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1.  Gestational intake of methyl donors and global LINE-1 DNA methylation in maternal and cord blood 
Epigenetics  2012;7(3):253-260.
Maternal diet affects offspring DNA methylation in animal models, but evidence from humans is limited. We investigated the extent to which gestational intake of methyl donor nutrients affects global DNA methylation in maternal and umbilical cord blood. Among mother-infant pairs in Project Viva, a folate-replete US population, we estimated maternal intakes of vitamin B12, betaine, choline, folate, cadmium, zinc and iron periconceptionally and during the second trimester. We examined associations of these nutrients with DNA methylation, measured as %5-methyl cytosines (%5mC) in Long Interspersed Nuclear Element-1 (LINE-1), in first trimester (n = 830) and second trimester (n = 671) maternal blood and in cord blood at delivery (n = 516). Cord blood methylation was higher for male than female infants {mean [standard deviation (SD)] 84.8 [0.6] vs. 84.4 [0.7]%}. In the multivariable-adjusted model, maternal intake of methyl donor nutrients periconceptionally and during the second trimester of pregnancy was not positively associated with first trimester, second trimester or cord blood LINE-1 methylation. Periconceptional betaine intake was inversely associated with cord blood methylation [regression coefficient = −0.08% (95% confidence interval (CI): −0.14, −0.01)] but this association was attenuated after adjustment for dietary cadmium, which itself was directly associated with first trimester methylation and inversely associated with cord blood methylation. We also found an inverse association between periconceptional choline [−0.10%, 95% CI: −0.17, −0.03 for each SD (∼63 mg/day)] and cord blood methylation in males only. In this folate-replete population, we did not find positive associations between intake of methyl donor nutrients during pregnancy and DNA methylation overall, but among males, higher early pregnancy intakes of choline were associated with lower cord blood methylation.
doi:10.4161/epi.7.3.19082
PMCID: PMC3335948  PMID: 22430801
DNA methylation; pregnancy; cord blood; maternal diet; cadmium
2.  Whole Animal Experiments Should Be More Like Human Randomized Controlled Trials 
PLoS Biology  2013;11(2):e1001481.
The quality of reporting of animal studies lags behind that of human randomized controlled trials but a series of additions to the ARRIVE guidelines will help ensure that the standards are comparable.
doi:10.1371/journal.pbio.1001481
PMCID: PMC3570551  PMID: 23424284
3.  Systematic review and meta-analysis of preterm birth and later systolic blood pressure 
Hypertension  2011;59(2):226-234.
Lower birth weight due to fetal growth restriction is associated with higher blood pressure later in life, but the extent to which preterm birth (<37 completed weeks’ gestation) or very low birth weight (<1500g) predicts higher blood pressure is less clear. We performed a systematic review of 27 observational studies that compared the resting or ambulatory systolic blood pressure, or diagnosis of hypertension, among children, adolescents, and adults born preterm or very low birth weight with those born full term. We performed a meta-analysis with the subset of 10 studies that reported the resting systolic blood pressure difference in mmHg with 95% confidence intervals or standard errors. We assessed methodological quality with a modified Newcastle-Ottawa scale. The 10 studies comprised 1342 preterm or very low birth weight and 1738 full term participants from 8 countries. The mean gestational age at birth of the preterm participants was 30.2 weeks (range, 28.8 to 34.1), birth weight 1280 grams (1098 to 1958), and age at systolic blood pressure measurement 17.8 years (6.3 to 22.4). Former preterm or very low birth weight infants had higher systolic blood pressure than full term infants (pooled estimate 2.5 mmHg, 95% CI: 1.7, 3.3). For the 5 highest quality studies, the systolic blood pressure difference was slightly greater, 3.8 mmHg (95% CI 2.6, 5.0). We conclude that infants who are born preterm or very low birth weight have modestly higher systolic blood pressure later in life, and may be at increased risk for developing hypertension and its sequelae.
doi:10.1161/HYPERTENSIONAHA.111.181784
PMCID: PMC3266458  PMID: 22158643
Blood pressure; meta-analysis; systematic review; preterm birth; very low birth weight
4.  Gestational Glucose Tolerance and Maternal Metabolic Profile at 3 Years Postpartum 
Obstetrics and Gynecology  2011;118(5):1065-1073.
OBJECTIVE
To estimate the independent effect of gestational impaired glucose tolerance, defined as a single abnormal oral glucose tolerance test (OGTT) value, on metabolic dysfunction at 3 years postpartum.
METHODS
We used multiple linear regression to measure associations between glucose testing during pregnancy and metabolic markers at 3 years postpartum in Project Viva, a prospective cohort study of maternal and infant health. We compared metabolic measures at 3 years postpartum among four groups: normal glucose challenge test (less than 140 mg/dL, n=461); abnormal glucose challenge test but normal glucose tolerance test (GTT) (n=39); impaired glucose tolerance (IGT) (a single abnormal GTT value, n=21); and gestational diabetes mellitus (GDM) (n=16).
