Effects of early-life poverty on health and human capital in children and adolescents: analyses of national surveys and birth cohort studies in LMICs.

The survival and nutrition of children and, to a lesser extent, adolescents have improved substantially in the past two decades. Improvements have been linked to the delivery of effective biomedical, behavioural, and environmental interventions; however, large disparities exist between and within countries. Using data from 95 national surveys in low-income and middle-income countries (LMICs), we analyse how strongly the health, nutrition, and cognitive development of children and adolescents are related to early-life poverty. Additionally, using data from six large, long-running birth cohorts in LMICs, we show how early-life poverty can have a lasting effect on health and human capital throughout the life course. We emphasise the importance of implementing multisectoral anti-poverty policies and programmes to complement specific health and nutrition interventions delivered at an individual level, particularly at a time when COVID-19 continues to disrupt economic, health, and educational gains achieved in the recent past.

Health and development from preconception to 20 years of age and human capital.

Optimal health and development from preconception to adulthood are crucial for human flourishing and the formation of human capital. The Nurturing Care Framework, as adapted to age 20 years, conceptualises the major influences during periods of development from preconception, through pregnancy, childhood, and adolescence that affect human capital. In addition to mortality in children younger than 5 years, stillbirths and deaths in 5-19-year-olds are important to consider. The global rate of mortality in individuals younger than 20 years has declined substantially since 2000, yet in 2019 an estimated 8·6 million deaths occurred between 28 weeks of gestation and 20 years of age, with more than half of deaths, including stillbirths, occurring before 28 days of age. The 1000 days from conception to 2 years of age are especially influential for human capital. The prevalence of low birthweight is high in sub-Saharan Africa and even higher in south Asia. Growth faltering, especially from birth to 2 years, occurs in most world regions, whereas overweight increases in many regions from the preprimary school period through adolescence. Analyses of cohort data show that growth trajectories in early years of life are strong determinants of nutritional outcomes in adulthood. The accrual of knowledge and skills is affected by health, nutrition, and home resources in early childhood and by educational opportunities in older children and adolescents. Linear growth in the first 2 years of life better predicts intelligence quotients in adults than increases in height in older children and adolescents. Learning-adjusted years of schooling range from about 4 years in sub-Saharan Africa to about 11 years in high-income countries. Human capital depends on children and adolescents surviving, thriving, and learning until adulthood.

Growth in Infancy and Childhood and Age at Menarche in Five Low- or Middle-Income Countries: Consortium of Health Orientated Research in Transitional Societies (COHORTS).

BACKGROUND: Earlier age at menarche is associated with behavioral and noncommunicable disease risks. The influence of birth weight (BW) (intrauterine) and postnatal growth on age at menarche is not well studied in low- and middle-income countries (LMICs). OBJECTIVE: Therefore, we investigated these associations in 5 LMIC birth cohorts. METHODS: We analyzed data from Brazil, Guatemala, India, the Philippines, and South Africa (n = 3983). We derived stunting (< -2 SD scores) at 24 mo using the WHO child growth standards. We generated interaction terms with categorized BW and conditional weight (lighter < 0 or heavier ≥ 0), and height (shorter < 0 or taller ≥ 0) z-scores. We categorized early-, modal-, and late-onset menarche and used multilevel ordinal regression. We used multilevel linear regression on continuous age at menarche. RESULTS: Mean age at menarche was 12.8 y (95% CI: 12.7 12.9). BW was not associated with age at menarche. Conditional height at 24 mo and mid-childhood (OR: 1.35; 95% CI: 1.27, 1.44 and 1.32; 1.25, 1.41, respectively) and conditional weight at 24 mo and mid-childhood (OR: 1.15; 1.08, 1.22 and 1.18; 1.11, 1.25, respectively) were associated with increased likelihood of early-onset menarche. Being heavier at birth and taller at 24 mo was associated with a 4-mo (95% CI: 0.8, 7.6) earlier age at menarche than being lighter at birth and shorter at 24 mo. Being heavier at birth but lighter in mid-childhood was associated with a 3-mo (95% CI: 0.8, 4.8) later age at menarche than being lighter at birth and mid-childhood. Age at menarche was 7 mo later in stunted than nonstunted girls. CONCLUSION: Age at menarche is inversely related to relative weight gain but also to rapid linear growth among those born shorter but remained stunted, and those born taller and grew excessively. These findings do not deter the global health goal to reduce growth faltering but emphasize the potential adverse effects of an obesogenic environment on adolescent development.

