Publications

BACKGROUND: Cesarean delivery has been linked with childhood obesity. Few studies have examined if this association is attenuated if there is labor prior to delivery. The objective of this current analysis was to examine the association of cesarean vs. vaginal delivery with measures of childhood adiposity, and whether the association differs by labor type (spontaneous, induced, or absent) preceding cesarean delivery.

METHODS: We ascertained delivery mode and type of labor from medical records in 1443 mother-child dyads from Project Viva with adiposity measures from at least one follow-up visit (3369 total observations) in early childhood (median age 3.2 y), mid-childhood (median 7.7 y), or early teen (median 12.9 y). Child adiposity outcomes were CDC age- and sex-specific body mass index (BMI) z-scores, sum of subscapular and triceps skinfold thicknesses (SS + TR; mm), and waist circumference (cm). We used linear regression models with generalized estimating equation estimates and adjusted for maternal age, education, race/ethnicity, prepregnancy BMI, rate of gestational weight gain, and child sex and age at outcome.

RESULTS: A total of 333 (23%) women delivered via cesarean, including 155 (11%) with spontaneous labor, 74 (5%) with induced labor, 99 (7%) with no labor, and 5 (<1%) with unknown labor status. Compared to vaginal-delivered children, cesarean-delivered children had higher BMI-z (0.15, 95% CI: 0.04, 0.26); and non-significantly higher waist circumference (0.50 cm, 95% CI: -0.34, 1.34) and SS + TR (0.47 mm, 95% CI: -0.52, 1.46). Cesarean deliveries that were preceded by spontaneous labor were not associated with childhood BMI-z (0.08, 95% CI: -0.07, 0.23), waist circumference (-0.12 cm, 95% CI: -1.09, 0.85), or SS + TR (-0.25 mm, 95% CI: -1.44, 0.93), as compared to vaginal deliveries.

CONCLUSION: Cesarean delivery was associated with higher childhood BMI-z, and although waist circumference and SS + TR trended in the same direction, these associations were not significant. Cesarean delivery preceded by spontaneous labor was not associated with adiposity outcomes.

BACKGROUND: While several heavy metals and trace minerals have been linked with hypertensive disorders during pregnancy (HDP) in women, no studies have estimated the relationship of exposure to these chemicals, both independently and as a mixture, with systolic blood pressure (SBP) or diastolic blood pressure (DBP) over gestation.

OBJECTIVES: We examined individual and joint effects of 1st trimester chemicals with SBP and DBP over gestation, and whether those chemicals were associated with HDP.

METHODS: We used data from 1832 non-obese pregnant women with low-risk antenatal profiles from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies - Singleton cohort (2009-2013). In plasma collected from women at 8-13 weeks' gestation (baseline enrollment), we measured heavy metals, barium (Ba), cesium (Cs), antimony (Sb), as well as trace minerals, cobalt (Co), copper (Cu), molybdenum (Mo), selenium (Se), and zinc (Zn). We obtained BP at baseline and throughout gestation until delivery and diagnosis of HDP from medical records. We used Bayesian Kernel Machine Regression (BKMR) as well as traditional linear and logistic regressions to examine the cross-sectional associations of chemicals with baseline BP and HDP. We used linear mixed effect regression to examine longitudinal associations between chemicals and rate of weekly change in BP in each trimester. We adjusted for sociodemographic and lifestyle factors and pre-pregnancy body mass index in all models.

RESULTS: BKMR revealed that comparing the entire chemical mixture at the 90th percentile vs. the 50th percentile was associated with a 1.61 mmHg (95% CI: 0.41, 2.81) higher SBP and a 1.09 mmHg (0.10, 2.09) higher DBP. No interactions were observed between chemicals. Accounting for chemical co-exposure in BKMR, each interquartile range (IQR) increment in Cu was associated with a 0.67 mmHg (0.02, 1.32) higher SBP and a 0.60 mmHg (0.08, 1.12) higher DBP at baseline; each IQR increment in Se was associated with a 0.67 mmHg (0.05, 1.29) higher SBP but not DBP. In longitudinal analyses, women with higher (i.e., above median concentration) baseline Cu had a 0.09 mmHg (0.01, 0.17) and 0.06 mmHg (0.001, 0.12) larger weekly decrease in SBP and DBP in 2nd trimester, respectively. Women with higher baseline Ba had a 0.12 mmHg (0.04, 0.20) larger weekly increase in SBP in 2nd trimester, while women with higher Cs had a 0.05 mmHg (0.01, 0.10) larger weekly increase in DBP in 3rd trimester. None of the chemicals examined were significantly associated with HDP.