RESULTS
Adjusting for age, race, parity, parental history of diabetes, and maternal BMI at 3 years postpartum, we found women with GDM had lower adiponectin (11.2 ng/mL vs. 20.7 ng/mL) and higher homeostatic model assessment – insulin resistance (3.1 vs. 1.3) and waist circumference (91.3 cm vs. 86.2 cm) compared with women with IGT or normal glucose tolerance. Women in both the IGT and GDM groups had lower high-density lipoprotein (GDM: 44.7 mg/dL; IGT: 45.4/dL vs normal glucose tolerance 55.8 mg/dL) and higher triglycerides (GDM: 136.1 mg/dL; IGT: 140.1 mg/dL, vs. normal glucose tolerance: 78.3), compared with women in the normal glucose tolerance group. We found the highest values for Hemoglobin A1c (GDM: 5.1%; IGT 5.3%, normal glucose tolerance 5.1%) and high-sensitivity c reactive protein (GDM 1.4 mg/dL IGT: 2.2 mg/dL; NGT 1.0 mg/dL) among women with IGT.
CONCLUSION
GDM and IGT during pregnancy are associated with persistent metabolic dysfunction at 3 years postpartum, independent of other clinical risk factors.
doi:10.1097/AOG.0b013e3182325f5a
PMCID: PMC3268071  PMID: 22015874
5.  Infant Growth Before and After Term: Effects on Neurodevelopment in Preterm Infants 
Pediatrics  2011;128(4):e899-e906.
OBJECTIVE:
To identify sensitive periods of postnatal growth for preterm infants relative to neurodevelopment at 18 months' corrected age.
PATIENTS AND METHODS:
We studied 613 infants born at <33 weeks' gestation who participated in the DHA for Improvement of Neurodevelopmental Outcome trial. We calculated linear slopes of growth in weight, length, BMI, and head circumference from 1 week of age to term (40 weeks' postmenstrual age), term to 4 months, and 4 to 12 months, and we estimated their associations with Bayley Scales of Infant Development, 2nd Edition, Mental (MDI) and Psychomotor (PDI) Development Indexes in linear regression.
RESULTS:
The median gestational age was 30 (range: 2–33) weeks. Mean ± SD MDI was 94 ± 16, and PDI was 93 ± 16. From 1 week to term, greater weight gain (2.4 MDI points per z score [95% confidence interval (CI): 0.8–3.9]; 2.7 PDI points [95% CI: 1.2–.2]), BMI gain (1.7 MDI points [95% CI: 0.4–3.1]; 2.5 PDI points [95% CI: 1.2–3.9]), and head growth (1.4 MDI points [95% CI: −0.0–2.8]; 2.5 PDI points [95% CI: 1.2–3.9]) were associated with higher scores. From term to 4 months, greater weight gain (1.7 points [95% CI: 0.2–3.1]) and linear growth (2.0 points [95% CI: 0.7–3.2]), but not BMI gain, were associated with higher PDI. From 4 to 12 months, none of the growth measures was associated with MDI or PDI score.
CONCLUSIONS:
In preterm infants, greater weight and BMI gain to term were associated with better neurodevelopmental outcomes. After term, greater weight gain was also associated with better outcomes, but increasing weight out of proportion to length did not confer additional benefit.
doi:10.1542/peds.2011-0282
PMCID: PMC3182845  PMID: 21949135
growth; motor development; cognitive development; preterm infants
6.  Longitudinal Association of Maternal Attempt to Lose Weight During the Postpartum Period and Child Obesity at Age 3 Years 
Obesity (Silver Spring, Md.)  2011;19(10):2046-2052.
The effect of maternal attempt to lose weight during the postpartum period on later child weight has not been explored. Among 1,044 mother–infant pairs in Project Viva, we estimated longitudinal associations of maternal attempt to lose weight during the postpartum period with child weight and adiposity at age 3 years and examined differences in associations by type of weight loss strategy used. Using covariate-adjusted linear and logistic regression models, we estimated associations before and after adjusting for maternal weight-related variables including prepregnancy BMI. At 6 months postpartum, 53% mothers were trying to lose weight. At age 3 years, mean (s.d.) child BMI z-score was 0.44 (1.01) and 8.9% of children were obese. Children whose mothers were trying to lose weight at 6 months postpartum had higher BMI z-scores (0.30 (95% confidence interval (CI) 0.18, 0.42)) and were more likely to be obese (3.0 (95% CI 1.6, 5.8)) at 3 years of age. Addition of maternal prepregnancy BMI to the models attenuated but did not eliminate the associations seen for BMI z-score (0.24 (95% CI 0.12, 0.36) and obesity (2.4 (95% CI 1.2, 4.7)). Attempting to lose weight by exercising alone was the only weight loss strategy that consistently predicted higher child BMI z-score (0.36 (95% CI 0.14, 0.58)) and odds of obesity (6.0 (95% CI 2.2, 16.5)) at age 3 years. In conclusion, we observed an association between maternal attempt to lose weight at 6 months postpartum, particularly through exercise alone, measured using a single item and child adiposity at age 3 years. This association should be thoroughly examined in future studies.
doi:10.1038/oby.2011.25
PMCID: PMC3219435  PMID: 21350436
7.  Relationships between Social Resources and Healthful Behaviors across the Age Spectrum 
Journal of Aging Research  2012;2012:501072.
