Differentiation between fetal and postnatal iron deficiency in altering brain substrates of cognitive control in pre-adolescence.

BACKGROUND: Early iron deficiency (ID) is a common risk factor for poorer neurodevelopment, limiting children's potential and contributing to global burden. However, it is unclear how early ID alters the substrate of brain functions supporting high-order cognitive abilities and whether the timing of early ID matters in terms of long-term brain development. This study aimed to examine the effects of ID during fetal or early postnatal periods on brain activities supporting proactive and reactive cognitive control in pre-adolescent children. METHODS: Participants were part of a longitudinal cohort enrolled at birth in southeastern China between December 2008 and November 2011. Between July 2019 and October 2021, 115 children aged 8-11 years were invited to participate in this neuroimaging study. Final analyses included 71 children: 20 with fetal ID, 24 with ID at 9 months (postnatal ID), and 27 iron-sufficient at birth and 9 months. Participants performed a computer-based behavioral task in a Magnetic Resonance Imaging scanner to measure proactive and reactive cognitive control. Outcome measures included accuracy, reaction times, and brain activity. Linear mixed modeling and the 3dlme command in Analysis of Functional NeuroImages (AFNI) were separately used to analyze behavioral performance and neuroimaging data. RESULTS: Faster responses in proactive vs. reactive conditions indicated that all groups could use proactive or reactive cognitive control according to contextual demands. However, the fetal ID group was lower in general accuracy than the other 2 groups. Per the demands of cues and targets, the iron-sufficient group showed greater activation of wide brain regions in proactive vs. reactive conditions. In contrast, such condition differences were reversed in the postnatal ID group. Condition differences in brain activation, shown in postnatal ID and iron-sufficient groups, were not found in the fetal ID group. This group specifically showed greater activation of brain regions in the reward pathway in proactive vs. reactive conditions. CONCLUSIONS: Early ID was associated with altered brain functions supporting proactive and reactive cognitive control in childhood. Alterations differed between fetal and postnatal ID groups. The findings imply that iron supplement alone is insufficient to prevent persisting brain alterations associated with early ID. Intervention strategies in addition to the iron supplement should consider ID timing.

Iron supplementation given to nonanemic infants: neurocognitive functioning at 16 years.

OBJECTIVE: There is concern that high iron uptake during the critical period of early brain development carries potential risks, especially for nonanemic infants. This study examined the neurocognitive functioning of 16-year-olds who were nonanemic as infants and received iron supplementation. METHODS: We studied 562 Chilean adolescents (M 16.2 years; 52.7% female) who participated in a randomized controlled iron supplementation trial in infancy. Between 6 and 12 months, 346 consumed an iron-fortified formula (12.7 Fe mg/L) or, if primarily breastfed, liquid vitamins with 15 mg elemental iron as ferrous sulfate, and 216 consumed unmodified cow milk without iron or liquid vitamins without iron if primarily breastfed. RESULTS: Compared to adolescents in the no-added iron condition in infancy, those in the iron-supplemented condition had poorer visual-motor integration, quantitative reasoning skills, and incurred more errors on neurocognitive tasks. Consuming larger amounts of iron-fortified formula in infancy was associated with lower arithmetic achievement. Of adolescents who had high hemoglobin at 6 months (Hb ≥ 125 g/L), those in the iron supplemented condition had poorer performance on arithmetic, quantitative reasoning, and response inhibition tests than those in the no-added iron condition. Of adolescents who had marginally low 6-month hemoglobin (Hb > 100 and < 110 g/L), those who received no-added iron incurred more errors on a visual searching task than those in the iron-supplemented condition. CONCLUSION: The physiologic need for iron during the period of rapid and critical brain development in young infants should be considered vis-à-vis the risks associated with supplementing nonanemic infants with high levels of iron.Clinical Trials number: NCT01166451.

Early-life adversity is associated with poor iron status in infancy.

Exposure to early-life adversity (ELA) and iron deficiency early in life are known risk factors for suboptimal brain and socioemotional development. Iron deficiency may arise from and co-occur with ELA, which could negatively affect development. In the present study, we investigated whether ELA is associated with iron deficiency in infants receiving no iron supplementation. This study is a secondary analysis of extant data collected in the 1990s; participants were healthy infants from working-class communities in Santiago, Chile (N = 534, 45.5% female). We measured stressful life events, maternal depression, and low home support for child development during infancy and assessed iron status when the infant was 12 months old. Slightly more than half of the infants were iron-deficient (51%), and 25.8% were iron-deficient anemic at 12 months. Results indicated that ELA was associated with lower iron levels and iron deficiency at 12 months. The findings are consistent with animal and human prenatal models of stress and iron status and provide evidence of the association between postnatal ELA and iron status in humans. The findings also highlight a nutritional pathway by which ELA may impact development and present a nutritionally-focused avenue for future research on ELA and psychopathology.

