Maternal chronic stress correlates with serum levels of cortisol, glucose and C-peptide in the fetus, and maternal non chronic stress with fetal growth
Introduction
“Stress’’ is a state of disharmony or threat to homeostasis. The hypothalamic-pituitary-adrenal (HPA) axis and the locus ceruleus–norepinephrine (LC/NE) autonomic systems are the main components of the endocrine response to stress (Chrousos and Gold, 1992). During pregnancy, a state of relative hypercortisolism ensues, with increased serum levels of CRH (secreted from the placenta) in the maternal circulation, especially during the 3rd trimester (Magiakou et al., 1996). Placental CRH has been proposed as a potential predictor for preterm, term, or post-term labor (Mastorakos and Ilias, 2000). During pregnancy, chronic or acute maternal stressors may influence the function of both maternal and fetal HPA axes in the short-term, and offspring physiology in the long-term. In sheep, chronic psychosocial maternal stress during early gestation associates with increased levels of serum cortisol (both baseline and stress-induced) and norepinephrine in the fetus, indicating hyperactivity in the fetal HPA-axis and sympathetic-adrenal-medullary system (Bischoff et al., 2018). Premature activation of the fetal HPA axis may result from an adverse intra-uterine environment, such as hypoxemia. Excessive serum levels of glucocorticoids in the fetus due to sustained endogenous fetal cortisol production, associates with intrauterine growth restriction (Challis et al., 2001).
Insulin resistance is a feature of normal pregnancy, described as an adaptive phenomenon to divert maternal glucose towards fetal needs (Radaelli et al., 2003). We have shown previously in a cohort of normal pregnant women, that long-term stress (assessed through use of the STAI trait questionnaire) associates with decreased maternal insulin sensitivity (Valsamakis et al., 2017). Other studies in humans have shown that exposure of the mother to prenatal psychosocial stress associates with development of insulin resistance in the offspring, assessed during young adulthood (Entringer et al., 2008). Similar studies in rats have shown that maternal exposure to prenatal stress associates with induction of intrauterine growth restriction (IUGR) and glucose intolerance (Lesage et al., 2004). Furthermore, chronic heat stress in maternal ewes induced a shift towards glucose metabolism within the fetal liver, which as the authors stated, could be explained by stress- and cortisol-induced increased activity of gluconeogenic enzymes within the fetal liver (Dreiling et al., 1991).
Low birth weight (LBW), prematurity and IUGR remain leading causes of perinatal morbidity, mortality, neurodevelopmental impairments and disabilities among newborn babies. Placental CRH, cortisol and other hormones that cross the placenta, could result in retardation of fetal growth rate, reduced birth weight and precipitation of preterm labor in prenatally stressed fetuses (Weinstock, 2005). Animal studies confirmed that increased serum levels of stress hormones and pro-inflammatory cytokines in the fetal compartment during sensitive or critical developmental windows, can have an impact on the structure and function of the brain and peripheral targets that are related to body composition, energy balance homeostasis and metabolic function (i.e., adipose tissue, pancreas, and liver) (Paternain et al., 2013 Lesage et al., 2004). Current evidence suggests that maternal stress experienced early in gestation, has more serious consequences for the offspring than stress experienced later in gestation (Mueller and Bale, 2007).
STAI is a well-standardized, self-reported questionnaire designed to measure both ‘state’ and ‘trait’ anxiety. Feelings of anxiety may occur in stressful situations. State anxiety refers to fear, nervousness, discomfort, and arousal of the autonomic nervous system, all induced temporarily by situations perceived as dangerous (i.e., how a person is feeling at the time of a perceived threat) reflecting non chronic stress. Conversely, trait anxiety refers to a relatively enduring predisposition to feelings of stress, worry, and discomfort (Spielberger and Sydeman, 1994). Within the literature, there is good establishment and usage of the STAI trait and state questionnaire for use in pregnancy for the purpose of assessment of maternal stress (Rondó et al., 2003 DiPietro et al., 2006). However, to date there is insufficient data regarding the impact of duration of maternal stress (acute or non chronic vs long-term) on fetal growth and/or metabolism. To address this, we investigated the impact of maternal non chronic and chronic stress (evaluated by STAI state and trait questionnaires respectively and maternal serum levels of CRH, cortisol, and IL6) on serum levels of cortisol, glucose metabolism and growth pattern within the fetus.
Section snippets
Subjects
Primigravidae caucasian women (n = 220) were recruited during the first trimester of pregnancy from an antenatal outpatient clinic of a university hospital in Greece, between May 2015 and December 2017. To avoid bias, we used a computer software random numbers generator for recruitment purposes. Women who presented with miscarriages during the first trimester of pregnancy (n = 12) were not included in the protocol. Following psychiatric assessment during the first trimester, women with past or
Anthropometric, hormonal, metabolic and psychometric variables
Maternal weight increased significantly between each trimester (p < 0.05), with a median increase of 11.5 kg between the 1st and 3rd trimester. Maternal systolic blood pressure values increased significantly from the 2nd to the 3rd trimester. Maternal fasting serum cortisol and CRH concentrations increased significantly from the 2nd to the 3rd trimester, whilst serum IL6 concentrations did not. STAI state scores showed a statistically significant increase from the 2nd to the 3rd trimester,
Discussion
We demonstrate that in normal weight pregnant women, maternal STAI state scores and fasting serum levels of CRH and cortisol concentrations increase from the 2nd to the 3rd trimester. In the 2nd trimester, maternal serum CRH concentrations correlate positively with maternal STAI state scores and maternal serum cortisol concentrations, whilst in the 3rd trimester, maternal serum CRH concentrations correlate positively with maternal STAI state scores ≥40 and maternal serum cortisol
Funding
Prof George Mastorakos received funding from Athens University. The funding source played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication
Author contribution paragraph
“G.V. designed the study, researched, analyzed and interpreted the data and wrote the manuscript; D.P., C.N., and M.M. researched data; I.P. and A.M. performed blood chemistry and revised the manuscript; S.K., T.M.B. and S.K. interpreted data and revised the manuscript; G.M. designed the study, interpreted data and reviewed the manuscript.
Declaration of Competing Interest
The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.
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