Stress, the Placenta, and Fetal Programming of Behavior: Genes' First Encounter With the Environment.

Stress and stressors to the pregnant mother have long been implicated in adverse pregnancy outcomes such as preterm birth (1–3) and low birth weight infants (4, 5), postpartum depression (6), and are a risk factor for later psychiatric illness in the developing child (7, 8). How stress leads to these outcomes has been difficult to elucidate, and long-term follow-up of mothers and their children, with incorporation of prenatal andpostnatal biomarkers, posesmany research and pragmatic challenges. Stressedmothers, who frequentlymeet criteria for anxiety and depression, partially transmit the risk for these illnesses to their babies through their genetics. These mothers may also have difficulties in parenting after birth that can further contribute adversely to the child’s development (9, 10). In this issue of the Journal, Catherine Monk, Ph.D., and her collaborators (11) describe a third mechanism, the epigenetic modification of glucocorticoid genes in the placenta as part of the mother’s perception of, and response to, stress. This investigation was driven by the hypothesis that higher maternal distress would alter DNA methylation of genes associated with glucocorticoid transfer across the placenta, thereby altering fetal exposure to maternal glucocorticoids. Furthermore, the authors hypothesized that elevated maternal cortisol would be associated with less DNA methylation of the gene that regulates the enzyme involved in blocking cortisol transfer across the placenta. Both psychological and physiologic measures of prenatal distress were hypothesized to influence fetal neurobehavior in association with placental methylation differences. In 61 pregnant women, the authors examined four psychological measures of stress and mood (perceived stress, depression, anxiety, and pregnancy-specific stress) and a maternal physiologic stress marker of hypothalamic-pituitaryadrenal (HPA) axis function (salivary cortisol area under the curve) measured between 24 and 27 weeks gestation. They included a fetal assessment of autonomic nervous system function and maturation, termed “coupling,” measured between 34 and 37 weeks gestation. The measure “coupling” is a ratio of fetal movement and fetal heart rate, with higher levels of coupling being associated with improved neural integration at birth (12, 13). Both psychological and physiologic maternal measures were analyzed in relation to methylation patterns of three glucocorticoid-related placental genes and in relation to fetal movement and fetal heart rate “coupling” in the late third trimester. Overall, the study population had low maternal distress scores, favorable pregnancy outcomes such as delivery at term of babies with a normal range of birth weights, and overall small absolute degrees of placental methylation variation for the three genes assessed. No association was noted between psychological and physiologic measures of maternal distress or between these measures and fetal coupling. Additionally, there was no association between maternal cortisol area under the curve and methylation of any of the glucocorticoid genes assessed. What the authors did discoverwere relationships betweenmaternalmood, placental DNA methylation of the gene that codes for the enzyme 11-beta-hydroxysteroid dehydrogenase type 2, a “barrier enzyme that inactivates cortisol,” and fetal coupling (14). Greater methylation of this gene was significantly associated with less fetal coupling. More methylation of this gene presumably leads to less enzyme expression and less inactivation of cortisol by the placenta. Thus, thisalterationwould lead to more fetal cortisol exposure, and more fetal cortisol exposure is associated with changes in brain-behavior development, including increased emotionality and impaired learning and motor development (15). While early childhood developmental changes resulting fromalteredplacentalmethylationwerenot assessed in this study, a difference in fetal coupling was ascertained. From the data presented, therefore, we may infer that the finding of less fetal coupling in this study may be driven by increased fetal cortisol exposure secondary to increased methylation. The authors further divided the participants into methylation tertiles and discovered that placentas in the lowest tertile of methylation of HSD11B2 were associated with lower mean Perceived Stress Scale scores than those in the highest tertile. Clinically, this suggests that mothers who are least distressed produce placentas that have lessmethylation of the cortisol deactivating gene and are more successful at buffering their fetuses from the negative influence of stress. Placentas in the lowest tertile of methylation of HSD11B2 Stress during pregnancy, interacting with both the mother’s and the baby’s genes, can have life-long effects on the baby’s development through childhood and into adulthood.