Publications by Year: 2024

IMPORTANCE: Fertility status is a marker for future health, and infertility has been associated with risk for later cancer and diabetes, but associations with midlife cardiovascular health (CVH) in female individuals remain understudied.

OBJECTIVE: To evaluate the association of infertility history with CVH at midlife (approximately age 50 years) among parous individuals.

DESIGN, SETTING, AND PARTICIPANTS: Project Viva is a prospective cohort study of pregnant participants enrolled between 1999 and 2002 who delivered a singleton live birth in the greater Boston, Massachusetts, area. Infertility history was collected at a midlife visit between 2017 and 2021, approximately 18 years after enrollment. Data analysis was performed from January to June 2023.

EXPOSURES: The primary exposure was any lifetime history of infertility identified by self-report, medical record, diagnosis, or claims for infertility treatment.

MAIN OUTCOMES AND MEASURES: The American Heart Association's Life's Essential 8 (LE8) is a construct for ranking CVH that includes scores from 0 to 100 (higher scores denote better health status) in 4 behavioral (diet, physical activity, sleep, and smoking status) and 4 biomedical (body mass index, blood pressure, blood lipids, and glycemia) domains to form an overall assessment of CVH. Associations of a history of infertility (yes or no) with mean LE8 total, behavioral, biomedical, and blood biomarker (lipids and glycemia) scores were examined, adjusting for age at outcome (midlife visit), race and ethnicity, education, household income, age at menarche, and perceived body size at age 10 years.

RESULTS: Of 468 included participants (mean [SD] age at the midlife visit, 50.6 [5.3] years) with exposure and outcome data, 160 (34.2%) experienced any infertility. Mean (SD) LE8 scores were 76.3 (12.2) overall, 76.5 (13.4) for the behavioral domain, 76.0 (17.5) for the biomedical domain, and 78.9 (19.2) for the blood biomarkers subdomain. In adjusted models, the estimated overall LE8 score at midlife was 2.94 points lower (95% CI, -5.13 to -0.74 points), the biomedical score was 4.07 points lower (95% CI, -7.33 to -0.78 points), and the blood subdomain score was 5.98 points lower (95% CI, -9.71 to -2.26 points) among those with vs without history of infertility. The point estimate also was lower for the behavioral domain score (β = -1.81; 95% CI, -4.28 to 0.66), although the result was not statistically significant.

CONCLUSIONS AND RELEVANCE: This cohort study of parous individuals found evidence for an association between a history of infertility and lower overall and biomedical CVH scores. Future study of enhanced cardiovascular preventive strategies among those who experience infertility is warranted.

OBJECTIVE: There is a secular trend towards earlier age of menarche in the US and globally. Earlier age at menarche (AAM) has been associated with metabolic disorders that increase risk for preterm delivery (PTD), yet no studies in the US have investigated whether AAM influences risk of PTD. This study tested the hypothesis that AAM is associated with PTD.

DESIGN: A case-control study.

SETTING: The Boston Medical Center (BMC) in Boston, Massachusetts.

POPULATION OR SAMPLE: 8264 mother-newborn dyads enrolled at birth at BMC between 1998 and 2019, of which 2242 mothers had PTD (cases) and 6022 did not have PTD (controls).

METHODS: Multivariable-adjusted logistic regression models and restricted cubic splines were used to examine the association between AAM and risk of PTD. The combined impact of AAM and age at delivery on the risk of PTD was also examined.

MAIN OUTCOME MEASURES: Preterm delivery and gestational age (GA) was defined by maternal last menstrual period and early ultrasound documented in medical records.

RESULTS: Maternal age at delivery was 28.1 ± 6.5 years and AAM was 12.85 ± 1.86 years. Multivariable-adjusted cubic spline suggested an inverse dose-response association of AAM with odds of PTD and, consistently, a positive association with GA. A 1-year earlier AAM was associated with 5% (95% CI 2%-8%) higher odds of PTD, after adjustment for maternal year of birth, parity, maternal place of birth, education, smoking status and Mediterranean-style diet score. The association between AAM and PTD was stronger among older mothers whose age at delivery was ≥35 years.

