Yuelong Ji

Preterm birth and random plasma insulin levels at birth and in early childhood.

IMPORTANCE Although previous reports have linked preterm birth with insulin resistance in children and adults, it is not known whether altered insulin homeostasis is detectable at birth and tracks from birth through childhood. OBJECTIVE To investigate whether preterm birth is associated with elevated plasma insulin levels at birth and whether this association persists into early childhood. DESIGN, SETTING, AND PARTICIPANTS A prospective birth cohort of 1358 children recruited at birth from 1998 to 2010 and followed-up with prospectively from 2005 to 2012 at the Boston Medical Center in Massachusetts. MAIN OUTCOMES AND MEASURES Random plasma insulin levels were measured at 2 time points: at birth (cord blood) and in early childhood (venous blood). The median age was 1.4 years (interquartile range [IQR], 0.8-3.3) among 4 gestational age groups: full term (≥39 wk), early term (37-38 wk), late preterm (34-36 wk), and early preterm (<34 wk). RESULTS The geometric mean of insulin levels at birth were 9.2 µIU/mL (95% CI, 8.4-10.0) for full term; 10.3 µIU/mL (95% CI, 9.3-11.5) for early term; 13.2 µIU/mL (95% CI, 11.8-14.8) for late preterm; and 18.9 µIU/mL (95% CI, 16.6-21.4) for early preterm. In early childhood, these levels were 11.2 µIU/mL (95% CI, 10.3-12.0) for full term; 12.4 µIU/mL (95% CI, 11.3-13.6) for early term; 13.3 µIU/mL (95% CI, 11.9-14.8) for late preterm; and 14.6 µIU/mL (95% CI, 12.6-16.9) for early preterm. Insulin levels at birth were higher by 1.13-fold (95% CI, 0.97-1.28) for early term, 1.45-fold (95% CI, 1.25-1.65) for late preterm, and 2.05-fold (95% CI, 1.69-2.42) for early preterm than for those born full term. In early childhood, random plasma insulin levels were 1.12-fold (95% CI, 0.99-1.25) higher for early term, 1.19-fold (95% CI, 1.02-1.35) for late preterm, and 1.31-fold (95% CI, 1.10-1.52) for early preterm than those born full term. The association was attenuated after adjustment for postnatal weight gain and was not significant after adjustment for insulin levels at birth. Infants ranked in the top insulin tertile at birth were more likely to remain in the top tertile (41.2%) compared with children ranked in the lowest tertile (28.6%) in early childhood. CONCLUSIONS AND RELEVANCE There was an inverse association between gestational age and elevated plasma insulin levels at birth and in early childhood. The implications for future development of insulin resistance and type 2 diabetes warrant further investigation.

Placental transfer and concentrations of cadmium, mercury, lead, and selenium in mothers, newborns, and young children

There is an emerging hypothesis that exposure to cadmium (Cd), mercury (Hg), lead (Pb), and selenium (Se) in utero and early childhood could have long-term health consequences. However, there are sparse data on early life exposures to these elements in US populations, particularly in urban minority samples. This study measured levels of Cd, Hg, Pb, and Se in 50 paired maternal, umbilical cord, and postnatal blood samples from the Boston Birth Cohort (BBC). Maternal exposure to Cd, Hg, Pb, and Se was 100% detectable in red blood cells (RBCs), and there was a high degree of maternal–fetal transfer of Hg, Pb, and Se. In particular, we found that Hg levels in cord RBCs were 1.5 times higher than those found in the mothers. This study also investigated changes in concentrations of Cd, Hg, Pb, and Se during the first few years of life. We found decreased levels of Hg and Se but elevated Pb levels in early childhood. Finally, this study investigated the association between metal burden and preterm birth and low birthweight. We found significantly higher levels of Hg in maternal and cord plasma and RBCs in preterm or low birthweight births, compared with term or normal birthweight births. In conclusion, this study showed that maternal exposure to these elements was widespread in the BBC, and maternal–fetal transfer was a major source of early life exposure to Hg, Pb, and Se. Our results also suggest that RBCs are better than plasma at reflecting the trans-placental transfer of Hg, Pb, and Se from the mother to the fetus. Our study findings remain to be confirmed in larger studies, and the implications for early screening and interventions of preconception and pregnant mothers and newborns warrant further investigation.