Iron Deficiency in Infancy and Sluggish Cognitive Tempo and ADHD Symptoms in Childhood and Adolescence.

OBJECTIVE: To determine whether iron deficiency in infancy is associated with sluggish cognitive tempo (SCT) or attention-deficit/hyperactive-impulsive (AD-HI) symptoms in childhood and adolescence, and whether such behaviors contribute concurrently and predictively to lower verbal and mathematical abilities. METHOD: Chilean children (N = 959; 50% male, of Spanish or indigenous descent from working-class backgrounds) were rated by mothers for SCT or AD-HI symptoms at ages 5, 10, and 16 years. Children completed standardized tests assessing verbal and mathematical abilities at ages 5, 10, and 16. At ages 12 and 18 months, children were assessed for iron deficiency. RESULTS: Adjusting for a comprehensive panel of covariates, greater severity of iron deficiency in infancy was associated with more frequent SCT and AD-HI symptoms at all ages studied. Most effects of iron deficiency on children's verbal and math skills were indirect, mediated through AD-HI behaviors. Children's AD-HI symptoms related to lower verbal and math test scores within age and across age. CONCLUSIONS: The long-term associations found between infant iron deficiency and SCT and AD-HI behaviors suggest that the neurodevelopmental alterations that stem from postnatal iron deficiency might play an etiological role in the development of ADHD. Screening for early-life nutritional deficiencies among children with SCT or ADHD symptoms might prove useful, and behavioral screening of children with a history of iron deficiency seems warranted. Interventions that support brain development after early nutritional deprivation also would be beneficial.

[A prospective cohort study on visual development in infants and young children].

Objective: This study aimed to analyze the trends and characteristics of early visual development in infants and young children. Methods: A prospective cohort study was conducted, including full-term infants born between 2008 and 2013 at the Maternal and Child Health Hospital in Sanhe City, Hebei Province, China. Visual acuity was assessed at three time points 42 days after birth, 9 months of age, and 18 months of age, using the Teller Acuity Card Ⅱ (TAC Ⅱ) grating visual acuity test. At 3 years of age, visual acuity was assessed using the Lea Symbols chart and converted to grating visual acuity. Visual acuity of both eyes was measured at 42 days, 9 months, and 18 months. For children at 9 and 18 months, monocular visual acuity was also assessed, while at 3 years of age, monocular visual acuity was measured. Visual acuity measurements at different time points and changes in visual acuity within each period were recorded. The visual development of the participants was analyzed and compared with previous literature results. Results: A total of 1 496 children were included in the study, including 773 males (51.67%) and 723 females (48.33%). The binocular visual acuity at 42 days, 9 months, and 18 months was 0.9 (0.6, 1.1), 6.4 (6.4, 9.6), and 9.6 (9.6, 9.6) cycles per degree (cpd), respectively, with statistically significant differences (P<0.001). Visual acuity increased by a factor of 3.21±0.70 between 42 days and 9 months, and by a factor of 0.23±0.48 between 9 and 18 months. At 9 months of age, the monocular visual acuity in the right and left eyes was 6.4 (4.8, 6.4) cpd, which remained the same at 18 months, and the median visual acuity at 3 years of age for both eyes was 18.75 cpd, with a Snellen visual acuity of 20/32 (20/40, 20/32). The differences in binocular visual acuity at each time point were not statistically significant (all P>0.05). At 9 months of age, 68.7%(633/921) of children had visual acuity of ≥6.5 cpd, which increased to 92.7%(342/369) at 18 months. Monocular visual acuity increased by a factor of 0.26±0.46 between 9 and 18 months, and by a factor of 1.36±0.52 between 18 months and 3 years. At 9 months of age, 72.01% (921 out of 1 279) of children who completed binocular visual acuity testing also underwent monocular visual acuity testing, while this proportion decreased to 35.83% (369 out of 1 030) at 18 months. Visual acuity improved with increasing age (P<0.001). The visual acuity of children at each age group in this study was higher than that reported in the literature for children in Guangzhou (P<0.001). Conclusions: The visual acuity of healthy infants and young children below 3 years of age improves with age. Visual development progresses rapidly before 9 months of age, slows down afterward, and then resumes rapid growth at 18 months of age.