Background. We examined cross-sectional relationships of social resources with health behaviors in adults ages 18–93 years. Methods. Baseline data from a 2009 risk behavior intervention trial were used to measure social resources, physical activity, and fruit and vegetable intake in 2,440 adults. To evaluate associations overall and within 4 age groups (18–34, 35–49, 50–64, and 65–93 y), we used multivariable regression. Results. Mean (SD) age was 49.4 (15) years, physical activity was 346 (304) minutes/week, and fruit and vegetable intake was 3.4 (2.4) servings/day. Mean social resource score was 1.2 (0–4 scale) in 18–34 year olds, 1.1 in all other age groups (P = 0.04). In multivariable models, for each one-point increment in social resource score, the odds ratio for getting 150–959 minutes of physical activity/wk (compared to <150 min/wk) was 3.7 (95% CI 3.0–4.6). Each one-point increment in score was also associated with 29% (95% CI: 23–35%) more servings of fruit and vegetables. We did not observe effect modification by age group. Conclusions. Although younger adults reported slightly higher resources than older adults, the magnitude of association between social resources and healthful behaviors did not differ between them.
doi:10.1155/2012/501072
PMCID: PMC3437283  PMID: 22970369
8.  Associations of LINE-1 DNA Methylation with Preterm Birth in a Prospective Cohort Study 
Preterm birth affects over 12% of all infants born in the US yet the biology of early delivery remains unclear, including whether epigenetic mechanisms are involved. We examined associations of maternal and umbilical cord blood long interspersed nuclear element-1 (LINE-1) DNA methylation with length of gestation and odds of preterm birth in singleton pregnancies in Project Viva. In white blood cells from maternal blood during 1st trimester (n=914) and 2nd trimester (n=922), and from venous cord blood at delivery (n=557), we measured LINE-1 by pyrosequencing (expressed as %5 methyl cytosines within the LINE-1 region analyzed [%5mC]). We ran linear regression models to analyze differences in gestation length, and logistic models for odds of preterm birth (<37 v. ≥37 weeks gestation), across quartiles of LINE-1. Mean(SD) LINE-1 levels were 84.3(0.6), 84.5(0.4), and 84.6(0.7) %5mC for 1st trimester, 2nd trimester and cord blood, respectively. Mean(SD) gestational age was 39.5(1.8) weeks, and 6.5% of infants were born preterm. After adjustment for maternal age, race/ethnicity, BMI, education, smoking status, and fetal sex, women with the highest vs. lowest quartile of 1st trimester LINE-1 had longer gestations (0.45 weeks [95% CI 0.12, 0.78]) and lower odds of preterm birth (OR 0.40 [0.17, 0.94]), whereas associations with cord blood LINE-1 were in the opposite direction (−0.45 weeks, −0.83, −0.08) and (OR 4.55 [1.18, 17.5]). In conclusion, higher early pregnancy LINE-1 predicts lower risk of preterm birth. In contrast, preterm birth is associated with lower LINE-1 in cord blood.
PMCID: PMC3377352  PMID: 22720130
Preterm; epigenetics; LINE-1; DNA methylation
9.  Developmental Origins of Childhood Overweight: Potential Public Health Impact 
Obesity (Silver Spring, Md.)  2008;16(7):1651-1656.
Several modifiable pre- and postnatal determinants of childhood overweight are known, but no one has examined how they influence risk of overweight in combination. We estimated the risk of overweight at age 3 years according to levels of maternal smoking during pregnancy, gestational weight gain, breastfeeding duration, and infant sleep duration. We studied 1,110 mother–child pairs in Project Viva, a prospective prebirth cohort study. The main outcome measure was child overweight (BMI for age and sex ≥95th percentile) at age 3. We ran logistic regression models with all four modifiable risk factors as well as the covariates maternal BMI and education, child race/ethnicity, and household income. From the model, we obtained the estimated probability of overweight for each of the 16 combinations of the four risk factors. During pregnancy, 9.8% of mothers smoked and 50% gained excessive weight. In infancy, 73% mother–child pairs breastfed for <12 m, and 31% of infants slept <12 h/day. Among the 3-year-old children in the cohort, 9.5% were overweight. In the prediction model, the estimated probability of overweight ranged from 0.06 among children exposed to favorable levels of all four risk factors, to 0.29 with adverse levels of all four. Healthful levels of four behaviors during early development predicted much lower probability of overweight at age 3 than adverse levels. Interventions to modify several factors during pregnancy and infancy could have substantial impact on prevention of childhood overweight.
doi:10.1038/oby.2008.260
PMCID: PMC2650814  PMID: 18451768
10.  Commentary: breastfeeding and obesity—the 2011 Scorecard 
doi:10.1093/ije/dyr085
PMCID: PMC3147075  PMID: 21666265
11.  Invited Commentary: Antecedents of Obesity—Analysis, Interpretation, and Use of Longitudinal Data 
American journal of epidemiology  2007;166(1):14-18.