Association Between Maternal Prepregnancy Body Mass Index and Plasma Folate Concentrations With Child Metabolic Health

IMPORTANCE Previous reports have linked maternal prepregnancy obesity with low folate concentrations and child overweight or obesity (OWO) in separate studies. To our knowledge, the role of maternal folate concentrations, alone or in combination with maternal OWO, in child metabolic health has not been examined in a prospective birth cohort. OBJECTIVE To test the hypotheses that maternal folate concentrations can significantly affect child metabolic health and that sufficient maternal folate concentrations can mitigate prepregnancy obesity-induced child metabolic risk. DESIGN, SETTING, AND PARTICIPANTS This prospective birth cohort study was conducted at the Boston Medical Center, Boston, Massachusetts. It included 1517 mother-child dyads recruited at birth from 1998 to 2012 and followed up prospectively up to 9 years from 2003 to 2014. MAIN OUTCOMES AND MEASURES Child body mass index z score calculated according to US reference data, OWO defined as a body mass index in the 85th percentile or greater for age and sex, and metabolic biomarkers (leptin, insulin, and adiponectin). RESULTS The mean (SD) age was 28.6 (6.5) years for mothers and 6.2 (2.4) years for the children. An L-shaped association between maternal folate concentrations and child OWO was observed: the risk for OWO was higher among those in the lowest quartile (Q1) as compared with those in Q2 through Q4, with an odds ratio of 1.45 (95% CI, 1.13-1.87). The highest risk for child OWO was found among children of obese mothers with low folate concentrations (odds ratio, 3.05; 95% CI, 1.91-4.86) compared with children of normal-weight mothers with folate concentrations in Q2 through Q4 after accounting for multiple covariables. Among children of obese mothers, their risk for OWO was associated with a 43% reduction (odds ratio, 0.57; 95% CI, 0.34-0.95) if their mothers had folate concentrations in Q2 through Q4 compared with Q1. Similar patterns were observed for child metabolic biomarkers. CONCLUSIONS AND RELEVANCE In this urban low-income prospective birth cohort, we demonstrated an L-shaped association between maternal plasma folate concentrations and child OWO and the benefit of sufficient folate concentrations, especially among obese mothers. The threshold concentration identified in this study exceeded the clinical definition of folate deficiency, which was primarily based on the hematological effect of folate. Our findings underscore the need to establish optimal rather than minimal folate concentrations for preventing adverse metabolic outcomes in the offspring.

Genome-wide DNA methylation associations with spontaneous preterm birth in US blacks: findings in maternal and cord blood samples

ABSTRACT Preterm birth (PTB) affects one in six Black babies in the United States. Epigenetics is believed to play a role in PTB; however, only a limited number of epigenetic studies of PTB have been reported, most of which have focused on cord blood DNA methylation (DNAm) and/or were conducted in white populations. Here we conducted, by far, the largest epigenome-wide DNAm analysis in 300 Black women who delivered early spontaneous preterm (sPTB, n = 150) or full-term babies (n = 150) and replicated the findings in an independent set of Black mother-newborn pairs from the Boston Birth Cohort. DNAm in maternal blood and/or cord blood was measured using the Illumina HumanMethylation450 BeadChip. We identified 45 DNAm loci in maternal blood associated with early sPTB, with a false discovery rate (FDR) <5%. Replication analyses confirmed sPTB associations for cg03915055 and cg06804705, located in the promoter regions of the CYTIP and LINC00114 genes, respectively. Both loci had comparable associations with early sPTB and early medically-indicated PTB, but attenuated associations with late sPTB. These associations could not be explained by cell composition, gestational complications, and/or nearby maternal genetic variants. Analyses in the newborns of the 110 Black women showed that cord blood methylation levels at both loci had no associations with PTB. The findings from this study underscore the role of maternal DNAm in PTB risk, and provide a set of maternal loci that may serve as biomarkers for PTB. Longitudinal studies are needed to clarify temporal relationships between maternal DNAm and PTB risk.

