Publications

BACKGROUND: We earlier reported prematurity as an independent risk factor for elevated insulin levels. Investigation is still lacking on the influence of prenatal and perinatal factors on childhood insulin levels.

METHODS: In this secondary analysis of a prospective birth cohort, plasma insulin levels were measured at birth and early childhood. Regression models identified early-life factors associated with the primary outcome: log-transformed childhood plasma insulin levels.

RESULTS: One thousand one hundred and nine children had insulin levels at birth and 825 at both time points. Compared to term, preterm infants had higher plasma insulin levels (geometric mean) at birth (612, 95% CI 552-679 vs. 372, 95% CI 345-402 pmol/ml) and in early childhood (547, 95% CI 494-605 vs. 445, 95% CI 417-475 pmol/ml). Factors associated with higher early childhood insulin levels included higher insulin level at birth, black race, female sex, maternal smoking during pregnancy, maternal perceived stress, in utero drug exposure, maternal pregestational diabetes mellitus, and maternal preconception overweight and obesity.

CONCLUSIONS: In this high-risk US birth cohort, we identified multiple prenatal and perinatal risk factors for higher early childhood insulin levels, in addition to prematurity. These findings lend support to primordial preventive strategies for diabetes mellitus.

IMPACT: In this secondary analysis of a large prospective study from a high-risk racially diverse cohort, we identify biological and social factors that contribute to elevated levels of plasma insulin in early childhood. Our study also investigates factors affecting plasma insulin in preterm infants along with comorbidities commonly seen during the neonatal intensive care stay. Our work reaffirms the importance of Developmental Origins of Health and Disease with regards to in utero programming of insulin levels. Our work supports the possibility that primordial preventive strategies for diabetes mellitus in high-risk populations may need to begin as early as the prenatal period.

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a "high" exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context.

BACKGROUND: Exposure to metals lead (Pb), mercury (Hg), and cadmium (Cd) and trace elements selenium (Se) and manganese (Mn) has been linked to the developmental origins of cardiometabolic diseases, but the mechanisms are not well-understood.

OBJECTIVE: Conduct a metabolome-wide association study to understand how in utero exposure to Pb, Hg, Cd, Se, and Mn affects the metabolic programming of fetuses.

METHODS: We used data from the Boston Birth Cohort, which enrolled mother-child pairs from Boston, MA. We measured metals and trace elements in maternal red blood cells (RBCs) collected 24-72 h after delivery, and metabolites in cord blood collected at birth. We used multivariable linear regression to examine associations of metals and trace elements with metabolites and Bonferroni correction to account for multiple comparisons. We assessed non-linear associations of metals and trace elements with metabolites using restricted cubic spline plots.

RESULTS: This analysis included 670 mother-child pairs (57% non-Hispanic Black and 24% Hispanic). After Bonferroni correction, there were 25 cord metabolites associated with at least one of the metals or trace elements. Pb was negatively associated with the xenobiotic piperine, Cd was positively associated with xenobiotics cotinine and hydroxycotinine, and Hg was associated with 8 lipid metabolites (in both directions). Se and Mn shared associations with 6 metabolites (in both directions), which mostly included nucleotides and amino acids; Se was additionally associated with 7 metabolites (mostly amino acids, nucleotides, and carnitines) and Mn was additionally associated with C36:4 hydroxy phosphatidylcholine. Restricted cubic spline plots showed that most associations were linear.

DISCUSSION: Maternal RBC metal and trace element concentrations were associated in a dose-dependent fashion with cord blood metabolites. What remains to be determined is whether these metals- and trace elements-associated changes in cord metabolites can influence a child's risk of cardiometabolic diseases.

Given inconsistent evidence on preconception or prenatal tobacco use and offspring autism spectrum disorder (ASD), this study assessed associations of maternal smoking with ASD and ASD-related traits. Among 72 cohorts in the Environmental Influences on Child Health Outcomes consortium, 11 had ASD diagnosis and prenatal tobaccosmoking (n = 8648). and 7 had Social Responsiveness Scale (SRS) scores of ASD traits (n = 2399). Cohorts had diagnoses alone (6), traits alone (2), or both (5). Diagnoses drew from parent/caregiver report, review of records, or standardized instruments. Regression models estimated smoking-related odds ratios (ORs) for diagnoses and standardized mean differences for SRS scores. Cohort-specific ORs were meta-analyzed. Overall, maternal smoking was unassociated with child ASD (adjusted OR, 1.08; 95% confidence interval [CI], 0.72-1.61). However, heterogeneity across studies was strong: preterm cohorts showed reduced ASD risk for exposed children. After excluding preterm cohorts (biased by restrictions on causal intermediate and exposure opportunity) and small cohorts (very few ASD cases in either smoking category), the adjusted OR for ASD from maternal smoking was 1.44 (95% CI, 1.02-2.03). Children of smoking (versus non-smoking) mothers had more ASD traits (SRS T-score + 2.37 points, 95% CI, 0.73-4.01 points), with results homogeneous across cohorts. Maternal preconception/prenatal smoking was consistently associated with quantitative ASD traits and modestly associated with ASD diagnosis among sufficiently powered United States cohorts of non-preterm children. Limitations resulting from self-reported smoking and unmeasured confounders preclude definitive conclusions. Nevertheless, counseling on potential and known risks to the child from maternal smoking is warranted for pregnant women and pregnancy planners. LAY SUMMARY: Evidence on the association between maternal prenatal smoking and the child's risk for autism spectrum disorder has been conflicting, with some studies reporting harmful effects, and others finding reduced risks. Our analysis of children in the ECHO consortium found that maternal prenatal tobacco smoking is consistently associated with an increase in autism-related symptoms in the general population and modestly associated with elevated risk for a diagnosis of autism spectrum disorder when looking at a combined analysis from multiple studies that each included both pre- and full-term births. However, this study is not proof of a causal connection. Future studies to clarify the role of smoking in autism-like behaviors or autism diagnoses should collect more reliable data on smoking and measure other exposures or lifestyle factors that might have confounded our results.