CONCLUSIONS: In this multi-ethnic cohort of women with low antenatal risk, plasma metals and trace minerals in early pregnancy, both individually and as a mixture, were statistically significantly associated with BP during gestation in small magnitude and in different directions, but not with HDP. The implications of these findings for women's postpartum BP and future cardiovascular health remains to be investigated.

OBJECTIVE: To determine the longer-term effects of metformin treatment and behavioral weight loss on gut microbiota and short-chain fatty acids (SCFAs).

RESEARCH DESIGN AND METHODS: We conducted a 3-parallel-arm, randomized trial. We enrolled overweight/obese adults who had been treated for solid tumors but had no ongoing cancer treatment and randomized them (n = 121) to either 1) metformin (up to 2,000 mg), 2) coach-directed behavioral weight loss, or 3) self-directed care (control) for 12 months. We collected stool and serum at baseline (n = 114), 6 months (n = 109), and 12 months (n = 105). From stool, we extracted microbial DNA and conducted amplicon and metagenomic sequencing. We measured SCFAs and other biochemical parameters from fasting serum.

RESULTS: Of the 121 participants, 79% were female and 46% were Black, and the mean age was 60 years. Only metformin treatment significantly altered microbiota composition. Compared with control, metformin treatment increased amplicon sequence variants for Escherichia (confirmed as Escherichia coli by metagenomic sequencing) and Ruminococcus torques and decreased Intestinibacter bartlettii at both 6 and 12 months and decreased the genus Roseburia, including R. faecis and R. intestinalis, at 12 months. Effects were similar in comparison of the metformin group with the behavioral weight loss group. Metformin versus control also increased butyrate, acetate, and valerate at 6 months (but not at 12 months). Behavioral weight loss versus control did not significantly alter microbiota composition but did increase acetate at 6 months (but not at 12 months). Increases in acetate were associated with decreases in fasting insulin. Additional whole-genome metagenomic sequencing of a subset of the metformin group showed that metformin altered 62 metagenomic functional pathways, including an acetate-producing pathway and three pathways in glucose metabolism.

CONCLUSIONS: Metformin, but not behavioral weight loss, impacted gut microbiota composition at 6 months and 12 months. Both metformin and behavioral weight loss altered circulating SCFAs at 6 months, including increasing acetate, which correlated with lower fasting insulin. Future research is needed to elucidate whether the gut microboime mediates or modifies metformin's health effects.

BACKGROUND: The in utero pathologies underlying the link between preterm birth and offspring high blood pressure (BP) are still unknown. We investigated the prospective associations of placental histopathological findings with childhood BP among children born preterm.

METHODS: Our study sample included 546 mother-child pairs with preterm birth (before 37 weeks gestation) enrolled from 1999 to 2013 at the Boston Medical Center. Early preterm birth was defined as gestational age between 23 and 34 weeks. We histologically classified maternal placental pathology using the latest recommended categories: no placental complications, histologic chorioamnionitis, maternal vascular malperfusion, and other placental complications. We calculated age-, sex-, and height-specific systolic BP (SBP) percentiles for children using the 2017 American Academy of Pediatrics Clinical Practice Guideline. We used linear regression models with generalized estimating equations to examine the associations.

RESULTS: The mean (standard deviation (SD)) postnatal follow-up of the study children was 9.29 (4.1) years. After adjusting for potential confounders, histologic chorioamnionitis was associated with a 5.42 percentile higher childhood SBP (95% confidence interval: 0.32, 10.52) compared with no placental pathologic findings. This association was stronger among early preterm children. Maternal vascular malperfusion was associated with a 8.44 percentile higher childhood SBP among early preterm children (95% confidence interval: 1.54, 15.34) but the association was attenuated (6.25, 95% confidence interval: -0.76, 13.26) after additional adjustment for child standardized birthweight, a potential mediator of the association.

