Publications by authors named "Sheryl L Rifas-Shiman"

360 Publications

Associations of hypertensive disorders of pregnancy and gestational diabetes mellitus with menopausal symptoms at midlife in Project Viva.

Menopause 2022 Aug 2. Epub 2022 Aug 2.

Department of Obstetrics and Gynecology, Midlife Women's Health Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Objective: The aim of this study was to evaluate the associations of a lifetime history of hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) with menopausal symptoms in midlife.

Methods: This was a secondary analysis of women participating in Project Viva, an ongoing cohort enrolled during pregnancy. The exposure was lifetime history of HDP or GDM assessed for the index pregnancy by review of outpatient and hospital medical records and for all other pregnancies by interview or questionnaire at study entry (1999-2002) and the midlife visit (2017-2021). The primary outcome was the Menopause Rating Scale (MRS) applied at the midlife study visit. We used linear or logistic regression models adjusted for covariates such as baseline age, race/ethnicity, education, married/cohabiting, household income, baseline parity, age at menarche, and body mass index at midlife.

Results: Of the 676 included participants, 120 (18%) had a history of HDP, and 47 (7%) had a history of GDM. The mean (SD) age was 52 (3.9) years at the midlife visit, and 48% of the participants had experienced menopause. There were no consistent differences in total, domain-specific, or individual symptoms in women with a history of HDP or GDM. A history of HDP and/or GDM was not associated with age at the onset of natural menopause.

Conclusions: Our findings do not support an association of a history of HDP or GDM with the severity of menopausal symptoms or age at the onset of natural menopause. Larger studies of women with a history of these pregnancy complications are needed to clarify their association with menopausal symptoms.
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http://dx.doi.org/10.1097/GME.0000000000002014DOI Listing
August 2022

Association of total lifetime breastfeeding duration with midlife handgrip strength: findings from Project Viva.

BMC Womens Health 2022 07 23;22(1):306. Epub 2022 Jul 23.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Drive, Suite 401, Boston, MA, 02215, USA.

Background: Lactation has long term effects on maternal health, but the relationship between lactation and long-term handgrip strength, a marker of musculoskeletal function and healthy aging, has not been explored.

Objective: Examine the relationship between total lifetime breastfeeding duration (BFD) and midlife handgrip strength.

Methods: We measured handgrip strength as a marker of overall strength among 631 women in the Project Viva cohort. At the same visit, women reported their BFD for each birth, and we derived total lifetime BFD. We used multivariable linear regression models to estimate associations of lifetime BFD in months with midlife handgrip strength in kilograms, adjusted for race/ethnicity, education, marital status, household income, age at first pregnancy and age at handgrip strength assessment.

Results: Mean (standard deviation) age was 50.7 (5.1) years, lifetime BFD was 21.6 (19.5) months, and handgrip strength was 28.0 kg (6.0) in the dominant and 26.0 kg (5.6) in the non-dominant hand. In fully adjusted models, each 3-month increment in lifetime BFD was associated with 0.10 kg (95% CI 0.02, 0.18) higher handgrip strength for the dominant hand and 0.10 kg (95% CI 0.03, 0.18) for the nondominant hand. Results were similar in models examining mean BFD per pregnancy rather than total BFD. There was no evidence of effect modification by race/ethnicity.

Conclusions: Our study suggests that there is a small beneficial effect of lifetime BFD on handgrip strength. Future studies can explore mechanisms by which BFD affects body composition and associations with other outcomes related to lean mass such as sarcopenia.
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http://dx.doi.org/10.1186/s12905-022-01880-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308919PMC
July 2022

Associations of maternal glucose markers in pregnancy with cord blood glucocorticoids and child hair cortisol levels.

J Dev Orig Health Dis 2022 Jul 8:1-8. Epub 2022 Jul 8.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Exposure to maternal hyperglycemia has been associated with adverse metabolic outcomes in offspring. However, few studies have investigated the relationship between maternal hyperglycemia and offspring cortisol levels. We assessed associations of gestational diabetes mellitus (GDM) with cortisol biomarkers in two longitudinal prebirth cohorts: Project Viva included 928 mother-child pairs and Gen3G included 313 mother-child pairs. In Project Viva, GDM was diagnosed in N = 48 (5.2%) women using a two-step procedure (50 g glucose challenge test, if abnormal followed by 100 g oral glucose tolerance test [OGTT]), and in N = 29 (9.3%) women participating in Gen3G using one-step 75 g OGTT. In Project Viva, we measured cord blood glucocorticoids and child hair cortisol levels during mid-childhood (mean (SD) age: 7.8 (0.8) years) and early adolescence (mean (SD) age: 13.2 (0.9) years). In Gen3G, we measured hair cortisol at 5.4 (0.3) years. We used multivariable linear regression to examine associations of GDM with offspring cortisol, adjusting for child age and sex, maternal prepregnancy body mass index, education, and socioeconomic status. We additionally adjusted for child race/ethnicity in the cord blood analyses. In both Project Viva and Gen3G, we observed null associations of GDM and maternal glucose markers in pregnancy with cortisol biomarkers in cord blood at birth (β = 16.6 nmol/L, 95% CI -60.7, 94.0 in Project Viva) and in hair samples during childhood (β = -0.56 pg/mg, 95% CI -1.16, 0.04 in Project Viva; β = 0.09 pg/mg, 95% CI -0.38, 0.57 in Gen3G). Our findings do not support the hypothesis that maternal hyperglycemia is related to hypothalamic-pituitary-adrenal axis activity.
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http://dx.doi.org/10.1017/S2040174422000381DOI Listing
July 2022

History of infertility and pregnancy outcomes in Project Viva: a prospective study.

BMC Pregnancy Childbirth 2022 Jul 7;22(1):549. Epub 2022 Jul 7.

Present affiliation: Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Ave, Boston, MA, 02115, USA.

Background: Infertility has been associated with the risk of adverse pregnancy outcomes. It is not clear whether infertility and underlying causes of infertility or the use of medically assisted reproduction (MAR) therapies are responsible for the observed associations. In this study, we aimed to evaluate the association of history of infertility with pregnancy outcomes and identify whether the associations, if present, differed by subgroups defined by the use of MAR.

Methods: Prospective study of 2201 pregnant women from the Boston-area Project Viva cohort. The exposure was history of infertility based on self-reported time to pregnancy ≥12 mo (or ≥ 6 mo if ≥35 y) or use of MAR; a diagnosis of infertility or claims for infertility treatments from medical records. The outcomes included: gestational glucose tolerance (gestational diabetes, impaired glucose tolerance, isolated hyperglycemia vs. normoglycemia), hypertensive disorders (gestational hypertension/preeclampsia vs. normotension), gestational weight gain (inadequate/excessive vs. adequate), systolic (SBP) and diastolic blood pressure, birthweight-for-gestational age z-score (tertile 2 and 3 vs. 1), preterm birth (<37 vs. ≥37 weeks at delivery), and birth outcome (pregnancy loss vs. live birth). We performed linear and logistic/multinomial regression analyses adjusted for age, race/ethnicity, age at menarche, pre-pregnancy BMI, and prenatal smoking.

Results: Mean (SD) age was 32.0 (5.0) years, and 18.8% of women had history of infertility, 32.6% of whom used MAR. SBP across pregnancy was 0.72 mmHg higher in women with vs. without infertility (95% CI 0.02, 1.42). The associations were stronger among women who used MAR (β 1.32 mmHg, 95% CI 0.21, 2.44), especially among those who used gonadotropins or gonadotropin-releasing hormone [GnRH] agonists (β 1.91 mmHg, 95% CI 0.48, 3.35). Other outcomes were not associated with history of infertility.