Infant Growth Trajectories and Lipid Levels in Adolescence: Evidence From a Chilean Infancy Cohort.

Growth in early infancy is hypothesized to affect chronic disease risk factors later in life. To date, most reports draw on European-ancestry cohorts with few repeated observations in early infancy. We investigated the association between infant growth before 6 months and lipid levels in adolescents in a Hispanic/Latino cohort. We characterized infant growth from birth to 5 months in male (n = 311) and female (n = 285) infants from the Santiago Longitudinal Study (1991-1996) using 3 metrics: weight (kg), length (cm), and weight-for-length (g/cm). Superimposition by translation and rotation (SITAR) and latent growth mixture models (LGMMs) were used to estimate the association between infant growth characteristics and lipid levels at age 17 years. We found a positive relationship between the SITAR length velocity parameter before 6 months of age and high-density lipoprotein cholesterol levels in adolescence (11.5, 95% confidence interval; 3.4, 19.5), indicating higher high-density lipoprotein cholesterol levels occurring with faster length growth. The strongest associations from the LGMMs were between higher low-density lipoprotein cholesterol and slower weight-for-length growth, following a pattern of associations between slower growth and adverse lipid profiles. Further research in this window of time can confirm the association between early infant growth as an exposure and adolescent cardiovascular disease risk factors.

Adjusting Ferritin Concentrations for Nonclinical Inflammation in Adolescents with Overweight or Obesity.

OBJECTIVE: To compare approaches for adjusting serum ferritin concentrations for inflammation in Chilean adolescents with overweight and obesity. STUDY DESIGN: Cross-sectional data from 518 adolescents (aged 16-17 years; 48% females) from Santiago, Chile were analyzed. Several approaches were compared for estimating the prevalence of depleted iron stores (defined as serum ferritin <15 µg/L), including unadjusted prevalence and higher cutoffs for various subgroups (excluding participants with inflammation), correction factors, and regression corrections. A "reference" prevalence estimate was calculated as the prevalence of serum ferritin <15 µg/L in normal weight individuals without inflammation. Each adjustment approach was compared with this reference prevalence. RESULTS: The sample comprised 61.2% normal weight, 23.7% overweight, and 15.1% obese individuals. The prevalence of inflammation (marked by C-reactive protein level >5.0 mg/L) was 6.3%, 8.1%, and 14.1% in the 3 groups, respectively. The correction factor approaches produced adjusted estimates closest to the reference estimate (24.1%-24.7% vs 22.9%), followed by the regression corrections (24.7%-25.1% vs 22.9%). Applying a higher serum ferritin cutoff (30 µg/L) to all participants or to participants with overweight/obesity produced adjusted estimates farthest from the reference (59.5% and 35.3%, respectively). CONCLUSIONS: Adjusting serum ferritin concentration may be necessary when assessing iron status in populations with high rates of overweight/obesity. After reviewing 6 approaches for adjusting for the influence of inflammation, this study suggests that using correction factors may be the most appropriate approach for adjusting serum ferritin in Chilean adolescents. Further research is needed to determine the optimal approach for adjusting serum ferritin concentrations for weight-related inflammation in broader populations.

Genetic determinants of metabolic biomarkers and their associations with cardiometabolic traits in Hispanic/Latino adolescents.

BACKGROUND: Metabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers-adiponectin, leptin, ghrelin, and orexin-and their associations with CMD risk factors. METHODS: We characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling. RESULTS: We identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels. CONCLUSIONS: The genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers. IMPACT: This study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

Young adult outcomes associated with lower cognitive functioning in childhood related to iron-fortified formula in infancy.

