Stress, infection and preterm birth: a biobehavioural perspective.

Preterm birth is currently the most important problem in maternal-child health in the United States. Epidemiological studies have suggested that two factors, maternal stress and maternal urogenital tract infection, are significantly and independently associated with an increased risk of spontaneous preterm birth. These factors are also more prevalent in the population of sociodemographically disadvantaged women who are at increased risk for preterm birth. Studies of the physiology of parturition suggest that neuroendocrine and immune processes play important roles in the physiology and pathophysiology of normal and preterm parturition. However, not all women with high levels of stress and/or infection deliver preterm, and little is understood about factors that modulate susceptibility to pathophysiological events of the endocrine and immune systems in pregnancy. We present here a comprehensive, biobehavioural model of maternal stress and spontaneous preterm delivery. According to this model, chronic maternal stress is a significant and independent risk factor for preterm birth. The effects of maternal stress on preterm birth may be mediated through biological and/or behavioural mechanisms. We propose that maternal stress may act via one or both of two physiological pathways: (a) a neuroendocrine pathway, wherein maternal stress may ultimately result in premature and/or greater degree of activation of the maternal-placental-fetal endocrine systems that promote parturition; and (b) an immune/inflammatory pathway, wherein maternal stress may modulate characteristics of systemic and local (placental-decidual) immunity to increase susceptibility to intrauterine and fetal infectious-inflammatory processes and thereby promote parturition through pro-inflammatory mechanisms. We suggest that placental corticotropin-releasing hormone may play a key role in orchestrating the effects of endocrine and inflammatory/immune processes on preterm birth. Moreover, because neuroendocrine and immune processes extensively cross-regulate one another, we further posit that exposure to both high levels of chronic stress and infectious pathogens in pregnancy may produce an interaction and multiplicative effect in terms of their combined risk for preterm birth. Finally, we hypothesise that the effects of maternal stress are modulated by the nature, duration and timing of occurrence of stress during gestation. A discussion of the components of this model, including a theoretical rationale and review of the available empirical evidence, is presented. A major strength of this biobehavioural perspective is the ability to explore new questions and to do so in a manner that is more comprehensive than has been previously attempted. We expect findings from this line of proposed research to improve our present state of knowledge about obstetric risk assessment for preterm birth by determining the characteristics of pregnant women who are especially susceptible to stress and/or infection, and to broaden our understanding of biological (endocrine, immune, and endocrine-immune interactions) mechanisms that may translate social adversity during pregnancy into pathophysiology, thereby suggesting intervention strategies.

When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy.

OBJECTIVE: The purpose of the study was to assess the effects of the timing of stress during pregnancy on emotional responses and birth outcome. We hypothesized that as pregnancy advanced women would become increasingly resistant to the adverse effects of stress, and so early stress would have more profound effects than later stress. STUDY DESIGN: Forty pregnant women who had experienced an earthquake during pregnancy or shortly afterward were identified. Using regression analyses we determined whether the timing of the earthquake was related to an affective response to this event and to length of gestation. RESULTS: The earthquake was rated as more stressful when it occurred early in pregnancy compared with late in pregnancy, and postpartum ratings were similar to first-trimester ratings (r (quad) =.39; P <.05). Stress experienced early in pregnancy was associated with shorter gestational length (r =.35; P <.05). CONCLUSIONS: As pregnancy advances, women become decreasingly sensitive to the effects of stress. This decrease in vulnerability may reflect increasing protection of the mother and fetus from adverse influences during pregnancy.

Uncoupling of proopiomelanocortin (POMC) fragments is related to self-injury.

Proopiomelanocortin (POMC) contains several interesting, behaviorally active peptides. Release patterns of these fragments have been related to bizarre episodes of self-injurious behavior (SIB) among autistic individuals. Moreover, elevation in beta-endorphin (betaE) but not ACTH levels was associated with a positive response to an acutely administered, centrally acting opioid blocker among autistic individuals exhibiting SIB. In the present study, POMC fragments were measured in 12 self-injurious patients before and after long term (3 month) treatment with an opiate blocker naltrexone (NTX). POMC fragments were sampled from blood collected at the beginning of the baseline and placebo-controlled treatment phases of the study. Results indicated that the co-release (coupling) of POMC fragments were stable over time and the profile of POMC fragments in plasma predicted the effectiveness of a CNS acting drug in autistic subjects who self-injure.

Sleep deprivation therapy in depressive illness and Parkinson's disease.