Conditional wealth to estimate association of wealth mobility with health and human capital in low- and middle-income country cohorts.

Temporally harmonized asset indices allow the study of changes in relative wealth (mean, variance, social mobility) over time and its association with adult health and human capital in cohort studies. Conditional measures are the unexplained residuals of an indicator regressed on its past values. Using such measures, previously used to study the relative importance of key life stages for anthropometric growth, we can identify specific life stages during which changes in relative wealth are important for adult health in longitudinal studies. We discuss the assumptions, strengths and limitations of this methodology as applied to relative wealth. We provide an illustrative example using a publicly-available longitudinal dataset and show how relative wealth changes at different life stages are differentially associated with body mass index in adulthood.

Early Life Influences on Hearing in Adulthood: a Systematic Review and Two-Step Individual Patient Data Meta-Analysis.

OBJECTIVES: Adverse prenatal and early childhood development may increase susceptibility of hearing loss in adulthood. The objective was to assess whether indices of early development are associated with adult-onset hearing loss in adults ≥18 years. DESIGN: In a systematic review and meta-analysis, four electronic databases were searched for studies reporting associations between indices of early development (birth weight and adult height) and adult-onset hearing loss in adults ≥18 years. We screened studies, extracted data, and assessed risk of bias. Authors were contacted to provide adjusted odds ratios from a logistic regression model for relationships between birth weight/adult height and normal/impaired hearing enabling a two-step individual patient data random-effects meta-analysis to be carried out. The study is registered with PROSPERO, CRD42020152214. RESULTS: Four studies of birth weight and seven of adult height were identified. Three studies reported smaller birth weight associated with poorer adult hearing. Six studies reported shorter height associated with poorer hearing. Risk of bias was low to moderate. Four studies provided data for two-step individual patient data random-effects meta-analysis. Odds of hearing impairment were 13.5% lower for every 1 kg increase in birth weight [OR: 0.865 (95% confidence interval: 0.824 to 0.909)] in adulthood over two studies (N=81,289). Every 1 cm increase in height was associated with a 3% reduction in the odds of hearing impairment [OR: 0.970 (95% confidence interval: 0.968 to 0.971)] over four studies (N=156,740). CONCLUSIONS: Emerging evidence suggests that adverse early development increases the likelihood of hearing impairment in adulthood. Research and public health attention should focus on the potential for prevention of hearing impairment by optimizing development in early life.

Peri-conceptional diet patterns and the risk of Gestational diabetes mellitus in South Indian women.

OBJECTIVE: To identify peri-conceptional diet patterns among women in Bangalore, and examine their associations with risk of gestational diabetes mellitus. DESIGN: BANGLES, started in June 2016, was a prospective observational study, in which women were recruited at 5-16 weeks' gestation. Peri-conceptional diet was recalled at recruitment, using a validated 224-item food frequency questionnaire. GDM was assessed by a 75-gram oral glucose tolerance test at 24-28 weeks' gestation, applying WHO 2013 criteria. Diet patterns were identified using principal component analysis and diet pattern-GDM associations were examined using multivariate logistic regression, adjusting for 'a priori' confounders. SETTING: Antenatal clinics of two hospitals, Bangalore, South India. PARTICIPANTS: 785 pregnant women of varied socio-economic status. RESULTS: GDM prevalence was 22%. Three diet patterns were identified: a) High-diversity, urban (HDU) characterised by diverse, home-cooked and processed foods was associated with older, more affluent, better-educated and urban women; b) Rice-fried snacks-chicken-sweets (RFCS), characterised by low diet-diversity, was associated with younger, less-educated, and lower income, rural and joint families; c) Healthy, traditional vegetarian (HTV), characterised by home-cooked-vegetarian and non-processed foods was associated with less-educated, more affluent, and rural and joint families. The HDU pattern was associated with a lower GDM risk (aOR: 0.80 per SD, 95% CI: 0.64, 0.99, p=0.04) after adjusting for confounders. BMI was strongly related to GDM risk and possibly mediated diet-GDM associations. CONCLUSIONS: The findings support global recommendations to encourage women to attain a healthy pre-pregnancy BMI and increase diet-diversity. Both healthy and unhealthy foods in the patterns indicate low-awareness about healthy foods and a need for public-education.

