Birth weight and postnatal microbial exposures predict the distribution of peripheral blood leukocyte subsets in young adults in the Philippines.

The immune system not only provides protection against infectious disease but also contributes to the etiology of neoplastic, atopic, and cardiovascular and metabolic diseases. Prenatal and postnatal nutritional and microbial environments have lasting effects on multiple aspects of immunity, indicating that immune processes may play important roles in the developmental origins of disease. The objective of this study is to evaluate the association between birth weight and the distribution of leukocyte (white blood cell) subsets in peripheral blood in young adulthood. Postnatal microbial exposures were also considered as predictors of leukocyte distribution. Participants (n=486; mean age=20.9 years) were drawn from a prospective birth cohort study in the Philippines, and analyses focused on the following cell types: CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, natural killer cells, monocytes, granulocytes. Higher birth weight was a strong predictor of higher proportion of CD4 T lymphocytes (B=0.12, s.e.=0.041, P=0.003), lower proportion of CD8 T lymphocytes (B=-0.874, s.e.=0.364, P=0.016), higher CD4:CD8 ratio (B=1.964, s.e.=0.658, P=0.003), and higher B lymphocytes (B=0.062, s.e.=0.031, P=0.047). Measures of microbial exposure in infancy were negatively associated with proportions of B lymphocytes and granulocytes, and lower CD4:CD8 ratio. Leukocytes are the key regulators and effectors of innate and specific immunity, but the origins of variation in the distribution of cell type across individuals are not known. Our findings point toward nutritional and microbial exposures in infancy as potentially important determinants of immune-phenotypes in adulthood, and they suggest that leukocyte distribution is a plausible mechanism through which developmental environments have lasting effects on disease risk in adulthood.

Maternal pregnancy C-reactive protein predicts offspring birth size and body composition in metropolitan Cebu, Philippines.

The gestational milieu is an important influence on fetal development and long-term disease risk. Here we assess relationships between maternal pregnancy inflammation, indicated by C-reactive protein (CRP), and offspring anthropometric outcomes measured soon after birth. Data come from female participants (n=327, age 24.4-30.2 years) in a longitudinal study located in Metropolitan Cebu, Philippines. Between 2009 and 2014, pregnancy interviews (n=429) were conducted during which questionnaire and anthropometric data were obtained along with dried blood spot cards for CRP measurement. Offspring body weight, length, head circumference and five skinfold thickness measures were obtained soon after birth. Maternal pregnancy CRP was borderline (-1.11±0.64 days/log-mg/l; P<0.1) inversely related to gestational age at delivery, but did not increase the likelihood of preterm delivery. After adjusting for maternal pre-pregnancy body mass index, height, pregnancy adiposity, age, parity and other covariates, CRP was significantly, inversely related to offspring body weight (-0.047±0.017 kg/log-mg/l), length (-0.259±0.092 cm/log-mg/l) and sum of skinfolds (-0.520±0.190 mm/log-mg/l) (all P<0.05), and borderline inversely related to offspring head circumference (-0.102±0.068 cm/log-mg/l; P<0.1). Notably, relationships were continuous across the full CRP range, and not limited to unusually high levels of inflammation. These findings point to an important role of maternal non-specific immune activation as a predictor of offspring birth outcomes. In light of evidence that early life microbial, nutritional and stress experiences influence adult inflammatory regulation, these findings point to inflammation as a potential pathway for the intergenerational transmission of maternal experience to offspring health.

Self-collected dried blood spots as a tool for measuring ovarian reserve in young female cancer survivors.