CONCLUSIONS: These findings suggest that among children born preterm, especially those born early preterm, both placental histologic chorioamnionitis and vascular malperfusion may help to differentiate a child's risk of high BP.

BACKGROUND: In utero exposure to heavy metals lead (Pb), mercury (Hg), and cadmium (Cd) may be associated with higher childhood blood pressure (BP), whereas trace elements selenium (Se) and manganese (Mn) may have protective antioxidant effects that modify metal-BP associations.

OBJECTIVES: We examined the individual and joint effects of in utero exposure to Pb, Hg, Cd, Se, and Mn on childhood BP.

METHODS: We used data from the Boston Birth Cohort (enrolled 2002-2013). We measured heavy metals and trace elements in maternal red blood cells collected 24-72 h after delivery. We calculated child BP percentile per the 2017 American Academy of Pediatrics Clinical Practice Guideline. We used linear regression models to estimate the association of each metal, and Bayesian kernel machine regression (BKMR) to examine metal coexposures, with child BP between 3 to 15 years of age.

RESULTS: Our analytic sample comprised 1,194 mother-infant pairs (61% non-Hispanic Black, 20% Hispanic). Hg and Pb were not associated with child systolic BP (SBP). Se and Mn were inversely associated with child SBP percentiles, which, on average, were 6.23 points lower with a doubling of Se (95% CI: -11.51, -0.96) and 2.62 points lower with a doubling of Mn (95% CI: -5.20, -0.04). BKMR models showed similar results. Although Cd was not associated with child SBP overall, the inverse association between Mn and child SBP was stronger at higher levels of Cd (p-interaction=0.04). Consistent with this finding, in utero exposure to cigarette smoke modified the Mn-child SBP association. Among children whose mothers smoked during pregnancy, a doubling of Mn was associated with a 10.09-point reduction in SBP percentile (95% CI: -18.03, -2.15), compared with a 1.49-point reduction (95% CI: -4.21, 1.24) in children whose mothers did not smoke during pregnancy (p-interaction=0.08).

CONCLUSION: Se and Mn concentrations in maternal red blood cells collected 24-72 h after delivery were associated with lower child SBP at 3 to 15 years of age. There was an interaction between Mn and Cd on child SBP, whereby the protective association of Mn on child SBP was stronger among mothers who had higher Cd. The association of Mn and child SBP was also modified by maternal cigarette smoking-a source of Cd-during pregnancy. Optimizing in utero Se levels, as well as Mn levels in women who had high Cd or smoked during pregnancy, may protect offspring from developing high BP during childhood. https://doi.org/10.1289/EHP8325.

OBJECTIVE: The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region.

METHODS: This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome.

RESULTS: The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (β = -0.12, 95% CI: -0.19 to -0.05) and West (β = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (β = 0.09, 95% CI: 0.05 to 0.14) and lower in the South (β = -0.12, 95% CI: -0.16 to -0.08) and West (β = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight.

CONCLUSIONS: Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.

The particularly interdisciplinary nature of human microbiome research makes the organization and reporting of results spanning epidemiology, biology, bioinformatics, translational medicine and statistics a challenge. Commonly used reporting guidelines for observational or genetic epidemiology studies lack key features specific to microbiome studies. Therefore, a multidisciplinary group of microbiome epidemiology researchers adapted guidelines for observational and genetic studies to culture-independent human microbiome studies, and also developed new reporting elements for laboratory, bioinformatics and statistical analyses tailored to microbiome studies. The resulting tool, called 'Strengthening The Organization and Reporting of Microbiome Studies' (STORMS), is composed of a 17-item checklist organized into six sections that correspond to the typical sections of a scientific publication, presented as an editable table for inclusion in supplementary materials. The STORMS checklist provides guidance for concise and complete reporting of microbiome studies that will facilitate manuscript preparation, peer review, and reader comprehension of publications and comparative analysis of published results.

BACKGROUND: Short chain fatty acids (SCFAs; e.g., acetate, propionate, and butyrate) are produced by microbial fermentation of fiber in the colon. Evidence is lacking on how high-fiber diets that differ in macronutrient composition affect circulating SCFAs.

