Elyssia Poggi Davis

IS THERE A VIABILITY-VULNERABILITY TRADEOFF? SEX DIFFERENCES IN FETAL PROGRAMMING

OBJECTIVE In this paper we evaluate the evidence for sex differences in fetal programming within the context of the proposed viability-vulnerability tradeoff. METHODS We briefly review the literature on the factors contributing to primary and secondary sex ratios. Sex differences in fetal programming are assessed by summarizing previously published sex difference findings from our group (6 studies) and also new analyses of previously published findings in which sex differences were not reported (6 studies). RESULTS The review and reanalysis of studies from our group are consistent with the overwhelming evidence of increasing risk for viability among males exposed to environmental adversity early in life. New evidence reported here support the argument that females, despite their adaptive agility, also are influenced by exposure to early adversity. Two primary conclusions are (i) female fetal exposure to psychobiological stress selectively influences fear/anxiety, and (ii) the effects of female fetal exposure to stress persist into preadolescence. These persisting effects are reflected in increased levels of anxiety, impaired executive function and neurological markers associated with these behaviors. CONCLUSIONS A tacit assumption is that females, with their adaptive flexibility early in gestation, escape the consequences of early life exposure to adversity. We argue that the consequences of male exposure to early adversity threaten their viability, effectively culling the weak and the frail and creating a surviving cohort of the fittest. Females adjust to early adversity with a variety of strategies, but their escape from the risk of early mortality and morbidity has a price of increased vulnerability expressed later in development.

Prescient Human Fetuses Thrive

Fetal detection of adversity is a conserved trait that allows many species to adapt their early developmental trajectories to ensure survival. According to the fetal-programming model, exposure to stressful or hostile conditions in utero is associated with compromised development and a lifelong risk of adverse health outcomes. In a longitudinal study, we examined the consequences of prenatal and postnatal exposure to adversity for infant development. We found increased motor and mental development during the 1st year of life among infants whose mothers experienced congruent levels of depressive symptoms during and after pregnancy, even when the levels of symptoms were relatively high and the prenatal and postnatal environments were unfavorable. Congruence between prenatal and postnatal environments prepares the fetus for postnatal life and confers an adaptive advantage for critical survival functions during early development.

Human Milk Cortisol is Associated With Infant Temperament

The implications of the biologically active elements in milk for the mammalian infant are largely unknown. Animal models demonstrate that transmission of glucocorticoids through milk influences behavior and modifies brain development in offspring. The aim of this study was to determine the relation between human milk cortisol levels and temperament of the breastfed infant. Fifty-two mother and infant pairs participated when the infants were three-months old. Milk cortisol levels were assessed and each mother completed the Infant Behavior Questionnaire (IBQ), a widely used parent-report measure of infant temperament. Analyses revealed a positive association between milk cortisol and the negative affectivity dimension of the IBQ (partial r=.37, p<.01). No correlation was found between elevated cortisol levels and the surgency/extraversion or the orienting/regulation dimensions. Further, the positive association between increased maternal milk cortisol and negative affectivity was present among girls (β=.59, p<.01), but not among boys. (Although, the sex by milk cortisol interaction term was not statistically significant, suggesting that these results require replication.) Environmental factors such as maternal demographics and negative maternal affect (depression and perceived stress) at the time of assessment did not account for the positive association. The findings support the proposal that exposure to elevated levels of cortisol in human milk influences infant temperament. The findings further suggest that mothers have the ability to shape offspring phenotype through the transmission of biologically active components in milk.

Longer Gestation among Children Born Full Term Influences Cognitive and Motor Development

Children born preterm show persisting impairments in cognitive functioning, school achievement, and brain development. Most research has focused on implications of birth prior to 37 gestational weeks; however, the fetal central nervous system continues to make fundamental changes throughout gestation. Longer gestation is associated with reduced morbidity and mortality even among infants born during the period clinically defined as full term (37–41 gestational weeks). The implications of shortened gestation among term infants for neurodevelopment are poorly understood. The present study prospectively evaluates 232 mothers and their full term infants (50.4% male infants) at three time points across the first postnatal year. We evaluate the association between gestational length and cognitive and motor development. Infants included in the study were full term (born between 37 and 41 weeks gestation). The present study uses the combination of Last Menstrual Period (LMP) and early ultrasound for accurate gestational dating. Hierarchical Linear Regression analyses revealed that longer gestational length is associated with higher scores on the Bayley scales of mental and motor development at 3, 6 and 12 months of age after considering socio-demographic, pregnancy, and infant-level covariates. Findings were identical using revised categories of early, term, and late term proposed by the Working Group for Defining Term Pregnancy. Our findings indicate that longer gestation, even among term infants, benefits both cognitive and motor development.