STUDY QUESTION: Are female young cancer survivors (YCS) able to self-collect high-quality dried blood spots (DBSs) at home to provide biospecimens for studying ovarian reserve? SUMMARY ANSWER: YCS can self-collect high-quality DBS specimens in non-clinical settings, and anti-Mullerian hormone (AMH) levels can be assayed in such specimens. WHAT IS KNOWN ALREADY: Large-scale biosample collection is a barrier to studying ovarian reserve in YCS. DBS collected by research personnel has high acceptability. AMH levels measured in DBS are highly correlated with those measured by serum-based methods. STUDY DESIGN, SIZE, DURATION: In a prospective cohort study, YCS were recruited to self-collect DBS samples. AMH levels were assayed in 112 samples. PARTICIPANTS/MATERIALS, SETTING, METHODS: YCS participants, ages 18-44, were recruited from a nationwide longitudinal cohort and DBS collection materials were posted to them. AMH levels were assayed by the Ansh DBS AMH ELISA and compared according to participant characteristics. MAIN RESULTS AND THE ROLE OF CHANCE: Among 163 potential participants, 123 (75%) were enrolled. Of those enrolled, 112 (91%) were able to complete DBS self-collection and submit mailed samples adequate for measuring AMH. Participants (mean age 31.6 [SD 5.5]) were 85% white, 87% college graduates and 46% reported higher income. Common cancer types were lymphoma and leukemia (34%), breast cancer (30%) and thyroid or skin cancer (8%). The geometric mean (95% confidence interval) AMH level in DBS samples was 0.24 ng/ml (0.16-0.36). In adjusted analysis, AMH levels for survivors of breast cancer (0.02 ng/ml [0.01-0.07]) or leukemia/lymphoma (0.03 ng/ml [0.01-0.08]) were lower than the levels in thyroid or skin cancer survivors (0.12 ng/ml [0.03-0.44]). Pelvic radiation remained associated with lower AMH levels (0.20 ng/ml [0.10-0.40] in unexposed versus 0.02 ng/ml [0.01-0.06] in exposed). Amenorrheic survivors had AMH levels (0.02 ng/ml [0.01-0.06]) that were lower than those of YCS with 7-9 (0.09 ng/ml [0.03-0.32]) or ≥10 (0.17 ng/ml [0.08-0.37]) menstrual periods in the past year. LIMITATIONS, REASONS FOR CAUTION: The results are generalizable to a population of highly educated, higher income YCS. It is unclear how generalizable the results are to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Self-collected DBS is a patient-friendly and minimally invasive tool for studying ovarian reserve in geographically diverse populations. STUDY FUNDING/COMPETING INTERESTS: Research related to the development of this paper was supported by the National Institutes of Health, grants UL1 RR024926 pilot and HD080952-02, and by the American Cancer Society MRSG-08-110-01-CCE. The authors report no competing interests.

Slow early growers have more muscle in relation to adult activity: evidence from Cebu, Philippines.

BACKGROUND/OBJECTIVES: Adult skeletal muscle mass (SMM) protects against type 2 diabetes, but little is known about its developmental antecedents. We examined whether pace of early weight gain predicted adult SMM in a birth cohort from Cebu City, Philippines. In addition, we examined whether increases in SMM associated with adult muscle-building exercise varied according to the early growth. SUBJECTS/METHODS: Data came from 1472 participants of the Cebu Longitudinal Health and Nutrition Survey. Weight was measured at birth and at 6-month intervals through the age of 24 months. Adult SMM was estimated from anthropometric measurements when participants were 20-22-years old. Interviews provided the information on adult exercise/lifestyle habits. RESULTS: SMM (mean ± s.d.) was 20.8 ± 3.9 kg (men) and 13.6 ± 3.4 kg (women). Faster early weight gain predicted a higher adult SMM. After adjustment for height and lifestyle factors, strongest associations with SMM were found for 6-12 months growth in men (ß=0.17, P=0.001) and for birth weight in women (ß=0.14, P=0.001). Individuals who had grown slowly displayed greater SMM in association with adult weightlifting, basketball playing and physically demanding forms of employment (men) or household chores (women). CONCLUSIONS: These results suggest heightened sensitivity of activity-induced muscle hypertrophy among the adults who were born light or who gained weight slowly as infants. Future research should test this finding by comparing responses of muscle mass to an intervention in slow vs fast early growers. Findings suggest that adults who display a reduced SMM following suboptimal early growth may be good candidates for new anti-diabetes interventions that promote muscle-building activities.

Influence of helminth infections on childhood nutritional status in lowland Bolivia.

Infectious disease, such as diarrheal disease, respiratory infections, and parasitic infections, are an important source of nutritional and energetic stress in many populations. Inspired by the research and methodological innovations of A. Roberto Frisancho, this work considers the impact of childhood environment and local disease ecology on child health and nutritional patterns among an indigenous group in lowland Bolivia. Specifically, we examine the association between soil-transmitted helminth infection, especially hookworm species, and anthropometric markers of short- and long-term nutritional status. Fecal samples, anthropometric dimensions, and health interviews were collected for 92 children ranging in age from 2.0 to 10.9 years. Microscopic examination revealed high levels of parasitic infection, with 76% of children positive for hookworm species infections (77% of girls and 74% of boys). Less common infections included Ascaris lumbricoides, Trichurius trichiura, and Strongyloides stercoralis with only 15% of children positive for multiple-species infections. After adjusting for sex and age, no statistically significant associations were observed between helminth infections and the frequency of reported illness or anthropometric measures of nutritional status. These data demonstrate the difficulty of assessing nutritional impacts of endemic infections.

