Maternal hypothalamus-pituitary-adrenal (HPA) system activity and stress during pregnancy: Effects on gestational age and infant’s anthropometric measures at birth
Introduction
Accumulating evidence from animal, epidemiological, clinical and experimental studies indicates that prenatal stress can profoundly affect fetal development and may have long-lasting effects on animal offspring, as well as on child and adult vulnerability to disease (e.g., Seckl and Holmes, 2007; O’Donnell et al., 2009; Glover et al., 2010). Barker’s ‘fetal programming’ hypothesis established a conceptual framework for prenatal stress research based on the observation that prenatal environmental conditions, low birth weight and propensity to cardio-metabolic disorders in adulthood are related (Barker and Osmond, 1986; Barker et al., 1993). Adjustments to the environment during pregnancy are thought to lead to permanent changes of fetal physiology which may be maladaptive in modified circumstances postnatally and, thus, predispose for later life disease (e.g., Gluckman et al., 2005).
Reduced neonatal anthropometric measurements at birth are a common clinical marker of an adverse intrauterine environment. For instance low birth weight, even within the normal range, is still a major issue in perinatal medicine (Wardlaw et al., 2004). It is related to negative health outcomes ranging from long-term physiological, emotional to behavioral disturbances (e.g, Glover, 2015; Harris and Seckl, 2011; Lee and Houk, 2012).
Findings from human stress research suggest a wide spectrum of prenatal stressors underlying fetal programming ranging from extreme stressors such as exposure to famine, disasters or terror (Lederman et al., 2004; Roseboom et al., 2006; Xiong et al., 2008) to minor strain caused by daily hassles or mood symptoms (Grote et al., 2010; Henrichs et al., 2010). While the impact of antenatal manifest psychiatric disorders (e.g., depression or anxiety as stress-related disorders) on negative obstetric and neonatal outcome has been demonstrated in various studies (e.g., Maina et al., 2008; Hobel et al., 2008; Loomans et al., 2013; Shapiro et al., 2013; Yedid Sion et al., 2015), the effect of moderate distress induced by subclinical psychiatric symptoms or pregnancy-related anxiety and worries is rarely investigated in this context (Rice et al., 2010; Wadhwa et al., 2011).
Prenatal stress effects are thought to be at least partly mediated by maternal-placental-fetal neuroendocrine mechanisms (Glover, 2015; Wadhwa, 2005). However, findings associating prenatal stress and mood symptoms with altered maternal glucocorticoid concentrations are controversial. In non-pregnant individuals an influence of psychosocial distress on altered HPA-function is assumed – in particular elevated diurnal cortisol patterns (e.g, Vreeburg et al., 2009). Findings on stress-induced alterations in cortisol secretion during pregnancy are still more controversial. Some studies associate psychosocial distress – such as stressful life events (Obel et al., 2005), symptoms of depression (O’Connor et al., 2014) and anxiety (Kivlighan et al., 2008)- in late pregnancy with altered diurnal cortisol concentrations, particularly decreased morning levels and flattened diurnal decline. Other studies were unable to find stress dependent alterations in maternal glucocorticoid values (Salacz et al., 2012).
Over-exposure of the developing fetus to glucocorticoids is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome (Cottrell et al., 2012; Edwards et al., 1993). The placental barrier enzyme 11ß-hydroxysteroid-dehydrogenase type 2 (11ß-HSD 2) converts about 80–90% of the biological active cortisol into its inactive metabolite cortisone (Murphy et al., 1974) and physiologically protects the developing fetus from the ten-fold higher maternal cortisol concentrations (Edwards et al., 1993).
To provide an appropriate intrauterine environment for the developing fetus the maternal hypothalamic-pituitary-adrenal (HPA) system undergoes crucial alterations. Throughout pregnancy maternal cortisol concentrations in serum rise up to three-fold non-pregnant level (Jung et al., 2011).
This is partly due to the release of large quantities of placental corticotropin-releasing hormone (CRH) (Campbell et al., 1987), which stimulates cortisol secretion from maternal adrenal gland directly and via maternal pituitary and subsequent adrenocorticotropic hormone (ACTH) release.
Thus, circadian cortisol rhythmicity (peaking in response to awakening and consecutive decline over the day) remains stable over the course of pregnancy (Entringer et al., 2010). These high levels of maternal cortisol during pregnancy drop postpartum, although it takes several weeks (up to 3–4 month postpartum) until level establish at normal values (Kirschbaum and Hellhammer, 1989).
About 10–20% of intact maternal cortisol crosses the placental barrier (Benediktsson et al., 1997). This doubles fetal concentrations at mid to late gestation (Gitau et al., 1998) although human placental 11ß-HSD2 increases according to the rising levels of maternal cortisol throughout gestation (McTernan et al., 2001).