Cardiovascular disease in people born to unmarried mothers in two historical periods: The Helsinki Birth Cohort Study 1934-1944.

Aims:Socio-economic conditions in early life are important contributors to cardiovascular disease - the leading cause of mortality globally - in later life. We studied coronary heart disease (CHD) and stroke in adulthood among people born out of wedlock in two historical periods: before and during World War II in Finland. Methods: We compared offspring born out of wedlock before (1934-1939) and during (1940-1944) World War II with the offspring of married mothers in the Helsinki Birth Cohort Study. The war affected the position of unmarried mothers in society. We followed the study subjects from 1971 to 2014 and identified deaths and hospital admissions from CHD and stroke. Data were analysed using a Cox regression, adjusting for other childhood and adulthood socio-economic circumstances. Results: The rate of out-of-wedlock births was 240/4052 (5.9%) before World War II and 397/9197 (4.3%) during World War II. Among those born before World War II, out-of-wedlock birth was associated with an increased risk of stroke (hazard ratio (HR)=1.44; 95% confidence interval (CI) 1.00-2.07) and CHD (HR=1.37; 95% CI 1.02-1.86). Among those born out of wedlock during World War II, the risks of stroke (HR=0.89; 95% CI 0.58-1.36) and CHD (HR=0.70; 95% CI 0.48=1.03) were similar to those observed for the offspring of married mothers. The p-values for interaction of unmarried×World War II were (p=0.015) for stroke and (p=0.003) for CHD. Conclusions: In a society in which marriage is normative, being born out of wedlock is an important predictor of lifelong health disadvantage. However, this may change rapidly when societal circumstances change, such as during a war.

Distinct opposing associations of upper and lower body fat depots with metabolic and cardiovascular disease risk markers.

BACKGROUND: To examine the associations of total and regional adiposity with metabolic and cardiovascular disease (CVD) risk markers. METHODS: This cross-sectional study included 1080 (53.8% men, aged 39-44 years) individuals from South India. Anthropometry (height, weight, waist and hip circumference), body composition assessment using dual-energy X-ray absorptiometry (DXA), blood pressure (BP), and plasma glucose, insulin and lipids were measured. Regression analysis was used to examine associations of standardized fat measurements with type 2 diabetes (T2D), insulin resistance (IR), hypertension and hypertriglyceridemia and continuous measurements of BP, glucose, insulin, HOMA-IR and lipids. Contour plots were constructed to visualize the differential effect of upper and lower fat depots. RESULTS: DXA-measured fat depots were positively associated with metabolic and CVD risk markers. After adjusting for fat mass index, upper body fat remained positively, while lower body fat was negatively associated with risk markers. A one standard deviation (SD) increase in android fat showed higher odds ratios (ORs) for T2D (6.59; 95% CI 3.17, 13.70), IR (4.68; 95% CI 2.31, 9.50), hypertension (2.57; 95% CI 1.56, 4.25) and hypertriglyceridemia (6.39; 95% CI 3.46, 11.90) in men. A 1 SD increase in leg fat showed a protective effect with ORs for T2D (0.42; 95% CI 0.24, 0.74), IR (0.31; 95% CI 0.17, 0.57) and hypertriglyceridemia (0.61; 95% CI 0.38, 0.98). The magnitude of the effect was greater with DXA-measured fat compared with anthropometry. CONCLUSION: At any level of total body fat, upper and lower body fat depots demonstrate opposite risk associations with metabolic and CVD risk markers in Asian Indians.

Consequences of ignoring clustering in linear regression.

