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Background <p>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 exposures and the methylation levels of the 558 individual CpGs comprising the RPC. Using data from the Extremely Low Gestational Age Newborns (ELGAN) study (<i>N</i> = 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.</p> Results <p>We observed a positive association between prenatal aspirin use and eGAA at borderline significance (β: + 0.35&#xa0;weeks gestation; 95% CI: − 0.01, 0.72). When stratified by sex, this finding was significant among females (β: + 0.63&#xa0;weeks gestation; 95% CI: 0.10, 1.17) but not males (β: − 0.05&#xa0;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 (<i>RXRA</i>), a nuclear receptor that can function as transcription factor and thereby influence multiple processes critical to placental development.</p> Conclusion <p>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.</p>

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Analysis of prenatal medication use and placental epigenetic gestational age in extremely low gestational age newborns (ELGANs) highlight relationships to aspirin use during pregnancy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Katelyn K. Huff,
  • Catherine M. Bulka,
  • Jeliyah Clark,
  • Kyle R. Roell,
  • T. Michael O’Shea,
  • Rebecca C. Fry

摘要

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 exposures and 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.