Interactive effects of corticotropin releasing hormone receptor 1, serotonin transporter linked polymorphic region, and child maltreatment on diurnal cortisol regulation and internalizing symptomatology

Within an allostatic load framework, the effect of Gene × Environment (G × E) interactions on diurnal cortisol regulation and internalizing symptomatology were investigated. Variation in the corticotropin releasing hormone receptor 1 (CRHR1) TAT haplotype and serotonin transporter linked polymorphic region (5-HTTLPR) was determined in a sample of maltreated (n = 238, 21.4% with early physical and sexual abuse) and nonmaltreated (n = 255) children (M age = 10.08) participating in a summer research camp. Internalizing and depressive symptoms were assessed by other and self-report. G × E effects for CRHR1 and maltreatment and early abuse on diurnal cortisol regulation were observed; CRHR1 variation was related to cortisol dysregulation only among maltreated children. Early abuse and high internalizing symptoms also interacted to predict atypical diurnal cortisol regulation. The interaction of CRHR1, 5-HTTLPR, and child maltreatment (G × G × E) identified a subgroup of maltreated children with high internalizing symptoms who shared the same combination of the two genes. The findings support an allostatic load perspective on the effects of the chronic stress associated with child maltreatment on cortisol regulation and internalizing symptomatology as moderated by genetic variation.     

Early deprivation and home basal cortisol levels: a study of internationally adopted children

Animal studies reveal that early deprivation impairs regulation of the hypothalamic-pituitary-adrenocortical (HPA) axis, potentially increasing vulnerability to stressors throughout life. To examine early deprivation effects on basal HPA axis activity in humans, basal cortisol levels were examined in 164 internationally adopted children who had experienced varying degrees of preadoption deprivation. Duration of institutional care, age at adoption, and parent ratings of preadoption neglect indexed a latent factor of Deprived Care. Adoption measures of height and weight standardized to World Health Organisation norms indexed a latent factor of Growth Delay that was viewed as another reflection of deprivation. Cortisol samples were collected 3.3-11.6 years postadoption (Md = 7.3 years) at home on 3 days approximately 30 min after wakeup and before bedtime. Both early a.m. levels and the decrease in cortisol across the day were examined. A structural equation model revealed that preadoption Deprived Care predicted Growth Delay at adoption and Growth Delay predicted higher morning cortisol levels and a larger diurnal cortisol decrease.     

Child maltreatment and allostatic load: consequences for physical and mental health in children from low-income families

Child maltreatment and biomarkers of allostatic load were investigated in relation to child health problems and psychological symptomatology. Participants attended a summer research day camp and included 137 maltreated and 110 nonmaltreated low-income children, who were aged 8 to 10 years (M = 9.42) and racially and ethnically diverse; 52% were male. Measurements obtained included salivary cortisol and dehydroepiandosterone, body mass index, waist-hip ratio, and blood pressure; these indicators provided a composite index of allostatic load. Child self-report and camp adult-rater reports of child symptomatology were obtained; mothers provided information on health problems. The results indicated that higher allostatic load and child maltreatment status independently predicted poorer health outcomes and greater behavior problems. Moderation effects indicated that allostatic load was related to somatic complaints, attention problems, and thought problems only among maltreated children. Risks associated with high waist-hip ratio, low morning cortisol, and high morning dehydroepiandosterone also were related to depressive symptoms only for maltreated children. The results support an allostatic load conceptualization of the impact of high environmental stress and child abuse and neglect on child health and behavioral outcomes and have important implications for long-term physical and mental health.     