The obesity epidemic causes misery and death. Most epidemiologists accept the hypothesis that characteristics of the early stages of human development have lifelong influences on obesity-related health outcomes. Unfortunately, there is a dearth of data of sufficient scope and individual history to help unravel the associations of prenatal, postnatal, and childhood factors with adult obesity and health outcomes. Here the authors discuss analytic methods, the interpretation of models, and the use to which such rare and valuable data may be put in developing interventions to combat the epidemic. For example, analytic methods such as quantile and multinomial logistic regression can describe the effects on body mass index range rather than just its mean; structural equation models may allow comparison of the contributions of different factors at different periods in the life course. Interpretation of the data and model construction is complex, and it requires careful consideration of the biologic plausibility and statistical interpretation of putative causal factors. The goals of discovering modifiable determinants of obesity during the prenatal, postnatal, and childhood periods must be kept in sight, and analyses should be built to facilitate them. Ultimately, interventions in these factors may help prevent obesity-related adverse health outcomes for future generations.
doi:10.1093/aje/kwm101
PMCID: PMC1989664  PMID: 17490988
birth weight; body mass index; body size; growth; obesity; overweight
12.  Maternal Corticotropin-Releasing Hormone Levels during Pregnancy and Offspring Adiposity 
Obesity (Silver Spring, Md.)  2006;14(9):1647-1653.
Objective
Animal models suggest that fetal exposure to glucocorticoids can program adiposity, especially central adiposity, later in life. We examined associations of maternal corticotropin-releasing hormone (CRH) levels in the late 2nd trimester of pregnancy, a marker of fetal glucocorticoid exposure, with child adiposity at age 3 years.
Research Methods and Procedures
We analyzed data from 199 participants in Project Viva, a prospective cohort study of pregnant women and their children, At age 3 years, the main outcomes were age-sex-specific BMI z score and the sum of subscapular (SS) and triceps (TR) skinfold thicknesses to represent overall adiposity, and ratio of SS to TR (SS:TR) to represent central adiposity.
Results
Mean (standard deviation) maternal 2nd trimester log CRH was 4.94 (0.56) pg/mL. At age 3, mean (standard deviation) for BMI z score was 0.52 (1.02); for SS + TR, 16.51 (3.94) mm; and for SS:TR, 0.67 (0.17). Log CRH was mildly inversely correlated with birth weight (r = −0.08), chiefly because of its association with length of gestation (r = −0.21) rather than fetal growth (r = −0.004). After adjustment for sociodemographic factors, maternal smoking, BMI, and gestational weight gain, fetal growth, length of gestation, breastfeeding duration, and (for SS:TR only) child’s 3-year BMI, each increment of 1 unit of log CRH was associated with a reduction in BMI z score [−0.43; 95% confidence interval (CI), −0.73, −0.14; p = 0.004] and possible reduction in SS + TR (−1.10; 95% CI, −2.33, 0.14; p = 0.08). In contrast, log CRH was associated with higher SS:TR (0.07; 95% CI, 0.02, 0.13; p = 0.007).
Discussion
Fetal exposure to glucocorticoids, although associated with an overall decrease in body size, may cause an increase in central adiposity.
PMCID: PMC1899091  PMID: 17030976
pregnancy; pediatrics; placenta; glucocorticoids; child overweight
13.  Lifetime maternal experiences of abuse and risk of pre-natal depression in two demographically distinct populations in Boston 
Background To investigate lifetime history of interpersonal abuse and risk of pre-natal depression in socio-economically distinct populations in the same city.
Methods We examined associations of physical and sexual abuse with the risk of pre-natal depression in two cohorts in the Boston area, including 2128 participants recruited from a large urban- and suburban-managed care organization (Project Viva) and 1509 participants recruited primarily from urban community health centres (Project ACCESS). Protocols for the studies were designed in parallel to allow us to merge data to enhance ethnic and socio-economic diversity in the combined sample. In mid-pregnancy, the Personal Safety Questionnaire and Edinburgh Postnatal Depression Scale (EPDS) were administered in both cohorts. An EPDS score ≥13 indicated probable pre-natal depression. Logistic regression was used to estimate the odds ratio (OR) of pre-natal depression associated with lifetime abuse history.
Results Project ACCESS participants were twice as likely as Project Viva participants to report symptoms consistent with pre-natal depression: 22% of Project ACCESS participants had EPDS scores ≥13, compared with 11% of Project Viva participants. Fifty-seven percent of women in ACCESS and 46% in Viva reported lifetime physical and/or sexual abuse. In merged analysis, women reporting lifetime physical or sexual abuse had an OR for mid-pregnancy depression of 1.63 [95% confidence interval (95% CI): 1.29–2.07], adjusted for age and race/ethnicity. Lifetime histories of physical abuse [OR 1.48 (95% CI 1.15–1.90)] and sexual abuse [OR 1.68 (95% CI 1.24–2.28)] were independently associated with pre-natal depression. When child/teen, pre-pregnancy adult and pregnancy life periods were considered simultaneously, abuse in childhood was independently associated with an OR of 1.23 (95% CI 1.00–1.59), pre-pregnancy adult abuse with an OR of 1.70 (95% CI 1.31–2.21) and abuse during pregnancy with an OR of 1.77 (95% CI 1.14–2.74). Further adjustment for childhood socio-economic position made no material difference, and there were no clear interactions between abuse and adult socio-economic position.
