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2: DNA methylation of genes in the maternal HPA axis during pregnancy is linked with birth outcomes

      Objective

      Exposure to psychosocial stress has been shown to be related to a variety of epigenetic changes including DNA methylation. The aim of this study was to examine exposure to psychosocial stress and DNA methylation during pregnancy on birth outcomes.

      Study Design

      A multi-site longitudinal study was conducted in a total of 744 pregnant women. Exposure to stress was assessed using a battery of self-reports to derive a latent stress factor as well as the interviewer-based Stressful Life Events Schedule (SLES). Pyrosequencing of bisulfite converted DNA was performed covering two regulatory regions in each of the Corticotropin Releasing Hormone (CRH), CRH Receptor 1 (CRHR1) and Nuclear Receptor Subfamily 3, Group C, Member 1 (Glucocorticoid Receptor) (NR3C1) genes measured during the 2nd and 3rd trimesters. Birth outcomes included small for gestational age (below 10th percentile), spontaneous pre-term birth (<37 weeks’ gestation) gestational age at delivery, and birth weight. Analyses controlled for age, body mass index, smoking, race, and newborn’s sex as well as cell-types based on the mRNA levels of CD4, CD19, CD3E, CD8A, and CD19 assessed in peripheral blood.

      Results

      Latent class trajectory analyses identified three SLES stress trajectories across pregnancy - low stable, moderate-decreasing, and high-increasing. Increased levels of SLES stress during pregnancy (high-increasing) had a significant association with spontaneous pre-term birth (p < 0.03). In addition, increased SLES stress was associated with a reduction in methylation in a highly-methylated region of CRH, which in turn was associated with earlier gestational age at delivery. Self-report stress was significantly and positively associated with the extent of DNA methylation of the CRHR1 gene (p < 0.03) during the third trimester and was significantly associated with an increase in methylation in CRHR1 gene from 2nd to 3rd trimester (p < 0.05) among women with preterm birth. Finally, increased methylation of NR3C1 at the 2nd trimester as associated with decreased birthweight (p < 0.04).

      Conclusion

      Maternal stress is associated with preterm birth and a reduction in birthweight that appears to be in part moderated by changes in DNA methylation in genes central to the stress response during pregnancy.