1. Sleep deprivation is commonly associated with feelings of fatigue and cognitive impairment. 2. Patients with depressive illness, however, often experience mood improvements under these same conditions. 3. Other studies now show that tremor and rigidity, in patients with Parkinson's disease, are also improved by sleep depression therapy. 4. The neural substrates which underlie these effects are unclear. Some recent evidence, however, suggests that sleep deprivation may activate mechanisms which are otherwise typical of conditions of metabolic stress. 5. A common feature of these mechanisms is the suppression of cholinergic activity which is thought to be excessive, in relation to monoamine transmission, in both depression and Parkinson's disease.

Ambulatory blood pressure, heart rate, and neuroendocrine responses in women nurses during work and off work days.

OBJECTIVE: This study examined women's 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 woman's domestic role, by the length of her employment, and by the demands of her job.

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.

Corticotrophin-releasing hormone and fetal responses in human pregnancy.

During human pregnancy, maternal and fetal compartments of the human placenta produce and release corticotrophic-releasing hormone (CRH). Elevations of placental CRH are associated with decreased gestational length (including preterm delivery). The effects of elevated placental CRH on human fetal neurological development are not known. Pregnant women in the 31st and 32nd week of gestation consented to procedures for collection of blood and measurement of fetal heart rate (FHR) in response to a series of 40 vibro-acoustic stimuli (VAS). Measures of habituation and dishabituation were calculated from the FHR. All subjects were followed to delivery. Fetuses (N = 33) of women with highly elevated CRH were least responsive (p < .03) to stimulation after presentation of a novel (dishabituating) stimulus with control for parity, fetal gender, medical (antepartum) risk, and gestational length at term. In a larger sample (N = 156) a polynomial model predicted the pattern of FHR reactivity for the first 15 trials. Placental CRH concentration significantly predicted FHR reactivity after controlling for the effects of trial number, baseline FHR, inter-trial interval, and presence of uterine contractions. Increased maternal CRH levels were significantly related to the length of gestation after controlling for the effects of fetal gender, parity, and medical risk (p = .05). The relationship between length of gestation and FHR was not significant suggesting separate actions of CRH on these events. Elevated placental CRH appears to accelerate certain developmental events (gestational length) and may influence the fetal nervous system. The impaired fetal responses to novelty and increased arousal observed in this study suggest that neurological systems may be targets for placental CRH during sensitive developmental periods.

Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy.

OBJECTIVE: Corticotropin releasing hormone, a hypothalamic neuropeptide, plays a major role in regulating pituitary-adrenal function and the physiologic response to stress. During pregnancy corticotropin-releasing hormone is synthesized in large amounts by the placenta and released into the maternal and fetal circulations. Various endocrine, autocrine, and paracrine roles have been suggested for placental corticotropin-releasing hormone. The aim of this study was to prospectively assess the relationship between maternal plasma concentrations of corticotropin-releasing hormone in the early third trimester of pregnancy and the length of gestation in two groups of deliveries, with and without spontaneous labor. STUDY DESIGN: In a sample of 63 women with singleton intrauterine pregnancies, maternal plasma samples were collected between 28 and 30 weeks' gestation and corticotropin-releasing hormone concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, antepartum risk conditions, presence or absence of spontaneous labor, and birth outcomes were abstracted from the medical record. RESULTS: Maternal corticotropin-releasing hormone levels between 28 and 30 weeks' gestation significantly and negatively predicted gestational length (P < .01) after adjustment for antepartum risk. Moreover, subjects who were delivered preterm had significantly higher corticotropin-releasing hormone levels in the early third trimester (P < .01) than did those who were delivered at term. In deliveries preceded by spontaneous onset of labor, maternal third-trimester corticotropin-releasing hormone levels significantly and independently predicted earlier onset of labor (P < .01) and preterm labor (P < .05), whereas in deliveries effected by induction of labor or cesarean delivery, maternal corticotropin-releasing hormone levels were a marker of antepartum risk but not a statistically independent predictor of gestational length. CONCLUSION: These findings support the premise that placental corticotropin-releasing hormone is potentially implicated in the timing of human delivery in at least two ways. First, placental corticotropin-releasing hormone may play a role in the physiology of parturition. Premature or accelerated activation of the placental corticotropin-releasing hormone system, as reflected by precocious elevation of maternal corticotropin-releasing hormone levels, may therefore be associated with earlier onset of spontaneous labor and resultant delivery. Second, placental corticotropin-releasing hormone may be a marker of antepartum risk for preterm delivery and therefore an indirect predictor of earlier delivery. The implications of these findings are discussed in the context of the neuroendocrinology of placental corticotropin-releasing hormone and human parturition. Furthermore, the role of corticotropin-releasing hormone as a possible effector of prenatal stress in producing alterations in the timing of normal delivery is detailed.

Dissociation of POMC peptides after self-injury predicts responses to centrally acting opiate blockers.