Conclusions Physical and sexual abuse histories were positively associated with pre-natal depression in two economically and ethnically distinct populations. Stronger associations with recent abuse may indicate that the association of abuse with depression wanes with time or may result from less accurate recall of remote events.
doi:10.1093/ije/dyq247
PMCID: PMC3066428  PMID: 21169318
Depression; pregnancy; violence; pre-natal care; adult survivors of child abuse; partner abuse; spouse abuse
14.  Duration of Lactation and Maternal Adipokines at 3 Years Postpartum 
Diabetes  2011;60(4):1277-1285.
OBJECTIVE
Lactation has been associated with reduced maternal risk of type 2 diabetes, the metabolic syndrome, and cardiovascular disease. We examined the relationship between breastfeeding duration and maternal adipokines at 3 years postpartum.
RESEARCH DESIGN AND METHODS
We used linear regression to relate the duration of lactation to maternal leptin, adiponectin, ghrelin, and peptide YY (PYY) at 3 years postpartum among 570 participants with 3-year postpartum blood samples (178 fasting), prospectively collected lactation history, and no intervening pregnancy in Project Viva, a cohort study of mothers and children.
RESULTS
A total of 88% of mothers had initiated breastfeeding, 26% had breastfed ≥12 months, and 42% had exclusively breastfed for ≥3 months. In multivariate analyses, we found that duration of total breastfeeding was directly related to PYY and ghrelin, and exclusive breastfeeding duration was directly related to ghrelin (predicted mean for never exclusively breastfeeding: 790.6 pg/mL vs. ≥6 months of exclusive breastfeeding: 1,008.1 pg/mL; P < 0.01) at 3 years postpartum, adjusting for pregravid BMI, gestational weight gain, family history of diabetes, parity, smoking status, and age. We found a nonlinear pattern of association between exclusive breastfeeding duration and adiponectin in multivariate-adjusted models.
CONCLUSIONS
In this prospective cohort study, we found a direct relationship between the duration of lactation and both ghrelin and PYY at 3 years postpartum.
doi:10.2337/db10-0637
PMCID: PMC3064101  PMID: 21350085
15.  Childhood body mass index trajectories: modeling, characterizing, pairwise correlations and socio-demographic predictors of trajectory characteristics 
Background
Modeling childhood body mass index (BMI) trajectories, versus estimating change in BMI between specific ages, may improve prediction of later body-size-related outcomes. Prior studies of BMI trajectories are limited by restricted age periods and insufficient use of trajectory information.
Methods
Among 3,289 children seen at 81,550 pediatric well-child visits from infancy to 18 years between 1980 and 2008, we fit individual BMI trajectories using mixed effect models with fractional polynomial functions. From each child's fitted trajectory, we estimated age and BMI at infancy peak and adiposity rebound, and velocity and area under curve between 1 week, infancy peak, adiposity rebound, and 18 years.
Results
Among boys, mean (SD) ages at infancy BMI peak and adiposity rebound were 7.2 (0.9) and 49.2 (11.9) months, respectively. Among girls, mean (SD) ages at infancy BMI peak and adiposity rebound were 7.4 (1.1) and 46.8 (11.0) months, respectively. Ages at infancy peak and adiposity rebound were weakly inversely correlated (r = -0.09). BMI at infancy peak and adiposity rebound were positively correlated (r = 0.76). Blacks had earlier adiposity rebound and greater velocity from adiposity rebound to 18 years of age than whites. Higher birth weight z-score predicted earlier adiposity rebound and higher BMI at infancy peak and adiposity rebound. BMI trajectories did not differ by birth year or type of health insurance, after adjusting for other socio-demographics and birth weight z-score.
Conclusions
Childhood BMI trajectory characteristics are informative in describing childhood body mass changes and can be estimated conveniently. Future research should evaluate associations of these novel BMI trajectory characteristics with adult outcomes.
doi:10.1186/1471-2288-12-38
PMCID: PMC3375197  PMID: 22458308
16.  Ongoing monitoring of data clustering in multicenter studies 
Background
Multicenter study designs have several advantages, but the possibility of non-random measurement error resulting from procedural differences between the centers is a special concern. While it is possible to address and correct for some measurement error through statistical analysis, proactive data monitoring is essential to ensure high-quality data collection.
Methods
In this article, we describe quality assurance efforts aimed at reducing the effect of measurement error in a recent follow-up of a large cluster-randomized controlled trial through periodic evaluation of intraclass correlation coefficients (ICCs) for continuous measurements. An ICC of 0 indicates the variance in the data is not due to variation between the centers, and thus the data are not clustered by center.
Results
Through our review of early data downloads, we identified several outcomes (including sitting height, waist circumference, and systolic blood pressure) with higher than expected ICC values. Further investigation revealed variations in the procedures used by pediatricians to measure these outcomes. We addressed these procedural inconsistencies through written clarification of the protocol and refresher training workshops with the pediatricians. Further data monitoring at subsequent downloads showed that these efforts had a beneficial effect on data quality (sitting height ICC decreased from 0.92 to 0.03, waist circumference from 0.10 to 0.07, and systolic blood pressure from 0.16 to 0.12).