Conclusions: A history of infertility was associated with higher SBP during pregnancy, with stronger associations among those who used gonadotropins or GnRH agonists. Future studies are needed to confirm these findings and determine their clinical implications.
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http://dx.doi.org/10.1186/s12884-022-04885-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261051PMC
July 2022

Longitudinal associations of DNA methylation and sleep in children: a meta-analysis.

Clin Epigenetics 2022 07 5;14(1):83. Epub 2022 Jul 5.

Department of Environmental Immunology, Helmholtz Centre for Environmental Research - UFZ, Leipzig, Germany.

Background: Sleep is important for healthy functioning in children. Numerous genetic and environmental factors, from conception onwards, may influence this phenotype. Epigenetic mechanisms such as DNA methylation have been proposed to underlie variation in sleep or may be an early-life marker of sleep disturbances. We examined if DNA methylation at birth or in school age is associated with parent-reported and actigraphy-estimated sleep outcomes in children.

Methods: We meta-analysed epigenome-wide association study results. DNA methylation was measured from cord blood at birth in 11 cohorts and from peripheral blood in children (4-13 years) in 8 cohorts. Outcomes included parent-reported sleep duration, sleep initiation and fragmentation problems, and actigraphy-estimated sleep duration, sleep onset latency and wake-after-sleep-onset duration.

Results: We found no associations between DNA methylation at birth and parent-reported sleep duration (n = 3658), initiation problems (n = 2504), or fragmentation (n = 1681) (p values above cut-off 4.0 × 10). Lower methylation at cg24815001 and cg02753354 at birth was associated with longer actigraphy-estimated sleep duration (p = 3.31 × 10, n = 577) and sleep onset latency (p = 8.8 × 10, n = 580), respectively. DNA methylation in childhood was not cross-sectionally associated with any sleep outcomes (n = 716-2539).

Conclusion: DNA methylation, at birth or in childhood, was not associated with parent-reported sleep. Associations observed with objectively measured sleep outcomes could be studied further if additional data sets become available.
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http://dx.doi.org/10.1186/s13148-022-01298-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258202PMC
July 2022

Timing of Cow's Milk Protein Introduction and Childhood Adverse Reactions to Cow's Milk.

J Allergy Clin Immunol Pract 2022 Jun 30. Epub 2022 Jun 30.

Division of Gastroenterology/Nutrition, Department of Pediatrics, University of Massachusetts Medical School, Worcester, Mass; Pediatric Gastroenterology, UMass Memorial Medical Center, Worcester, Mass.

Background: Current guidelines emphasize early introduction to potentially allergenic foods, but the optimal timing, amount, and exposure routes for foods other than peanut are not well-established. Cow's milk is often the first allergenic food introduced through infant formulas.

Objective: To examine timing of cow's milk protein introduction (CMPI), including interaction with formula supplementation after delivery, in relation to reported cow's milk adverse reactions throughout childhood.

Methods: Among children in the Boston, Mass-area Project Viva cohort, we assessed timing of CMPI (<2 weeks, 2 weeks-<6 months, ≥6 months) with questionnaires administered in infancy. Outcomes were (1) parent-reported cow's milk adverse reactions via annual questionnaires from age 2 to 13 years (n = 1298) and (2) milk sensitization (n = 505) and IgE-mediated milk allergy (n = 491) at age approximately 8 years. We used multivariable logistic regression models adjusted for parental atopy history, delivery mode, gestational age at delivery, child race, and census tract median household income, and investigated effect modification by ever/never breast-fed status and formula supplementation in the delivery hospital.

Results: A total of 32% were introduced to cow's milk protein at age less than 2 weeks, 38% at age 2 weeks to less than 6 months, and 30% at age 6 months or more. Compared with children with CMPI at age less than 2 weeks, children with CMPI at age 6 months or more had a higher risk of cow's milk adverse reaction at age 2 to 5 years (odds ratio, 2.4 [1.2-4.7]). Children given formula after delivery + CMPI at age less than 2 weeks had the lowest risk overall. Among children not given formula after delivery, CMPI at age 2 weeks to 6 months appeared most protective. Results were similar among ever-breast-fed children. Timing of CMPI was not associated with milk sensitization or IgE-mediated milk allergy in mid-childhood.

Conclusions: Early, consistent cow's milk exposure appears protective against adverse reactions to cow's milk.
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http://dx.doi.org/10.1016/j.jaip.2022.06.022DOI Listing
June 2022

History of infertility and long-term weight, body composition, and blood pressure among women in Project Viva.

Ann Epidemiol 2022 Jun 28;74:43-50. Epub 2022 Jun 28.

Department of Nutrition and Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Purpose: To evaluate the association of a history of infertility with long-term weight, body composition, and blood pressure.

Methods: We studied 1581 women from the prospective cohort Project Viva. History of infertility was based on self-reported time to pregnancy ≥12 months or use of medical treatment to conceive for the index or any prior pregnancy; a diagnosis of infertility; claims for infertility treatments/prescriptions abstracted from medical records. The outcomes were weight, waist circumference, and body fat assessed through 12 years postpartum; and blood pressure assessed through 3 years postpartum. We used linear mixed-effect models adjusted for age, race/ethnicity, income, education, marital status, parity, and age at menarche.

Results: Three hundred forty-two women (21.6%) had a history of infertility. In adjusted models, women with versus without infertility, had higher average weight (3.29 kg, 95% confidence interval [CI]: 1.35-5.24), waist circumference (2.46 cm, 95% CI: 0.78-4.13) and body fat (1.76 kg, 95% CI: 0.09-3.43). Among younger (18-29 years), but not older (≥30 years) women, infertility was associated with higher systolic (4.08 mmHg, 95% CI: 0.93, 7.23) and diastolic blood pressure (2.16 mmHg, 95% CI: 0.11-4.20).

Conclusions: A history of infertility may serve as a marker to identify women at higher cardiometabolic risk.
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http://dx.doi.org/10.1016/j.annepidem.2022.06.033DOI Listing
June 2022

Street-view greenspace exposure and objective sleep characteristics among children.

Environ Res 2022 Jun 25;214(Pt 1):113744. Epub 2022 Jun 25.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Greenspace may benefit sleep by enhancing physical activity, reducing stress or air pollution exposure. Studies on greenspace and children's sleep are limited, and most use satellite-derived measures that do not capture ground-level exposures that may be important for sleep. We examined associations of street view imagery (SVI)-based greenspace with sleep in Project Viva, a Massachusetts pre-birth cohort. We used deep learning algorithms to derive novel metrics of greenspace (e.g., %trees, %grass) from SVI within 250m of participant residential addresses during 2007-2010 (mid-childhood, mean age 7.9 years) and 2012-2016 (early adolescence, 13.2y) (N = 533). In early adolescence, participants completed >5 days of wrist actigraphy. Sleep duration, efficiency, and time awake after sleep onset (WASO) were derived from actigraph data. We used linear regression to examine cross-sectional and prospective associations of mid-childhood and early adolescence greenspace exposure with early adolescence sleep, adjusting for confounders. We compared associations with satellite-based greenspace (Normalized Difference Vegetation Index, NDVI). In unadjusted models, mid-childhood SVI-based total greenspace and %trees (per interquartile range) were associated with longer sleep duration at early adolescence (9.4 min/day; 95%CI:3.2,15.7; 8.1; 95%CI:1.7,14.6 respectively). However, in fully adjusted models, only the association between %grass at mid-childhood and WASO was observed (4.1; 95%CI:0.2,7.9). No associations were observed between greenspace and sleep efficiency, nor in cross-sectional early adolescence models. The association between greenspace and sleep differed by racial and socioeconomic subgroups. For example, among Black participants, higher NDVI was associated with better sleep, in neighborhoods with low socio-economic status (SES), higher %grass was associated with worse sleep, and in neighborhoods with high SES, higher total greenspace and %grass were associated with better sleep time. SVI metrics may have the potential to identify specific features of greenspace that affect sleep.
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http://dx.doi.org/10.1016/j.envres.2022.113744DOI Listing
June 2022

Early-pregnancy plasma per- and polyfluoroalkyl substance (PFAS) concentrations and hypertensive disorders of pregnancy in the Project Viva cohort.