Objective: This study examined how the lower cognitive skills in children who consumed iron-fortified formula in infancy relate to outcomes in young adulthood.Methods: Participants were 443 Chilean young adults (M age = 21.2y, 55% female) who took part in a randomized controlled iron-deficiency anemia preventive trial during infancy (6-12 m). Slightly over half of participants (n = 237) received iron-fortified formula (12.7 mg/L) and 206 received a low-iron formula (2.3 mg/L). Spatial memory, IQ, and visual-motor integration were measured at age 10, and neurocognition, emotion regulation, educational level, and attainment of adult developmental milestones were assessed at age 21.Results: Consumption of iron-fortified formula in infancy was associated with poorer performance on neurocognitive tests in childhood, and these effects related to poorer neurocognitive, emotional, and educational outcomes in young adulthood. Dosage effects associated with consumption of iron-fortified formula were found for lower educational attainment and, marginally, slower mental processing. Those who received iron-fortified formula and had low age 10 cognitive abilities performed most poorly on neurocognitive tests at age 21.Conclusion: Findings suggest that the long-term development of infants who consume iron-fortified formula may be adversely affected.Clinical Trials number: NCT01166451.

Timing of iron deficiency and recognition memory in infancy.

Objective: To determine the relationship between iron deficiency (or iron-deficient, ID) and neural correlates of recognition memory depending on ID timing (gestation vs. infancy) and infant age at testing (9 vs. 18 months).Study design: Event-related potentials (ERP) were used in a visual recognition memory task (mother vs. stranger face) to compare healthy term infants according to iron status at birth and 9 months. Fetal-neonatal ID was defined as cord serum ferritin < 75 µg/l or zinc protoporphrin/heme ratio > 118 µmol/mol, postnatal ID as ≥ 2 abnormal iron measures at 9 months with normal cord-blood iron status, and iron-sufficient as not ID at birth or 9 months. Recognition of mother faces was measured by negative component (Nc) and late slow wave (LSW). These ERP components reflect attention and memory updating processes, respectively.Results: All groups showed differences in Nc amplitude elicited by mother and stranger faces at 9 months. At 18 months, only postnatal ID and iron-sufficient groups showed condition differences in Nc amplitude. However, the 2 groups were different in the involved brain regions. For LSW, only the 2 ID groups showed condition differences in amplitude at 9 months. At 18 months, condition differences were not observed in any group.Conclusions: This study indicates that the timing of ID in early life (fetal-neonatal vs. postnatal) modulates the impact of ID on recognition memory. Such impact also varies depending on the age of infants at testing (9 vs. 18 months).

Dynamic relationships between body fat and circulating adipokine levels from adolescence to young adulthood: The Santiago Longitudinal Study.

BACKGROUND AND AIMS: Adipose tissue secretes adipokines such as adiponectin and leptin, playing important roles in energy metabolism. The longitudinal associations between such adipokines and body fat accumulation have not been established, especially during adolescence and young adulthood and in diverse populations. The study aims to assess the longitudinal association between body fat measured with dual X-ray absorptiometry and plasma adipokines from adolescence to young adulthood. METHODS AND RESULTS: Among Hispanic/Latino participants (N = 537) aged 16.8 (SD: 0.3) years of the Santiago Longitudinal Study, we implemented structural equation modeling to estimate the sex-specific associations between adiposity (body fat percent (BF%) and proportion of trunk fat (PTF)) and adipokines (adiponectin and leptin levels) during adolescence (16 y) and these values after 6 years of follow-up (22 y). In addition, we further investigated whether the associations differed by baseline insulin resistance (IR) status. We found evidence for associations between 16 y BF% and 22 y leptin levels (ß (SE): 0.58 (0.06) for females; 0.53 (0.05) for males), between 16 y PTF and 22 y adiponectin levels (ß (SE): -0.31 (0.06) for females; -0.18 (0.06) for males) and between 16 y adiponectin levels and 22 y BF% (ß (SE): 0.12 (0.04) for both females and males). CONCLUSION: We observed dynamic relationships between adiposity and adipokines levels from late adolescence to young adulthood in a Hispanic/Latino population further demonstrating the importance of this period of the life course in the development of obesity.

Maternal Overweight and Obesity during Pregnancy Are Associated with Neonatal, but Not Maternal, Hepcidin Concentrations.