Intervention effects on foster parent stress: associations with child cortisol levels

Foster children exhibit high rates of atypical neuroendocrine functioning compared to children in the general population. In particular, alterations in the daytime diurnal activity of the hypothalamic-pituitary-adrenal (HPA) axis have been observed in foster children, often characterized by blunted salivary cortisol levels (i.e., low morning levels that remain low throughout the day). There is emerging evidence that therapeutic interventions for foster children can affect this pattern of HPA axis activity, but the specific intervention components responsible for change have not been fully explicated. Within a randomized trial to evaluate a therapeutic intervention for foster preschoolers (n = 57 intervention condition; n = 60 comparison condition; n = 60 community comparison condition), the present study examined whether diurnal cortisol activity was associated with caregiver self-reported stress in response to child problem behavior. Results showed immediate reductions in caregiver stress that were sustained through 12 months postbaseline in the intervention condition. In contrast, caregivers in the regular foster care condition showed higher rates of stress across time and increased stress sensitivity to child problem behaviors. In addition, among caregivers in regular foster care, higher self-reported stress was associated with lower morning cortisol levels and more blunted diurnal cortisol activity. These results provide evidence that interventions can simultaneously impact caregiver stress and buffer children from the negative impacts of caregiver stress on HPA axis regulation.     

Hypocortisolism as a potential marker of allostatic load in children: associations with family risk and internalizing disorders

Although the majority of research attention to the hypothalamic-pituitary-adrenal (HPA) axis in stress-related disorders and as a marker of allostatic load has focused on overactivation of this stress system, theory and data clearly indicate that underactivation is also an important type of dysregulation. In the current study we focused on low cortisol, exploring a constellation of risk factors including stress exposure, maternal depression, and attenuated basal and stress reactive cortisol in two samples of children. The first sample was comprised of 110 preschoolers living in high-stress environments. Cortisol was assessed across the day at home and at child care as well as across two stress paradigms. These data were used to classify whether children's HPA axis activity was attenuated. Serious family financial strain, maternal depression, and attenuated cortisol all made unique contributions in models predicting current clinical levels of internalizing symptoms as rated by mothers and teachers. The second sample was 166 third, sixth, and ninth graders studied five times across a 1-year period. Maternal and child depression were determined through structured clinical interviews, and stress exposure was assessed via checklist and interview techniques with the child and parent. Cortisol was assessed multiple times across a lab visit at Time 1, and these data were combined into a single continuous measure. Cortisol concentrations across the lab visit interacted with stress exposure across the year such that children with lower average cortisol at Time 1 and increased stress across the 12 months showed elevated levels of internalizing symptoms. Based on these and related data we propose that prior to puberty low cortisol may be an important marker of allostatic load, particularly for risk of depression and anxiety.     

Neuroendocrine dysregulation following early social deprivation in children

Human and nonhuman animal studies reveal that early experiences with caregivers shape children's ability to regulate their responses to stress. To understand the effects of early deprivation on the regulation of the hypothalamic-pituitary-adrenal axis following social interactions, we examined urinary cortisol levels in a group of internationally adopted children who had experienced institutional care, and thus, species-atypical attachment relationships, early in life prior to adoption. Cortisol regulation was assessed both basally and following standardized interpersonal interactions between the child and his/her mother and the child and an unfamiliar adult. Postinstitutionalized children showed prolonged elevations in cortisol levels following the mother, but not the stranger, interaction. More severe neglect was associated with the highest basal cortisol levels and the most impaired cortisol regulation following the mother interaction. These results suggest that early social deprivation may contribute to long-term regulatory problems of the stress-responsive system, and that these differences are most evident within the context of ongoing, close interpersonal relationships.     

Homeless street children in Nepal: use of allostatic load to assess the burden of childhood adversity

As challenges to child well-being through economic disadvantage, family disruption, and migration or displacement escalate world wide, the need for cross-culturally robust understanding of childhood adversity proportionately increases. Toward this end, developmental risk was assessed in four contrasting groups of 107 Nepali children ages 10-14 years that represent distinctive, common conditions in which contemporary children grow up. Relative cumulative burden (allostatic load) indexed by multiple dimensions of physical and psychosocial stress was ascertained among homeless street boys and three family-based groups, from poor urban squatter settlements, urban middle class, and a remote rural village. Biomarkers of stress and vulnerability to stress included growth status, salivary cortisol, antibodies to Epstein-Barr virus, acute phase inflammatory responses (alpha1-antichymotrypsin), and cardiovascular fitness and reactivity (flex heart rate and pressor response). Individual biomarkers of risk and allostatic load differed markedly among groups, were highest in villagers, and varied by components of allostatic load. Such data suggest a need for critical appraisal of homelessness and migration as a risk factor to youth, given prevailing local conditions such as rural poverty, and represents the only multidimensional study of childhood allostatic load and developmental risk in non-Western settings.     

