Aleksandra Chicz-DeMet

Prenatal psychosocial factors and the neuroendocrine axis in human pregnancy.

Objective Physiological processes including neuroendocrine function have been proposed as mediators of the relationship between prenatal psychological state and pregnancy outcome; however, there are virtually no human studies that have systematically assessed such mechanisms. Neuroendocrine processes are significantly altered during pregnancy, and are characterized by the evolution of a transient neuroendocrine system, the placenta, and modifications in endocrine control mechanisms. Because these alterations have implications for neuroendocrine responsivity to exogenous conditions, the aim of the present study was to examine the cross-sectional association between prenatal psychosocial factors and stress-related neuroendocrine parameters during human pregnancy. Method Fifty-four adult women with a singleton, intrauterine pregnancy were recruited before 28 weeks of gestation. Maternal antecubital venous blood samples were withdrawn at 28 weeks of gestation for bioassays of adrenocorticotropin hormone (ACTH), beta-endorphin (betaE), and cortisol. Measures of prenatal stress, social support, and personality were collected using a two-part, self-report questionnaire administered at 28 and 30 weeks of gestation. Biomedical data were obtained from the medical record. Factors known to influence neuropeptide and hormone levels during pregnancy were controlled, including gestational age, circadian variation, and obstetric risk. Results In the present sample, prenatal psychosocial stress, social support, and personality variables were associated with neuroendocrine parameters in two primary ways. First, certain psychosocial factors were significantly associated with plasma levels of ACTH, betaE, and cortisol, and second, psychosocial factors were associated with a measure of disregulation of the normal relationship between two pro-opiomelanocortin (POMC) derivatives, ACTH and betaE. Furthermore, a combination of the maternal psychosocial and sociodemographic factors during pregnancy accounted for 36% of the variance in ACTH, 22% of the variance in the ACTH-betaE disregulation index, 13% of the variance in cortisol, and 3% of the variance in betaE. Conclusions The present findings are consistent with the premise that maternal-placental-fetal neuroendocrine parameters are significantly associated, both in magnitude and specificity, with features of maternal psychosocial functioning in pregnancy despite the systemic alterations associated with the endocrinology of pregnancy. These findings provide a basis for further investigations of the role of the neuroendocrine system as a putative mediating pathway between prenatal psychosocial factors and birth outcome, and possibly also as a mechanism linking features of the maternal psychosocial environment to fetal/infant brain development.

Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): Priming the placental clock

The purposes of this study were to determine the intervals when placental corticotrophic-releasing hormone (CRH) was most responsive to maternal cortisol. A sample of 203 women each were evaluated at 15, 19, 25 and 31 weeks gestation and followed to term. Placental CRH and maternal adrenocorticotropin hormone (ACTH), B-endorphin and cortisol were determined from plasma. CRH levels increased faster and were higher in women who delivered preterm compared with women who delivered at term (F3,603 = 5.73, p < .001). Simple effects indicated that CRH levels only at 31 weeks predicted preterm birth (F1,201 = 5.53, p = .02). Levels of cortisol were higher in women who delivered preterm at 15 weeks gestation (F1,201 = 4.45, p = .03) with a similar trend at 19 weeks gestation. Hierarchical regression suggested that the influence on birth outcome of maternal cortisol early in pregnancy was mediated by its influence on placental CRH at 31 weeks. Elevated cortisol at 15 weeks predicted the surge in placental CRH at 31 weeks (R = .49, d.f. = 1,199, Fchange = 61.78, p < .0001). Every unit of change in cortisol (microg/dl) at 15 weeks was associated with a 34 unit change of CRH (pg/ml) at 31 weeks. These findings suggested that early detection of stress signals by the placenta stimulated the subsequent release of CRH and resulted in increased risk for preterm delivery.

AMBULATORY BLOOD PRESSURE, HEART RATE, AND NEUROENDOCRINE RESPONSES IN WOMEN NURSES DURING WORK AND OFF WORK DAYS

OBJECTIVE This study examined womens cardiovascular and neuroendocrine responsiveness to work. METHODS Ambulatory blood pressure (BP) and heart rate (HR) were recorded over 24-hour periods on 2 work and 2 off days during the luteal and follicular phases of the menstrual cycle in 138 registered nurses, aged 25 to 50 years. Urinary catecholamines and cortisol were measured for day and night periods. RESULTS During waking hours systolic BP (SBP), HR, and epinephrine were higher on work than off days. Diastolic BP (DBP) and HR were highest at work. Nurses scoring high on job demands had elevations in daytime SBP, daytime HR only on work days, and nighttime epinephrine on work days. Compared with those with short work histories, nurses employed longer had consistently higher norepinephrine levels during days and nights, and higher nighttime DBP during off days. In unmarried nurses compared with married nurses, nighttime cortisol was lower during all 4 days and norepinephrine was lower during days off. All findings were independent of actigraph-recorded activity. CONCLUSIONS Although the work environment leads to increased activity of the cardiovascular and sympathoadrenal medullary system in healthy women, the effects are modified by the womans domestic role, by the length of her employment, and by the demands of her job.