Exposure to unpredictable maternal sensory signals influences cognitive development across species

Significance The receipt of high-quality maternal care is an established promoter of optimal neurodevelopment, but the processes by which maternal care influences development remain unclear. Using a cross-species approach, we probe the possibility that predictability of sensory signals from the mother is a process by which maternal behavior influences cognitive circuits within the developing brain. This is in accord with established roles of patterns of sensory information in the organization of visual and auditory systems of the brain during sensitive periods. Our data support the argument that the degree of predictability of maternal sensory signals affects subsequent cognitive function in both rats and humans and suggest that these signals contribute to the shaping of the underlying neural circuits, including the hippocampus. Maternal care is a critical determinant of child development. However, our understanding of processes and mechanisms by which maternal behavior influences the developing human brain remains limited. Animal research has illustrated that patterns of sensory information is important in shaping neural circuits during development. Here we examined the relation between degree of predictability of maternal sensory signals early in life and subsequent cognitive function in both humans (n = 128 mother/infant dyads) and rats (n = 12 dams; 28 adolescents). Behaviors of mothers interacting with their offspring were observed in both species, and an entropy rate was calculated as a quantitative measure of degree of predictability of transitions among maternal sensory signals (visual, auditory, and tactile). Human cognitive function was assessed at age 2 y with the Bayley Scales of Infant Development and at age 6.5 y with a hippocampus-dependent delayed-recall task. Rat hippocampus-dependent spatial memory was evaluated on postnatal days 49–60. Early life exposure to unpredictable sensory signals portended poor cognitive performance in both species. The present study provides evidence that predictability of maternal sensory signals early in life impacts cognitive function in both rats and humans. The parallel between experimental animal and observational human data lends support to the argument that predictability of maternal sensory signals causally influences cognitive development.

Antenatal glucocorticoid treatment is associated with diurnal cortisol regulation in term-born children

Due to the rapid developmental changes that occur during the fetal period, prenatal influences can affect the developing central nervous system with lifelong consequences for physical and mental health. Glucocorticoids are one of the proposed mechanisms by which fetal programing occurs. Glucocorticoids pass through the blood-brain barrier and target receptors throughout the central nervous system. Unlike endogenous glucocorticoids, synthetic glucocorticoids readily pass through the placental barrier to reach the developing fetus. The synthetic glucocorticoid, betamethasone, is routinely given prenatally to mothers at risk for preterm delivery. Over 25% of the fetuses exposed to betamethasone will be born at term. Few studies have examined the lasting consequences of antenatal treatment of betamethasone on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study is to examine whether antenatal exposure to betamethasone alters circadian cortisol regulation in children who were born full term. School-aged children prenatally treated with betamethasone and born at term (n=19, mean (SD)=8.1 (1.2) years old) were compared to children not treated with antenatal glucocorticoids (n=61, mean (SD)=8.2 (1.4) years old). To measure the circadian release of cortisol, saliva samples were collected at awakening; 30, 45, and 60min after awakening; and in the evening. Comparison children showed a typical diurnal cortisol pattern that peaked in the morning (the cortisol awakening response) and gradually decreased throughout the day. In contrast, children exposed to antenatal betamethasone lacked a cortisol awakening response and had a flatter diurnal slope (ps<0.01). These data suggest that antenatal glucocorticoid treatment may disrupt the circadian regulation of the HPA axis among children born at term. Because disrupted circadian regulation of cortisol has been linked to mental and somatic health problems, future research is needed to determine whether children exposed to antenatal synthetic glucocorticoids are at risk for poor mental and physical health.

Neurobehavioral Consequences of Fetal Exposure to Gestational Stress

Through intimate communications with the mother, the fetus receives information that is integrated into its neurodevelopmental program to prepare for life after birth. Because the fetal nervous system develops at rapid speed, at precise times and in a specific sequence from conception to birth, disruption in the timing or sequence of development results in tissue remodeling and altered function. Fetal exposures to maternal signals of psychobiological stress are associated with increased risk for behavioral disorders and alterations in brain structures. We have devoted nearly three decades exploring the effects of psychobiological stress in several large cohorts of mothers and their offspring. The focus of this chapter is on the persisting developmental plasticity induced by fetal exposure and adaptation to signals of stress and adversity. Specifically the emphasis is on the emotional, cognitive, and neurological consequences for the newborn, infant, toddler, and child, exposed as fetuses to maternal stress. We review evidence that maternal psychological states and experiences during pregnancy, including stress exposures, mood, fears, and concerns about the course of her pregnancy as well as the level of biological stress signals, exert programming influences on the developing fetus.

