Review articleCardiovascular effects of prenatal stress—Are there implications for cerebrovascular, cognitive and mental health outcome?
Introduction
Prenatal exposure to adverse environmental influences during critical periods of development determines offspring health in later life to a great extent (‘Developmental Origins of Health and Disease (DOHaD) hypothesis’). Prenatal stress and low nutrient availability comprise major adverse prenatal environmental influences affecting the development of multiple fetal organ systems such as the cardiovascular system and the brain as well as their function in later life. Prenatal stress, i.e. increased fetal exposure to stress hormones or to indirect effects of maternal stress (Rakers et al., 2017a,b), mainly results from maternal stress and therapeutic glucocorticoid (GC) administration which shall be the focus of this review (Fig. 1). Other sources of prenatal stress such as malnutrition, smoking, substance abuse, preeclampsia and obesity are beyond the scope of this review since they may have direct (i.e. stress hormone independent) effects on fetal development. According to the studies available, we consider the following types of maternal stress: (1) maternal psychological distress including nonspecific perceived psychological stress, pregnancy-specific stress, anxiety and depression, and (2) negative life events experienced by the pregnant woman such as illnesses in the close family or financial and relationship problems About of pregnant women in industrialized countries and of pregnant women in low and middle income countries report maternal stress during pregnancy (UNFPA, 2008). Studying the effects of maternal stress is complicated by the fact that stress perception is subjective. In general, designing an experimental stress model relevant to the human situation has proved challenging. To overcome the subjective view and study the effects of maternal stress objectively, several researchers have examined the therapeutic administration of synthetic GCs on fetal development and offspring outcome (Anwar et al., 2016; Fowden and Forhead, 2015; Millage et al., 2016; Moisiadis and Matthews, 2014b). Synthetic GCs such as betamethasone (BM) and dexamethasone (DM) are widely used to accelerate fetal lung maturation in babies at risk of preterm delivery (Panel, 2001). Annually, around 15 million or of pregnant women worldwide deliver preterm (Blencowe et al., 2012) and GC therapy is administered to % of these mothers (Boesveld et al., 2014; Chandrasekaran and Srinivas, 2014; Lee et al., 2011). Synthetic GCs are used therapeutically since they easily cross the placenta and are not a substrate of placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The enzyme 11β-HSD2 inactivates of maternal cortisol (corticosterone in rats) and, thus, partially protects the fetus from maternal stress (Harris and Seckl, 2011). It is important to note that the effects of synthetic GCs on the fetus may differ from the effects of maternal stress in several ways. Maternal stress can be transferred from mother to fetus not only by cortisol but also by other mechanisms such as the catecholamine-mediated impairment of uterine blood supply (Rakers et al., 2017a,b). The latter does not occur after synthetic GC treatment (Schwab et al., 2006). Endogenous GCs such as cortisol or corticosterone in rodents bind to both glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) but synthetic glucocorticoids bind predominantly to GR (Kliewer et al., 1998). GR are ubiquitously expressed in the brain while MR are mainly located in the limbic system (Ahima et al., 1991). Activation of GR produce neurotoxic and apoptosis-inducing effects (Hassan et al., 1996; Packan and Sapolsky, 1990) and MR induce neuroprotective effects (Hassan et al., 1996). Saturation of MR occurs at much lower steroid concentrations than saturation of GR because MR have approximately a tenfold higher affinity for cortisol / corticosterone (Reul and Kloet, 1985). Cortisol at higher concentrations, typical for stressed individuals (McEwen et al., 1987), and synthetic GCs activate GR and induce neurotoxic effects (Hassan et al., 1996). Moreover, the biological potency of synthetic GCs is higher comparedto that of cortisol (Yang et al., 1990a). In the vasculature, GR and MR receptors are expressed in both endothelial and vascular smooth muscle cells (VSMCs) but activate different pathways (Tarjus et al., 2015; Yang and Zhang, 2004).
The fetal cardiovascular system and brain are particularly vulnerable to prenatal stress due to their long period of development and intrinsic plasticity (Bock et al., 2015; Brunton, 2015; Dyer and Rosenfeld, 2011; Polanska et al., 2017; Souza et al., 2017; Thornburg, 2015). This may occur as a result of the direct effect on the developmental trajectory of the brain and the vascular system or by changes in the activities of functional systems such as the renin-angiotensin-aldosterone-system (RAAS) and the stress axis with its two limbs, the hypothalamus-pituitary-adrenocortical (HPA) axis and the sympathetic-adrenomedullary system (SAS) which affect brain and cardiovascular function in later life (for reviews see (Anwar et al., 2016; Kapoor et al., 2006).
