ACEs, Depressive and Anxiety Symptoms, and NAS in Early Pregnancy Among Low-Income Women of Color

Perinatal mental health disorders are common, with about 6.5% to 12.9% of women experiencing depression during the perinatal period and about 19.4% of women experiencing anxiety during pregnancy. Women, especially women of color, also experience increased rates of adverse childhood experiences (ACEs), which are potentially traumatic events that occur before age 18. ACEs are associated with an increased likelihood of developing depression and anxiety, especially during the perinatal period. Changes in the sex steroid hormones estrogen and progesterone (P4) contribute to the development of perinatal mood disorders. Endogenous neuroactive steroids (NAS), metabolites of P4, rapidly affect neuronal signaling and modulate the inhibitory γ-aminobutyric acid (GABA) system and membrane-bound GABA type A receptors (GABAARs). Allopregnanolone (ALLO) and pregnanolone (PA) are positive allosteric modulators (PAMs) of GABAARs, and isoallopregnanolone (ISO) and epipregnanolone (EPI) are negative modulators of the GABAAR that antagonize the effects of ALLO and PA. ALLO influences the hypothalamic-pituitary-adrenal (HPA) axis, which controls stress responses. Exogenous ALLO shows efficacy in the clinical treatment of postpartum depression (PPD), but research to date shows inconsistent associations of ALLO with depression and anxiety and PA with anxiety and post-traumatic stress disorder (PTSD) across pregnancy. Early life stress (ELS) in animals and chronic stress both appear to lower ALLO levels and ALLO:P4 ratios, likely due to NAS modulation and disruptions in the HPA axis, potentially resulting from GABAAR dysregulation and impairment of the HPA axis stress response feedback loop. ACEs and ELS alter the HPA axis during pregnancy and postpartum in both animal and human models. No clinical studies to date have examined NAS levels in relation to ACEs in pregnant women. This study aimed to determine if antenatal NAS levels and ratios of NAS metabolites to precursor P4 mediate any association of ACE with depression and anxiety in a cohort of primarily low-income women of color (about 50% non-Hispanic Black and 33% Hispanic) in early pregnancy. Data include self-reported ACE, depression, and anxiety symptoms from 147 women under 20 weeks gestation. A subset of participants (N=80) also completed neuroactive steroid assays. An increase in self-report ACE score was significantly positively associated with the symptom severity of antenatal depression and anxiety. The ratio of EPI to P4 was positively associated with the number of total ACE categories experienced, while other NAS, including ALLO, PA, and ISO levels, and their ratios to P4, as well as EPI and P4 levels alone, were unrelated to mental health outcomes. There was no mediation effect of the ratio of EPI:P4 on the associations of ACEs with depression and anxiety symptom severity. This thesis emphasizes the significant impact of ACEs on the severity of mental health during early pregnancy and recommends that future studies focus on the lesser-explored metabolites and enzymes involved in the NAS biosynthesis pathway.