Conclusions
We describe a simple but formal mechanism for identifying ongoing problems during data collection. The calculation of the ICC can easily be programmed and the mechanism has wide applicability, not just to cluster randomized controlled trials but to any study with multiple centers or with multiple observers.
doi:10.1186/1471-2288-12-29
PMCID: PMC3313871  PMID: 22413923
17.  Timing of Solid Food Introduction and Risk of Obesity in Preschool-Aged Children 
Pediatrics  2011;127(3):e544-e551.
OBJECTIVE:
To examine the association between timing of introduction of solid foods during infancy and obesity at 3 years of age.
METHODS:
We studied 847 children in Project Viva, a prospective pre-birth cohort study. The primary outcome was obesity at 3 years of age (BMI for age and gender ≥95th percentile). The primary exposure was the timing of introduction of solid foods, categorized as <4, 4 to 5, and ≥6 months. We ran separate logistic regression models for infants who were breastfed for at least 4 months (“breastfed”) and infants who were never breastfed or stopped breastfeeding before the age of four months (“formula-fed”), adjusting for child and maternal characteristics, which included change in weight-for-age z score from 0 to 4 months–a marker of early infant growth.
RESULTS:
In the first 4 months of life, 568 infants (67%) were breastfed and 279 (32%) were formula-fed. At age 3 years, 75 children (9%) were obese. Among breastfed infants, the timing of solid food introduction was not associated with odds of obesity (odds ratio: 1.1 [95% confidence interval: 0.3–4.4]). Among formula-fed infants, introduction of solid foods before 4 months was associated with a sixfold increase in odds of obesity at age 3 years; the association was not explained by rapid early growth (odds ratio after adjustment: 6.3 [95% confidence interval: 2.3–6.9]).
CONCLUSIONS:
Among formula-fed infants or infants weaned before the age of 4 months, introduction of solid foods before the age of 4 months was associated with increased odds of obesity at age 3 years.
doi:10.1542/peds.2010-0740
PMCID: PMC3065143  PMID: 21300681
obesity; infant feeding; complementary foods
18.  Higher adiposity in infancy associated with recurrent wheeze in a prospective cohort of children 
Background
Few prospective data link early childhood adiposity with asthma-related symptoms.
Objective
We sought to examine the associations of weight-for-length (WFL) at age 6 months with incidence of wheezing by age 3 years.
Methods
We studied 932 children in a prospective cohort of children. The main outcome was recurrent wheezing, which was defined as parents’ report of wheezing between 2 and 3 years of age plus wheezing in either year 1 or 2 of life. Secondary outcomes included any wheezing from 6 months to 3 years and current asthma. We used multiple logistic regression to examine associations of 6-month WFL z scores with these outcomes.
Results
At 6 months, the infants’ mean WFL z score was 0.68 (SD, 0.94; range −2.96 to 3.24). By age 3 years, 14% of children had recurrent wheezing. After adjustment for a variety of potential confounders, we found that each 1-unit increment in 6-month WFL z score was associated with greater odds of recurrent wheezing (odds ratio [OR], 1.46; 95% CI, 1.11–1.91) and any wheezing (OR, 1.23; 95% CI, 1.03–1.48). We observed a weaker association between 6-month WFL z score and current asthma (OR, 1.22; 95% CI, 0.94–1.59).
Conclusion
Infants with higher WFL z scores at 6 months of age had a greater risk of recurrent wheezing by age 3 years. It is unclear whether the relationship of infant adiposity and early-life wheeze extends to allergic asthma or wheeze that can persist into later childhood. Our findings suggest that early interventions to prevent excess infant adiposity might help reduce children’s risk of asthma-related symptoms.
doi:10.1016/j.jaci.2008.03.021
PMCID: PMC3253368  PMID: 18466784
Asthma; wheeze; adiposity; children; prospective study
19.  Trends in Birth Weight and Gestational Length Among Singleton Term Births in the United States 
Obstetrics and gynecology  2010;115(2 Pt 1):357-364.
OBJECTIVE
To estimate changes over time in birth weight for gestational age and in gestational length among term singleton neonates born from 1990 to 2005.
METHODS
We used data from the U.S. National Center for Health Statistics for 36,827,828 singleton neonates born at 37–41 weeks of gestation, 1990–2005. We examined trends in birth weight, birth weight for gestational age, large and small for gestational age, and gestational length in the overall population and in a low-risk subgroup defined by maternal age, race or ethnicity, education, marital status, smoking, gestational weight gain, delivery route, and obstetric care characteristics.
RESULTS
In 2005, compared with 1990, we observed decreases in birth weight (−52 g in the overall population, −79 g in a homogenous low-risk subgroup) and large for gestational age birth (−1.4% overall, −2.2% in the homogenous subgroup) that were steeper after 1999 and persisted in regression analyses adjusted for maternal and neonate characteristics, gestational length, cesarean delivery, and induction of labor. Decreases in mean gestational length (−0.34 weeks overall) were similar regardless of route of delivery or induction of labor.