Infants' responsiveness, attachment, and indiscriminate friendliness after international adoption from institutions or foster care in China: application of Emotional Availability Scales to adoptive families

In a short-term longitudinal design we investigated maternal sensitivity, child responsiveness, attachment, and indiscriminate friendliness in families with children internationally adopted from institutions or foster care in China. Ninety-two families with 50 postinstitutionalized and 42 formerly fostered girls, aged 11-16 months on arrival, were studied 2 and 6 months after adoption. Maternal sensitivity and child responsiveness were observed with the Emotional Availability Scales, attachment was assessed with the Strange Situation procedure, and mothers reported on children's indiscriminate friendliness. The postinstitutionalized children showed less secure attachment, whereas the former foster children did not differ from the normative distribution of attachment security. However, at both assessments the two groups of adopted children showed more disorganized attachments compared to normative data. Adoptive mothers of postinstitutionalized and former foster children were equally sensitive and their sensitivity did not change over time. Postinstitutionalized and former foster children did not differ on indiscriminate friendliness, but children with more sensitive adoptive mothers showed less indiscriminate friendliness. The former foster children showed a larger increase in responsiveness over time than the postinstitutionalized children, suggesting that children's responsiveness is more sensitive to change than attachment, and that preadoption foster care is more beneficial for the development of children's responsiveness after adoptive placement than preadoption institutional care.     

Salivary cortisol levels in children adopted from romanian orphanages

Six and a half years after adoption. 6- to 12-year-old children reared in Romanian orphanages for more than 8 months in their first years of life (RO. n = 18) had higher cortisol levels over the daytime hours than did early adopted (EA, < or = 4 months of age, n = 15) and Canadian born (CB, n = 27) children. The effect was marked, with 22% of the RO children exhibiting cortisol levels averaged over the day that exceeded the mean plus 2 SD of the EA and CB levels. Furthermore, the longer beyond 8 months that the RO children remained institutionalized the higher their cortisol levels. Cortisol levels for EA children did not differ in any respect from those of CB comparison children. This latter finding reduces but does not eliminate concerns that the results could be due to prenatal effects or birth family characteristics associated with orphanage placement. Neither age at cortisol sampling nor low IQ measured earlier appeared to explain the findings. Because the conditions in Romanian orphanages at the time these children were adopted were characterized by multiple risk factors, including gross privation of basic needs and exposure to infectious agents, the factor(s) that produced the increase in cortisol production cannot be determined. Nor could we determine whether these results reflected effects on the limbic-hypothalamic-pituitary-adrenal axis directly or were mediated by differences in parent-child interactions or family stress occasion by behavioral problems associated with prolonged orphanage care in this sample.     

Cortisol circadian rhythms and stress responses in infants at risk of allergic disease

BACKGROUND: The cortisol circadian rhythm and response to stressful stimuli are altered in children and adults with allergic disease, including asthma. It is not known whether these alterations precede or follow the onset of allergic disease. OBJECTIVE: We sought to evaluate the cortisol circadian rhythm and stress response among infants at risk for the development of allergic disease. METHODS: Infants with and without risk factors for allergic disease were evaluated at age 6 months. Saliva was obtained at 8 am, 2 pm, and 8 pm at home (n = 68) by parents when their infants were comfortable and in the clinic (n = 88) before and after their physical examination and vaccinations. Information regarding parental allergy and exposure to other children at home or in child care were obtained by questionnaire. RESULTS: In multivariate analysis the circadian rhythm of cortisol was flattened because of the lack of the expected morning surge of cortisol, resulting in decreased diurnal variation of cortisol in infants of mothers with allergy (P = .035) or asthma (P = .002) or an asthmatic father (P = .022). The cortisol stress response was greater in infants of mothers with allergy (P = .045) or asthma (P = .039), those with fewer siblings (P = .066), and those not entering day care early in life (P = .017). CONCLUSIONS: These alterations in both basal and stress levels of endogenous cortisol among infants predisposed to allergic disease might affect the development of allergic immune responses early in life through interactions with inflammatory mediators.     