Environ Int 2022 07 6;165:107335. Epub 2022 Jun 6.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States. Electronic address:

Background: Hypertensive disorders of pregnancy (HDP), defined here as hypertensive disorders with onset in pregnancy (i.e., gestational hypertension, preeclampsia, and preeclampsia superimposed on chronic hypertension), affect up to 10% of pregnancies in the United States and are associated with substantial maternal and neonatal morbidity and mortality. Per- and polyfluoroalkyl substances (PFAS) are associated with adverse cardiometabolic outcomes during pregnancy, but associations between PFAS and HDP are inconsistent and joint effects of PFAS mixtures have not been evaluated.

Methods: We studied 1,558 pregnant individuals from the Project Viva cohort, recruited during 1999-2002. We quantified concentrations of eight PFAS in plasma samples (median 9.7 weeks of gestation). Using clinical records, we calculated trimester-specific mean systolic (SBP) and diastolic (DBP) blood pressure and categorized HDP status [no HDP (normotensive & chronic hypertension), gestational hypertension, preeclampsia]. We estimated associations of individual PFAS with HDP using multinomial logistic regression and estimated associations with blood pressure using linear regression. We used Bayesian kernel machine regression (BKMR) and quantile g-computation to assess joint effects of the PFAS mixture on HDP and blood pressure measures.

Results: Four percent of participants developed preeclampsia and 7% developed gestational hypertension. We observed higher odds of gestational hypertension, but not preeclampsia, per doubling of perfluorooctanoate (PFOA) [OR = 1.51 (95% confidence interval: 1.12, 2.03)], perfluorooctane sulfonate (PFOS) [OR = 1.38 (1.04, 1.82)], and perfluorohexane sulfonate [OR = 1.28 (1.06, 1.54)] concentrations. We observed higher mean DBP per doubling of PFOA [2nd trimester (T2): 0.39 mmHg (-0.01, 0.78); 3rd trimester (T3): 0.56 mmHg (0.14, 0.98)] and PFOS [T2: 0.46 mmHg (0.11, 0.82); T3: 0.43 mmHg (0.05, 0.80)]. The PFAS mixture was positively associated with odds of gestational hypertension [75th vs. 50th percentile: OR = 1.14 (95% credible interval:1.03, 1.25), BKMR] and mean DBP [T2 = 0.17 mmHg (-0.06, 0.40); T3 = 0.22 mmHg (-0.03, 0.48), BKMR].

Conclusions: These findings suggest that exposure to certain PFAS may increase the odds of gestational hypertension during pregnancy, with potential implications for subsequent maternal and child health outcomes.
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http://dx.doi.org/10.1016/j.envint.2022.107335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348856PMC
July 2022

Self-Reported Total Screen Time and Viewing Modes Are Associated with Body Dissatisfaction, Disordered Eating, and Cosmetic Surgery Intentions among Young Adults.

Nutrients 2022 May 12;14(10). Epub 2022 May 12.

Department of Family Relations and Applied Nutrition, University of Guelph, Guelph, ON N1G 2W1, Canada.

While numerous studies have shown that media exposure is linked to body dissatisfaction and disordered eating behavior, limited research has examined these associations by screen-viewing mode. This study examined associations of total screen-time and screen-viewing modes with body dissatisfaction, disordered eating, and cosmetic surgery intention among young adults. Men ( = 3466) and women ( = 7300), aged 19 to 34 years, self-reported their screen-time on various TV viewing modes, and their body dissatisfaction, overeating, disordered weight control behaviors, and cosmetic surgery intentions. We fit linear, logistic, and multivariate models to examine cross-sectional associations between total screen-time and screen-viewing modes and body dissatisfaction, disordered eating, and cosmetic surgery intention. Handheld viewing was associated with body dissatisfaction for women only, and online viewing was associated with greater body dissatisfaction among both men (βˆ = 0.40; 95% CI, 0.15 to 0.65) and women (βˆ = 0.25; 95% CI, 0.10 to 0.40). Downloaded viewing was associated with higher odds of overeating behaviors among both men (OR = 1.24; 95% CI, 1.10 to 1.40) and women (OR = 1.21; 95% CI, 1.12 to 1.32), respectively. Although total screen time was associated with greater cosmetic surgery intention for both men (βˆ = 0.24; 95% CI, 0.09 to 0.39) and women (βˆ = 0.43; 95% CI, 0.28 to 0.58), sex differences were found for the viewing modes. Our results suggest that different viewing modes may be differently associated with men and women's body image, disordered eating behavior, and cosmetic surgery intention. Future research should consider all modes of screen-viewing in our media environment.
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http://dx.doi.org/10.3390/nu14102027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145134PMC
May 2022

Lifetime Exposure to Traffic-Related Pollution and Lung Function in Early Adolescence.

Ann Am Thorac Soc 2022 May 17. Epub 2022 May 17.

Beth Israel Deaconess Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, Boston, Massachusetts, United States.

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http://dx.doi.org/10.1513/AnnalsATS.202112-1352RLDOI Listing
May 2022

Association of cow's milk intake in early childhood with adiposity and cardiometabolic risk in early adolescence.

Am J Clin Nutr 2022 Aug;116(2):561-571

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Prior studies have provided conflicting evidence regarding associations of pediatric milk consumption with subsequent adiposity.

Objectives: We aimed to estimate associations of the consumption frequency and fat content of early childhood milk intake with early adolescent adiposity and cardiometabolic risk.

Methods: We analyzed data collected prospectively from 796 children in Project Viva, a Boston-area prebirth cohort. Parents reported the frequency (times/day) and fat content [higher-fat: whole (3.25%) or 2% milk; lower-fat: 1% or skim milk] of cow's milk consumed in early childhood (mean, 3.2 years) via food-frequency questionnaires. We measured adiposity and cardiometabolic markers in early adolescence (mean, 13.2 years) and conducted multivariable regressions to assess associations adjusted for baseline parental and child sociodemographic, anthropometric, and dietary factors.

Results: In early childhood, mean milk intake was 2.3 times/day (SD, 1.2 times/day), and 63% of children drank primarily higher-fat milk. The early childhood BMI z-score (BMIz) was inversely associated with the fat content of milk consumed in early childhood. After adjustment for baseline parent and child factors, early childhood intake of higher-fat compared with lower-fat milk was associated with lower adiposity; however, the 95% CIs for most adiposity outcomes-except for the odds of overweight or obesity (OR, 0.60; 95% CI, 0.38-0.93)-crossed the null after adjustment for the baseline child BMIz and BMIz change between ages 2 and 3 years. Early childhood consumption of higher-fat milk (compared with lower-fat milk) was not associated with adverse cardiometabolic outcomes. The frequency of cow's milk consumption in early childhood was not associated with adiposity or cardiometabolic risk in early adolescence.