CONCLUSIONS: Earlier AAM is associated with higher odds for PTD, and this association is stronger among women at advanced reproductive age.

INTRODUCTION: Metabolite signatures for blood pressure (BP) may reveal biomarkers, elucidate pathogenesis, and provide prevention targets for high BP. Knowledge regarding metabolites associated with BP in adolescence remains limited.

OBJECTIVES: Investigate the associations between metabolites and adolescent BP, both cross-sectionally (in early and late adolescence) and prospectively (from early to late adolescence).

METHODS: Participants are from the Project Viva prospective cohort. During the early (median: 12.8 years; N = 556) and late (median: 17.4 years; N = 501) adolescence visits, we conducted untargeted plasma metabolomic profiling and measured systolic (SBP) and diastolic BP (DBP). We used linear regression to identify metabolites cross-sectionally associated with BP at each time point, and to assess prospective associations of changes in metabolite levels from early to late adolescence with late adolescence BP. We used Weighted Gene Correlation Network Analysis and Spearman's partial correlation to identify metabolite clusters associated with BP at each time point.

RESULTS: In the linear models, higher androgenic steroid levels were consistently associated with higher SBP and DBP in early and late adolescence. A cluster of 59 metabolites, mainly composed of androgenic steroids, correlated with higher SBP and DBP in early adolescence. A cluster primarily composed of fatty acid lipids was marginally associated with higher SBP in females in late adolescence. Multiple metabolites, including those in the creatine and purine metabolism sub-pathways, were associated with higher SBP and DBP both cross-sectionally and prospectively.

CONCLUSION: Our results shed light on the potential metabolic processes and pathophysiology underlying high BP in adolescents.

INTRODUCTION: Hair cortisol concentration (HCC) is a biomarker of long-term stress. Higher HCC is associated with higher adiposity in adults; however, associations are not well characterized in adolescents.

OBJECTIVE: To examine cross-sectional associations of HCC with adiposity in late adolescence.

METHODS: Amongst 336 non-Hispanic White participants (48.5% female, mean 17.7 years) in Project Viva, we used multivariable linear regression models, overall and sex-stratified, to estimate associations of HCC with body mass index (BMI), bioelectric impedance (BIA) percent body fat, waist circumference (WC) and dual X-ray absorptiometry-measured percent and total fat or trunk fat mass. We adjusted models for age and known predictors of adiposity.

RESULTS: Median (interquartile range) HCC was 2.1 pm/mg (1.0-4.5) and mean (SD) BMI was 23.1 kg/m2 (3.9), BIA %body fat 20.2% (9.9) and WC 80.6 cm (10.9). In adjusted models, higher HCC (per doubling) was associated with higher BMI (β = 0.19 kg/m2; 95%CI 0.00, 0.37) and BIA percent body fat (β = 0.41%; 95%CI 0.04, 0.77). We observed no evidence of effect modification by sex.

CONCLUSIONS: Higher HCC was associated with greater adiposity in late adolescence. Further research is needed to disentangle the relationship between HCC and adolescent adiposity, including the temporal direction of the relationship and sex-specific associations.

BACKGROUND: Hypertensive disorders of pregnancy (HDP) such as preeclampsia and gestational hypertension are major contributors to maternal and child morbidity and mortality. Previous studies have reported associations with selected metals and vitamins but are limited in sample size and non-prospective study designs. We evaluated prospective associations of metal mixtures with HDP and tested interactions by vitamins.

STUDY DESIGN: We measured first trimester (median = 10.1 weeks) concentrations of essential (copper, magnesium, manganese, selenium, zinc) and nonessential (arsenic, barium, cadmium, cesium, mercury, lead) metals in red blood cells (n = 1,386) and vitamins (B12 and folate) in plasma (n = 924) in Project Viva, a pre-birth US cohort. We collected diagnosis of HDP by reviewing medical records. We used multinomial logistic regression and Bayesian Kernel Machine Regression to estimate individual and joint associations of metals with HDP and interactions by vitamins, after adjusting for key covariates.