A Prospective Birth Cohort Study on Maternal Cholesterol Levels and Offspring Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences

Growing evidence suggests that maternal cholesterol levels are important in the offspring’s brain growth and development. Previous studies on cholesterols and brain functions were mostly in adults. We sought to examine the prospective association between maternal cholesterol levels and the risk of attention deficit hyperactivity disorder (ADHD) in the offspring. We analyzed data from the Boston Birth Cohort, enrolled at birth and followed from birth up to age 15 years. The final analyses included 1479 mother-infant pairs: 303 children with ADHD, and 1176 neurotypical children without clinician-diagnosed neurodevelopmental disorders. The median age of the first diagnosis of ADHD was seven years. The multiple logistic regression results showed that a low maternal high-density lipoprotein level (≤60 mg/dL) was associated with an increased risk of ADHD, compared to a higher maternal high-density lipoprotein level, after adjusting for pertinent covariables. A “J” shaped relationship was observed between triglycerides and ADHD risk. The associations with ADHD for maternal high-density lipoprotein and triglycerides were more pronounced among boys. The findings based on this predominantly urban low-income minority birth cohort raise a new mechanistic perspective for understanding the origins of ADHD and the gender differences and future targets in the prevention of ADHD.

Distribution and Determinants of Plasma Homocysteine Levels in Rural Chinese Twins across the Lifespan

Plasma homocysteine (Hcy) is a modifiable, independent risk factor for cardiovascular disease (CVD) and is affected by both environmental and genetic factors. This study aimed to describe the gender- and age-specific distribution of Hcy concentration for 1117 subjects aged 10–66 years, a subset of a community-based rural Chinese twin cohort. In addition, we examined environmental and genetic contributions to variances in Hcy concentration by gender and age groups. We found that the distribution pattern for Hcy varied by both age and gender. Males had higher Hcy than females across all ages. Elevated Hcy was found in 43% of male adults and 13% of female adults. Moreover, nearly one fifth of children had elevated Hcy. Genetic factors could explain 52%, 36% and 69% of the variation in Hcy concentration among children, male adults and female adults, respectively. The MTHFR C677T variant was significantly associated with Hcy concentrations. Smokers with the TT genotype had the highest Hcy levels. Overall, our results indicate that elevated Hcy is prevalent in the children and adults in this rural Chinese population. The early identification of elevated Hcy will offer a window of opportunity for the primary prevention of CVD and metabolic syndrome.

A Prospective Birth Cohort Study on Early Childhood Lead Levels and Attention Deficit Hyperactivity Disorder: New Insight on Sex Differences

Objective To investigate the prospective associations between early childhood lead exposure and subsequent risk of attention deficit hyperactivity disorder (ADHD) in childhood and its potential effect modifiers. Study design We analyzed data from 1479 mother–infant pairs (299 ADHD, 1180 neurotypical) in the Boston Birth Cohort. The childs first blood lead measurement and physician‐diagnosed ADHD was obtained from electronic medical records. Graphic plots and multiple logistic regression were used to examine dose–response associations between lead exposure and ADHD and potential effect modifiers, adjusting for pertinent covariables. Results We found that 8.9% of the children in the Boston Birth Cohort had elevated lead levels (5‐10 &mgr;g/dL) in early childhood, which was associated with a 66% increased risk of ADHD (OR, 1.66; 95% CI, 1.08‐2.56). Among boys, the association was significantly stronger (OR, 2.49; 95% CI, 1.46‐4.26); in girls, the association was largely attenuated (P value for sex‐lead interaction = .017). The OR of ADHD associated with elevated lead levels among boys was reduced by one‐half if mothers had adequate high‐density lipoprotein levels compared with low high‐density lipoprotein, or if mothers had low stress compared with high stress during pregnancy. Conclusions Elevated early childhood blood lead levels increased the risk of ADHD. Boys were more vulnerable than girls at a given lead level. This risk of ADHD in boys was reduced by one‐half if the mother had adequate high‐density lipoprotein levels or low stress. These findings shed new light on the sex difference in ADHD and point to opportunities for early risk assessment and primary prevention of ADHD.

