Analysis of Prenatal Medication Use and Placental Epigenetic Gestational Age in Extremely Low Gestational Age Newborns (ELGANs)

Sep 28, 2026

Uploaded by kopisore

Maternal medication exposures during pregnancy are linked to altered placental DNA methylation, yet their relationship to epigenetic gestational age remains unclear. This study evaluates prenatal medication use (antibiotics, acetaminophen, aspirin, and ibuprofen) against placental epigenetic gestational age acceleration (eGAA) using the Robust Placental Clock in ELGANs (N=408). Linear mixed-effects models and sex-stratified analyses account for multiple births. Prenatal aspirin shows sex-dependent associations, including methylation changes at specific CpGs, with implications for placental development.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Background

Results

Conclusion

Huff et al. Clinical Epigenetics (2026) 18:5 [https://doi.org/10.1186/s13148-025-01988-9](https://doi.org/10.1186/s13148-025-01988-9) Clinical Epigenetics RESEARCH Open Access Analysis of prenatal medication use and placental epigenetic gestational age in extremely low gestational age newborns (ELGANs) highlight relationships to aspirin use during pregnancy Katelyn K. Huff1,2, Catherine M. Bulka3, Jeliyah Clark2,4, Kyle R. Roell2,4, T. Michael O’Shea5 and Rebecca C. Fry 1,2,4* Abstract Background Several maternal exposures such as acetaminophen during pregnancy have been previously associated with altered placental CpG methylation. Epigenetic gestational age measures biological aging using DNA methylation from gestational tissues such as placenta and cord blood. We hypothesize that placental epigenetic gestational age (eGA) could serve as a biomarker for maternal exposures or pathological processes that influence placental development. To investigate relationships between maternal exposures and placental eGA, we evaluated prenatal medication use (antibiotics, acetaminophen, aspirin, and ibuprofen) in relation to placental epigenetic gestational age acceleration (eGAA) using the Robust Placental Clock (RPC) . We also examined associations between these four exposuresand the methylation levels of the 558 individual CpGs comprising the RPC. Using data from the Extremely Low Gestational Age Newborns (ELGAN) study (N = 408), we ran linear mixed-effects regression models that accounted for multiple births to the same mother. We further stratified by infant sex assigned at birth to assess effect measure modification. Results We observed a positive association between prenatal aspirin use and eGAA at borderline significance (β: + 0.35 weeks gestation; 95% CI: − 0 . 01, 0 . 72) . When stratified by sex, this finding was significant among females (β: + 0.63 weeks gestation; 95% CI: 0 . 10, 1. 17) but not males (β: − 0.05 weeks gestation; 95% CI: − 0 . 60, 0 .49) . Prenatal aspirin use in female pregnancies was further associated with ten differentially methylated RPC CpGs, mapping to genes including Retinoid X Receptor Alpha (RXRA), a nuclear receptor that can function as transcription factor and thereby influence multiple processes critical to placental development. Conclusion These findings highlight that prenatal aspirin use is associated with placental eGAA in a sex-dependent manner, and RPC CpG methylation is sensitive to maternal medication exposures. Additional research is required to validate these eGAA observations, and future research should investigate the mechanisms underlying these relationships and their potential long-term clinical implications in the infant. Keywords DNA methylation, Epigenetic gestational age, Placenta, Prenatal aspirin use *Correspondence: Rebecca C. Fry [rfry@unc.edu](rfry@unc.edu) Full list of author information is available at the end of the article © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by-nc-nd/4.0

FAQs

Which prenatal medications were analyzed in relation to placental epigenetic gestational age?

The study evaluated prenatal medication use for antibiotics, acetaminophen, aspirin, and ibuprofen, assessing their relationship to placental eGAA.

How was epigenetic gestational age acceleration (eGAA) measured?

eGAA was measured using the Robust Placental Clock (RPC), leveraging DNA methylation from placental-related gestational tissues and analyzing 558 individual CpGs included in the RPC.

What key finding links prenatal aspirin use to placental epigenetic aging?

Prenatal aspirin use was positively associated with eGAA at borderline significance overall, and the association was significant in females but not males. It also correlated with differentially methylated RPC CpGs mapping to genes such as RXRA.

Sep 28, 2026

Uploaded by kopisore