BACKGROUND: Clustering of observations is a common phenomenon in epidemiological and clinical research. Previous studies have highlighted the importance of using multilevel analysis to account for such clustering, but in practice, methods ignoring clustering are often employed. We used simulated data to explore the circumstances in which failure to account for clustering in linear regression could lead to importantly erroneous conclusions. METHODS: We simulated data following the random-intercept model specification under different scenarios of clustering of a continuous outcome and a single continuous or binary explanatory variable. We fitted random-intercept (RI) and ordinary least squares (OLS) models and compared effect estimates with the "true" value that had been used in simulation. We also assessed the relative precision of effect estimates, and explored the extent to which coverage by 95% confidence intervals and Type I error rates were appropriate. RESULTS: We found that effect estimates from both types of regression model were on average unbiased. However, deviations from the "true" value were greater when the outcome variable was more clustered. For a continuous explanatory variable, they tended also to be greater for the OLS than the RI model, and when the explanatory variable was less clustered. The precision of effect estimates from the OLS model was overestimated when the explanatory variable varied more between than within clusters, and was somewhat underestimated when the explanatory variable was less clustered. The cluster-unadjusted model gave poor coverage rates by 95% confidence intervals and high Type I error rates when the explanatory variable was continuous. With a binary explanatory variable, coverage rates by 95% confidence intervals and Type I error rates deviated from nominal values when the outcome variable was more clustered, but the direction of the deviation varied according to the overall prevalence of the explanatory variable, and the extent to which it was clustered. CONCLUSIONS: In this study we identified circumstances in which application of an OLS regression model to clustered data is more likely to mislead statistical inference. The potential for error is greatest when the explanatory variable is continuous, and the outcome variable more clustered (intraclass correlation coefficient is ≥ 0.01).

Size at birth, lifecourse factors, and cognitive function in late life: findings from the MYsore study of Natal effects on Ageing and Health (MYNAH) cohort in South India.

OBJECTIVE: To examine if smaller size at birth, an indicator of growth restriction in utero, is associated with lower cognition in late life, and whether this may be mediated by impaired early life brain development and/or adverse cardiometabolic programming. DESIGN: Longitudinal follow-up of a birth cohort. SETTING: CSI Holdsworth Memorial Hospital (HMH), Mysore South India. PARTICIPANTS: 721 men and women (55-80 years) whose size at birth was recorded at HMH. Approximately 20 years earlier, a subset (n = 522) of them had assessments for cardiometabolic disorders in mid-life. MEASUREMENTS: Standardized measurement of cognitive function, depression, sociodemographic, and lifestyle factors; blood tests and assessments for cardiometabolic disorders. RESULTS: Participants who were heavier at birth had higher composite cognitive scores (0.12 SD per SD birth weight [95% CI 0.05, 0.19] p = 0.001) in late life. Other lifecourse factors independently positively related to cognition were maternal educational level and participants' own educational level, adult leg length, body mass index, and socioeconomic position, and negatively were diabetes in mid-life and current depression and stroke. The association of birth weight with cognition was independent cardiometabolic risk factors and was attenuated after adjustment for all lifecourse factors (0.08 SD per SD birth weight [95% CI -0.01, 0.18] p = 0.07). CONCLUSIONS: The findings are consistent with positive effects of early life environmental factors (better fetal growth, education, and childhood socioeconomic status) on brain development resulting in greater long-term cognitive function. The results do not support a pathway linking poorer fetal development with reduced late life cognitive function through cardiometabolic programming.

The duration of embryo culture after mouse IVF differentially affects cardiovascular and metabolic health in male offspring.