Maternal smoking during pregnancy and cord blood DNA methylation: new insight on sex differences and effect modification by maternal folate levels

ABSTRACT Maternal smoking during pregnancy may affect newborn DNA methylation (DNAm). However, little is known about how these associations vary by a newborn’s sex and/or maternal nutrition. To fill in this research gap, we investigated epigenome-wide DNAm associations with maternal smoking during pregnancy in African American mother-newborn pairs. DNAm profiling in cord (n = 379) and maternal blood (n = 300) were performed using the Illumina HumanMethylation450 BeadChip array. We identified 12 CpG sites whose DNAm levels in cord blood were associated with maternal smoking, at a false discovery rate <5%. The identified associations in the GFI1 gene were more pronounced in male newborns than in females (P = 0.002 for maternal smoking × sex interaction at cg18146737). We further observed that maternal smoking and folate level may interactively affect cord blood DNAm level at cg05575921 in the AHRR gene (P = 5.0 × 10−4 for interaction): compared to newborns unexposed to maternal smoking and with a high maternal folate level (>19.2 nmol/L), the DNAm level was about 0.03 lower (P = 3.6 × 10−4) in exposed newborns with a high maternal folate level, but was 0.08 lower (P = 1.2 × 10−8) in exposed newborns with a low maternal folate level. Our data suggest that adequate maternal folate levels may partly counteract the impact of maternal smoking on DNAm. These findings may open new avenues of inquiry regarding sex differences in response to environmental insults and novel strategies to mitigate their intergenerational health effects through optimization of maternal nutrition.

The Joint Association of Small for Gestational Age and Nighttime Sleep with Blood Pressure in Childhood

Children born small for gestational age (SGA) are more likely to develop high blood pressure. In prior studies, longer sleep duration is associated with lower BP, and SGA is associated with shorter sleep duration in childhood. We investigated whether sleep duration in early childhood modifies the association between SGA and higher childhood SBP in 1178 children recruited at birth and followed up to age 9 years. We ascertained birthweight and gestational age from medical records. We derived child sleep duration from maternal questionnaire interview. We calculated child SBP percentile according to U.S. reference data. We defined elevated SBP as SBP ≥75th percentile. In this sample, 154 (13.1%) children were born SGA. Children born SGA had higher SBP percentiles and higher risk of elevated SBP. Among children born SGA, those in the highest compared to the lowest tertile for sleep had a 12.28 lower (−22.00, −2.57) SBP percentile and 0.44 (0.25 to 0.79) times lower risk of developing elevated SBP. Our data are consistent with an interaction between SGA and sleep duration on childhood elevated SBP (Pinteraction = 0.0056). In conclusion, in this prospective birth cohort, longer sleep duration in early childhood may mitigate the blood pressure-raising effect of being born small.

Maternal psychosocial stress and children’s ADHD diagnosis: a prospective birth cohort study

Abstract Objective: Examine the association of mothers’ psychosocial stressors before and during pregnancy with their children’s diagnosis of attention deficit hyperactivity disorder (ADHD). Methods: This study included 2140 mother–child pairs who had at least one postnatal pediatric visit at the Boston Medical Center between 2003 and 2015. Child ADHD was determined via International Classification of Diseases, Ninth Revision (ICD-9) codes documented in electronic medical records. Latent factors of maternal stress and social support and measures of the physical home environment and psychosocial adversities were constructed using exploratory factor analysis. The association between the latent factors and child ADHD diagnosis was examined using multiple logistic regression, controlling for known risk factors for ADHD. Results: Children were 1.45 (95% CI: 1.06, 1.99) and 3.03 (95% CI: 2.19, 4.20) times more likely to receive an ADHD diagnosis if their mother experienced a major stressful event during pregnancy or reported a high level of perceived stress, respectively. The number of family adversities increases the risk of ADHD diagnosis [second quartile: OR = 1.90; CI (1.31, 2.77); third quartile: OR = 1.96 CI (1.34, 2.88); fourth quartile: OR = 2.89 CI (2.01, 4.16)] compared to first quartile. Conclusions: In this prospective, predominantly urban, low-income, minority birth cohort, mothers’ psychosocial stress before and during pregnancy appears to be an independent risk factor for the development of ADHD in their children.