Rain, temperature, and child-adolescent height among Native Amazonians in Bolivia.

BACKGROUND: Global climate change and recent studies on early-life origins of well-being suggest that climate events early in life might affect health later in life. AIM: The study tested hypotheses about the association between the level and variability of rain and temperature early in life on the height of children and adolescents in a foraging-farming society of native Amazonians in Bolivia (Tsimane'). SUBJECT AND METHODS: Measurements were taken for 525 children aged 2-12 and 218 adolescents aged 13-23 in 13 villages in 2005. Log of standing height was regressed on mean annual level and mean intra-annual monthly coefficient of variation (CV) of rain and mean annual level of temperature during gestation, birth year, and ages 2-4. Controls include age, quinquennium and season of birth, parent's attributes, and dummy variables for surveyors and villages. RESULTS: Climate variables were only related with the height of boys age 2-12. The level and CV of rain during birth year and the CV of rain and level of temperature during ages 2-4 were associated with taller stature. There were no secular changes in temperature (1973-2005) or rain (1943-2005). CONCLUSION: The height of young females and males is well protected from climate events, but protection works less well for boys ages 2-12.

Maintenance versus growth: investigating the costs of immune activation among children in lowland Bolivia.

Immune function is a central component of maintenance effort, and it provides critical protection against the potentially life threatening effects of pathogens. However, immune defenses are energetically expensive, and the resources they consume are not available to support other activities related to growth and/or reproduction. In our study we use a life history theory framework to investigate tradeoffs between maintenance effort and growth among children in a remote area of Amazonian Bolivia. Baseline concentrations of C-reactive protein (CRP) were measured in 309 2- to 10-year olds as an indicator of immune activation, and height was measured at baseline and three months later. Elevated CRP at baseline predicts smaller gains in height over the subsequent three months, with the costs to growth particularly high for 2- to 4-year olds and for those with low energy reserves (in the form of body fat) at the time of immunostimulation. These results provide evidence for a significant tradeoff between investment in immunity and growth in humans, and highlight an important physiological mechanism through which maintenance effort may have lasting effects on child growth and development.

Ethnobotanical knowledge is associated with indices of child health in the Bolivian Amazon.

Culture is a critical determinant of human behavior and health, and the intergenerational transmission of knowledge regarding the use of available plant resources has historically been an essential function of culture. Local ethnobotanical knowledge is important for health and nutrition, particularly in rural low-resource settings, but cultural and economic transitions associated with globalization threaten such knowledge. This prospective study investigates the association between parental ethnobotanical knowledge and child health among the Tsimane', a horticulturalist and foraging society in Amazonian Bolivia. Anthropometric data and capillary blood samples were collected from 330 Tsimane' 2- to 10-year-olds, and mothers and fathers were interviewed to assess ethnobotanical knowledge and skills. Comprehensive measures of parental schooling, acculturation, and economic activities were also collected. Dependent variables included three measures of child health: (i) C-reactive protein, assayed in whole-blood spots as an indicator of immunostimulation; (ii) skinfold thickness, to estimate subcutaneous fat stores necessary to fuel growth and immune function; and (iii) height-for-age, to assess growth stunting. Each child health measure was associated with maternal ethnobotanical knowledge, independent of a wide range of potentially confounding variables. Each standard deviation of maternal ethnobotanical knowledge increased the likelihood of good child health by a factor of >1.5. Like many populations around the world, the Tsimane' are increasingly facing the challenges and opportunities of globalization. These results underscore the importance of local cultural factors to child health and document a potential cost if ethnobotanical knowledge is lost.

Predictors of C-reactive protein in Tsimane' 2 to 15 year-olds in lowland Bolivia.

Infectious disease is a major global determinant of child morbidity and mortality, and energetic investment in immune defenses (even in the absence of overt disease) is an important life-history variable, with implications for human growth and development. This study uses a biomarker of immune activation (C-reactive protein) to investigate an important aspect of child health among the Tsimane', a relatively isolated Amerindian population in lowland Bolivia. Our objectives are twofold: 1) to describe the distribution of CRP by age and gender in a cross-sectional sample of 536 2-15-year-olds; and 2) to explore multiple measures of pathogen exposure, economic resources, and acculturation as predictors of increased CRP. The median blood-spot CRP concentration was 0.73 mg/l, with 12.9% of the sample having concentrations greater than 5 mg/L, indicating a relatively high degree of immune activation in this population. Age was the strongest predictor of CRP, with the highest concentrations found among younger individuals. Increased CRP was also associated with higher pathogen exposure, lower household economic resources, and increased maternal education and literacy. The measurement of CRP offers a direct, objective indicator of immune activation, and provides insights into a potentially important pathway through which environmental quality may shape child growth and health.