STUDY QUESTION: Do the long-term health outcomes following IVF differ depending upon the duration of embryo culture before transfer? SUMMARY ANSWER: Using a mouse model, we demonstrate that in male but not female offspring, adverse cardiovascular (CV) health was more likely with prolonged culture to the blastocyst stage, but metabolic dysfunction was more likely if embryo transfer (ET) occurred at the early cleavage stage. WHAT IS KNOWN ALREADY: ART associate with increased risk of adverse CV and metabolic health in offspring, and these findings have been confirmed in animal models in the absence of parental infertility issues. It is unclear which specific ART treatments may cause these risks. There is increasing use of blastocyst, versus cleavage-stage, transfer in clinical ART which does not appear to impair perinatal health of children born, but the longer-term health implications are unknown. STUDY DESIGN, SIZE, DURATION: Five mouse groups were generated comprising: (i) natural mating (NM)-naturally mated, non-superovulated and undisturbed gestation; (ii) IV-ET-2Cell-in-vivo derived two-cell embryos collected from superovulated mothers, with immediate ET to recipients; (iii) IVF-ET-2Cell-IVF generated embryos, from oocytes from superovulated mothers, cultured to the two-cell stage before ET to recipients; (iv) IV-ET-BL-in-vivo derived blastocysts collected from superovulated mothers, with immediate ET to recipients; (v) IVF-ET-BL-IVF generated embryos, from oocytes from superovulated mothers, cultured to the blastocyst stage before ET to recipients. Both male and female offspring were analysed for growth, CV and metabolic markers of health. There were 8-13 litters generated for each group for analyses; postnatal data were analysed by multilevel random effects regression to take account of between-mother and within-mother variation and litter size. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: C57/BL6 female mice (3-4 weeks old) were used for oocyte production; CBA males for sperm with human tubal fluid medium were used for IVF. Embryos were transferred (ET) to MF1 pseudo-pregnant recipients at the two-cell stage or cultured in synthetic oviductal medium enriched with potassium medium to the blastocyst stage before ET. Control in-vivo embryos from C57BL6 × CBA matings were collected and immediately transferred at the two-cell or blastocyst stage. Postnatal assays included growth rate up to 27 weeks; systolic blood pressure (SBP) at 9, 15 and 21 weeks; lung and serum angiotensin-converting enzyme (ACE) activity at time of cull (27 weeks); glucose tolerance test (GTT; 27 weeks); basal glucose and insulin levels (27 weeks); and lipid accumulation in liver cryosections using Oil Red O imaging (27 weeks). MAIN RESULTS AND THE ROLE OF CHANCE: Blastocysts formed by IVF developed at a slower rate and comprised fewer cells that in-vivo generated blastocysts without culture (P < 0.05). Postnatal growth rate was increased in all four experimental treatments compared with NM group (P < 0.05). SBP, serum and lung ACE and heart/body weight were higher in IVF-ET-BL versus IVF-ET-2Cell males (P < 0.05) and higher than in other treatment groups, with SBP and lung ACE positively correlated (P < 0.05). Glucose handling (GTT AUC) was poorer and basal insulin levels were higher in IVF-ET-2Cell males than in IVF-ET-BL (P < 0.05) with the glucose:insulin ratio more negatively correlated with body weight in IVF-ET-2Cell males than in other groups. Liver/body weight and liver lipid droplet diameter and density in IVF-ET-2Cell males were higher than in IVF-ET-BL males (P < 0.05). IVF groups had poorer health characteristics than their in-vivo control groups, indicating that outcomes were not caused specifically by background techniques (superovulation, ET). No consistent health effects from duration of culture were identified in female offspring. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Results from experimental animal models cannot be extrapolated to humans. Nevertheless, they are valuable to develop conceptual models, in this case, in the absence of confounding parental infertility, in assessing the safety of ART manipulations. WIDER IMPLICATIONS OF THE FINDINGS: The study indicates that longer duration of embryo culture after IVF up to blastocyst before ET leads to increased dysfunction of CV health in males compared with IVF and shorter cleavage-stage ET. However, the metabolic health of male offspring was poorer after shorter versus longer culture duration. This distinction indicates that the origin of CV and metabolic health phenotypes after ART may be different. The poorer metabolic health of males after cleavage-stage ET coincides with embryonic genome activation occurring at the time of ET. STUDY FUNDING/COMPETING INTEREST(S): This work was supported through the European Union FP7-CP-FP Epihealth programme (278418) and FP7-PEOPLE-2012-ITN EpiHealthNet programme (317146) to T.P.F., the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F007450/1) to T.P.F., and the Saudi government, University of Jeddah and King Abdulaziz University to A.A. The authors have no conflicts of interest to declare.

Association of childhood adversities and home atmosphere with functioning in old age: the Helsinki birth cohort study.

Objective: childhood adversities have been linked with adverse health outcomes, but less is known about the long-term consequences of childhood home atmosphere. We investigated whether childhood adversities and home atmosphere were associated with physical and mental functioning in older age. Methods: in the Helsinki Birth Cohort Study 2003, participants born in the year 1934-44 had data available on nine childhood home atmosphere items, e.g. whether it was supportive and warm (sum score ranged between 0 and 36, higher score indicating better atmosphere), and nine childhood adversities, e.g. unemployment and divorce (sum score 0-9, coded into no; one; and two or more adversities) assessed in 2001-04. Of those, 835 had data on physical and mental functioning assessed using the Short Form 36 questionnaire in 2011-13. Results: those who had experienced two or more childhood adversities were more likely to have poorer physical and mental functioning in older age compared to those with no adversities. A better home atmosphere score was associated with better mental functioning (per one unit higher score ß 0.24, 95% CI 0.16-0.32, P < 0.001). In models including both childhood adversities and home atmosphere, a more favourable home atmosphere was associated with better mental functioning while the association for childhood adversities attenuated. There were no associations between childhood adversities or home atmosphere and physical functioning in the models that included both childhood exposures. Conclusions: childhood adversities and home atmosphere have long-term associations with physical and mental functioning in older age.