Conclusions: Consumption of higher-fat cow's milk in early childhood was not associated with increased adiposity or adverse cardiometabolic health over a decade later. Our findings do not support current recommendations to consume lower-fat milk to reduce the risk of later obesity and adverse cardiometabolic outcomes. This trial was registered at clinicaltrials.gov as NCT02820402.
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http://dx.doi.org/10.1093/ajcn/nqac103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9348987PMC
August 2022

Household income, fetal size and birth weight: an analysis of eight populations.

J Epidemiol Community Health 2022 07 12;76(7):629-636. Epub 2022 Apr 12.

CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Background: The age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth.

Methods: Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis.

Results: The eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model.

Conclusions: The association between HI, an index of poverty, and fetal size is already present in the second trimester.
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http://dx.doi.org/10.1136/jech-2021-218112DOI Listing
July 2022

Maternal Mediterranean diet in pregnancy and newborn DNA methylation: a meta-analysis in the PACE Consortium.

Epigenetics 2022 Mar 2:1-13. Epub 2022 Mar 2.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Higher adherence to the Mediterranean diet during pregnancy is related to a lower risk of preterm birth and to better offspring cardiometabolic health. DNA methylation may be an underlying biological mechanism. We evaluated whether maternal adherence to the Mediterranean diet was associated with offspring cord blood DNA methylation.We meta-analysed epigenome-wide association studies (EWAS) of maternal adherence to the Mediterranean diet during pregnancy and offspring cord blood DNA methylation in 2802 mother-child pairs from five cohorts. We calculated the relative Mediterranean diet (rMED) score with range 0-18 and an adjusted rMED excluding alcohol (rMEDp, range 0-16). DNA methylation was measured using Illumina 450K arrays. We used robust linear regression modelling adjusted for child sex, maternal education, age, smoking, body mass index, energy intake, batch, and cell types. We performed several functional analyses and examined the persistence of differential DNA methylation into childhood (4.5-7.8 y).rMEDp was associated with cord blood DNA methylation at cg23757341 (0.064% increase in DNA methylation per 1-point increase in the rMEDp score, SE = 0.011, = 2.41 × 10). This cytosine-phosphate-guanine (CpG) site maps to , associated with adipogenesis and glycaemic phenotypes. We did not identify associations with childhood gene expression, nor did we find enriched biological pathways. The association did not persist into childhood.In this meta-analysis, maternal adherence to the Mediterranean diet (excluding alcohol) during pregnancy was associated with cord blood DNA methylation level at cg23757341. Potential mediation of DNA methylation in associations with offspring health requires further study.
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http://dx.doi.org/10.1080/15592294.2022.2038412DOI Listing
March 2022

Menstrual cycle length and adverse pregnancy outcomes among women in Project Viva.

Paediatr Perinat Epidemiol 2022 05 16;36(3):347-355. Epub 2022 Feb 16.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Background: Retrospective studies suggest that menstrual cycle length may be a risk marker of adverse pregnancy outcomes, but this evidence is susceptible to recall bias.

Objective: To evaluate the prospective association between menstrual cycle length and the risk of adverse pregnancy outcomes.

Methods: Secondary analysis of 2046 women enrolled in Project Viva at ~10 weeks of gestation and followed through delivery. The exposure was menstrual cycle length. The outcomes included gestational glucose tolerance (gestational diabetes/impaired glucose tolerance [GDM/IGT] and isolated hyperglycaemia), hypertensive disorders of pregnancy (gestational hypertension/preeclampsia), gestational weight gain, birthweight-for-gestational age z-scores (BWZ) categorised in tertiles, preterm birth and birth outcome (live birth and pregnancy loss). We used modified Poisson and multinomial logistic regression adjusted for age, race/ethnicity, parity, age at menarche and pre-pregnancy body mass index.

Results: Mean (SD) age at enrolment was 32.1 (4.9) years. Most women (74.3%) had a cycle length of 26-34 days (reference group), 16.2% reported short cycles (≤25 days), and 9.5% reported long/irregular cycles (≥35 days/too irregular to estimate). Compared with the reference group, women with short cycles had lower odds of GDM/IGT (odds ratio [OR] 0.50, 95% confidence interval [CI] 0.28, 0.89), whereas women with long/irregular cycles had higher odds (OR 1.72, 95% CI 1.04, 2.83). Additionally, women with short cycles had higher odds of having a newborn in the lowest tertile of BWZ (OR 1.45, 95% CI 1.06, 1.98). There was a U-shaped relation between cycle length and preterm birth with both short (relative risk [RR] 1.49, 95% CI 0.98, 2.27) and long/irregular (RR 2.04, 95% CI 1.30, 3.20) cycles, associated with a higher risk.

Conclusions: Variation in menstrual cycle length may be a risk marker of GDM/IGT, lower birth size and preterm birth and flag women who may benefit from targeted monitoring and care before and during pregnancy.
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http://dx.doi.org/10.1111/ppe.12866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050743PMC
May 2022

Meta-analysis of epigenome-wide associations between DNA methylation at birth and childhood cognitive skills.

Mol Psychiatry 2022 04 10;27(4):2126-2135. Epub 2022 Feb 10.

Medical Research Council Integrative Epidemiology Unit (MRC IEU), Bristol Medical School, Population Health Science, University of Bristol, Bristol, UK.

Cognitive skills are a strong predictor of a wide range of later life outcomes. Genetic and epigenetic associations across the genome explain some of the variation in general cognitive abilities in the general population and it is plausible that epigenetic associations might arise from prenatal environmental exposures and/or genetic variation early in life. We investigated the association between cord blood DNA methylation at birth and cognitive skills assessed in children from eight pregnancy cohorts within the Pregnancy And Childhood Epigenetics (PACE) Consortium across overall (total N = 2196), verbal (total N = 2206) and non-verbal cognitive scores (total N = 3300). The associations at single CpG sites were weak for all of the cognitive domains investigated. One region near DUSP22 on chromosome 6 was associated with non-verbal cognition in a model adjusted for maternal IQ. We conclude that there is little evidence to support the idea that variation in cord blood DNA methylation at single CpG sites is associated with cognitive skills and further studies are needed to confirm the association at DUSP22.
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http://dx.doi.org/10.1038/s41380-022-01441-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126809PMC
April 2022

Prenatal metal exposure, cord blood DNA methylation and persistence in childhood: an epigenome-wide association study of 12 metals.

Clin Epigenetics 2021 11 19;13(1):208. Epub 2021 Nov 19.

Division of Environmental Health Sciences, School of Public Health, University of California Berkeley, 2121 Berkeley Way, Room 5302, Berkeley, CA, 94720, USA.

Background: Prenatal exposure to essential and non-essential metals impacts birth and child health, including fetal growth and neurodevelopment. DNA methylation (DNAm) may be involved in pathways linking prenatal metal exposure and health. In the Project Viva cohort, we analyzed the extent to which metals (As, Ba, Cd, Cr, Cs, Cu, Hg, Mg, Mn, Pb, Se, and Zn) measured in maternal erythrocytes were associated with differentially methylated positions (DMPs) and regions (DMRs) in cord blood and tested if associations persisted in blood collected in mid-childhood. We measured metal concentrations in first-trimester maternal erythrocytes, and DNAm in cord blood (N = 361) and mid-childhood blood (N = 333, 6-10 years) with the Illumina HumanMethylation450 BeadChip. For each metal individually, we tested for DMPs using linear models (considered significant at FDR < 0.05), and for DMRs using comb-p (Sidak p < 0.05). Covariates included biologically relevant variables and estimated cell-type composition. We also performed sex-stratified analyses.