Background Preeclampsia is a major cause of maternal and fetal morbidity and mortality. Given its large public health burden, there is a need to identify modifiable factors that can be targeted for preeclampsia prevention. In this study, we examined whether a Mediterranean-style diet is protective for preeclampsia in a large cohort of racially and ethnically diverse, urban, low-income women. Methods and Results We used data from the Boston Birth Cohort. Maternal sociodemographic and dietary data were obtained via interview and food frequency questionnaire within 24 to 72 hours postpartum, respectively. Additional clinical information, including physician diagnoses of preexisting conditions and preeclampsia, were extracted from medical records. We derived a Mediterranean-style diet score from the food frequency questionnaire and performed logistic regression to examine the association of the Mediterranean-style diet score with preeclampsia. Of 8507 women in the sample, 848 developed preeclampsia. 47% were Black, 28% were Hispanic, and the remaining were White/Other. After multivariable adjustment, greatest adherence with MSD was associated with lower preeclampsia odds (adjusted odds ratio comparing tertile 3 to tertile 1, 0.78; 95% CI, 0.64-0.96). A subgroup analysis of Black women demonstrated a similar benefit with an adjusted odds ratio comparing tertile 3 to tertile 1 of 0.74 (95% CI, 0.76-0.96). Conclusions Self-report of higher adherence to a Mediterranean-style diet is associated with lower preeclampsia odds, and benefit of this diet is present among Black women as well.

BACKGROUND: Cohort collaborations often require meta-analysis of exposure-outcome association estimates across cohorts as an alternative to pooling individual-level data that requires a laborious process of data harmonization on individual-level data. However, it is likely that important confounders are not all measured uniformly across the cohorts due to differences in study protocols. This imbalance in measurement of confounders leads to association estimates that are not comparable across cohorts and impedes the meta-analysis of results.

METHODS: In this article, we empirically show some asymptotic relations between fully adjusted and unadjusted exposure-outcome effect estimates, and provide theoretical justification for the same. We leverage these results to obtain fully adjusted estimates for the cohorts with no information on confounders by borrowing information from cohorts with complete measurement on confounders. We implement this novel method in CIMBAL (confounder imbalance), which additionally provides a meta-analyzed estimate that appropriately accounts for the dependence between estimates arising due to borrowing of information across cohorts. We perform extensive simulation experiments to study CIMBAL's statistical properties. We illustrate CIMBAL using National Children's Study (NCS) data to estimate association of maternal education and low birth weight in infants, adjusting for maternal age at delivery, race/ethnicity, marital status, and income.

RESULTS: Our simulation studies indicate that estimates of exposure-outcome association from CIMBAL are closer to the truth than those from commonly-used approaches for meta-analyzing cohorts with disparate confounder measurements. CIMBAL is not too sensitive to heterogeneity in underlying joint distributions of exposure, outcome and confounders but is very sensitive to heterogeneity of confounding bias across cohorts. Application of CIMBAL to NCS data for a proof-of-concept analysis further illustrates the utility and advantages of CIMBAL.

CONCLUSIONS: CIMBAL provides a practical approach for meta-analyzing cohorts with imbalance in measurement of confounders under a weak assumption that the cohorts are independently sampled from populations with the same confounding bias.

BACKGROUND: Trimethylamine N-oxide (TMAO) and its precursors choline, betaine, and carnitine have been associated with cardiometabolic disease in nonpregnant adults. However, studies examining TMAO and its precursors in relation to cardiometabolic conditions during pregnancy are lacking.

OBJECTIVES: The primary objective was to estimate the association of TMAO and its precursors in maternal and cord plasma with gestational diabetes mellitus (GDM) and pre-eclampsia (PE) among women in the Boston Birth Cohort. A secondary objective was to determine whether associations vary by race/ethnicity.