BACKGROUND: Overweight or obesity among pregnant women may compromise maternal and neonatal iron status by upregulating hepcidin. OBJECTIVES: This study determined the association of 1) maternal and neonatal iron status with maternal and neonatal hepcidin concentrations, and 2) maternal prepregnancy weight status with maternal and neonatal hepcidin concentrations. METHODS: We examined hematologic data from 405 pregnant women and their infants from the placebo treatment group of a pregnancy iron supplementation trial in rural China. We measured hepcidin, serum ferritin (SF), soluble transferrin receptor (sTfR), and high-sensitivity C-reactive protein in maternal blood samples at mid-pregnancy and in cord blood at delivery. We used regression analysis to examine the association of maternal prepregnancy overweight or obese status with maternal hepcidin concentration in mid-pregnancy and cord hepcidin concentrations. We also used path analysis to examine mediation of the association of maternal prepregnancy overweight or obese status with maternal iron status by maternal hepcidin, as well as with neonatal hepcidin by neonatal iron status. RESULTS: Maternal iron status was positively correlated with maternal hepcidin at mid-pregnancy (SF: r = 0.63, P < 0.001; sTfR: r = -0.37, P < 0.001). Neonatal iron status was also positively correlated with cord hepcidin (SF: r = 0.61, P < 0.001; sTfR: r = -0.39, P < 0.001). In multiple linear regression models, maternal prepregnancy overweight or obese status was not associated with maternal hepcidin at mid-pregnancy but was associated with lower cord hepcidin (coefficient = -0.21, P = 0.004). Using path analysis, we observed a significant indirect effect of maternal prepregnancy overweight or obese status on cord hepcidin, mediated by neonatal iron status. CONCLUSIONS: In both pregnant women and neonates, hepcidin was responsive to iron status. Maternal prepregnancy overweight status, with or without including obese women, was associated with lower cord blood hepcidin, likely driven by lower iron status among the neonates of these mothers.

Infant iron deficiency, iron supplementation, and psychosocial stress as predictors of neurocognitive development in Chilean adolescents.

Objective: The aim of the current study was to examine the unique and joint contributions of iron deficiency, iron supplementation, and psychosocial stress in infancy and stress in adolescence to neurocognitive functioning in adolescence.Methods: The current study (N = 796; Mage = 14.4y) involved a prospective cohort of low- and middle-socioeconomic status adolescents in Santiago, Chile. As infants, they had participated in an iron supplementation trial. Infant iron status was assessed at 12-18 months, and mothers answered questions about family psychosocial stress at 6-12 months and in adolescence (maternal depressive symptoms, home support for child development, stressful life events, father absence, socioeconomic status, and parental education). Neurocognitive functioning was assessed in adolescence using the Balloon Analogue Risk Task, Stockings of Cambridge, Trail Making Test, Purdue Pegboard Test, and Wisconsin Card Sorting Test.Results: Greater psychosocial stress in infancy predicted less risk-taking, poorer planning abilities and fluid cognition, and slower processing speed in adolescence. Iron deficiency anemia in infancy predicted less risk-taking. Greater adolescent psychosocial stress predicted difficulties in set-shifting. There were no interactions between infant psychosocial stress and iron deficiency predicting adolescent neurocognitive functioning.Conclusion: These results suggest that interventions to reduce infant psychosocial stress may be more likely to prevent multiple neurocognitive deficits in adolescence than interventions to reduce infant iron deficiency.

Vitamin D Deficiency in Middle Childhood Is Related to Behavior Problems in Adolescence.

BACKGROUND: Vitamin D deficiency (VDD) is associated with depression and schizophrenia in adults. The effect of VDD in childhood on behavioral development is unknown. OBJECTIVES: We aimed to study the associations of VDD and vitamin D binding protein (DBP) in middle childhood with behavior problems in adolescence. METHODS: We quantified plasma total 25-hydroxyvitamin D [25(OH)D] and DBP in 273 schoolchildren aged 5-12 y at recruitment into a cohort study in Bogota, Colombia. Externalizing and internalizing behavior problems were assessed after a median 6-y follow-up by parental report [Child Behavior Checklist (CBCL)] and self-report [Youth Self-Report (YSR)]. We estimated mean problem score differences with 95% CIs between exposure categories using multivariable linear regression. We also compared the prevalence of clinical behavior problems (score >63) between exposure groups. We assessed whether the associations between DBP and behavior problems were mediated through VDD. RESULTS: Mean ± SD CBCL and YSR externalizing problems scores were 56.5 ± 9.3 and 53.2 ± 9.5, respectively. Internalizing problems scores averaged 57.1 ± 9.8 and 53.7 ± 9.8, respectively. VDD [25(OH)D <50 nmol/L] prevalence was 10.3%. VDD was associated with an adjusted 6.0 (95% CI: 3.0, 9.0) and 3.4 (95% CI: 0.1, 6.6) units higher CBCL and YSR externalizing problems scores, respectively, and an adjusted 3.6 (95% CI: 0.3, 6.9) units higher CBCL internalizing problems scores. The prevalence of clinical total externalizing problems was 1.8 (95% CI: 1.1, 3.1) times higher in children with VDD than that in children without VDD. DBP concentration below the population median was related to higher YSR aggressive behavior and anxious/depressed subscale scores and to higher prevalence of clinical total externalizing problems. The associations between DBP and behavior problems were not mediated through VDD. CONCLUSIONS: VDD and low DBP in middle childhood are related to behavior problems in adolescence.