Apparent insensitivity to pain, ritualistic patterns of behavior, and improvement in symptoms after administration of opiate receptor blockers implicated the endogenous opioid system in the initiation and maintenance of SIB. This study was designed to determine whether plasma levels of proopiomelanocortin (POMC)-derived peptides, beta-endorphin-like activity (beta E), ACTH, and adrenal cortisol immediately after an episode of SIB predicted subsequent response to an opiate blocker. Blood samples were collected from 10 patients with mental retardation within minutes of a self-injuring act and during an SIB-free control period. On another day, morning and afternoon samples were collected at least one week apart from the other samples. Effects on SIB of naltrexone hydrochloride (NTX) were examined in a double-blind, placebo-controlled crossover study. After an SIB episode, beta E, but not ACTH, was elevated compared with morning levels, p < .003. Patients with increased plasma levels of beta E after SIB had the most positive response to 2 mg/kg NTX, p < .03. Results suggest that changes in the hypothalamic-pituitary-adrenal axis after SIB may predict differences in individual patient response to opiate blockers.

Apomorphine induced alteration in corneofundal potentials in depression.

1. The role of dopamine (DA) in mood regulation remains controversial. 2. Previous studies have examined DA sensitivity by measuring neuroendocrine responses following an agonist challenge. For the most part the results of such tests have failed to provide convincing evidence of a DA abnormality in affective disorders. 3. Neuroendocrine responses, however, are subject to complex regulatory influences and respond to DA systems which differ from those thought to modulate mood. 4. Recent animal and human studies suggest that light-dark adaptive electrical responses of the retinal pigment epithelium may serve as a better model of dopaminergic function. 5. The present study reports neuroendocrine and ocular results prior to, and following, an apomorphine (APO; 0.75 mg sc) challenge in 12 depressed patients and 12 normal controls. 6. Apomorphine administration increased both light and dark retinal potentials in patients whereas those of controls decreased and this group difference was significant (p < 0.002). 7. No group differences were detected in any measure at baseline, or in prolactin, or growth hormone levels after the APO challenge. 8. The results indicate that the retina may serve as a more sensitive indicator of dopamine abnormalities in depressive illness.

Maternal stress, HPA activity, and fetal/infant outcome.

Preliminary conclusions from our research include the possibility that each of the HPA products evaluated, even though correlated (e.g., ACTH and beta E), may be linked to unique and specific outcomes. Maternal stress during the 28-30 weeks of gestation is associated with birth outcome. Increased levels of psychosocial stress were significantly related to gestational age at birth and infant birth weight. Maternal stress during the third trimester was associated with increased maternal plasma levels of ACTH and cortisol. This finding is consistent with possible mechanisms whereby psychosocial stress influences birth outcome. CRH controls the timing of labor and delivery. Precocious elevation of CRH is related to the risk of preterm delivery. This system may be "stress-sensitive." Even though pregnant women may be immunized from stress, the stress signal that is transmitted (release of ACTH and cortisol) is amplified by the placental release of CRH. This possibility has at least two consequences: (1) influencing the timing of delivery and (2) desensitization of hypophyseal corticotrophs and further "protection" of the pregnant women from the results of stress (i.e., release of ACTH and beta E). Beta E appears to influence fetal learning and perhaps the developing nervous system.

Umbilical cord beta-endorphin and early childhood motor development.

Stress during delivery has been associated with elevated umbilical cord plasma beta-endorphin levels. Published research suggests that much cord beta-endorphin originates from fetal pituitary. Intact pituitary function is required for normal growth and development. Relationships between cord beta-endorphin and child development have not been previously reported. We measured paired maternal and cord plasma beta-endorphin concentration in a set of 106 low risk deliveries by solid phase two-site immunoradiometric assay. Geometric mean maternal and cord beta-endorphin concentrations were 128 pg/ml and 196 pg/ml, respectively, with corresponding ranges of 33-533 pg/ml and 70-579 pg/ml. Cord beta-endorphin concentration was significantly higher than maternal, regardless of delivery mode, and the two were significantly correlated (r = 0.231; P = 0.017). Multiple regression modeling showed that forceps delivery, maternal beta-endorphin concentration, bradycardia, vaginal delivery, and birth weight each made independent contributions to elevated cord beta-endorphin. Depressed cord beta-endorphin predicted more day 2 neurological soft signs, lower 6-month mental development, and lower 36-month motor score on psychometric tests of the children. Poorer fine motor control and coordination were predominantly associated with lower beta-endorphin. Level of cord beta-endorphin independent of delivery stress exerted the primary influence upon child motor development. Higher levels of stress-independent beta-endorphin may play a direct role in motor development.

