Publications by Year: 2022

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.

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.

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: 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: 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.

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: No studies have examined whether the cord blood metabolome-a reflection of in utero metabolism-influences blood pressure (BP) in children.

OBJECTIVES: To examine prospective associations of cord blood metabolites with systolic BP (SBP), diastolic BP (DBP), and risk of elevated BP in childhood and adolescence.

METHODS: In the Boston Birth Cohort, we measured metabolites in cord blood plasma, and SBP and DBP at clinic visits between 3 and 18 years. We examined associations of cord metabolites with SBP and DBP percentiles using linear mixed models and with elevated BP using mixed-effects Poisson regression.

RESULTS: Our study included 902 mother-child dyads (60% Black, 23% Hispanic, 45% female). Children were followed for a median of 9.2 (interquartile range, 6.7-11.7) years, and the median number of BP observations per child was 7 (interquartile range, 4-11). After false discovery rate correction, 3 metabolites were associated with SBP, 96 with DBP, and 24 with elevated BP; 2 metabolites (1-methylnicotinamide, dimethylguanidino valeric acid) were associated with all 3 outcomes, and 21 metabolites were associated with both DBP and elevated BP. After multivariable adjustment, 48 metabolites remained significantly associated with DBP. Metabolites that showed the strongest associations with SBP, DBP, and elevated BP included nucleotides (eg, xanthosine, hypoxanthine, xanthine) and acylcarnitines (eg, C6 and C7 carnitines), which represent fatty acid oxidation and purine metabolism pathways.

CONCLUSIONS: In our urban and predominantly racial/ethnic minority cohort, we provide evidence that metabolomic alterations in utero, in particular, acylcarnitine- and purine-metabolism metabolites, may be involved in the early life origins of hypertension.

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.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a major public health concern worldwide due to their ubiquitous exposures, environmental persistence, maternal-to-fetal transfer, and multi-organ toxicity. This pilot study aimed to generate preliminary data to inform future studies to address data gaps in the field, including early life PFAS exposure levels, longitudinal changes, determinants, and associated metabolomic alterations in understudied Black and Hispanic children in the United States (U.S.).

METHODS: This study leveraged existing biosamples and data in the Boston Birth Cohort and measured 12 legacy and emerging PFAS, including Me-PFOSA-AcOH, PFDA, PFDoA, PFHxS, PFNA, PFOA, PFOS, PFUnA, GenX, ADONA, 9Cl-PF3ONS, and PFHpS, in paired cord and early childhood plasma samples. Summary statistics and graphic plots were used to depict PFAS levels at the two time points and their longitudinal changes. Linear regression models were used to identify the early-life factors associated with cord and early childhood PFAS levels. Associations of cord PFAS with cord metabolites were explored using a metabolome-wide association approach and a targeted approach.

RESULTS: This study included 39 children, of whom 25 (64%) were Black, 14 (36%) were Hispanic, and 15 (38%) were female. PFOA, PFOS, PFNA, and PFHpS were detectable in all cord and early childhood plasma samples, while GenX and ADONA were not detectable in any sample. Cord PFAS levels were weakly-to-moderately correlated with early childhood PFAS levels (r = -0.03 to 0.40). Several maternal and child factors, including gestational age, year at blood collection, and race/ethnicity, were associated with cord and early childhood PFAS levels. The metabolome-wide association study and the targeted study identified several cord metabolites that may have been affected by in utero PFAS exposure.

CONCLUSIONS: This pilot study found ubiquitous exposure to multiple PFAS in cord plasma (reflects in utero exposure) and in early childhood plasma (reflects both prenatal and postnatal exposure) among U.S. Black and Hispanic children. Metabolomic analysis suggests that in utero PFAS exposures may alter fetal metabolism. Future large-scale studies are needed to replicate the findings and further examine the associations of fetal PFAS exposure with long-term health outcomes and underlying metabolic pathways.

BACKGROUND: Most studies on the association of in utero exposure to cigarette smoking and childhood overweight or obesity (OWO) were based on maternal self-reported smoking status, and few were based on objective biomarkers. The concordance of self-report smoking, and maternal and cord blood biomarkers of cigarette smoking as well as their effects on children's long-term risk of overweight and obesity are unclear.

METHODS: In this study, we analyzed data from 2351 mother-child pairs in the Boston Birth Cohort, a sample of US predominantly Black, indigenous, and people of color (BIPOC) that enrolled children at birth and followed prospectively up to age 18 years. In utero smoking exposure was measured by maternal self-report and by maternal and cord plasma biomarkers of smoking: cotinine and hydroxycotinine. We assessed the individual and joint associations of each smoking exposure measure and maternal OWO with childhood OWO using multinomial logistic regressions. We used nested logistic regressions to investigate the childhood OWO prediction performance when adding maternal and cord plasma biomarkers as input covariates on top of self-reported data.

RESULTS: Our results demonstrated that in utero cigarette smoking exposure defined by self-report and by maternal or cord metabolites was consistently associated with increased risk of long-term child OWO. Children with cord hydroxycotinine in the fourth quartile (vs. first quartile) had 1.66 (95% confidence interval [CI] 1.03-2.66) times the odds for overweight and 1.57 (95% CI 1.05-2.36) times the odds for obesity. The combined effect of maternal OWO and smoking on offspring risk of obesity is 3.66 (95% CI 2.37-5.67) if using self-reported smoking. Adding maternal and cord plasma biomarker information to self-reported data improved the prediction accuracy of long-term child OWO risk.

CONCLUSIONS: This longitudinal birth cohort study of US BIPOC underscored the role of maternal smoking as an obesogen for offspring OWO risk. Our findings call for public health intervention strategies to focus on maternal smoking - as a highly modifiable target, including smoking cessation and countermeasures (such as optimal nutrition) that may alleviate the increasing obesity burden in the United States and globally.