CONCLUSION
Recent decreases in fetal growth among U.S., term, singleton neonates were not explained by trends in maternal and neonatal characteristics, changes in obstetric practices, or concurrent decreases in gestational length.
LEVEL OF EVIDENCE
III
doi:10.1097/AOG.0b013e3181cbd5f5
PMCID: PMC3219436  PMID: 20093911
20.  Breast-Feeding and Risk for Childhood Obesity 
Diabetes care  2006;29(10):2231-2237.
OBJECTIVE
We sought to evaluate whether maternal diabetes or weight status attenuates a previously reported beneficial effect of breast-feeding on childhood obesity.
RESEARCH DESIGN AND METHODS
Growing Up Today Study (GUTS) participants were offspring of women who participated in the Nurses’ Health Study II. In the present study, 15,253 girls and boys (aged 9–14 years in 1996) were included. Maternal diabetes and weight status and infant feeding were obtained by maternal self-report. We defined maternal overweight as BMI ≥25 kg/m2. Childhood obesity, from self-reported height and weight, was based on the Centers for Disease Control and Prevention definitions as normal, at risk for overweight, or overweight. Maternal status categories were nondiabetes/normal weight, nondiabetes/overweight, or diabetes. Logistic regression models used generalized estimating equations to account for nonindependence between siblings.
RESULTS
For all subjects combined, breast-feeding was associated with reduced overweight (compared with normal weight) in childhood. Compared with exclusive use of formula, the odds ratio (OR) for exclusive breast-feeding was 0.66 (95% CI 0.53– 0.82), adjusted for age, sex, and Tanner stage. Results did not differ according to maternal status (nondiabetes/normal weight OR 0.73 [95% CI 0.49 –1.09]; nondiabetes/overweight 0.75 [0.57– 0.99]; and diabetes 0.62 [0.24 –1.60]). Further adjustment for potential confounders attenuated results, but results remained consistent across strata of maternal status (P value for interaction was 0.50).
CONCLUSIONS
Breast-feeding was inversely associated with childhood obesity regardless of maternal diabetes status or weight status. These data provide support for all mothers to breast-feed their infants to reduce the risk for childhood overweight.
doi:10.2337/dc06-0974
PMCID: PMC3210833  PMID: 17003298
21.  Maternal diet and cord blood leptin and adiponectin concentrations at birth 
Background & Aims
The purpose of this study was to determine the effects of total energy intake, macronutrient intake, and maternal adherence to Mediterranean diet or Alternative Healthy Eating Index (AHEI) on cord blood leptin and adiponectin levels, which have been associated with childhood adiposity.
Methods
We used multivariable linear regression to assess associations of maternal diet, averaged over 1st and 2nd trimesters, with cord blood adipokines of 780 women from the prospective cohort study Project Viva.
Results
Mean (SD) energy intake during pregnancy was 2135 (596) kcal. Mean (SD) cord blood levels of leptin and adiponectin were 9.0 (6.6) ng/ml and 28.6 (6.7) μg/ml, respectively. Neither closer adherence to a Mediterranean/AHEI pattern diet nor energy intake was associated with either cord blood leptin or adiponectin. Protein intake was associated with both marginally lower leptin (−0.22 ng/ml [95% CI −0.41, −0.02] for each 1% of energy) and adiponectin (−0.25 μg/ml [95% CI −0.48, −0.02]).
Conclusions
Closer adherence to a Mediterranean/AHEI pattern diet during pregnancy was not associated with cord blood leptin or adiponectin. Maternal protein intake was weakly but significantly associated with lower cord blood leptin and adiponectin.
doi:10.1016/j.clnu.2010.03.004
PMCID: PMC2916023  PMID: 20363059
leptin; adiponectin; Mediterranean diet; Alternative healthy eating index (AHEI); Protein intake
22.  Maternal dietary pattern during pregnancy is not associated with recurrent wheeze in children 
Background
The rise in asthma prevalence over the last few decades may be due changes in pre-natal or early life environment including maternal diet during pregnancy. Previous studies have found associations between individual foods or nutrients consumed during pregnancy and asthma or wheeze in children, but these may be confounded by overall dietary pattern.
Objective
To determine if overall maternal dietary pattern during pregnancy is associated with recurrent wheeze in children.
Methods
1376 mother-infant pairs from Project Viva, a longitudinal pre-birth cohort, who had responses for food frequency questionnaires in the 1st and 2nd trimester and outcome data at 3 years of age were included. Multivariable logistic regression was used to look at associations between dietary pattern and the primary outcome of recurrent wheeze at 3 years. Overall dietary pattern was examined using Mediterranean diet score, Alternate Healthy Eating Index modified for pregnancy (AHEI-P), and principal components analysis to look at Western and Prudent diets.
Results
None of these dietary patterns was associated with the primary outcome of recurrent wheeze in children in either the crude or in the multivariable models (multivariable model: OR per one point increase Mediterranean diet 0.98 [95% CI 0.89, 1.08] AHEI-P 1.07 [0.87, 1.30] Prudent 1.02 [0.83, 1.26] Western 0.98 [0.81, 1.19]).