Attenuation of maternal psychophysiological stress responses and the maternal cortisol awakening response over the course of human pregnancy

The effects of maternal stress during pregnancy may depend, in part, on the timing in gestation of the occurrence of stress. The aim of the present study was to examine the effect of stage of gestation on maternal psychophysiological responses to stress using a standardized laboratory paradigm and on the cortisol response to awakening (CAR). A longitudinal design was employed to quantify maternal psychophysiological stress reactivity [changes in heart rate (HR), blood pressure, salivary cortisol, and psychological distress in response to the trier social stress test (TSST)] and the CAR at approximately 17 and 31 weeks gestation in a sample of 148 women. To account for the possible effects of habituation when being exposed to the same stress protocol twice, a non-pregnant comparison group (CG, N = 36) also underwent these assessments at two time points, with a comparable time interval between the assessments. In both groups, the TSST elicited significant changes in maternal HR, mean arterial pressure, and psychological distress levels but not a significant increase in cortisol levels. Among the pregnant women (pregnant group(PG)), the stressor-induced increases in HR, blood pressure, and psychological distress were significantly lower at the second (31 weeks gestation) compared to the first (17 weeks gestation) assessment of pregnancy (all p < 0.01). The maternal CAR was also significantly attenuated in later compared to earlier gestation (p = 0.003). In the CG, there were no significant differences in psychophysiological stress responses and in the CAR across the two assessments. Among pregnant women there is a progressive attenuation of psychophysiological stress responses with advancing gestation. This attenuation is unlikely to be attributable to habituation. Individual differences in the degree of attenuation of stress responses over gestation may represent a novel marker of stress susceptibility in human pregnancy.

Maternal corticotropin-releasing hormone and habituation in the human fetus.

Elevated concentrations of maternal corticotrophin-releasing hormone (CRH) during the 2nd and early 3rd trimester of human pregnancy are associated with spontaneous preterm birth, but the effects of maternal CRH on the fetus are unknown. Maternal plasma was collected for analysis of CRH concentration, m = 156.24 +/- 130.91 pg/ml, from 33 pregnant women during Weeks 31-33 of gestation. Immediately after collection of plasma, fetal heart rate (FHR) measures were obtained in response to a challenge with a series of vibroacoustic stimuli. Fetuses of mothers with highly elevated CRH did not respond significantly to the presence of a novel stimulus in a repeated series, p = 0.016. These effects on the FHR response were not related to parity, fetal gender, medical (antepartum) risk, or eventual birth outcomes. Impaired dishabituation in these fetuses of mothers with high concentrations of CRH suggests that neurological systems rich with CRH receptors that support learning and memory, such as parahippocampal regions, may be targets for maternal/placental CRH, with implications for fetal neurological development.

Effect of High Dietary Manganese Intake of Neonatal Rats on Tissue Mineral Accumulation, Striatal Dopamine Levels, and Neurodevelopmental Status

Mn is an essential element, but may become neurotoxic at high levels. Recent reports of high Mn levels in hair of children with neurodevelopmental deficits suggest that these deficits could be due to Mn-induced neurotoxic effects on brain dopamine (DA) systems, although the mechanism is not well understood. Infant formulas contain considerably higher concentrations of Mn than human milk. Thus, formula-fed infants are exposed to high levels of Mn at a time when Mn homeostasis is incompletely developed. We studied the effects of dietary Mn supplementation of rat pups on tissue Mn accumulation, brain dopamine levels, infant neurodevelopmental status, and behavior at maturity. Newborn rats were supplemented daily with 0, 50, 250, or 500 microg Mn given orally from day 1 to day 20. Mineral analysis of small intestine and brain at day 14 showed a significant increase of tissue Mn in supplemented rats. Neurodevelopmental tests conducted at various ages showed significant delays as a function of Mn supplementation. At day 32, there was a significant positive relationship between passive avoidance errors and Mn supplementation levels. Brains of animals killed on day 40 showed a significant inverse relationship between Mn supplementation level and striatal dopamine concentration. These observations suggest that dietary exposure to high levels of Mn during infancy can be neurotoxic to rat pups and result in developmental deficits.

Behavioral perinatology: biobehavioral processes in human fetal development.