Results: Pb was associated with decreased methylation of cg20608990 (CASP8) (FDR = 0.04), and Mn was associated with increased methylation of cg02042823 (A2BP1) in cord blood (FDR = 9.73 × 10). Both associations remained significant but attenuated in blood DNAm collected at mid-childhood (p < 0.01). Two and nine Mn-associated DMPs were identified in male and female infants, respectively (FDR < 0.05), with two and six persisting in mid-childhood (p < 0.05). All metals except Ba and Pb were associated with ≥ 1 DMR among all infants (Sidak p < 0.05). Overlapping DMRs annotated to genes in the human leukocyte antigen (HLA) region were identified for Cr, Cs, Cu, Hg, Mg, and Mn.

Conclusions: Prenatal metal exposure is associated with DNAm, including DMRs annotated to genes involved in neurodevelopment. Future research is needed to determine if DNAm partially explains the relationship between prenatal metal exposures and health outcomes.
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http://dx.doi.org/10.1186/s13148-021-01198-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605513PMC
November 2021

Prospective Associations of Early Pregnancy Metal Mixtures with Mitochondria DNA Copy Number and Telomere Length in Maternal and Cord Blood.

Environ Health Perspect 2021 11 19;129(11):117007. Epub 2021 Nov 19.

Division of Environmental Health Sciences, School of Public Health and Center for Computational Biology, University of California, Berkeley, Berkeley, California, USA.

Background: Metal exposure during pregnancy influences maternal and child health. Oxidative stress and inflammation may mediate adverse effects of heavy metals, whereas essential metals may act as antioxidants. Mitochondrial DNA is a prime target for metal-induced oxidative damage. Telomere dysfunction is attributed to imbalances between reactive oxidant species and antioxidants.

Objectives: We evaluated individual and joint associations of prenatal metals with mitochondrial DNA copy number (mtDNAcn) and telomere length (TL) in maternal and cord blood as biomarkers of inflammation and oxidative stress.

Methods: We measured six nonessential metals (arsenic, barium, cadmium, cesium, lead, mercury) and four essential metals (magnesium, manganese, selenium, zinc) in first-trimester maternal red blood cells in Project Viva, a U.S. prebirth cohort. We measured relative mtDNAcn () and TL () in second-trimester maternal blood and mtDNAcn () and TL () in cord blood. We used multivariable linear regression and quantile g-computation to estimate associations between prenatal metals and the biomarkers. We used generalized additive models and Bayesian kernel machine regression to examine nonlinearity and interactions.

Results: A 2-fold increase in maternal magnesium was associated with lower maternal [, 95% confidence interval (CI): , ] and cord blood (, 95% CI: , ) mtDNAcn. Lead was associated with higher maternal mtDNAcn (, 95% CI: 0.01, 0.06). Selenium was associated with longer cord blood TL (, 95% CI: 0.01 0.50). An association was observed between the nonessential metal mixture and higher maternal mtDNAcn (, 95% CI: 0.01, 0.07). There was a nonlinear relationship between cord blood mtDNAcn and magnesium; maternal mtDNAcn and barium, lead, and mercury; and maternal TL and barium.

Discussion: Maternal exposure to metals such as lead, magnesium, and selenium was associated with mtDNAcn and TL in maternal second trimester and cord blood. Future work will evaluate whether these biomarkers are associated with child health. https://doi.org/10.1289/EHP9294.
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http://dx.doi.org/10.1289/EHP9294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604047PMC
November 2021

Association of mode of delivery with offspring pubertal development in Project Viva: a prospective pre-birth cohort study in the USA.

Hum Reprod 2021 12;37(1):54-65

Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.

Study Question: Is cesarean delivery associated with earlier offspring pubertal development?

Summary Answer: We identified that boys born by cesarean delivery developed puberty earlier, evidenced by an earlier age at peak height velocity and earlier attainment of puberty score > 1, than boys born by vaginal delivery.

What Is Known Already: Cesarean delivery is posited to have long-term effects on health outcomes. However, few studies have examined whether mode of delivery is related to pubertal development.

Study Design, Size, Duration: Prospective pre-birth cohort study consisting of 1485 mother-child pairs enrolled during pregnancy from obstetric practices and followed up until early adolescence (median age 12.9 years). Participant inclusion required data on mode of delivery and at least one measure of pubertal development.

Participants/materials, Setting, Methods: Participants are children from the Project Viva study. We abstracted information on delivery mode from electronic medical records from children followed since birth (1999-2002) and examined the following markers of pubertal development: age at peak height velocity (APHV); age at menarche (girls only); parent-reported pubertal development score; and child-reported pictograph Tanner pubic hair staging. We used multivariable regression models to examine associations of delivery mode with these four pubertal indices, adjusting for the following confounders: demographic and socioeconomic factors; maternal height, pre-pregnancy BMI, total gestational weight gain, pregnancy conditions, parity, and maternal age at menarche; paternal height and BMI; gestational age at delivery and birthweight-for-gestational-age z-score.

Main Results And The Role Of Chance: In this study, 23.2% of children were born by cesarean delivery. Girls had an earlier APHV, had a higher pubertal score throughout childhood and in early adolescence, and were more likely to attain puberty score >1 and Tanner pubic hair Stage >1 earlier compared to boys. Mean (SD) age at menarche in girls was 12.4 (1.0) years. Boys born by cesarean delivery had significantly earlier APHV (β -0.23 years; 95% CI -0.40, -0.05) and higher risk of earlier attainment of puberty score > 1 (hazard ratio 1.09; 95% CI 1.01, 1.19) than boys born by vaginal delivery, after adjusting for confounders. These associations were not mediated by pre-pubertal BMI and were similar for planned (no labor) and unplanned (labor) cesarean delivery. No associations were observed between delivery mode and time to attain Tanner pubic hair Stage > 1 in boys. In girls, mode of delivery was not associated with any of the measured pubertal development markers.

Limitations, Reasons For Caution: This study used, as secondary outcomes, parent- and child-reported measures of pubertal development, which may be more prone to error and misclassification than information collected by trained observers or physicians during clinical examinations. The findings may also not be generalizable to populations from different settings, because all participants lived in one geographic area, were well educated, and had health care.

Wider Implications Of The Findings: Our findings provide support for cesarean delivery as a potential indicator of identifying children who are likely to experience earlier pubertal development; however, more studies are needed to confirm or refute these observations.

Study Funding/competing Interest(s): The project was funded by grants from the National Institutes of Health. The authors have no financial relationships or competing interests to disclose.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8730300PMC
December 2021

Association of Mode of Obstetric Delivery With Child and Adolescent Body Composition.

JAMA Netw Open 2021 10 1;4(10):e2125161. Epub 2021 Oct 1.

Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Although the literature on the association between birth by cesarean delivery and children's anthropometry has continued to increase, only a few studies have examined the association of cesarean delivery with measures of body composition assessed using dual-energy x-ray absorptiometry (DXA), which allows the differentiation of fat and lean mass overall and in specific regions of the body.

Objective: To investigate whether differences exist in DXA-measured body composition between children and adolescents born by cesarean delivery and those born by vaginal delivery.