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 (beta E), 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, beta E, 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 beta E. 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-beta E disregulation index, 13% of the variance in cortisol, and 3% of the variance in beta E. 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.

Seasonal patterns in platelet ligand binding are related to membrane proteins.

A seasonal pattern of platelet [3H]imipramine (3H-IMI) binding was explained by a similar but inverted pattern in membrane protein levels in repeated measures of 20 normal volunteers. No seasonal pattern was evident when 3H-IMI binding was expressed on the basis of surface area rather than membrane protein. Platelet Bmax levels in 50 depressed patients were lower than those of controls when values were expressed in terms of platelet surface area. The results support previous reports of low Bmax values in unipolar major depression, but indicate that seasonal changes in 3H-IMI binding are due to fluctuations in membrane protein and not to changes in the number of receptive sites. The present findings also have similar implications for other platelet measures expressed in terms of membrane protein.

REM latency, dexamethasone suppression test, and thyroid releasing hormone stimulation test in posttraumatic stress disorder.

1. Twenty-one patients with post-traumatic stress disorder (PTSD) were included in a study utilizing baseline rapid eye movement (REM) latency measurements, the dexamethasone suppression test (DST), and the protirelin (thyroid releasing hormone; TRH) stimulation test. The DST and TRH stimulation test were repeated after double blind treatment with desipramine. 2. A high number of patients (75%) exhibited a REM latency of 60 min or less and blunted thyroid stimulating hormone (TSH) response to TRH (61.9%) on baseline tests while only one patient showed cortisol escape from dexamethasone suppression. 3. After four weeks of desipramine treatment, significant improvements were reported in the Hamilton Rating Scale for depression, but not for anxiety symptoms, PTSD symptoms, or self-rated depressive symptoms. 4. Desipramine treatment did not affect hormonal responses to TRH. 5. The findings of shortened REM latency and altered TRH stimulation test suggest PTSD and depression may share some pathophysiological abnormalities.

Third trimester POMC disregulation predicts use of anesthesia at vaginal delivery.

In a prospective study, third trimester plasma levels of BE and ACTH were determined in 58 women who delivered vaginally. Peptide regulation was compared between subjects who used conduction anesthesia at delivery and subjects who did not. Third trimester levels of maternal BE and ACTH were significantly related; however, the relationship was significant only in subjects who did not receive conduction anesthesia (n = 24) at delivery. The normal co-release pattern between BE and ACTH in subjects receiving conduction anesthesia (n = 34) during birth was uncoupled. The use of conduction analgesia during vaginal delivery was significantly related to a disregulation index created to quantify the BE-ACTH release pattern. Uncoupled ACTH and BE patterns may result from modified control of pro-opiomelanocortin (POMC) expression during pregnancy or unique proteolytic processing of POMC, and may alter pain tolerance during delivery.

Acidosis stimulates beta-endorphin release during exercise.

Elevated blood levels of beta-endorphin have been associated with high-intensity exertion, but the stimulus for beta-endorphin release is unknown. Some studies of exercise have associated beta-endorphin release with increased exertion levels, but other evidence suggests that acidosis may stimulate the release of beta-endorphin. This study examines acidosis as a possible stimulus for beta-endorphin release by examining the effects of arterial blood gases, whole blood lactate, and respiratory changes on beta-endorphin levels and by examining the effects of buffering during exercise on these levels. Initially, seven healthy adult males were evaluated during incremental exercise. During incremental exertion, indicators of acidosis correlated with endorphin levels: pH (r = -0.94), PCO2 (r = -0.85), HCO3- (r = -0.88), base excess (r = -0.94), and lactate (r = 0.89). A multivariate model showed that beta-endorphin levels were predicted best by the change in base excess. A time course analysis showed that beta-endorphin responses peaked postexercise and paralleled blood acid levels. Subsequently, subjects were compared after alkali loading and placebo during constant-intensity exercise at 85% of maximal exertion to determine whether acidosis is necessary for endorphin release. Treatment with a buffer, which effectively maintained pH above 7.40, significantly suppressed endorphin release (F = 3.07; P < 0.0001). The results of this study indicate that acidosis rather than any other physiological change associated with high-intensity exertion is the primary stimulus for beta-endorphin release.

Adrenal androgens and cortisol in major depression.

Nine depressed subjects and nine comparison subjects completed a study of abnormalities in adrenal androgen and cortisol metabolism. Serum levels of cortisol and dehydroepiandrosterone (DHA) at 8:00 a.m. and 4:00 p.m. revealed hypercortisolemia and loss of diurnal DHA variation but not cortisol variation in the depressed group. These findings suggest that in depression, adrenal androgens, in contrast to cortisol, are partially regulated by mechanisms independent of ACTH.