Prenatal and early postnatal environments are significant predictors of total immunoglobulin E concentration in Filipino adolescents.

BACKGROUND: Recent evidence suggests that atopic disease may in part be mediated by fetal growth, as well as exposure to infectious disease early in life. Few studies have been able to evaluate these associations simultaneously, or to investigate prospectively the long-term effects of early environments while adequately controlling for potentially confounding variables. OBJECTIVE: To examine how prenatal growth and infectious disease in infancy are related to total IgE production in adolescence. METHODS: Ninety-nine adolescents (aged 14-15 years) were selected from a larger cohort study according to the following criteria: full-term birth, currently healthy, and small-for-gestational age (N=53) or appropriate-for-gestational age (N=46). Plasma total IgE was measured with ELISA, and analysed in relation to anthropometric, nutritional, and environmental quality data collected prospectively beginning in the third trimester prior to birth. RESULTS: Each episode of infectious morbidity recorded at bimonthly intervals in the first 6 months of life was associated with a 0.12 log IU/mL reduction in total IgE in adolescence (P=0.004). Prenatal undernutrition was associated with increased adolescent IgE, but only under conditions of an unsanitary household environment (P=0.002). Each additional kilogram gained per month in the first 6 months of life was associated with an increase in adolescent IgE of 0.74 log IU/mL (P=0.03). Each quartile increase in weekly household income at the time of blood sampling was associated with a 0.10 log IU/mL reduction in total IgE (P=0.02). CONCLUSION: Infectious disease in infancy, as well as interactions between prenatal and postnatal environments, appear to have long-term effects on adolescent total IgE production. Future research should investigate the mechanisms behind these effects, and their implications for symptoms of atopic disease.

Lifestyle incongruity, social integration, and immune function in Samoan adolescents.

The health consequences of rapid cultural and economic change have been explored for adults in a range of low-income countries, but comparable research in children and adolescents is currently lacking. Concurrently, the immunosuppressive effects of psychosocial stress have been documented in Western populations, but have yet to be considered in cross-cultural contexts. This study uses lifestyle incongruity (inconsistency between a household's material style of life and its socioeconomic status) as a model of culture change and stress, and considers its impact on immune function in a sample of 230 10-20 year-olds from (Western) Samoa. Anthropometric, lifestyle, and psychosocial data were collected, as well as finger prick blood spot samples for analysis of C-reactive protein (marker of infection) and antibodies against the Epstein-Barr virus (marker of cell-mediated immune function). Controlling for potential confounders, adolescents from households with a material style of life that exceeds its socioeconomic status have reduced cell-mediated immune function, indicating an increased burden of psychosocial stress. Social relationships moderate this effect: lifestyle incongruity stress is pronounced among adolescents with a high degree of social integration, and absent in adolescents with low social integration. This finding is counter to the buffering role of social support reported in previous applications of lifestyle incongruity to adults, and suggests that the moderating role of social integration may be unique to adolescents. The potential utility of the lifestyle incongruity model for future cross-cultural studies of child and adolescent stress is discussed.

Prenatal undernutrition, postnatal environments, and antibody response to vaccination in adolescence.

BACKGROUND: Recently, researchers have considered the fetal and infant origins of several adult cardiovascular and metabolic diseases, but the implications of early events for immune function and infectious disease are unclear. OBJECTIVE: We investigated the association between prenatal undernutrition and immunocompetence in adolescence and hypothesized that intrauterine growth retardation is associated with a lower likelihood of mounting an adequate antibody response later in life. DESIGN: A subsample of one hundred three 14-15-y-olds was recruited from an ongoing longitudinal study in which data collection began while participants were in utero. A typhoid vaccine was given, and anti-typhoid antibodies were measured 2 wk and 3 mo later as a functional marker of immunocompetence. The likelihood of mounting an adequate antibody response was compared for adolescents who were small for gestational age or appropriate for gestational age at birth while controlling for a range of postnatal exposures. RESULTS: The predicted probability of mounting a positive antibody response for adolescents who were prenatally and currently undernourished was 0.32, compared with probabilities of 0.49-0.70 for adequately nourished adolescents (P = 0.023). Diarrhea in the first year of life (P = 0.009) and fast weight gain during the first 6 mo (P = 0.003) were also associated with a higher probability of response. CONCLUSIONS: These findings extend the concept of fetal and early infant programming of adult diseases to the immune system and suggest that early environments may have long-term implications for immunocompetence and infectious disease risk, particularly in developing countries.

