Research Paper Volume 11, Issue 15 pp 5412—5432

Sex differences in the associations of placental epigenetic aging with fetal growth

Fasil Tekola-Ayele 1, , Tsegaselassie Workalemahu 1, , Gezahegn Gorfu 2, , Deepika Shrestha 1, , Benjamin Tycko 3, , Ronald Wapner 4, , Cuilin Zhang 1, , Germaine M. Buck Louis 5, ,

  • 1 Epidemiology Branch, Division of Intramural Population Health Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
  • 2 Department of Clinical Laboratory Science, College of Nursing and Allied Health Sciences, Howard University, Washington, DC 20059, USA
  • 3 Hackensack-Meridian Health Center for Discovery and Innovation and the Hackensack-Meridian Health School of Medicine at Seton Hall University, Nutley, NJ 07110, USA
  • 4 Department of Obstetrics and Gynecology, Columbia University, New York, NY 10032, USA
  • 5 Dean’s Office, College of Health and Human Services, George Mason University, Fairfax, VA 22030, USA

received: March 28, 2019 ; accepted: July 21, 2019 ; published: August 8, 2019 ;
How to Cite

Copyright © 2019 Tekola-Ayele et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Identifying factors that influence fetal growth in a sex-specific manner can help unravel mechanisms that explain sex differences in adverse neonatal outcomes and in-utero origins of cardiovascular disease disparities. Premature aging of the placenta, a tissue that supports fetal growth and exhibits sex-specific epigenetic changes, is associated with pregnancy complications. Using DNA methylation-based age estimator, we investigated the sex-specific relationship of placental epigenetic aging with fetal growth across 13-40 weeks gestation, neonatal size, and risk of low birth weight. Placental epigenetic age acceleration (PAA), the difference between DNA methylation age and gestational age, was associated with reduced fetal weight among males but with increased fetal weight among females. PAA was inversely associated with fetal weight, abdominal circumference, and biparietal diameter at 32-40 weeks among males but was positively associated with all growth measures among females across 13-40 weeks. A 1-week increase in PAA was associated with 2-fold (95% CI 1.2, 3.2) increased odds for low birth weight and 1.5-fold (95% CI 1.1, 2.0) increased odds for small-for-gestational age among males. In all, fetal growth was significantly reduced in males but not females exposed to a rapidly aging placenta. Epigenetic aging of the placenta may underlie sex differences in neonatal outcomes.


BMI: body mass index; CpG: cytosine-phosphate-guanine genomic site; NICHD: Eunice Kennedy Shriver National Institutes of Child Health and Human Development; PAA: placental age acceleration; SGA: small-for-gestational age.