Due to the large gradient in concentration between both compartments (maternal/fetal-ratio 11:4), the fetus is directly dependent on maternal cortisol values, depending on the time of gestation. The fetus is more dependent on the maternal cortisol early in gestation and less so toward the end of gestation, with fetal HPA activity beginning at midgestation (e.g., Gitau et al., 2001; Mastorakos and Ilias, 2003). The placental CRH also stimulates fetal hormone output and is linked with the activation of the fetal HPA (Challis et al., 2001). The fetal HPA activity begins at midgestation and fetal stress responses are independent of maternal responses (Gitau et al., 2001). However, minor changes in maternal cortisol concentrations and placental 11ß-HSD2 function might be able to profoundly influence fetal glucocorticoid exposure and may play a crucial role in transmitting prenatal early life stress (ELS) to the fetus (Gitau et al., 1998).
Evidence for the glucocorticoid hypothesis mostly results from animal studies which allow experimental stress induction using various manipulations (e.g., inhibition of 11ß-HSD2, administration of exogenous steroids) to induce fetal exposure to glucocorticoids. Lower birth weight and alterations of neuroendocrine function were linked with increasing glucocorticoid levels (Cottrell et al., 2012; Harris and Seckl, 2011). Human studies link impaired placental barrier function with negative birth outcomes moderated by prenatal maternal distress and symptoms of depression or anxiety (O’Donnell et al., 2012). Research on prenatal stress effects and mediating maternal-placental-fetal neuroendocrine mechanism underlying fetal programming cannot draw firm conclusion yet.
Here, we studied a large cohort of women during their 3rd trimester of pregnancy as well as their neonates in order to test the hypothesis that distress during pregnancy is related to HPA system dysfunction as well as anthropometric variation in the neonate.
Section snippets
Study participants
Data were obtained from a cohort of mothers-to-be (n = 405) and their neonates (n = 405), recruited in the 3rd trimester of pregnancy (4–8 weeks prior to term) from the Rhine-Neckar Region of Germany. All mothers were informed about the ‘POSEIDON’ (Pre-, Peri- and Postnatal Stress: Epigenetic Impact on Depression) study and provided written informed consent prior to participation. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of
Association between prenatal ELS and anthropometric measures at birth
‘Prenatal ELS’ was significantly negatively correlated with all neonatal anthropometric measures (r = −0.133 to r = −0.183; all p < .01). Except for the Life experiences survey, subscore ‘negative life events’ (LES_negative life events), stress variables showed significant negative correlations with all anthropometric measures at birth (all p > .05). However, to avoid multiple testing effects, we refer to factors ‘prenatal ELS’ and ‘anthropometric measures at birth’. Because the birth weight,
Discussion
Our prospective study provided evidence for a substantial influence of maternal prenatal distress on negative anthropometric measures at birth. Maternal experiences of prenatal ELS were associated with an average reduction in infant’s anthropometric measurements of 217 g (6.7%) in birth weight, 1.2 cm (2.3%) in length and 0.8 cm (2.3%) in head circumference. This relation remained after controlling various confounding variables (including: gestational age at birth, infant’s sex, maternal and
Conclusion
In summary, maternal distress during late gestation is associated with fetal development including anthropometric measures at birth –particularly a reduction in birth weight, birth length, head circumference and gestational age. Prenatal stress effects may be at least partly mediated by maternal-placental-fetal neuroendocrine mechanisms. Although in our study cortisol decline did not mediate the association between prenatal stress and anthropometric measures at birth, dysregulations of diurnal
Ethics approval and consent to participate
The study protocol was approved by the Ethics Committee of the Medical Faculty Mannheim of the University of Heidelberg and the Ethics Committee of the Medical Association of Rhineland-Palatinate and conducted in accordance with the Declaration of Helsinki. All mothers provided written informed consent prior to enrolment in the study.
Conflicts of interest
Michael Deuschle and his research group received speaker and consulting fees from BristolMyers Squibb, Lundbeck Otsuka Pharma, and Servier. Michael Deuschle is a national coordinator and principal investigator of phase II and III trials for Lilly Pharma and Roche. The remaining co-authors have no conflict or competing interests to declare.
Funding
The study was supported by an Era-Net Neuron grant to Michael Deuschle, Manfred Laucht and Marcella Rietschel. Michael Deuschle, Manfred Laucht and Marcelle Rietschel received support from the Dietmar-Hopp Foundation, Germany.
Author’s contributions
Each author made a substantial contribution to the conception and design of the study, and to the interpretation of the data. ML, MD and MR conceptualized and designed the study. MG, HO, IACW, VP, and BS recruited the pregnant mothers, collected the biomaterials and behavioral data. MG, MS (Michael Schredl) and HO calculated the early life stress scores. MG and HO interpreted the data and contributed equally to the preparation of the paper. All authors read and approved the final manuscript.
Acknowledgments
We thank Barbara Filsinger (head of the Department of Gynecology and Obstetrics, St. Marienkrankenhaus Ludwigshafen), Marc W. Sütterlin (head of the department of Gynecology and Obstetrics, University Medical Center Mannheim) and Hans-Michael Thon (head of the Department of Gynecology and Obstetrics, St. Hedwigsklinik Mannheim) for their support. We thank Clemens Kirschbaum and his lab for the cortisol analyses. We thank Dr. Nina Arnold for specific statistical advice. We truly thank the
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