Sex-specific impact of maternal–fetal risk factors on depression and cardiovascular risk 40 years later

Abstract

Major depressive disorder (MDD) and cardiovascular disease (CVD) represent leading causes of morbidity and mortality worldwide. We tested the hypothesis that growth restriction and preeclampsia (referred to as fetal risk) are significant predictors of these conditions, with women at higher risk in adulthood. Adult offspring exposed to fetal risk factors and their discordant siblings were from two prenatal cohorts, whose mothers were followed through pregnancy and whom we recruited as adults 40 years later (n=538; 250 males and 288 females). Subjects were psychiatrically diagnosed and underwent a stress challenge during which parasympathetic regulation was assessed by electrocardiogram, operationalized as high-frequency R-R interval variability (HF-RRV). Linear mixed models and generalized estimating equations were used to examine the relationship of fetal risk on HF-RRV, MDD and comorbidity of low HF-RRV (lowest 25th percentile) and MDD, including interactions with sex and socioeconomic status (SES). Fetal risk was significantly associated with low HF-RRV response (F=3.64, P=0.05), particularly among low SES (interaction: F=4.31, P<0.04). When stratified by MDD, the fetal risk impact was three times greater among MDD compared with non-MDD subjects (effect size: 0.21 v. 0.06). Females had a significantly higher risk for the comorbidity of MDD and low HF-RRV than males (relative risk (RR)=1.36, 95% CI: 1.07–1.73), an association only seen among those exposed to fetal risk (RR=1.38, 95% CI: 1.04–1.83). Findings suggest that these are shared fetal antecedents to the comorbidity of MDD and CVD risk 40 years later, an association stronger in females than in males.

Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease

“…Further, the comorbidity is significantly higher in women than in men (Naqvi et al, 2005; Moller-Leimkuhler, 2007; Goldstein et al, 2011). MDD alone has a higher prevalence in women (almost 2-fold) (Kessler et al, 1993; Kessler et al, 2003; Kendler et al, 2006), and is an independent risk factor for the development and progression of coronary artery disease (Kawachi et al, 1994a; Kawachi et al, 1994b; Barefoot et al, 1996; Everson et al, 1997; Musselman et al, 1998), even though the risk for CVD alone is higher in men (Lloyd-Jones et al, 2010).…”

Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: A preliminary study

“…The comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) will be the leading cause of disability world wide by 2020 [28], and is significantly higher in women [8, 30]. Literature on the pathophysiology of sex differences in MDD provides evidence of disruption of several circuits involved in the response to stress [13, 18], including hypothalamic-pituitary-gonadal (HPG) axis, the network of brain regions associated with arousal, and the parasympathetic component of the autonomic nervous system (ANS) [5].…”

“…In particular, MDD has been associated with parasympathetic cardiac dysregulation [10]. We recently demonstrated, in a large population-level cohort study, that fetal risk factors have a significant impact on the comorbidity between MDD and low parasympathetic reactivity in adulthood, a finding specific to women [8], suggesting that MDD-CVD comorbidity in women has its origins during fetal development. With the current pilot study, we take the next step in this research, extending the focus to examine the pathophysiology of this sex-specific comorbidity in two additional key systems, stress response circuitry in the brain and the HPG-axis, in parallel with RRV.…”

Impact of fetal versus perinatal hypoxia on sex differences in childhood outcomes: developmental timing matters

“…For example, a recent study documented a link between emotional causes of pain in primary and secondary school and anxiety in adulthood [77]. Further, fetal risk factors, particularly occurring during mid-gestation, have been implicated in major depressive disorder [7, 9–10, 78], which may be associated with birth outcomes, such as low birth weight or neonatal intensive care unit admission, and their association with depression in adulthood [2, 78]. In fact, animal studies of fetal risk factors in stress response circuitry (i.e.…”