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.

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.

Parental childhood growth and offspring birthweight: pooled analyses from four birth cohorts in low and middle income countries.

OBJECTIVE: Associations between parental and offspring size at birth are well established, but the relative importance of parental growth at different ages as predictors of offspring birthweight is less certain. Here we model parental birthweight and postnatal conditional growth in specific age periods as predictors of offspring birthweight. METHODS: We analyzed data from 3,392 adults participating in four prospective birth cohorts and 5,506 of their offspring. RESULTS: There was no significant heterogeneity by study site or offspring sex. 1SD increase in maternal birthweight was associated with offspring birthweight increases of 102 g, 1SD in maternal length growth 0-2 year with 46 g, and 1SD in maternal height growth Mid-childhood (MC)-adulthood with 27 g. Maternal relative weight measures were associated with 24 g offspring birth weight increases (2 year- MC) and 49 g for MC-adulthood period but not with earlier relative weight 0-2 year. For fathers, birthweight, and linear/length growth from 0-2 year were associated with increases of 57 and 56 g in offspring birthweight, respectively but not thereafter. CONCLUSIONS: Maternal and paternal birthweight and growth from birth to 2 year each predict offspring birthweight. Maternal growth from MC-adulthood, relative weight from 2-MC and MC-adulthood also predict offspring birthweight. These findings suggest that shared genes and/or adequate nutrition during early life for both parents may confer benefits to the next generation, and highlight the importance of maternal height and weight prior to conception. The stronger matrilineal than patrilineal relationships with offspring birth weight are consistent with the hypothesis that improving the early growth conditions of young females can improve birth outcomes in the next generation.

A dose-response relationship between fish consumption and human milk DHA content among Filipino women in Cebu City, Philippines.

AIMS: Human milk is the primary source of docosahexaenoic acid (DHA) for most infants, an important fatty acid for neurological development. Milk DHA is largely incorporated from the maternal diet. Little is known about whether milk DHA varies within populations with differences in maternal fish consumption. Here, we investigate this association in a sample of marginally nourished Filipino women. METHODS: Milk samples were collected during in-home interviews with 117 lactating Filipino mothers from Cebu City, Philippines, nursing infants <24 months of age. Anthropometric data and dietary recalls were also collected. Samples were analysed for total fatty acid composition using gas chromatography. Multivariate regression was used to test the association between fish consumption and milk DHA. RESULTS: Milk DHA showed a positive, dose-response relationship with maternal fish consumption (p < 0.011, r(2 ) =( ) 0.21). Milk DHA was also positively related to protein intake, likely reflecting the association between fish and protein intake (p < 0.009). Unlike prior studies, parity predicted increased milk DHA (p = 0.03). CONCLUSIONS: Increasing fish consumption during lactation may be a cost-effective means of maximizing DHA delivery to infants particularly in populations with marginal energy intakes during lactation. However, this must be weighed against the potential dangers of increasing exposure to fish-based pollutants.

A supply-demand model of fetal energy sufficiency predicts lipid profiles in male but not female Filipino adolescents.

OBJECTIVE: To test the hypothesis that the balance between fetal nutritional demand and maternal nutritional supply during pregnancy will predict lipid profiles in offspring measured in adolescence. SUBJECTS AND METHODS: A total of 296 male and 307 female Filipino offspring (aged 14-16 y) and mothers enrolled in a longitudinal birth cohort study (begun in 1983-84) had lipid profiles measured. Data on maternal height (as a proxy for offspring growth potential and thus fetal nutritional demand) and third trimester maternal arm fat area (as a proxy for maternal supply) were used to create four groups hypothesized to reflect a gradient of fetal energy sufficiency. RESULTS: As fetal energy sufficiency increased among males, there was a decrease in total cholesterol (TC) (P<0.05 for trend), low-density lipoprotein cholesterol (LDL-C), and the ratios of TC/HDL-C cholesterol and LDL-C/HDL-C (all P<0.001), while HDL-C increased (P<0.05). Similar associations were identified when lipid levels were modeled as dichotomous 'high-risk' cut-points used in cardiovascular disease prevention in adolescents. These relationships were stronger, or only present, among offspring of mothers in the lower half of the third trimester energy intake distribution, and were independent of the child's current adiposity, dietary energy and fat intake, maturity, household income, and birth weight. In females, the supply-demand model did not predict any lipid outcome or clinical risk criteria. CONCLUSIONS: Our findings in males support the hypothesis that the balance between fetal nutritional demand and maternal nutritional supply has implications for future lipid profiles. The lack of significant associations in females adds to mounting evidence for sex differences in lipid metabolism programming, and may reflect sex differences in fetal nutritional demand. SPONSORSHIP: The National Science Foundation, the Mellon Foundation, the Nestle Foundation, and the Emory University Internationalization Program.