Intergenerational Transmission of Birth Weight Across 3 Generations.

While previous studies have shown intergenerational transmission of birth weight from mother to child, whether the continuity persists across 3 generations has rarely been assessed. We used the Aberdeen Maternity and Neonatal Databank (United Kingdom) to examine the intergenerational correlations of birth weight, birth weight adjusted for gestational age and sex, and small- and large-for-gestational-age births across 3 generations among 1,457 grandmother-mother-child triads. All participants were born between 1950 and 2015. The intergenerational transmission was examined with linear regression analyses. We found that grandmaternal birth weight was associated with grandchild birth weight, independently of prenatal and sociodemographic covariates and maternal birth weight (B = 0.12 standard deviation units, 95% confidence interval: 0.07, 0.18). Similar intergenerational continuity was found for birth weight adjusted for sex and gestational age as well as for small-for-gestational-age births. In conclusion, birth weight and fetal growth showed intergenerational continuity across 3 generations. This supports the hypothesis that the developmental origins of birth weight and hence later health and disease are already present in earlier generations.

Insulin and branched-chain amino acid depletion during mouse preimplantation embryo culture programmes body weight gain and raised blood pressure during early postnatal life.

Mouse maternal low protein diet exclusively during preimplantation development (Emb-LPD) is sufficient to programme altered growth and cardiovascular dysfunction in offspring. Here, we use an in vitro model comprising preimplantation culture in medium depleted in insulin and branched-chain amino acids (BCAA), two proposed embryo programming inductive factors from Emb-LPD studies, to examine the consequences for blastocyst organisation and, after embryo transfer (ET), postnatal disease origin. Two-cell embryos were cultured to blastocyst stage in defined KSOM medium supplemented with four combinations of insulin and BCAA concentrations. Control medium contained serum insulin and uterine luminal fluid amino acid concentrations (including BCAA) found in control mothers from the maternal diet model (N-insulin+N-bcaa). Experimental medium (three groups) contained 50% reduction in insulin and/or BCAA (L-insulin+N-bcaa, N-insulin+L-bcaa, and L-insulin+N-bcaa). Lineage-specific cell numbers of resultant blastocysts were not affected by treatment. Following ET, a combined depletion of insulin and BCAA during embryo culture induced a non sex-specific increase in birth weight and weight gain during early postnatal life. Furthermore, male offspring displayed relative hypertension and female offspring reduced heart/body weight, both characteristics of Emb-LPD offspring. Combined depletion of metabolites also resulted in a strong positive correlation between body weight and glucose metabolism that was absent in the control group. Our results support the notion that composition of preimplantation culture medium can programme development and associate with disease origin affecting postnatal growth and cardiovascular phenotypes and implicate two important nutritional mediators in the inductive mechanism. Our data also have implications for human assisted reproductive treatment (ART) practice.

Prenatal Growth and CKD in Older Adults: Longitudinal Findings From the Helsinki Birth Cohort Study, 1924-1944.

BACKGROUND: According to the Developmental Origins of Health and Disease (DOHaD) hypothesis, several noncommunicable diseases, including hypertension, type 2 diabetes, and coronary heart disease, have their origins in early life. Chronic kidney disease (CKD) has traditionally been assumed to develop as the result of an interaction between genetic and environmental factors, although more recently, the importance of factors present early in life has been recognized. STUDY DESIGN: Longitudinal birth cohort study. SETTING & PARTICIPANTS: 20,431 people born in 1924 to 1944 in Helsinki, Finland, who were part of the Helsinki Birth Cohort Study were followed up through their life course from birth until death or age 86 years. PREDICTOR: Prenatal growth and socioeconomic factors. OUTCOMES: Death or hospitalization for CKD. RESULTS: Smaller body size at birth was associated with increased risk for developing CKD. Each standard deviation higher birth weight was associated with an HR for CKD of 0.82 (95% CI, 0.74-0.91; P<0.001). Associations with ponderal index at birth, placental weight, and birth length were also statistically significant (P<0.001, P<0.001, and P=0.002, respectively), but only among men. Prematurity also predicted increased risk for CKD. LIMITATIONS: The study was restricted to people who were born in Helsinki in 1924 to 1944. CONCLUSIONS: Smaller body size at birth was associated with increased risk for developing CKD in men. Prematurity was also associated with increased risk for CKD in women. These findings in the Helsinki Birth Cohort Study support the importance of early life factors in the development of CKD.