Design, Setting, And Participants: This prospective cohort study included singleton children of mothers enrolled between April 1999 and July 2002 in Project Viva, a longitudinal prebirth cohort of mother-child pairs in Massachusetts. The children had at least 1 DXA scan at a follow-up visit during middle childhood (2007-2010) and/or early adolescence (2013-2016). Data analysis was performed from October 16, 2020, to May 9, 2021.

Exposures: Mode of delivery (cesarean vs vaginal).

Main Outcomes And Measures: Total lean mass index, total and truncal fat mass indexes, visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue, and total abdominal adipose tissue (TAAT) were estimated using DXA. Multivariable linear regression models were used to estimate the association between mode of delivery and DXA-derived outcomes with adjustment for confounders. Stabilized inverse probability weights were used to control for potential selection bias owing to loss to follow-up.

Results: A total of 975 mother-child pairs were included in the study. The mean (SD) maternal age at study entry was 32.0 (5.5) years, and the mean (SD) self-reported prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 25.0 (5.4). Of the children included in the study, 491 (50%) were female; 212 (22%) were born by cesarean delivery and 763 (78%) by vaginal delivery. Body composition in middle childhood as measured by DXA did not differ by mode of delivery. In early adolescence, participants born by cesarean delivery had a significantly greater total lean mass index (β, 0.4; 95% CI, 0.0-0.7), total fat mass index (β, 0.6; 95% CI, 0.1-1.1), truncal fat mass index (β, 0.3; 95% CI, 0.0-0.5), VAT area (β, 4.7; 95% CI, 0.9-8.6), and TAAT area (β, 23.8; 95% CI, 0.8-46.8) in a model adjusted for child sex and age at the time of DXA measurements; maternal age, educational level, race and ethnicity, total gestational weight gain, and smoking status during pregnancy; birth-weight-per-gestational-age z score; and paternal BMI. Associations between mode of delivery and measures of adiposity were found for cesarean deliveries performed in the absence of labor (total fat mass index: β, 1.3; 95% CI, 0.3-2.3; truncal fat mass index: β, 0.6; 95% CI, 0.1-1.0; VAT area: β, 10.7; 95% CI, 3.1-18.3; TAAT area: β, 47.3; 95% CI, 2.3-92.2). There were no associations after adjustment for maternal self-reported prepregnancy BMI (total lean mass index: β, 0.2; 95% CI, -0.1 to 0.6; total fat mass index: β, 0.4; 95% CI, -0.1 to 0.9; truncal fat mass index: β, 0.2; 95% CI, -0.1 to 0.4; VAT area: β, 3.0; 95% CI, -0.6 to 6.7; TAAT area: β, 13.6; 95% CI, -8.2 to 35.3).

Conclusions And Relevance: In this cohort study, adolescents born by cesarean delivery had significantly higher measures of lean mass, fat mass, and central adiposity compared with those born by vaginal delivery, but associations did not remain after adjustment for the mothers' self-reported prepregnancy BMI. The findings suggest that the association between birth by cesarean delivery and adolescent adiposity may partly be explained by maternal self-reported prepregnancy BMI.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501392PMC
October 2021

Associations of maternal non-nutritive sweetener intake during pregnancy with offspring body mass index and body fat from birth to adolescence.

Int J Obes (Lond) 2022 01 5;46(1):186-193. Epub 2021 Oct 5.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background/objective: The evidence that maternal non-nutritive sweetener (NNS) intake during pregnancy increases childhood obesity risk is conflicting. A potential reason for this is that all prior studies examined childhood body mass index (BMI) at only one timepoint and at different ages. We examined the extent to which NNS intake during pregnancy is associated with offspring BMI z-score and body fat longitudinally from birth to 18 years.

Subjects: A total of 1683 children from Project Viva, a prospective pre-birth cohort, were recruited from 1999 to 2002 in Massachusetts.

Methods: We assessed maternal NNS intake in the first and second trimesters of pregnancy using a semiquantitative food frequency questionnaire. Our outcomes were offspring BMI z-score, (at birth, infancy (median 6.3 months), early childhood (3.2 years), mid-childhood (7.7 years), and early adolescence (12.9 years)), sum of skinfolds (SS), fat mass index (FMI) measured by dual x-ray absorptiometry, and BMI z-score trajectory from birth to 18 years. We adjusted models for maternal pre-pregnancy BMI, age, race/ethnicity, education, parity, pre-pregnancy physical activity, smoking, and paternal BMI and education.

Results: A total of 70% of mothers were white and pre-pregnancy BMI was 24.6 ± 5.2 kg/m. The highest quartile of NNS intake (Q4: 0.98 ± 0.91 servings/day) was associated with higher BMI z-score in infancy (β 0.20 units; 95% CI 0.02, 0.38), early childhood (0.21; 0.05, 0.37), mid-childhood (0.21; 0.02, 0.40), and early adolescence (0.14; -0.07, 0.35) compared with Q1 intake (Q1: 0.00 ± 0.00 servings/day). Q4 was also associated with higher SS in early childhood (1.17 mm; 0.47, 1.88), mid-childhood (2.33 mm; 0.80, 3.87), and early adolescence (2.27 mm; -0.06, 4.60) and higher FMI in mid-childhood (0.26 kg/m; -0.07, 0.59). Associations of maternal NNS intake with offspring BMI z-score became stronger with increasing age from 3 to 18 years (P < 0.0001).

Conclusions: Maternal NNS intake during pregnancy is associated with increased childhood BMI z-score and body fat from birth to teenage years. This is relevant given the escalating obesity epidemic, and popularity of NNS.
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http://dx.doi.org/10.1038/s41366-021-00897-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784986PMC
January 2022

Maternal diet quality during pregnancy and child cognition and behavior in a US cohort.

Am J Clin Nutr 2022 01;115(1):128-141

Dorothy J and Gerald R Friedman School of Nutrition and Science Policy, Tufts University, Boston, MA, USA.

Background: Maternal intake of several nutrients during pregnancy is linked to offspring cognition. The relation between maternal dietary patterns and offspring cognition is less established.

Objectives: We aimed to examine associations of maternal diet quality during pregnancy with child cognition and behavior.

Methods: Among 1580 mother-child pairs in Project Viva, a prospective prebirth cohort, we assessed maternal diet during pregnancy using FFQs and evaluated diet quality using versions modified for pregnancy of the Mediterranean Diet Score (MDS-P) and Alternate Healthy Eating Index (AHEI-P). Child cognitive and behavioral outcomes were assessed using standardized tests and questionnaires at infancy and in early and mid-childhood. We conducted multivariable linear regression analyses.

Results: Mothers were predominantly white, college-educated, and nonsmokers. After adjustment for child age and sex and maternal sociodemographic and lifestyle characteristics, maternal high (6-9) compared with low (0-3) MDS-P during pregnancy was associated with higher child Kaufman Brief Intelligence Test (KBIT-II) nonverbal (mean difference for first trimester: 4.54; 95% CI: 1.53, 7.56) and verbal scores (3.78; 95% CI: 1.37, 6.19) and lower Behavioral Rating Inventory of Executive Function (BRIEF) Metacognition Index (-1.76; 95% CI: -3.25, -0.27), indicating better intelligence and fewer metacognition problems in mid-childhood. Maternal Q4 compared with Q1 AHEI-P during pregnancy was associated with higher Wide Range Assessment of Visual Motor Abilities matching scores in early childhood (mean difference for first trimester: 2.79; 95% CI: 0.55, 5.04) and higher KBIT-II verbal scores (2.59; 95% CI: 0.13, 5.04) and lower BRIEF Global Executive Composite scores in mid-childhood (-1.61; 95% CI: -3.20, -0.01), indicating better visual spatial skills, verbal intelligence, and executive function.

