Prenatal Major Depressive Disorder, Placenta Glucocorticoid and Serotonergic Signaling, and Infant Cortisol Response

Abstract

Objectives: Extending prior studies of prenatal adversity and depressive symptoms, we tested associations between maternal prenatal major depressive disorder (MDD) and infant cortisol regulation. Based on prior findings by our group, we also tested placenta glucocorticoid (HSD11B2 methylation) and serotonin (SLC6A4 gene expression) signaling as moderators of links between prenatal MDD and infant cortisol.

Methods: Participants were 153 mother-infant pairs from a low-income, diverse sample (M [SD] age = 26 [6] years). Repeated structured diagnostic interviews were used to identify mothers with (a) prenatal MDD, (b) preconception-only MDD, and (c) controls. Placenta samples were assayed for HSD11B2 methylation and SLC6A4 gene expression. Infant salivary cortisol response to a neurobehavioral examination was assessed at 1 month.

Results: Daughters of prenatal MDD mothers had 51% higher baseline (ratio = 1.51; 95% confidence interval [CI] = 1.01-2.27; p = .045) and 64% higher stress responsive cortisol (ratio = 1.64; 95% CI = 1.05-2.56; p = .03) than daughters of controls and 75% higher stress-responsive cortisol (ratio = 1.75; 95% CI = 1.04-2.94; p = .04) than daughters of preconception-only MDD mothers. HSD11B2 methylation moderated links between prenatal MDD and baseline cortisol (p = .02), with 1% methylation decreases associated with 9% increased baseline cortisol in infants of prenatal MDD mothers (ratio = 1.09; 95% CI = 1.01-1.16). SLC6A4 expression moderated links between prenatal MDD and cortisol response among boys alone (p = .007), with 10-fold increases in expression associated with threefold increases in stress-responsive cortisol (ratio = 2.87; 95% CI = 1.39-5.93) in sons of control mothers.

Conclusions: Results highlight specificity of associations between prenatal versus preconception MDD and cortisol regulation and the importance and complexity of placenta glucocorticoid and serotonergic pathways underlying the intergenerational transmission of risk from maternal adversity.

Figure 1.

Cortisol response to the NICU Network Neurobehavioral Scale (NNNS) in three groups of one-month old neonates: Prenatal MDD (neonates exposed to mothers with prenatal major depressive disorder), Preconception MDD (neonates exposed to mothers with MDD prior to but not during pregnancy), and Controls for (A) overall sample and (B) daughters only. Note. Four saliva samples were collected for cortisol during and after the NNNS (baseline, end of NNNS, 20 and 40 minutes following the NNNS). Although baseline and area under the curve (AUC) cortisol were modeled in the logarithmic scale for statistical analyses, results are presented with raw mean cortisol values for ease of visual display.

Figure 2.

Model-based interaction between prenatal depression group and placental HSD11B2 methylation on baseline cortisol at one month. Note. Although baseline cortisol was modeled in the logarithmic scale for statistical analyses, fitted values are presented in the original cortisol scale. Fitted values are presented controlling for education, and time since feeding.