RESULTS: The majority of participants were non-Hispanic white (72.5 %), never smokers (68.5 %) with a mean (SD) age of 32.3 (4.6) years. Fifty-two (3.8 %) developed preeclampsia and 94 (6.8 %) gestational hypertension. A doubling in first trimester erythrocyte copper was associated with 78 % lower odds of preeclampsia (OR=0.22, 95 % confidence interval: 0.08, 0.60). We also observed significant associations between higher erythrocyte total arsenic and lower odds of preeclampsia (OR=0.80, 95 % CI: 0.66, 0.97) and higher vitamin B12 and increased odds of gestational hypertension (OR=1.79, 95 % CI: 1.09, 2.96), but associations were attenuated after adjustment for dietary factors. Lower levels of the overall metal mixture and essential metal mixture were associated with higher odds of preeclampsia. We found no evidence of interactions by prenatal vitamins or between metals.

CONCLUSION: Lower levels of a first-trimester essential metal mixture were associated with an increased risk of preeclampsia, primarily driven by copper. No associations were observed between other metals and HDP after adjustment for confounders and diet.

BACKGROUND: Prenatal per- and polyfluoroalkyl substance (PFAS) exposures are associated with adverse offspring health outcomes, yet the underlying pathological mechanisms are unclear. Cord blood metabolomics can identify potentially important pathways associated with prenatal PFAS exposures, providing mechanistic insights that may help explain PFAS' long-term health effects.

METHODS: The study included 590 mother-infant dyads from the Boston Birth Cohort. We measured PFAS in maternal plasma samples collected 24-72 h after delivery and metabolites in cord plasma samples. We used metabolome-wide association studies and pathway enrichment analyses to identify metabolites and pathways associated with individual PFAS, and quantile-based g-computation models to examine associations of metabolites with the PFAS mixture. We used False Discovery Rate to account for multiple comparisons.

RESULTS: We found that 331 metabolites and 18 pathways were associated with ≥ 1 PFAS, and 38 metabolites were associated with the PFAS mixture, predominantly amino acids and lipids. Amino acids such as alanine and lysine and their pathways, crucial to energy generation, biosynthesis, and bone health, were associated with PFAS and may explain PFAS' effects on fetal growth restriction. Carnitines and carnitine shuttle pathway, associated with 7 PFAS and the PFAS mixture, are involved in mitochondrial fatty acid β-oxidation, which may predispose higher risks of fetal and child growth restriction and cardiovascular diseases. Lipids, such as glycerophospholipids and their related pathway, can contribute to insulin resistance and diabetes by modulating transporters on cell membranes, participating in β-cell signaling pathways, and inducing oxidative damage. Neurotransmission-related metabolites and pathways associated with PFAS, including cofactors, precursors, and neurotransmitters, may explain the PFAS' effects on child neurodevelopment. We observed stronger associations between prenatal PFAS exposures and metabolites in males.

CONCLUSIONS: This prospective birth cohort study contributes to the limited literature on potential metabolomic perturbations for prenatal PFAS exposures. Future studies are needed to replicate our findings and link prenatal PFAS associated metabolomic perturbations to long-term child health outcomes.

IMPORTANCE: Limited access to healthy foods, resulting from residence in neighborhoods with low food access, is a public health concern. The contribution of this exposure in early life to child obesity remains uncertain.

OBJECTIVE: To examine associations of neighborhood food access during pregnancy or early childhood with child body mass index (BMI) and obesity risk.

DESIGN, SETTING, AND PARTICIPANTS: Data from cohorts participating in the US nationwide Environmental Influences on Child Health Outcomes consortium between January 1, 1994, and March 31, 2023, were used. Participant inclusion required a geocoded residential address in pregnancy (mean 32.4 gestational weeks) or early childhood (mean 4.3 years) and information on child BMI.

EXPOSURES: Residence in low-income, low-food access neighborhoods, defined as low-income neighborhoods where the nearest supermarket is more than 0.5 miles for urban areas or more than 10 miles for rural areas.