Pathways to inflammation in adolescence through early adversity, childhood depressive symptoms, and body mass index: A prospective longitudinal study of Chilean infants.

Early adversity, depression, and obesity are associated with increases in low-grade inflammation. However, there are few prospective and longitudinal studies to elucidate how these associations unfold in children. The present study used latent growth curve models to examine pathways between family adversity in infancy, depressive symptoms in childhood, body mass index (BMI) in childhood, and inflammation in adolescence (age = 16-18). The study is an adolescent follow-up of infants from working-class communities around Santiago, Chile, who participated in a preventive trial of iron supplementation at 6 months of age. Anthropometrics, stressful life events, maternal depression, socioeconomic status, and developmental assessments were measured at 12 months, 5 years, 10 years, and adolescence. In adolescence, participants provided blood samples for high-sensitivity C-reactive protein (hsCRP) assessment. Greater exposure to early adversity in the form of interpersonal conflict stress in infancy indirectly associated with increased hsCRP through its association to increased intercept and slope of childhood BMI. Depressive symptoms at any time were not directly or indirectly associated with increased hsCRP. These findings contribute to our understanding of how early family adversity and its associations with obesity and depressive symptoms across childhood are linked to low-grade, chronic inflammation in adolescence. The model identified as best capturing the data supported the pivotal role of childhood BMI in explaining how early-life adversity is associated with inflammation in adolescence.

Mechanisms linking childhood weight status to metabolic risk in adolescence.

BACKGROUND: Obesity is a risk factor for insulin resistance (IR) and metabolic disease. OBJECTIVE: To examine potential metabolic pathways linking childhood weight status to adolescent IR and metabolic risk. METHODS: Participants were 600 low- to middle-income Chilean adolescents from a cohort studied since infancy as part of an iron deficiency anemia preventive trial and follow-up study. We examined body mass index z-score at 10 y (BMIz-10y) and blood pressure, total fat, and fasting glucose, adiponectin to leptin ratio (A:L), ghrelin, and HOMA-IR at 16 y. A total count for metabolic risk factors (MRF) was calculated using the International Diabetes Federation criteria. We used path analysis to estimate pathways and model indirect effects from BMIz-10y, controlling for child age and sex and maternal body mass index (BMI). RESULTS: Participants were 54% male; mean BMIz-10y of 0.53 (SD = 1.02); mean MRF of 1.3 (SD = 0.9); mean HOMA-IR of 1.8 (SD = 1.3). Path analysis showed that BMIz-10y directly and indirectly related to increased MRF via A:L and HOMA-IR. Ghrelin was not in the metabolic pathway from BMIz-10y to MRF but was related to MRF via HOMA-IR. CONCLUSION: These results elucidate metabolic pathways involving child weight status, IR and metabolic risk in adolescents. Childhood BMI was an indirect risk factor for adolescent cardiometabolic risk via several pathways that involved BMI, appetite hormones, markers of inflammation, and insulin resistance during adolescence. Findings illustrate the adverse effect that childhood obesity has on adolescent health outcomes, which sets precedence for health outcomes over the life course.

Adolescent Internalizing, Externalizing, and Social Problems Following Iron Deficiency at 12-18 Months: The Role of Maternal Responsiveness.

This study tested whether maternal responsiveness moderated or mediated pathways from iron deficiency (ID) at 12-18 months to adolescent behavior problems. Participants were part of a large Chilean cohort (N = 933). Iron status was assessed at 12 and 18 months. Maternal responsiveness was assessed at 9 months and 5 years. Parents reported their child's symptomology at 5 years, 10 years, and adolescence (11-17 years; M = 14.4). Structural equation modeling identified a previously unrecognized pathway by which child externalizing problems and negative maternal responsiveness at 5 years mediated associations between ID at 12-18 months and adolescent internalizing, externalizing, and social problems. Positive maternal responsiveness in infancy did not buffer those with ID anemia from developing 5-year internalizing problems.