Conclusions: Maternal intake of a better-quality diet during pregnancy was associated with better visual spatial skills in the offspring at early childhood and with better intelligence and executive function in the offspring at mid-childhood.
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http://dx.doi.org/10.1093/ajcn/nqab325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755080PMC
January 2022

Impact of paternal education on epigenetic ageing in adolescence and mid-adulthood: a multi-cohort study in the USA and Mexico.

Int J Epidemiol 2022 06;51(3):870-884

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages.

Methods: We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm).

Results: EAA was associated with paternal education in CARDIA [GEEs: βsome college = -1.01 years (-1.91, -0.11) and β
Conclusions: These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.
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http://dx.doi.org/10.1093/ije/dyab196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9189973PMC
June 2022

Associations of midchildhood to early adolescence central adiposity gain with cardiometabolic health in early adolescence.

Obesity (Silver Spring) 2021 11 16;29(11):1882-1891. Epub 2021 Sep 16.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Objective: This study examined the associations of central adiposity gain from midchildhood to early adolescence with cardiometabolic health markers in early adolescence.

Methods: A total of 620 participants were studied in Project Viva. In midchildhood (mean age = 7.8 years) and early adolescence (12.9 years), waist circumference and dual-energy x-ray absorptiometry-measured visceral adipose tissue, subcutaneous abdominal adipose tissue, and trunk fat were obtained. Central adiposity gain was calculated as change per year between visits. Cardiometabolic health markers, including blood pressure, lipids, markers of insulin resistance, inflammation, and adipokines, were collected in early adolescence.

Results: Greater waist circumference gain was associated with higher log triglycerides (β 0.07 mg/dL; 95% CI: 0.02-0.13), log alanine aminotransferase (0.07 U/L; 95% CI: 0.03-0.12), log high-sensitivity C-reactive protein (0.43 mg/L; 95% CI: 0.28-0.58), and other cardiometabolic markers in early adolescence. Directly measured central adiposity gains were associated with higher systolic blood pressure z score in early adolescence (visceral adipose tissue [0.13 SD units; 95% CI: 0.04-0.23], subcutaneous abdominal adipose tissue [0.18 SD units; 95% CI: 0.04-0.31], and trunk fat [0.21 SD units; 95% CI: 0.06-0.36]). These associations were independent of baseline and change in total adiposity from midchildhood to early adolescence.

Conclusions: Monitoring central adiposity gain may enable identification and intervention in children vulnerable to developing cardiometabolic health risks.
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http://dx.doi.org/10.1002/oby.23261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571062PMC
November 2021

Analysis of Maternal Prenatal Weight and Offspring Cognition and Behavior: Results From the Promotion of Breastfeeding Intervention Trial (PROBIT) Cohort.

JAMA Netw Open 2021 08 2;4(8):e2121429. Epub 2021 Aug 2.

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Importance: Prenatal experiences can influence fetal brain development.

Objective: To examine associations of maternal prenatal body mass index (BMI) with cognition and behavior of offspring born full-term.

Design, Setting, And Participants: This cohort study examined follow-up data from a breastfeeding promotion intervention at 31 hospitals and affiliated polyclinics in the Republic of Belarus. Participants included 11 276 children who were evaluated from birth (1996-1997) to adolescence (2017-2019), with maternal BMI information available in prenatal medical records.

Exposures: Maternal BMI, calculated as weight in kilograms divided by height in meters squared, after 35 weeks gestation; secondary analyses examined maternal BMI at other time points and paternal BMI.

Main Outcomes And Measures: Trained pediatricians assessed child cognition with the Wechsler Abbreviated Scales of Intelligence (WASI) at 6.5 years and the computerized self-administered NeuroTrax battery at 16 years, both with an approximate mean (SD) of 100 (15). Parents and teachers rated behaviors at 6.5 years using the Strengths and Difficulties Questionnaire (SDQ, range 0-40). Mixed-effects linear regression analyses corrected for clustering, adjusted for the randomized intervention group and baseline parental sociodemographic characteristics, and were considered mediation by child BMI.

Results: Among 11 276 participants, 9355 women (83%) were aged 20 to 34 years, 10 128 (89.8%) were married, and 11 050 (98.0%) did not smoke during pregnancy. Each 5-unit increase in of maternal late-pregnancy BMI (mean [SD], 27.2 [3.8]) was associated with lower offspring WASI performance intelligence quotient (IQ) (-0.52 points; 95% CI, -0.87 to -0.17 points) at 6.5 years and lower scores on 5 of 7 NeuroTrax subscales and the global cognitive score at 16 years (-0.67 points; 95% CI, -1.06 to -0.29 points). Results were similar after adjustment for sociodemographic characteristics, pregnancy complications, and paternal BMI and were not mediated by child weight. Higher late pregnancy maternal BMI was also associated with more behavioral problems reported on the SDQ by teachers but not associated with parent-reported behaviors (externalizing behaviors: 0.13 points; 95% CI, 0.02 to 0.24 points; and total difficulties: 0.14 points, 95% CI, -0.02 to 0.30 points). Results were similar for maternal BMI measured in the first trimester or postpartum. In contrast, higher 6.5-year paternal BMI was associated with slightly better child cognition (WASI verbal IQ: 0.42 points; 95% CI, 0.02 to 0.82 points; NeuroTrax executive function score: 0.68 points; 95% CI, 0.24 to 1.12 points) and fewer teacher-reported behavioral problems (total difficulties: -0.29 points; 95% CI, -0.46 to -0.11 points).

Conclusions And Relevance: This cohort study supports findings from animal experiments and human observational studies in settings with higher maternal BMI and obesity rates. Higher maternal prenatal BMI may be associated with poorer offspring brain development, although residual confounding cannot be excluded.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377565PMC
August 2021

Early-Life Exposure to Green Space and Mid-Childhood Cognition in the Project Viva Cohort, Massachusetts.

Am J Epidemiol 2022 01;191(1):115-125

The association between early-life greenness and child cognition is not well understood. Using prospective data from Project Viva (n = 857) from 1999-2010, we examined associations of early-life greenness exposure with mid-childhood cognition. We estimated residential greenness at birth, early childhood (median age 3.1 years), and mid-childhood (7.8 years) using 30-m resolution Landsat satellite imagery (normalized difference vegetation index). In early childhood and mid-childhood, we administered standardized assessments of verbal and nonverbal intelligence, visual-motor abilities, and visual memory. We used natural splines to examine associations of early life-course greenness with mid-childhood cognition, adjusting for age, sex, race, income, neighborhood socioeconomic status, maternal intelligence, and parental education. At lower levels of greenness (greenness <0.6), greenness exposure at early childhood was associated with a 0.48% increase in nonverbal intelligence and 2.64% increase in visual memory in mid-childhood. The association between early-childhood greenness and mid-childhood visual memory was observed after further adjusting for early childhood cognition and across different methodologies, while the association with nonverbal intelligence was not. No other associations between early life-course greenness and mid-childhood cognition were found. Early childhood greenness was nonlinearly associated with higher mid-childhood visual memory. Our findings highlight the importance of nonlinear associations between greenness and cognition.
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http://dx.doi.org/10.1093/aje/kwab209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8897997PMC
January 2022

Dietary fat intake during early pregnancy is associated with cord blood DNA methylation at IGF2 and H19 genes in newborns.

Environ Mol Mutagen 2021 08 31;62(7):388-398. Epub 2021 Jul 31.