MAIN OUTCOMES AND MEASURES: BMI z score, obesity (age- and sex-specific BMI ≥95th percentile), and severe obesity (age- and sex-specific BMI ≥120% of the 95th percentile) from age 0 to 15 years.

RESULTS: Of 28 359 children (55 cohorts; 14 657 [51.7%] male and 13 702 [48.3%] female; 590 [2.2%] American Indian, Alaska Native, Native Hawaiian, or Other Pacific Islander; 1430 [5.4%] Asian; 4034 [15.3%] Black; 17 730 [67.2%] White; and 2592 [9.8%] other [unspecified] or more than 1 race; 5754 [20.9%] Hispanic and 21 838 [79.1%] non-Hispanic) with neighborhood food access data, 23.2% resided in low-income, low-food access neighborhoods in pregnancy and 24.4% in early childhood. After adjusting for individual sociodemographic characteristics, residence in low-income, low-food access (vs non-low-income, low-food access) neighborhoods in pregnancy was associated with higher BMI z scores at ages 5 years (β, 0.07; 95% CI, 0.03-0.11), 10 years (β, 0.11; 95% CI, 0.06-0.17), and 15 years (β, 0.16; 95% CI, 0.07-0.24); higher obesity risk at 5 years (risk ratio [RR], 1.37; 95% CI, 1.21-1.55), 10 years (RR, 1.71; 95% CI, 1.37-2.12), and 15 years (RR, 2.08; 95% CI, 1.53-2.83); and higher severe obesity risk at 5 years (RR, 1.21; 95% CI, 0.95-1.53), 10 years (RR, 1.54; 95% CI, 1.20-1.99), and 15 years (RR, 1.92; 95% CI, 1.32-2.80). Findings were similar for residence in low-income, low-food access neighborhoods in early childhood. These associations were robust to alternative definitions of low income and low food access and additional adjustment for prenatal characteristics associated with child obesity.

CONCLUSIONS: Residence in low-income, low-food access neighborhoods in early life was associated with higher subsequent child BMI and higher risk of obesity and severe obesity. We encourage future studies to examine whether investments in neighborhood resources to improve food access in early life would prevent child obesity.

BACKGROUND: PFAS may impair bone health, but effects of PFAS exposure assessed during pregnancy and the perimenopause-life stages marked by rapidly changing bone metabolism-on later life bone health are unknown.

METHODS: We studied 531 women in the Boston-area Project Viva cohort. We used multivariable linear, generalized additive, and mixture models to examine associations of plasma PFAS concentrations during early pregnancy [median (IQR) maternal age 32.9 (6.2) years] and midlife [age 51.2 (6.3)] with lumbar spine, total hip, and femoral neck areal bone mineral density (aBMD) and bone turnover biomarkersassessed in midlife. We examined effect modification by diet and physical activity measured at the time of PFAS exposure assessment and by menopausal status in midlife.

RESULTS: Participants had higher PFAS concentrations during pregnancy [1999-2000; e.g., PFOA median (IQR) 5.4 (3.8) ng/mL] than in midlife [2017-2021; e.g.

, PFOA: 1.5 (1.2) ng/mL]. Women with higher PFOA, PFOS and PFNA during pregnancy had higher midlife aBMD, especially of the spine [e.g., 0.28 (95% CI: 0.07, 0.48) higher spine aBMD T-score, per doubling of PFOA], with stronger associations observed among those with higher diet quality. In contrast, higher concentrations of all PFAS measured in midlife were associated with lower concurrent aBMD at all sites [e.g., -0.21 (-0.35, -0.07) lower spine aBMD T-score, per doubling of PFOA]; associations were stronger among those who were postmenopausal. The associations of several PFAS with bone resorption (loss) were also stronger among postmenopausal versus premenopausal women.

DISCUSSION: Plasma PFAS measured during pregnancy versus in midlife had different associations with midlife aBMD. We found an adverse association of PFAS measured in midlife with midlife aBMD, particularly among postmenopausal women. Future studies with longer follow-up are needed to elucidate the effect of PFAS on bone health during the peri- and postmenopausal years.