Sensitive periods for psychosocial risk in childhood and adolescence and cardiometabolic outcomes in young adulthood.

Greater psychosocial risk in childhood and adolescence predicts poorer cardiometabolic outcomes in adulthood. We assessed whether the timing of psychosocial risk from infancy through adolescence predicts cardiometabolic outcomes in young adulthood. Young adults and their mothers participated in a longitudinal study beginning in infancy in Santiago, Chile (N = 1040). At infancy, 5 years, 10 years, and adolescence, mothers reported on depressive symptoms, stressful experiences, support for child development in the home, father absence, parental education, and socioeconomic status (SES) to create a psychosocial risk composite at each time point. Young adults (52.1% female; 21-27 years) provided fasting serum samples and participated in anthropometric and blood pressure (BP) assessments, including a dual-energy X-ray absorptiometry (DXA) scan for measuring body fat. Greater infant psychosocial risk was associated with a greater young adult metabolic syndrome score (ß = 0.07, 95% confidence intervals (CI): 0.01 to 0.13, p = 0.02), a higher body mass index and waist circumference composite (ß = 0.08, 95% CI: 0.03 to 0.13, p = 0.002), and a higher body fat (DXA) composite (ß = 0.07, 95% CI: 0.01 to 0.12, p = 0.02). No psychosocial risk measure from any time point was associated with BP. Infant psychosocial risk predicted cardiometabolic outcomes in young adulthood better than psychosocial risk at 5 years, 10 years, or adolescence, mean of psychosocial risk from infancy through adolescence, and maximum of psychosocial risk at any one time. Consistent with the Developmental Origins of Health and Disease model, findings suggest that infancy is a sensitive period for psychosocial risk leading to poorer cardiometabolic outcomes in young adulthood.

Greater analgesic effects of sucrose in the neonate predict greater weight gain to age 18 months.

Intraoral sucrose has analgesic effects in the newborn period. The hedonic and analgesic effects of sucrose overlap and hedonic response to sweet food is associated with adiposity. The potential association between the analgesic effects of intraoral sucrose in the newborn period and subsequent weight gain has not been examined. Healthy, term newborns received 25% intraoral sucrose or water prior to metabolic screen heel stick. Negative affect, quiet alert behavior, and sleepiness were coded during heel stick. Weight and length were measured and z-score (WLZ) calculated at birth, 9, and 18 months. Mixed models tested associations of behavioral response to heel stick with WLZ trajectory among infants receiving sucrose (n = 154) versus water (n = 117). Among infants receiving sucrose prior to heel stick with birth WLZ ≥ the median, less negative affect and more sleepiness during heel stick were each associated with greater increases in WLZ. These associations were not present among infants receiving water only prior to heel stick. Greater analgesic effects of sucrose in the neonate were associated with greater future increases in WLZ, especially among infants with higher birth WLZ. Greater opioid-mediated newborn behavioral response to intraoral sucrose may be a marker for future obesity risk. CLINICAL TRIALS NUMBER: NCT02728141.

Risk taking, sensation seeking and personality as related to changes in substance use from adolescence to young adulthood.

INTRODUCTION: This study examined changes in substance use from adolescence to young adulthood as related to adolescents' risk taking, sensation seeking, antisocial activities, and personality traits. METHODS: Chilean youth (N = 890, 52% female) were studied in adolescence (14.5 and 16.2 years) and young adulthood (M age 21.3 years). Risk taking was assessed via a laboratory-based performance task (Balloon Analogue Risk Task), and self-administered questionnaires assessed sensation seeking, antisocial behaviors, personality and substance use. RESULTS: Frequent involvement in sensation seeking and antisocial activities were associated with increased odds of continued marijuana use from adolescence to young adulthood and of illicit substance use at young adulthood. High risk taking was associated with a reduced likelihood of discontinuing marijuana use at young adulthood, and high agreeableness and conscientiousness were associated with reduced likelihood of new onset marijuana use and illicit substance use at young adulthood. CONCLUSIONS: Results highlight specific risk-taking tendencies and personality characteristics that relate to initiating, continuing, or discontinuing substance use at entry into adulthood. Sensation seeking and involvement in antisocial activities were the two foremost risk factors for continued use, which is a forecaster of drug dependence. Findings suggest potential prevention and intervention targets for abstaining from or discontinuing substance use as youth transition to adulthood.