Development of Fetal Movement between 26 and 36-Weeks’ Gestation in Response to Vibro-Acoustic Stimulation

Background: Ultrasound observation of fetal movement has documented general trends in motor development and fetal age when motor response to stimulation is observed. Evaluation of fetal movement quality, in addition to specific motor activity, may improve documentation of motor development and highlight specific motor responses to stimulation. Aim: The aim of this investigation was to assess fetal movement at 26 and 36-weeks gestation during three conditions (baseline, immediate response to vibro-acoustic stimulation (VAS), and post-response). Design: A prospective, longitudinal design was utilized. Subjects: Twelve normally developing fetuses, eight females and four males, were examined with continuous ultrasound imaging. Outcome Measures: The fetal neurobehavioral coding system (FENS) was used to evaluate the quality of motor activity during 10-s epochs over the three conditions. Results: Seventy-five percent of the fetuses at the 26-week assessment and 100% of the fetuses at the 36-week assessment responded with movement immediately following stimulation. Significant differences in head, fetal breathing, general, limb, and mouthing movements were detected between the 26 and 36-week assessments. Movement differences between conditions were detected in head, fetal breathing, limb, and mouthing movements. Conclusion: Smoother and more complex movement was observed with fetal maturation. Following VAS stimulation, an immediate increase of large, jerky movements suggests instability in fetal capabilities. Fetal movement quality changes over gestation may reflect sensorimotor synaptogenesis in the central nervous system, while observation of immature movement patterns following VAS stimulation may reflect movement pattern instability.

Gestational hormone profiles predict human maternal behavior at 1-year postpartum

In many non-human species, including primates, gestational reproductive hormones play an essential role in the onset of maternal motivation and behaviors. We investigated the associations between prepartum estradiol and progesterone and maternal behavior at 1-year postpartum in 177 women. Blood was obtained at five gestational time points and an index of quality of maternal care was determined using a well-validated mother-child interaction protocol. Women who exhibited higher quality maternal care at 1-year postpartum were characterized by unique gestational profiles of estradiol, progesterone and the estrogen to progesterone ratio; specifically by slower accelerations and levels of these hormone trajectories beginning in midgestation. Further, it appeared that both fetal sex and parity moderated these findings, with first time mothers and mothers of females showing stronger associations. In sum, these data document persisting associations between prepartum hormone profiles and human maternal behavior. More broadly, these findings add to the growing literature highlighting the perinatal period as one of critical neurodevelopment in the lifespan of the human female.

Abnormal Dendritic Maturation of Developing Cortical Neurons Exposed to Corticotropin Releasing Hormone (CRH): Insights into Effects of Prenatal Adversity?

Corticotropin releasing hormone (CRH) produced by the hypothalamus initiates the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the body’s stress response. CRH levels typically are undetectable in human plasma, but during pregnancy the primate placenta synthesizes and releases large amounts of CRH into both maternal and fetal circulations. Notably, placental CRH synthesis increases in response to maternal stress signals. There is evidence that human fetal exposure to high concentrations of placental CRH is associated with behavioral consequences during infancy and into childhood, however the direct effects on of the peptide on the human brain are unknown. In this study, we used a rodent model to test the plausibility that CRH has direct effects on the developing cortex. Because chronic exposure to CRH reduces dendritic branching in hippocampal neurons, we tested the hypothesis that exposure to CRH would provoke impoverishment of dendritic trees in cortical neurons. This might be reflected in humans as cortical thinning. We grew developing cortical neurons in primary cultures in the presence of graded concentrations of CRH. We then employed Sholl analyses to measure dendritic branching and total dendritic length of treated cells. A seven-day exposure to increasing levels of CRH led to a significant, dose-dependent impoverishment of the branching of pyramidal-like cortical neurons. These results are consistent with the hypothesis that, rather than merely being a marker of prenatal stress, CRH directly decreases dendritic branching. Because dendrites comprise a large portion of cortical volume these findings might underlie reduced cortical thickness and could contribute to the behavioral consequences observed in children exposed to high levels of CRH in utero.