The salivary alpha amylase over cortisol ratio as a marker to assess dysregulations of the stress systems

Different factors have been associated with changes in the regulation of the two major stress response systems of the human body, the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. Changes in these systems have been associated with various (psycho)pathologies across adulthood, and are thus frequently assessed within the context of allostatic load. Early Life Adversity (ELA) has been identified as one such factor. Individuals with histories of ELA show evidence of elevated basal and reactive salivary alpha amylase (sAA) levels (a marker of SNS activity), blunted cortisol levels (a marker of HPA axis activity), and an asymmetrical relationship between the two variables. However, variable methods used in the past to measure each variable, and the relationship between the two systems, prevent us from drawing firm conclusions. This preliminary study investigated whether the ratio of reactive sAA over reactive cortisol would be more informative to investigate the relationship between the two stress systems than the ratio of cortisol over sAA, or either marker alone, and whether there is a systematic link between this marker and subjective indexes of chronic stress and depression. We studied this in a total of 37 subjects (n=20 with signs of early life adversity and n=17 without) exposed to the Trier social stress test. Using a specific formula to determine the ratio of sAA over cortisol, we found a systematically stronger positive relationship with indexes of chronic stress and depression when compared to cortisol over sAA, or either marker alone. Our findings suggest that the ratio of sAA over cortisol might be a better marker of stress systems dysregulation than the ratio of cortisol over sAA, sAA or cortisol alone. The usefulness of this marker for other chronic stress states as found in allostatic load is discussed.     

Kindergarten stressors and cumulative adrenocortical activation: the "first straws" of allostatic load?

Using an ethnically diverse longitudinal sample of 338 kindergarten children, this study examined the effects of cumulative contextual stressors on children's developing hypothalamic-pituitary-adrenocortical (HPA) axis regulation as an early life indicator of allostatic load. Chronic HPA axis regulation was assessed using cumulative, multiday measures of cortisol in both the fall and spring seasons of the kindergarten year. Hierarchical linear regression analyses revealed that contextual stressors related to ethnic minority status, socioeconomic status, and family adversity each uniquely predicted children's daily HPA activity and that some of those associations were curvilinear in conformation. Results showed that the quadratic, U-shaped influences of family socioeconomic status and family adversity operate in different directions to predict children's HPA axis regulation. Results further suggested that these associations differ for White and ethnic minority children. In total, this study revealed that early childhood experiences contribute to shifts in one of the principal neurobiological systems thought to generate allostatic load, confirming the importance of early prevention and intervention efforts. Moreover, findings suggested that analyses of allostatic load and developmental theories accounting for its accrual would benefit from an inclusion of curvilinear associations in tested predictive models.     

Behavior problems in postinstitutionalized internationally adopted children

Using the Child Behavior Checklist (CBCL), the rate and type of behavior problems associated with being reared in an institution prior to adoption were examined in 1,948, 4- through 18-year-old internationally adopted children, 899 of whom had experienced prolonged institutional care prior to adoption. The children's adoptions were decreed between 1990 and 1998 in Minnesota. Binomial logistic regression analyses revealed that early institutional rearing was associated with increased rates of attention and social problems, but not problems in either the internalizing or externalizing domains. Independent of institutional history, children who were adopted >or=24 months had higher rates of behavior problems across many CBCL scales, including internalizing and externalizing problems. In general, time in the adoptive home, which also reflected age at testing, was positively associated with rates of problem behavior. Thus, there was little evidence that the likelihood of behavior problems wane with time postadoption. Finally, children adopted from Russia/Eastern Europe appeared at greater risk of developing behavior problems in several domains compared to children adopted from other areas of the world.     