Weight Gain and Height Growth during Infancy, Childhood, and Adolescence as Predictors of Adult Cardiovascular Risk.

OBJECTIVES: To investigate independent relationships of childhood linear growth (height gain) and relative weight gain to adult cardiovascular disease (CVD) risk traits in Asian Indians. STUDY DESIGN: Data from 2218 adults from the Vellore Birth Cohort were examined for associations of cross-sectional height and body mass index (BMI) and longitudinal growth (independent conditional measures of height and weight gain) in infancy, childhood, adolescence, and adulthood with adult waist circumference (WC), blood pressure (BP), insulin resistance (homeostatic model assessment-insulin resistance [HOMA-IR]), and plasma glucose and lipid concentrations. RESULTS: Higher BMI/greater conditional relative weight gain at all ages was associated with higher adult WC, after 3 months with higher adult BP, HOMA-IR, and lipids, and after 15 years with higher glucose concentrations. Taller adult height was associated with higher WC (men ß = 2.32 cm per SD, women ß = 1.63, both P < .001), BP (men ß = 2.10 mm Hg per SD, women ß = 1.21, both P ≤ .001), and HOMA-IR (men ß = 0.08 log units per SD, women ß = 0.12, both P ≤ .05) but lower glucose concentrations (women ß = -0.03 log mmol/L per SD P = .003). Greater height or height gain at all earlier ages were associated with higher adult CVD risk traits. These positive associations were attenuated when adjusted for adult BMI and height. Shorter length and lower BMI at birth were associated with higher glucose concentration in women. CONCLUSIONS: Greater height or weight gain relative to height during childhood or adolescence was associated with a more adverse adult CVD risk marker profile, and this was mostly attributable to larger adult size.

Peripheral inflammatory cytokines and immune balance in Generalised Anxiety Disorder: Case-controlled study.

INTRODUCTION: Previous investigations have demonstrated that major depression is associated with particular patterns of cytokine signalling. The primary aim of this study was to examine peripheral pro-inflammatory and anti-inflammatory cytokines and immune balance in Generalised Anxiety Disorder (GAD). METHODS: A case-controlled cross-sectional study design was employed: 54 patients with GAD and 64 healthy controls were recruited. Participants completed self-report measures of anxiety and depression. Two pro-inflammatory and two anti-inflammatory cytokines were measured using multiplex technology. RESULTS: Case-control logistic regression analyses revealed significant differences in serum levels of IL-10, TNF-α, and IFN-γ between GAD and control groups after adjusting for age, gender, body mass index, smoking and alcohol consumption: these group differences were independent of the presence or degree of depression. Comparison of pro-inflammatory to anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF-α/IL10, TNF-α/IL4, IFN-γ/IL10, and IFN-γ/IL4 in the GAD group compared to the control group. CONCLUSIONS: This study is the first to investigate both pro- and anti-inflammatory cytokines and their balance in patients with GAD in comparison to healthy controls. The findings indicate a relatively increased pro-inflammatory response and decreased anti-inflammatory response and provide the first demonstration of an altered cytokine balance in GAD. Serum cytokine levels in GAD were independent of the presence of depression.

Gestational hypertension is associated with increased risk of type 2 diabetes in adult offspring: the Helsinki Birth Cohort Study.