METHODS: ORs for each outcome according to tertiles and to an SD increment of TMAO, choline, betaine, and carnitine were estimated using logistic regression. Final models were adjusted for covariates.

RESULTS: Among 1496 women, 115 women had GDM and 159 had PE during the index pregnancy. Intermetabolite correlations of TMAO and its precursors were stronger within cord plasma (r = 0.38-0.87) than within maternal plasma (r = 0.08-0.62). Maternal TMAO was associated with higher odds of GDM (third compared with first tertile OR: 1.75; 95% CI: 1.04, 2.94), whereas maternal choline, betaine, and carnitine were not associated with GDM. Maternal TMAO and choline were not associated with PE, whereas carnitine was associated with higher (OR: 1.86; 95% CI: 1.18, 2.94) and betaine with lower odds of PE (OR: 0.37; 95% CI: 0.23, 0.59). In cord plasma, TMAO was not associated with GDM or PE, but choline, betaine, and carnitine were associated with higher odds of PE (OR: 3.11; 95% CI: 1.62, 5.96; OR: 2.65; 95% CI: 1.42, 4.93; OR: 2.56; 95% CI: 1.39, 4.69, respectively). Cord choline was associated with lower odds of GDM (OR: 0.52; 95% CI: 0.27, 0.99), whereas other cord metabolites were not significantly associated with GDM. Associations did not vary by race/ethnicity.

CONCLUSIONS: TMAO and its precursors were associated with GDM and PE, but the associations differed based on the metabolite medium (maternal compared with cord plasma).This trial was registered at clinicaltrials.gov as NCT03228875.

BACKGROUND: Understanding of maternal and fetal factors affecting leptin, adiponectin, and adiponectin:leptin ratio at birth may provide valuable insights into potential future risk of metabolic alterations and inform primordial prevention and precision nutrition strategies. The objective of this study is to identify maternal and fetal risk factors that affect leptin and adiponectin levels (markers of adiposity) and adiponectin/leptin ratio (a marker of dysfunctional adipose tissue) at birth.

METHODS: We studied mother-infant pairs in the Boston Birth Cohort. Cord blood was collected at birth. We used student t- tests to compare log normalized cord leptin and adiponectin levels. Regression analysis was performed to examine the association of maternal and fetal factors with leptin and adiponectin levels and adiponectin:leptin ratio at birth in both term and preterm infants.

RESULTS: We analyzed 1012 infants (245 preterm). Both cord leptin and adiponectin were higher in term infants than preterm infants (10.2 ± 0.9 vs. 9.2 ± 1.3, P < 0.0001 and 9.5 ± 0.7 vs. 8.9 ± 0.8, P < 0.0001, respectively). Cord leptin was higher for Black infants (10.1 ± 1.1 vs. 9.9 ± 1.2; P < 0.001) although Black (ref: non-Black) infants had lower cord adiponectin levels (9.3 ± 0.8 vs. 9.5 ± 0.7; P = 0.01). Ratio of adiponectin to leptin (log normalized) was higher in preterm infants (-0.24) vs. term infants (-0.69). On regression analysis, cord leptin was positively associated with longer gestational age (GA), birth weight z score, Black race, maternal overweight and obesity, gestational diabetes and pregestational diabetes mellitus and negatively associated with male sex. Cord adiponectin was positively associated with GA, birth weight z score and negatively with Black race and male sex. Adiponectin:leptin ratio was positively with male sex and negatively with GA, birth weight z score, Black race, gestational DM, pregestational DM and maternal overweight and obesity.

CONCLUSIONS: We identified several factors that affect leptin and adiponectin levels along with adiponectin-leptin ratio at birth beyond GA and birth weight which could also play an important role in influencing the trajectory of these hormones and future cardiometabolic outcomes. This knowledge can help tailor precision nutrition interventions.

OBJECTIVE: To examine the efficacy of dual medication therapy (intervention) (DMT: acetaminophen and ibuprofen) vs. single medication therapy (control) (SMT: ibuprofen) for medical management of PDA (outcomes) in preterm infants (population).

STUDY DESIGN: We systematically searched multiple sources to identify randomized controlled trials (RCT) and non-randomized studies (NRS) that compared DMT to SMT for management of hemodynamically significant PDA.

RESULTS: We identified two RCTs and four NRS. There were no differences in the rates of successful PDA closure following the first treatment course between DMT and SMT (RR = 1.23 [95% CI 0.89-1.70] for NRS and RR = 1.18 [95% CI 0.66-2.10] for RCTs), nor were there significant differences in secondary outcomes and adverse events including PDA ligation, bronchopulmonary dysplasia, and necrotizing enterocolitis etc. Markers of hepatic/renal function did not change significantly during treatment.

CONCLUSION: We found no evidence for superiority of DMT over SMT in PDA management.