Influence of early life stress on later hypothalamic-pituitary-adrenal axis functioning and its covariation with mental health symptoms: a study of the allostatic process from childhood into adolescence

The hypothalamic-pituitary-adrenal (HPA) axis is a primary mechanism in the allostatic process through which early life stress (ELS) contributes to disease. Studies of the influence of ELS on children's HPA axis functioning have yielded inconsistent findings. To address this issue, the present study considers multiple types of ELS (maternal depression, paternal depression, and family expressed anger), mental health symptoms, and two components of HPA functioning (traitlike and epoch-specific activity) in a long-term prospective community study of 357 children. ELS was assessed during the infancy and preschool periods; mental health symptoms and cortisol were assessed at child ages 9, 11, 13, and 15 years. A three-level hierarchical linear model addressed questions regarding the influences of ELS on HPA functioning and its covariation with mental health symptoms. ELS influenced traitlike cortisol level and slope, with both hyper- and hypoarousal evident depending on type of ELS. Further, type(s) of ELS influenced covariation of epoch-specific HPA functioning and mental health symptoms, with a tighter coupling of HPA alterations with symptom severity among children exposed previously to ELS. Results highlight the importance of examining multiple types of ELS and dynamic HPA functioning in order to capture the allostatic process unfolding across the transition into adolescence.     

Interparental aggression and children's adrenocortical reactivity: testing an evolutionary model of allostatic load

Guided by an evolutionary model of allostatic load, this study examined the hypothesis that the association between interparental aggression and subsequent changes in children's cortisol reactivity to interparental conflict is moderated by their temperamental dispositions. Participants of the multimethod, longitudinal study included 201 2-year-old toddlers and their mothers. These children experienced elevated levels of aggression between parents. Consistent with the theory, the results indicated that interparental aggression predicted greater cortisol reactivity over a 1-year period for children who exhibited high levels of temperamental inhibition and vigilance. Conversely, for children with bold, aggressive temperamental characteristics, interparental aggression was marginally associated with diminished cortisol reactivity. Further underscoring its implications for allostatic load, increasing cortisol reactivity over the one year span was related to concomitant increases in internalizing symptoms but decreases in attention and hyperactivity difficulties. In supporting the evolutionary conceptualization, these results further supported the relative developmental advantages and costs associated with escalating and dampened cortisol reactivity to interparental conflict.     

Maternal depression and cortisol in pregnancy predict offspring emotional reactivity in the preschool period

Prenatal exposures to higher levels of maternal cortisol and depression have been linked to a variety of adverse physiological, neurological, and behavioral outcomes, such as dysregulated cortisol production, structural and functional differences in limbic areas of the brain, and greater negative emotionality. This study investigated prospective associations between maternal prepartum depression/cortisol levels and offspring emotional reactivity in 163 mother–child pairs. Women were assessed repeatedly during pregnancy, and later participated in a laboratory visit with their preschool‐aged children. Mothers self‐reported on depressive symptomatology during pregnancy and provided saliva samples for cortisol assay. Offspring emotional reactivity was assessed through multiple measures, including caregiver reports, cortisol response following a stressor, and laboratory observations of behavior. The findings suggest potential prenatal timing effects, with depression and maternal cortisol measured in the first and second trimesters being more strongly associated with child emotional reactivity. Sex was found to moderate associations between maternal prepartum depression/cortisol and child emotional reactivity, with the general pattern reflecting positive associations in girls, and negative associations in boys.     

Attachment, cognitive, and motor development in adopted children: short-term outcomes after international adoption

OBJECTIVE: To examine infant attachment and developmental functioning shortly after international adoption. METHODS: At 14 months, infant-mother attachment and mental (MDI) and psychomotor (PDI) development were assessed in 70 internationally adopted children. Mean age at arrival was 5.5 months, mean stay in the adoptive family 8.7 months. RESULTS: Adopted children's MDI and PDI did not deviate from normative scores. Also, their secure-insecure attachment distribution was comparable with that of normative groups. However, more adoptees were disorganized attached (36 vs. 15% in normative groups). Temporary residence in a foster home in the country of origin before adoption was related to higher MDI and PDI, whereas disorganized attachment in the adoptive family was related to lower MDI and PDI scores. CONCLUSIONS: The majority of internationally adopted children form secure attachment relationships and function at normative developmental levels shortly after adoption. Residence in a foster family before adoption may partly prevent developmental delays.     

Safety of inhaled corticosteroid therapy in young children with asthma.