Behavioral perinatology is as an interdisciplinary area of research that involves conceptualization of theoretical models and conduct of empirical studies of the dynamic time-, place-, and context-dependent interplay between biological and behavioral processes in fetal, neonatal, and infant life using an epigenetic framework of development. The biobehavioral processes of particular interest to our research group relate to the effects of maternal pre- and perinatal stress and maternal-placental-fetal stress physiology. We propose that behavioral perinatology research may have important implications for a better understanding of the processes that underlie or contribute to the risk of three sets of outcomes: prematurity, adverse neurodevelopment, and chronic degenerative diseases in adulthood. Based on our understanding of the ontogeny of human fetal development and the physiology of pregnancy and fetal development, we have articulated a neurobiological model of pre- and perinatal stress. Our model proposes that chronic maternal stress may exert a significant influence on fetal developmental outcomes. Maternal stress may act via one or more of three major physiological pathways: neuroendocrine, immune/inflammatory, and vascular. We further suggest that placental corticotropin-releasing hormone (CRH) may play a central role in coordinating the effects of endocrine, immune/inflammatory, and vascular processes on fetal developmental outcomes. Finally, we hypothesize that the effects of maternal stress are modulated by the nature, duration, and timing of occurrence of stress during gestation. In this paper, we elaborate on the conceptual and empirical basis for this model, highlight some relevant issues and questions, and make recommendations for future research in this area.

Corticotropin-Releasing Hormone during Pregnancy Is Associated with Infant Temperament

During pregnancy corticotropin-releasing hormone (CRH) is released into maternal and fetal circulation from the placenta. Elevated concentrations of placental CRH are associated with spontaneous preterm birth, but the consequences for infant development, independent of birth outcome, are unknown. In this study, the effects of placental CRH on infant temperament were examined in a sample of 248 full-term infants. Maternal blood samples were collected at 19, 25 and 31 weeks of gestation for CRH analysis. Infant temperament was assessed with measures of fear and distress at 2 months of age. Infants of mothers with low CRH at 25 weeks of gestation scored lower in fear and distress at 2 months. CRH at 19 and 31 weeks’ gestation was not significantly associated with measures of infant temperament, suggesting the possibility that there is a sensitive period for its effects. These data suggest that prenatal exposure to CRH may exert influences that persist into the postnatal period.

Effects of Neonatal Dietary Manganese Exposure on Brain Dopamine Levels and Neurocognitive Functions

Neonatal exposure to high levels of manganese (Mn) has been indirectly implicated as a causal agent in attention deficit hyperactivity disorder (ADHD), since Mn toxicity and ADHD both involve dysfunction in brain dopamine (DA) systems. This study was undertaken to examine this putative relationship in an animal model by determining if levels of neonatal dietary Mn exposure were related to brain DA levels and/or behavioral tests of executive function (EF) when the animals reached maturity. We used 32 newborn male Sprague-Dawley rats and randomly assigned them to one of the four dietary Mn supplementation conditions: 0, 50, 250 and 500 microg per day, administered daily in water from postnatal days 1-21. During days 50-64, the animals were given a burrowing detour test and a passive avoidance test. At day 65, the animals were killed and brains were assayed for DA. There was a statistically significant relationship (P = 0.003) between dietary Mn exposure and striatal DA. On the burrowing detour and passive avoidance, greater deficits were observed for animals subjected to higher Mn exposure, but these differences did not reach statistical significance. However, tests for heterogeneity of variance between groups were statistically significant for all measures, with positive relationship between Mn exposure and degree of within-group behavioral variability. Kendalls nonparametric test of the relationship between the three behavioral measures and striatal DA levels was also statistically significant (P = 0.02). These results lend support to the hypothesis that neonatal Mn exposure is related to brain DA levels and neurocognitive deficit in the rodent.

Ecological momentary assessment of maternal cortisol profiles over a multiple-day period predicts the length of human gestation.

Objective: Biobehavioral models of prenatal stress highlight the importance of the stress-related hormone cortisol. However, the association between maternal cortisol levels and the length of human gestation requires further investigation because most previous studies have relied on one-time cortisol measures assessed at varying gestational ages. This study assessed whether ecological momentary assessment (EMA) of cortisol sampling improves the ability to predict the length of human gestation. In addition, associations between EMA-based measures of psychological state (negative affect) with cortisol levels during pregnancy were assessed. Methods: For a 4-day period, 25 healthy pregnant women (mean gestational age at assessment = 23.4 [standard deviation = 9.1] weeks) collected seven salivary samples per day for the assessment of cortisol and provided a rating of negative affect every waking hour using an electronic diary. Results: Higher salivary cortisol concentrations at awakening and throughout the day (p =.001), as well as a flatter cortisol response to awakening (p =.005), were associated with shorter length of gestation. Women who delivered an infant at 36 weeks of gestations had 13% higher salivary cortisol levels at awakening than women who delivered an infant at 41 weeks of gestation. The EMA-based measure of negative affect was associated with higher cortisol throughout the day (p =.006) but not to gestational length (p =.641). The one-time measure of cortisol was not associated with length of gestation, and traditional retrospective recall measures of negative affect were not associated with cortisol. Conclusions: Our findings support the ecological validity of repeated ambulatory assessments of cortisol in pregnancy and their ability to improve the prediction of adverse birth outcomes.CAR = cortisol awakening response; CRH = corticotropin-releasing hormone; EMA = ecological momentary assessment; HLM = hierarchical linear modeling; HPA = hypothalamic-pituitary-adrenal; SD = standard deviation.