BACKGROUND: Women with hypertensive disorders in pregnancy are at an increased risk of cardiovascular disease and type 2 diabetes later in life. Offspring born from these hypertensive pregnancies have increased levels of cardiovascular risk factors; whether they are at an increased risk of type 2 diabetes is not known. OBJECTIVE: The objective of the investigation was to study the risk of type 2 diabetes in the adult offspring exposed to maternal preeclampsia or gestational hypertension in utero. STUDY DESIGN: We studied 5335 members of the Helsinki Birth Cohort Study, who were born between 1934 and 1944 and who lived in Finland in 1995 when the National Medication Purchase Register was initiated. We ascertained gestational hypertension and preeclampsia according to modern criteria by using maternal and birth records. We defined type 2 diabetes through purchases of antidiabetic medication recorded in the comprehensive National Medication Purchase Register, excluding the 31 subjects who had purchased only insulin. We used Cox regression to assess hazard ratios for type 2 diabetes. RESULTS: A total of 590 men (21.6%) and 433 women (16.9%) had purchased medication for diabetes. The hazard ratio for type 2 diabetes for offspring exposed to any maternal hypertension in pregnancy was 1.13 (95% confidence interval, 1.00-1.29; n = 1780). For maternal gestational hypertension, it was 1.15 (95% confidence interval, 1.00-1.33; n = 1336) and for preeclampsia 0.98 (95% confidence interval, 0.71-1.34; n = 231). For type 2 diabetes with first medication purchase before 62 years, the corresponding hazard ratios were 1.25 (95% confidence interval, 1.04-1.51); 1.28 (95% confidence interval, 1.05-1.58), and 1.18 (95% confidence interval, 0.75-1.84). The hazard ratios were similar when adjusted for birthweight SD score for gestation, length of gestation, maternal body mass index in late pregnancy, height, age, and parity and for childhood or adult socioeconomic position. An increased risk of type 2 diabetes was also associated with low birthweight SD score, independent of the association with gestational hypertension. CONCLUSION: Offspring exposed to maternal gestational hypertension in utero have an increased risk of type 2 diabetes in late adult life. This finding underlines the role of the whole spectrum of hypertensive disorders of pregnancy as risk factors of offspring disease throughout life. It also reinforces previous suggestions that adult health care providers should incorporate birth histories when evaluating an individual's risk to develop type 2 diabetes.

Prenatal exposure to vitamin D from fortified margarine and risk of fractures in late childhood: period and cohort results from 222 000 subjects in the D-tect observational study.

Prenatal low vitamin D may have consequences for bone health. By means of a nationwide mandatory vitamin D fortification programme, we examined the risk of fractures among 10-18-year-old children from proximate birth cohorts born around the date of the termination of the programme. For all subjects born in Denmark during 1983-1988, civil registration numbers were linked to the Danish National Patient Registry for incident and recurrent fractures occurring at ages 10-18 years. Multiplicative Poisson models were used to examine the association between birth cohort and fracture rates. The variation in fracture rates across birth cohorts was analysed by fitting an age-cohort model to the data. We addressed the potential modification of the effect of vitamin D availability by season of birth. The risk of fractures was increased among both girls and boys who were born before the vitamin D fortification terminated in 1985 (rate ratio (RR) exposed v. non-exposed girls: 1·15 (95 % CI 1·11, 1·20); RR exposed v. non-exposed boys: 1·11 (95 % CI 1·07, 1·14). However, these associations no longer persisted after including the period effects. There was no interaction between season of birth and vitamin D availability in relation to fracture risk. The study did not provide evidence that prenatal exposure to extra vitamin D from a mandatory fortification programme of 1·25 µg vitamin D/100 g margarine was sufficient to influence the risk of fractures in late childhood, regardless of season of birth. Replication studies are needed.

Objectively measured physical activity and physical performance in old age.

Background: physical performance is a key factor that determines how older people cope with daily tasks and maintain independency. There is strong evidence suggesting that physical activity (PA) is important in maintaining physical performance in old age. However, most studies have been done using self-reported PA. Our aim was to explore the association between objectively measured PA and physical performance in old age. Methods: we studied 695 participants (mean age 70.7 years, SD 2.7) from the Helsinki Birth Cohort Study. Physical performance was assessed with the Senior Fitness Test (SFT) and PA with a multisensory activity monitor SenseWear Pro 3 Armband. Results: total volume of PA was significantly associated with the overall SFT score (ß = 0.08; 95% confidence interval: 0.07-0.10, P < 0.001). There were no significant differences between men and women. Both light and moderate to vigorous level of PA were positively associated with the overall SFT score, while sedentary time was negatively associated with the overall SFT score. Conclusions: volume of objectively measured PA among older people was positively associated with the physical performance measured with a validated fitness test battery.