The effects of maternal stress and therapeutic prenatal GC exposure on offspring cognitive, behavioral and mental health problems in later life as well as the underlying changes in neurodevelopment and activity of the stress axis are well studied (van den Bergh, this issue). Less studied are the effects of maternal stress and prenatal GC exposure on the function of the cardiovascular system during both fetal and postnatal life (McMillen and Robinson, 2005; Nijland et al., 2008; Palinski, 2014). These effects are also of major interest with regard to the cognitive and mental health outcomes for several reasons. Firstly, disturbances in maternal-fetal circulation and fetal cerebrovascular function may affect neurodevelopment by restriction of nutrient and oxygen availability (Fig. 1). The developing brain consumes about 50% of the nutrient and oxygen supply (Gibbons, 1998). A severe decrease in nutrient supply, for example via disturbances in maternal-fetal circulation can lead to restriction in fetal growth in general (Malhotra et al., 2017a). Despite a compensatory redistribution of blood flow to the brain, fetal brain development is frequently altered under such conditions (Miller et al., 2016; Wang et al., 2016). Secondly, prenatal stress may program offspring cardiovascular dysfunction either by changing the function of the stress axis and the RAAS, or by programming vascular sensitivity to vasomediators (Fig. 1). Programming of vascular sensitivity may result in cardiovascular dysfunction and cerebrovascular disorders which could both be linked to cognitive and mental health disorders (Fig. 1). It has been suggested that a decrease in brain perfusion is due to alterations in the cerebral vasculature, rather than due to changes in the neural activity that underlies age-related cognitive changes during brain aging (Bell et al., 2010; Li and Freeman, 2010; Martin et al., 1991). Alteration in the contractility of cerebral vessels may diminish the supply of oxygen, energy substrates and nutrients to the brain. The importance of an adequate fuel supply for brain function is highlighted by the fact that although the brain comprises ∼2% of total body mass, it receives as much as 20% of cardiac output and is responsible for ∼20% and ∼25% of the body’s oxygen and glucose consumption, respectively (Nelson et al., 2016). Mild hypoperfusion affects protein synthesis which is required for synaptic plasticity, and for mediating learning and memory. In fact, moderate to severe reductions in cerebral blood flow (CBF) and hypoxia can affect ATP synthesis and the ability of neurons to generate action potentials (Kalaria, 2010).
Here, we review the acute, short-term (<7 days), long-term (<30 days), and persistent effects of maternal stress and prenatal GC exposure on maternal-fetal circulation as well as fetal cardiovascular and cerebrovascular development and function in later life (Fig. 1). We elucidate the potential mechanisms by which maternal stress and prenatal GC exposure affect maternal-fetal circulation and program the cardiovascular system taking into account the translational value of experimental research for the human situation. We search for knowledge on the relationship between fetal programming of cardiovascular function by maternal stress and prenatal GC exposure and cerebrovascular, cognitive and mental health outcomes. A comprehensive knowledge of the relevant mechanisms involved is invaluable to identify innovative targets for early prevention of cardiovascular as well as cerebrovascular, cognitive and mental health diseases.
Section snippets
Effects of maternal stress
Since impairment of placental circulation is considered a key mechanism by which maternal stress may affect the human fetus (Gitau et al., 2001; Rakers et al., 2017a, b), several studies investigated a possible relationship between different types of maternal stress (Table 1) and maternal-fetal circulation. A total of 13 prospective studies met the following criteria: use of standardized methods for assessing maternal stress, use of ultrasound Doppler sonography to measure fetal and placental
Effects of maternal stress
There are very few studies in the literature linking maternal stress to cardiovascular disease in later life compared to the numerous studies examining the relationship between low birth weight (LBW) and cardiovascular disease (for reviews see (Järvelin et al., 2004; Raaijmakers et al., 2017; Ylihärsilä et al., 2004). In the Amsterdam Born Children and their Development study, depressive symptoms, state anxiety, pregnancy-related anxiety, daily parenting stress, and job strain were recorded by
Underlying mechanisms
The cardiovascular effects in the offspring resulting from prenatal stress may be due to an increase in peripheral resistance or cardiac output. Increased vascular tone can either be the consequence of alterations in vascular composition or functional activity. If not stated otherwise, all results discussed below were obtained in sheep studies after prenatal GC administration.
Gender effects
Human studies. There are very few human studies in the literature that address the effects of maternal stress or prenatal GC treatment on maternal-fetal circulation and programming of cardiovascular function with respect to the sex of the fetus. The association between maternal stress and an increase in umbilical resistance (Helbig et al., 2013) seems to be independent of the of the sex of the fetus although these effects of an association between maternal stress and an increase in uterine
Overall summary
The inconsistent evidence available suggests at best that maternal stress in the form of maternal anxiety increases uterine resistance. The secondary decrease in nutrient and oxygen supply potentially affects neurodevelopment but this has not yet been shown and should be a focus of future research. In contrast, there is very limited evidence in humans on the programming effects of maternal stress on offspring cardiovascular function in later life. A moderately increased risk for cardiovascular
Acknowledgement
The authors received support from the EU FP7/Health.2011.2.22-2 GA 279281.
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Authors contributed equally to the paper.