OBJECTIVES: We aimed to compare the effects of 3 high-fiber isocaloric diets differing in %kcal of carbohydrate, protein, or unsaturated fat on circulating SCFAs. Based on previous literature, we hypothesized that serum acetate, the main SCFA in circulation, increases on all high-fiber diets, but differently by macronutrient composition of the diet.

METHODS: OmniHeart is a randomized crossover trial of 164 men and women (≥30 y old); 163 participants with SCFA data were included in this analysis. We provided participants 3 isocaloric high-fiber (∼30 g/2100 kcal) diets, each for 6 wk, in random order: a carbohydrate-rich (Carb) diet, a protein-rich (Prot) diet (protein predominantly from plant sources), and an unsaturated fat-rich (Unsat) diet. We used LC-MS to quantify SCFA concentrations in fasting serum, collected at baseline and the end of each diet period. We fitted linear regression models with generalized estimating equations to examine change in ln-transformed SCFAs from baseline to the end of each diet; differences between diets; and associations of changes in SCFAs with cardiometabolic parameters.

RESULTS: From baseline, serum acetate concentrations were increased by the Prot (β: 0.24; 95% CI: 0.12, 0.35), Unsat (β: 0.21; 95% CI: 0.10, 0.33), and Carb (β: 0.12; 95% CI: 0.01, 0.24) diets; between diets, only Prot compared with Carb was significant (P = 0.02). Propionate was decreased by the Carb (β: -0.10; 95% CI: -0.16, -0.03) and Unsat (β: -0.10; 95% CI: -0.16, -0.04) diets, not the Prot diet; between diet comparisons of Carb vs. Prot (P = 0.006) and Unsat vs. Prot (P = 0.002) were significant. The Prot diet increased butyrate (β: 0.05; 95% CI: 0.00, 0.09) compared with baseline, but not compared with the other diets. Increases in acetate were associated with decreases in insulin and glucose; increases in propionate with increases in leptin, LDL cholesterol, and blood pressure; and increases in butyrate with increases in insulin and glucose, and decreases in HDL cholesterol and ghrelin (Ps < 0.05).

CONCLUSIONS: Macronutrient composition of high-fiber diets affects circulating SCFAs, which are associated with measures of appetite and cardiometabolic health. This trial was registered at clinicaltrials.gov as NCT00051350.

OBJECTIVES: To examine the effects of high-fiber, isocaloric, macronutrient substitutions on bloating.

METHODS: The OmniHeart study is a randomized 3-period crossover feeding trial conducted from April 2003 to June 2005. Participants were provided 3 isocaloric versions of high-fiber (∼30 g per 2,100 kcal) diet, each different in carbohydrate, protein, and unsaturated fat composition. Each feeding period lasted for 6 weeks with a 2- to 4-week washout period between diets. Participants reported the presence and severity of bloating at baseline (participants were eating their own diet) and at the end of each feeding period.

RESULTS: One hundred sixty-four participants were included in the analysis (mean age: 53.1 years; 45% women; 55% black). The prevalence of bloating at baseline and at the end of the carbohydrate-rich, protein-rich, and unsaturated fat-rich diet period was 18%, 24%, 33%, and 30%, respectively. Compared with baseline, the relative risk of bloating for the carbohydrate-rich, protein-rich, and unsaturated fat-rich high-fiber diet was 1.34 (95% confidence interval [CI]: 0.93, 1.92), 1.78 (95% CI: 1.32, 2.40), and 1.63 (95% CI: 1.17, 2.26), respectively. The protein-rich diet increased the risk of bloating more than the carbohydrate-rich diet (relative risk = 1.40; 95% CI: 1.03, 1.88). Bloating did not significantly vary between protein-rich vs unsaturated fat-rich or unsaturated fat-rich vs carbohydrate-rich diets. Black participants compared with non-black participants had a higher risk of bloating after all 3 versions of the high-fiber OmniHeart diet (P-value for interaction = 0.012).

DISCUSSION: Substitution of protein with carbohydrate may be an effective strategy to decrease bloating among individuals experiencing gastrointestinal bloating from a high-fiber diet.