, Violin plots show the difference between estimated epigenetic age and reported chronologic age (linear regression residuals) for neonates with and without prenatal exposure to gestational diabetes. Lines within boxes denote medians, tops of boxes denote 75th percentiles, bottoms of boxes denote 25th percentiles, black vertical lines denote complete ranges, and black dots denote outliers.

Figure 2.. Association of Prenatal Exposure to Preeclampsia With Decelerated Epigenetic Gestational Age in Neonates

A, Graph shows correlation between associated epigenetic age and reported chronological age. Each data point represents a participant’s gestational age at birth among neonates with and without exposure to preeclampsia during development. Lines represent the average residual values among a group of participants with or without exposure and in the overall sample (dark blue line). B, Violin plots show the difference between estimated epigenetic age and reported chronological age (linear regression residuals) for neonates with and without prenatal exposure to preeclampsia. Lines within boxes denote medians, tops of boxes denote 75th percentiles, bottoms of boxes denote 25th percentiles, black vertical lines denote complete ranges, and black dots denote outliers.

Figure 3.. Association of Prenatal Exposure to Gestational Hypertension With Decelerated Epigenetic Gestational Age in Neonates

A, Graph shows correlation between estimated epigenetic age and reported chronological age. Each data point represents a participant’s gestational age among neonates with and without exposure to gestational hypertension during development. Lines represent the average residual values among a group of participants with or without exposure and in the overall sample (dark blue line). B, Violin plots show the difference between predicted epigenetic age and reported chronologic age (linear regression residuals) for neonates with and without prenatal exposure to gestational hypertension. Lines within boxes denote medians, tops of boxes denote 75th percentiles, bottoms of boxes denote 25th percentiles, black vertical lines denote complete ranges, and black dots denote outliers.