Defining the "urban" in urbanization and health: a factor analysis approach.

Urban environments have been linked to a range of human health issues, and as the pace of urbanization accelerates, new challenges arise to characterize these environments, and to understand their positive and negative implications for health. We seek to contribute to future studies of urbanization and health by exploring multiple definitions of urbanicity in the Philippines, using data from an ongoing, longitudinal study. We use factor analysis to identify meaningful clusters of household- and community-level variables, and to generate factor scores that summarize each household's position with respect to access to infrastructure and health services, and level of affluence. Factor scores are considered for 1983 and 1994 to assess the type and pace of change that has occurred in the Philippines, and scores are compared across urban and rural areas, and across six different settlement types, to explore household- and community-level markers of urbanicity. This analysis demonstrates the heterogeneity of environments within urban and rural areas, and emphasizes the need for a finer level of investigation in future studies of urbanization and health.

Prenatal undernutrition and postnatal growth are associated with adolescent thymic function.

The fetal and early infant origins of a number of adult cardiovascular and metabolic diseases have received considerable attention, but the long-term consequences of early environments for human immune function have not been reported. We investigated the effects of pre- and postnatal environments on thymic hormone production in adolescents participating in an ongoing longitudinal study in the Philippines. Prospective data collected at birth, during y 1 of life, in childhood and in adolescence were used to predict plasma thymopoietin concentration in 14- to 15-y-old adolescents (n = 103). Thymopoietin concentration was compared for small-for-gestational-age and appropriate-for-gestational-age individuals while controlling for a range of postnatal exposures. Prenatal undernutrition was significantly associated with reduced thymopoietin production in interaction with the duration of exclusive breast-feeding (P = 0.006). Growth in length during y 1 of life was positively associated with adolescent thymopoietin production (P = 0.002). These associations remained significant after adjusting for a range of potentially confounding variables. These findings provide support for the importance of fetal and early infant programming of thymic function, and suggest that early environments may have long-term implications for immunocompetence and adult disease risk.

Parent-offspring conflict and the cultural ecology of breast-feeding.

Lactation constitutes a major focus for research in international health because of its dramatic impact on child survival; evolutionary biology has investigated lactation as an important aspect of parenting strategy, with implications for understanding parent-offspring conflict. These perspectives are brought together in an attempt to develop integrated models for an issue of key international health concern: the duration of exclusive breast-feeding and the timing of weaning. This analysis highlights the relevance of evolutionary theory for practical problems in public health, and it suggests the utility of public health outcomes for addressing evolutionary questions.

Epstein-Barr virus antibodies in whole blood spots: a minimally invasive method for assessing an aspect of cell-mediated immunity.

OBJECTIVE: Study 1: Introduce and validate a method for measuring EBV p18-VCA antibodies in whole blood spots to provide a minimally invasive marker of cell-mediated immune function. Study 2: Apply this method to a large community-based study of psychopathology in children and adolescents. METHODS: The EBV antibody method was evaluated through analysis of precision, reliability, stability, and comparisons with plasma and indirect immunofluorescence methods. The effects of life events on p18-VCA antibody level were considered in a subsample of 9, 11, and 13 year-old children participating in the Great Smoky Mountains Study in North Carolina. The subsample was stratified by age, sex, and degree of overall life strain. RESULTS: Dried blood spots provided a convenient, sensitive, precise, and reliable method for measuring EBV p18-VCA antibody titer. Life events were positively associated with p18-VCA antibodies in girls but not in boys. CONCLUSIONS: The validity of the blood spot EBV p18-VCA antibody assay, as well as the ease of sample collection, storage, and transportation, may provide an opportunity for psychoneuroimmunology to explore a wider range of stress models in larger, community-based studies.

The weanling's dilemma reconsidered: a biocultural analysis of breastfeeding ecology.

Infant feeding practices exert recognized effects on infant survival and command close attention from pediatricians, nutritionists, public health workers, demographers, social scientists, and parents. Despite considerable research and public health efforts, models to inform decision-making about timing of supplementation in policy and practice remain unsatisfactory. In the present review, new models are derived through analysis of the weanling's dilemma. After approximately 6 months, breast milk alone cannot meet the infant's nutritional requirements for growth, but nutritional supplementation raises risks of illness and malnutrition. Timing of supplementation is conditioned by complex short- and long-term trade-offs among infant and maternal needs and constraints. No formulaic solution can be prescribed for this dilemma, but optimal timing of supplementation can be ascertained from infant-, maternal-, and locale-specific conditions. Models for these determinants and trade-offs are presented and applied to data from longitudinal studies of breastfeeding, infant development, and interbirth interval.