BACKGROUND: Physicians have had some reluctance to use inhaled corticosteroids in very young children with asthma because of the possible risks of adverse systemic effects. OBJECTIVE: The purpose of this study was to evaluate the effects of fluticasone propionate on growth and adrenocortical function in young children with asthma. METHODS: We performed an open, prospective study for 24 weeks of 20 children with asthma, 2.5 to 5.0 years of age, who had received fluticasone by a large volume spacer at dosages ranging from 190.50 to 565.40 microg/m2 daily. Growth was evaluated by height standard deviation scores measured by a stadiometer. Adrenocortical function was evaluated twice in each child, before and after the study, by determining fasting serum cortisol concentrations at 8 AM and also at 30 and 60 minutes after adrenocorticotropic hormone stimulation. Posttreatment values of height standard deviation scores and fasting morning serum cortisol concentrations were compared with those of 18 age-matched children, who constituted the control group. RESULTS: The evaluation of mean +/- SEM (and range) of height standard deviation scores revealed a significant decrease from 0.44 +/- 0.27 (-1.46 to 2.22) to 0.28 +/- 0.26 (-1.51 to 2.07; P = 0.01) at week 18 and to 0.25 +/- 0.24 (-1.90 to 2.13; P = 0.04) at the week 24 in fluticasone-treated children. At the end of the treatment, however, height standard deviation scores of these children did not differ significantly (P = 0.35) from those of the control group. Delayed growth with medium-duration treatment was not associated with alterations in serum cortisol measurements, either at baseline or after stimulation. The mean fasting morning serum cortisol concentrations did not differ significantly between the fluticasone-treated patients and the control group. CONCLUSIONS: Some concern prevails about the safety of medium- or long-term treatment with regularly inhaled corticosteroids in young children with asthma. The prepubertal growth may be delayed, but the effect on ultimate height remains uncertain in such children. Growth should be regularly monitored in children who begin inhaled corticosteroid therapy for mild persistent asthma at an age <5 years old.     

Allostasis and allostatic load in the context of poverty in early childhood

This paper examined the relation of early environmental adversity associated with poverty to child resting or basal level of cortisol in a prospective longitudinal sample of 1135 children seen at 7, 15, 24, 35, and 48 months of age. We found main effects for poor housing quality, African American ethnicity, and low positive caregiving behavior in which each was uniquely associated with an overall higher level of cortisol from age 7 to 48 months. We also found that two aspects of the early environment in the context of poverty, adult exits from the home and perceived economic insufficiency, were related to salivary cortisol in a time-dependent manner. The effect for the first of these, exits from the home, was consistent with the principle of allostatic load in which the effects of adversity on stress physiology accumulate over time. The effect for perceived economic insufficiency was one in which insufficiency was associated with higher levels of cortisol in infancy but with a typical but steeper decline in cortisol with age at subsequent time points.     

Characteristics and perspectives of families waiting to adopt a child with Down syndrome.

PURPOSE: The study's purpose was to obtain information on the characteristics and perspectives of families interested in adopting children with Down syndrome. METHODS: A questionnaire-based survey was administered to individuals and families on a waiting list to adopt children with Down syndrome. Information on (1) demographic, (2) family structure, (3) Down syndrome exposure, (4) Down syndrome knowledge, (5) reasons for considering adoption, (6) adoption process, and (7) perspective on raising children with Down syndrome was assessed. RESULTS: From 199 mailed surveys, there were 72 respondents (36.2%) of whom six had previously adopted a child with Down syndrome. Forty-eight percent learned of the possibility of adopting children with Down syndrome through the Internet, whereas only one respondent obtained this information from a medical professional. The primary reasons for considering adoption were that prospective adoptive families were equipped with the necessary resources and had previous positive experiences with individuals who have Down syndrome. CONCLUSIONS: Many families are eager to adopt children with Down syndrome. Interest in this option stems from having resources to care for these children and previous positive experiences with individuals with Down syndrome. Information regarding adoption was rarely obtained from health care providers. When counseling pregnant women diagnosed with a Down syndrome fetus, adoption should be discussed so that all options regarding pregnancy management may be explored.