Conclusion
Overall dietary pattern during pregnancy is not associated with recurrent wheeze in this cohort. Maternal intake of individual nutrients may be more important determinants ofoffspring wheeze-associated illness than is dietary pattern.
doi:10.1016/j.jaci.2010.05.009
PMCID: PMC2917539  PMID: 20584543
asthma; dietary pattern; Mediterranean diet; healthy diet; principal components; childhood wheeze; pregnancy
23.  Effect of Treatment of Gestational Diabetes Mellitus on Obesity in the Next Generation 
Diabetes Care  2010;33(5):964-968.
OBJECTIVE
Gestational diabetes mellitus (GDM) may cause obesity in the offspring. The objective was to assess the effect of treatment for mild GDM on the BMI of 4- to 5-year-old children.
RESEARCH DESIGN AND METHODS
Participants were 199 mothers who participated in a randomized controlled trial of the treatment of mild GDM during pregnancy and their children. Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance program in the state of South Australia. The main outcome measure was age- and sex-specific BMI Z score based on standards of the International Obesity Task Force.
RESULTS
At birth, prevalence of macrosomia (birth weight ≥4,000 g) was 5.3% among the 94 children whose mothers were in the intervention group, and 21.9% among the 105 children in the routine care control group. At 4- to 5-years-old, mean (SD) BMI Z score was 0.49 (1.20) in intervention children and 0.41 (1.40) among controls. The difference between treatment groups was 0.08 (95% CI −0.29 to 0.44), an estimate minimally changed by adjustment for maternal race, parity, age, and socio-economic index (0.08 [−0.29 to 0.45]). Evaluating BMI ≥85th percentile rather than continuous BMI Z score gave similarly null results.
CONCLUSIONS
Although treatment of GDM substantially reduced macrosomia at birth, it did not result in a change in BMI at age 4- to 5-years-old.
doi:10.2337/dc09-1810
PMCID: PMC2858199  PMID: 20150300
24.  Association of maternal prenatal depressive symptoms with child cognition at age 3 years 
SUMMARY
We examined the association of prenatal depressive symptoms at mid-pregnancy with child cognition at age 3 years in Project Viva, a pre-birth cohort study of 1030 mother-child pairs in eastern Massachusetts. We measured maternal depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS), a self-report measure validated for use during pregnancy. Measures of child cognition included the Peabody Picture Vocabulary Test (PPVT) and the Wide Range Achievement of Visual Motor Abilties (WRAVMA). At mid-pregnancy, 81 mothers (7.9%) scored 13 or above on the EPDS, indicating probable depression. In the unadjusted model, children born to mothers with prenatal depressive symptoms had PPVT scores that were 3.8 points lower [95% confidence interval (CI) −7.1, −0.5]. With adjustment for sociodemographics, the association substantially attenuated [adjusted β for PPVT score = −0.7 (95% CI −3.6, 2.3)]. In both unadjusted and multivariable models, prenatal depressive symptoms were not associated with WRAVMA scores [adjusted β for total WRAVMA score = −0.5 (95% CI −3.0, 2.1)]. We found no evidence to suggest that maternal prenatal depression is independently associated with early child cognition.
doi:10.1111/j.1365-3016.2010.01113.x
PMCID: PMC2860615  PMID: 20415752
25.  Associations of Early Life Risk Factors with Infant Sleep Duration 
Academic pediatrics  2010;10(3):187-193.
Objective
Insufficient sleep in children is associated with adverse health effects. We examined the associations of early life risk factors with infant sleep duration.
Methods
We studied 1676 mother-infant pairs in a pre-birth cohort study. Main outcomes were mothers’ report of their infants’ average 24-hour sleep duration at 6 months, 1 year, and 2 years of age.
Results
Infants slept mean (SD) durations of 12.2 (2.0) hours/day at 6 months, 12.8 (1.6) hours/day at 1 year, and 11.9 (1.3) hours/day at 2 years. In multivariable regression models, maternal antenatal depression, introduction of solids < 4 months, and infant TV/video viewing were associated with shorter sleep durations at both 1 and 2 years of age. Estimates were 0.36 fewer hours/day of sleep for maternal antenatal depression, 0.39 fewer hours/day of sleep if infant was introduced to solids < 4 months, and 0.11 fewer hours/day of sleep for each 1-hour of TV viewed per week. Attendance at child care outside the home was associated with 0.18 fewer hours/day of sleep at age 2 years. At 2 years of age, black, Hispanic, and Asian infants slept 0.40, 0.82, and 0.95 fewer hours per day, respectively, than white infants.
Conclusions
Maternal depression during pregnancy, early introduction of solid foods, infant TV viewing, and attendance of child care were associated with shorter infant sleep duration. Racial/ethnic minority children slept fewer hours in the first two years of life than white children. Our results suggest that various risk factors, some potentially modifiable, are worthy of clinical consideration when addressing infant sleep duration.
doi:10.1016/j.acap.2010.01.007
PMCID: PMC2866807  PMID: 20347414

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