Division of Environmental Health Sciences, University of California, Berkeley School of Public Health, Berkeley, Berkeley, California, USA.

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m . Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (-1.2%; 95% confidence interval [CI]: -2.2%, -0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (-4.3%; 95% CI: -7.9%, -0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.
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http://dx.doi.org/10.1002/em.22452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364885PMC
August 2021

Association of Early Antibiotic Exposure With Childhood Body Mass Index Trajectory Milestones.

JAMA Netw Open 2021 07 1;4(7):e2116581. Epub 2021 Jul 1.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts.

Importance: Past studies have showed associations between antibiotic exposure and child weight outcomes. Few, however, have documented alterations to body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) trajectory milestone patterns during childhood after early-life antibiotic exposure.

Objective: To examine the association of antibiotic use during the first 48 months of life with BMI trajectory milestones during childhood in a large cohort of children.

Design, Setting, And Participants: This retrospective cohort study used electronic health record data from 26 institutions participating in the National Patient-Centered Clinical Research Network from January 1, 2009, to December 31, 2016. Participant inclusion required at least 1 valid set of same-day height and weight measurements at each of the following age periods: 0 to 5, 6 to 11, 12 to 23, 24 to 59, and 60 to 131 months (183 444 children). Data were analyzed from June 1, 2019, to June 30, 2020.

Exposures: Antibiotic use at 0 to 5, 6 to 11, 12 to 23, 24 to 35, and 36 to 47 months of age.

Main Outcomes And Measures: Age and magnitude of BMI peak and BMI rebound.

Results: Of 183 444 children in the study (mean age, 3.3 years [range, 0-10.9 years]; 95 228 [51.9%] were boys; 80 043 [43.6%] were White individuals), 78.1% received any antibiotic, 51.0% had at least 1 episode of broad-spectrum antibiotic exposure, and 65.0% had at least 1 episode of narrow-spectrum antibiotic exposure at any time before 48 months of age. Exposure to any antibiotics at 0 to 5 months of age (vs no exposure) was associated with later age (β coefficient, 0.05 months [95% CI, 0.02-0.08 months]) and higher BMI (β coefficient, 0.09 [95% CI, 0.07-0.11]) at peak. Exposure to any antibiotics at 0 to 47 months of age (vs no exposure) was associated with an earlier age (-0.60 months [95% CI, -0.81 to -0.39 months]) and higher BMI at rebound (β coefficient, 0.02 [95% CI, 0.01-0.03]). These associations were strongest for children with at least 4 episodes of antibiotic exposure. Effect estimates for associations with age at BMI rebound were larger for those exposed to antibiotics at 24 to 35 months of age (β coefficient, -0.63 [95% CI, -0.83 to -0.43] months) or 36 to 47 (β coefficient, -0.52 [95% CI, -0.72 to -0.31] months) than for those exposed at 0 to 5 months of age (β coefficient, 0.26 [95% CI, 0.01-0.51] months) or 6 to 11 (β coefficient, 0.00 [95% CI, -0.20 to 0.20] months).

Conclusions And Relevance: In this cohort study, antibiotic exposure was associated with statistically significant, but small, differences in BMI trajectory milestones in infancy and early childhood. The small risk of an altered BMI trajectory milestone pattern associated with early-life antibiotic exposure is unlikely to be a key factor during prescription decisions for children.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.16581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276083PMC
July 2021

Prenatal and childhood exposure to per- and polyfluoroalkyl substances (PFAS) and child executive function and behavioral problems.

Environ Res 2021 11 6;202:111621. Epub 2021 Jul 6.

Center for Environmental Research and Children's Health, University of California, Berkeley School of Public Health, Berkeley, CA, USA; Division of Epidemiology, University of California, Berkeley School of Public Health, Berkeley, CA, USA.

Early life exposure to per- and polyfluoroalkyl substances (PFAS) may adversely impact neurodevelopment, but epidemiological findings are inconsistent. In the Project Viva pre-birth cohort, we examined associations of prenatal and childhood PFAS plasma concentrations with parent and teacher assessments of children's behavior problems [Strengths and Difficulties Questionnaire (SDQ)] and executive function abilities [Behavior Rating Inventory of Executive Function (BRIEF)] at age 6-10 years (sample sizes 485-933). PFAS concentrations in pregnant Project Viva mothers (in 1999-2002) and children at ages 6-10 (in 2007-10) were similar to concentrations at similar time points in women and children in the nationally representative U.S. National Health and Nutrition Examination Survey. We observed no consistent associations of prenatal PFAS concentrations with behavior or executive function. Childhood concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) were associated with higher parent-rated SDQ Total Difficulties scores (mean = 6.7, standard deviation (SD) = 4.9), suggesting greater behavioral problems (top (Q4) versus bottom (Q1) quartile PFOA: 1.5, 95% confidence interval (CI): 0.3, 2.7; PFOS: 1.4, 95% CI: 0.3, 2.5; PFHxS: 1.2, 95% CI: 0.1, 2.3; PFNA: 1.2, 95% CI: 0.1, 2.2; PFDA: 1.1, 95% CI: 0.0, 1.1); teacher-rated SDQ scores did not show associations. Higher childhood PFOS was associated with higher (indicating more problems) parent-rated BRIEF General Executive Composite (GEC) scores (standardized to mean = 50, SD = 10) (Q4 vs. Q1: 2.4, 95% CI: 0.2, 4.6), while teacher BRIEF GEC scores indicated more problems among children with higher PFHxS (Q4 vs. Q1: 3.5, 95% CI: -0.8, 6.3). There were no consistent patterns of sexual dimorphism in associations. In a cohort of U.S. children, we observed cross-sectional associations of childhood PFAS concentrations with greater behavioral and executive function problems, but no consistent associations with prenatal PFAS.
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http://dx.doi.org/10.1016/j.envres.2021.111621DOI Listing
November 2021

Genetic Interactions with Intrauterine Diabetes Exposure in Relation to Obesity: The EPOCH and Project Viva Studies.

Pediatr Rep 2021 Jun 1;13(2):279-288. Epub 2021 Jun 1.

Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.

To examine whether BMI-associated genetic risk variants modify the association of intrauterine diabetes exposure with childhood BMI z-scores, we assessed the interaction between 95 BMI-associated genetic variants and in utero exposure to maternal diabetes among 459 children in the Exploring Perinatal Outcomes among Children historical prospective cohort study (n = 86 exposed; 373 unexposed) in relation to age- and sex-standardized childhood BMI z-scores (mean age = 10.3 years, standard deviation = 1.5 years). For the genetic variants showing a nominally significant interaction, we assessed the relationship in an additional 621 children in Project Viva, which is an independent longitudinal cohort study, and used meta-analysis to combine the results for the two studies. Seven of the ninety-five genetic variants tested exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to the offspring BMI z-score in EPOCH. Five of the seven variants exhibited a consistent direction of interaction effect across both EPOCH and Project Viva. While none achieved statistical significance in the meta-analysis after accounting for multiple testing, three variants exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to offspring BMI z-score: rs10733682 near (interaction β = 0.39; standard error (SE) = 0.17), rs17001654 near (β = 0.53; SE = 0.22), and rs16951275 near (β = 0.37; SE = 0.17). BMI-associated genetic variants may enhance the association between exposure to in utero diabetes and higher childhood BMI, but larger studies of in utero exposures are necessary to confirm the observed nominally significant relationships.
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http://dx.doi.org/10.3390/pediatric13020036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293453PMC
June 2021
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