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.

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.

Maternal energy stores and diet composition during pregnancy program adolescent blood pressure.

BACKGROUND: Fetal undernutrition is hypothesized to program blood pressure (BP) later in life. Human epidemiological studies that use birth weight as a proxy for fetal malnutrition fail to identify specific aspects of maternal nutrition responsible for programming. METHODS AND RESULTS: We examined how maternal nutrition during pregnancy and infant birth weight relate to systolic and diastolic BP (SBP and DBP) in 2026 Filipino adolescents. Data were collected prospectively during the Cebu (Philippines) Longitudinal Health and Nutrition Survey. Women were assessed at approximately 30 weeks gestation, and children were followed from birth through adolescence. Regression models were used to examine how the mothers' total energy intake, percentage of energy from protein and fat, triceps skinfold thickness during pregnancy, and infant birth weight relate to adolescent BP, controlling for current age, height, and body mass index and other potential confounders. Maternal triceps skinfold thickness was significantly inversely related to SBP among boys and to DBP in boys and girls. Maternal nutrition variables attenuated but did not eliminate an inverse birth weight-SBP relationship in boys. SBP was significantly inversely related to the mothers' percent of dietary energy from protein in boys. Among girls, SBP and DBP were inversely related to the mothers' percentage of calories from fat. There was no evidence of confounding of these relationships by current diet, maturation status, physical activity, or socioeconomic status. CONCLUSIONS: Maternal diet composition and energy stores in the form of subcutaneous fat have long-term effects on offspring BP in adolescence.

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.

Adipose tissue in human infancy and childhood: an evolutionary perspective.

Humans diverge from most mammals, including nonhuman primates, by depositing significant quantities of body fat in utero and are consequently one of the fattest species on record at birth. While explanations for the fat layer of human neonates have commonly assumed that it serves as insulation to compensate for hairlessness, empirical support for this hypothesis is presently weak. Whether the tissue's abundance at birth and growth changes in adiposity during infancy and childhood might be explained in light of its role as energy buffer has not been assessed, and this possibility is explored through development of a model of fat function and growth centered on two related hypotheses. The first is that the greater adiposity of human neonates is at least partially explainable as an accompaniment of the enlarged human brain, which demands a larger energy reserve to ensure that its obligatory needs are met when the flow of resources from mother or other caretakers is disrupted. The second is that age-related changes in the likelihood of experiencing such disruption have influenced the pattern of investment in the tissue, reflected today in peak adiposity during infancy and a decline to a leaner childhood period. Nutritional disruption is common at birth and until lactation is established, during which time human newborns survive from fats deposited prenatally, suggesting one possible explanation for the early onset of fat deposition. At weaning, the transition from breast milk to supplemental foods and the parallel transition from maternal to endogenous immune protection interact to increase the frequency and impact of nutritional disruption, and this may help explain why newborns devote roughly 70% of growth expenditure to fat deposition during the early postnatal months. Evidence is presented that fat stores are mobilized during infections, hinting at one possible mechanism underlying the association between nutritional status and infectious morbidity and mortality among infants in nutritionally stressed human populations. Consistent with the proposed hypothesis, well-fed infants acquire peak fat reserves by an age of peak prevalence of malnutrition, infectious disease, and fat reserve depletion in less-buffered contexts, and childhood--characterized by minimal investment in the tissue--is a stage of reduced risk of energy stress. The model presented here foregrounds energy storage in adipose tissue as an important life-history strategy and a means to modify mortality risk during the nutritionally turbulent period of infancy.