How the Environmental Influences on Child Health Outcome (ECHO) cohort can spur discoveries in environmental epidemiology.

The Environmental Influences on Child Health Outcome (ECHO) program at the National Institutes of Health is an innovative, large, collaborative research initiative whose mission is to enhance the health of children for generations to come. The goal of the ECHO program is to examine effects of a broad array of early environmental exposures on child health and development. The information includes longitudinal data and biospecimens from more than 100 000 children and family members from diverse settings across the United States ECHO investigators have published collaborative analyses showing associations of environmental exposures-primarily in the developmentally sensitive pre-, peri-, and postnatal periods-with preterm birth and childhood asthma, obesity, neurodevelopment, and positive health. Investigators have addressed health disparities, joint effects of environmental and social determinants, and effects of mixtures of chemicals. The ECHO cohort is now entering its second 7-year cycle (2023-2030), which will add the preconception period to its current focus on prenatal through adolescence. Through a controlled access public-use database, ECHO makes its deidentified data available to the general scientific community. ECHO cohort data provide opportunities to fill major knowledge gaps in environmental epidemiology and to inform policies, practices, and programs to enhance child health. This article is part of a Special Collection on Environmental Epidemiology.

Principles and Practices of Returning Individual Research Results to Participants in Large Studies of Pregnancy and Childhood.

Investigators conducting human subject research have typically conveyed only clinically actionable results back to individual participants. Shifting scientific culture around viewing participants as partners in research, however, is prompting investigators to consider returning as much data or results as the participant would like, even if they are not clearly actionable. Expanding return of individual results may add value for individual participants and their communities, refine future research questions and methods, build trust, and enhance retention of participants. Yet, gaps remain in understanding the implications of these changes for groups of 'vulnerable' participants, including pregnant and pediatric participants. We present the findings of a National Institutes of Health workshop on returning individual research results, particularly as applicable to pregnant and pediatric participants. Research participants who were panelists at the workshop agreed that they desire to receive their results. Workshop findings and current literature indicate that participants have differing preferences for what results they receive. One way to address the limits of current practice is to develop flexible digital platforms that convey individual results along with researchers' availability to answer questions, and to provide as much information as possible about actionable steps to control environmental exposures associated with disease risk.

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva.

BACKGROUND: Corticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood. METHODS: We investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn. RESULTS: Maternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, ß = 0.64, SE = 0.30). CONCLUSION: In our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood.

Maternal antibiotic use during pregnancy and childhood obesity at age 5 years.

OBJECTIVE: The benefits of antibiotic treatment during pregnancy are immediate, but there may be long-term risks to the developing child. Prior studies show an association between early life antibiotics and obesity, but few have examined this risk during pregnancy. SUBJECTS: To evaluate the association of maternal antibiotic exposure during pregnancy on childhood BMI-z at 5 years, we conducted a retrospective cohort analysis. Using electronic health record data from seven health systems in PCORnet, a national distributed clinical research network, we included children with same-day height and weight measures who could be linked to mothers with vital measurements during pregnancy. The primary independent variable was maternal outpatient antibiotic prescriptions during pregnancy (any versus none). We examined dose response (number of antibiotic episodes), spectrum and class of antibiotics, and antibiotic episodes by trimester. The primary outcome was child age- and sex-specific BMI-z at age 5 years. RESULTS: The final sample was 53,320 mother-child pairs. During pregnancy, 29.9% of mothers received antibiotics. In adjusted models, maternal outpatient antibiotic prescriptions during pregnancy were not associated with child BMI-z at age 5 years (ß = 0.00, 95% CI -0.03, 0.02). When evaluating timing during pregnancy, dose-response, spectrum and class of antibiotics, there were no associations of maternal antibiotics with child BMI-z at age 5 years. CONCLUSION: In this large observational cohort, provision of antibiotics during pregnancy was not associated with childhood BMI-z at 5 years.

Association of vitamin E intake at early childhood with alanine aminotransferase levels at mid-childhood.

The extent to which vitamin E (alpha-tocopherol) intake early in childhood is associated with alanine aminotransferase (ALT) level later in childhood is unknown. The objective of this research is to test the hypothesis that higher alpha-tocopherol intake during early childhood is associated with lower odds of elevated ALT levels during mid-childhood and to examine how body mass index (BMI) influences these relationships. We studied 528 children in Project Viva. Mothers reported child dietary intake at early childhood visits (median 3.1 years) using a validated food frequency questionnaire. At mid-childhood (median 7.6 years), we collected child blood and anthropometric data. The main outcome was elevated sex-specific mid-childhood ALT level (≥22.1 U/L for female children and ≥25.8 U/L for male children). In multivariable logistic regression models, we assessed the association of energy-adjusted alpha-tocopherol intake with ALT levels, adjusting for child age, sex, race/ethnicity, diet, and age-adjusted sex-specific BMI z-score at mid-childhood. Among children in this study, 48% were female, 63% were non-Hispanic white, 19% were non-Hispanic black, and 4% were Hispanic/Latino. Mean alpha-tocopherol intake was 3.7 ± 1.0 mg/day (range, 1.4-9.2) at early childhood. At mid-childhood, mean BMI z-score was 0.41 ± 1.0 units and 22% had an elevated ALT level. In multivariable-adjusted logistic regression models, children with higher early childhood vitamin E intake had lower odds of elevated mid-childhood ALT (adjusted odds ratio [AOR], 0.62; 95% confidence interval [CI], 0.39, 0.99) for quartiles 2-4 compared with the lowest quartile of intake. Findings persisted after accounting for early childhood diet (AOR, 0.62; 95% CI, 0.36, 1.08) and were strengthened after additionally accounting for mid-childhood BMI z-score (AOR, 0.56; 95% CI, 0.32, 0.99). CONCLUSION: In this cohort, higher early childhood intake of alpha-tocopherol was associated with lower odds of elevated mid-childhood ALT level. (Hepatology 2018;67:1339-1347).

Addressing the impact of opioids on women and children.

Women and children bear a substantial part of the burden of opioid overuse in the United States. Opioid use during pregnancy can lead to neonatal opioid withdrawal syndrome, and both the mothers and babies may be at higher risk of opioid use and its consequences later in the life course, setting up intergenerational cycles of opioid overuse. As part of the HEAL (Helping to End Addiction Long-term) Initiative of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Environmental influences on Child Health Outcomes program are together launching observational and intervention research programs to interrupt these cycles, beginning with opportunities in pregnancy and the newborn period. The Eunice Kennedy Shriver National Institute of Child Health and Human Development has also launched programs to find alternatives to opioids for painful conditions in women of reproductive age, including a range of gynecologic conditions. These coordinated efforts promise to help turn the tide against the opioid crisis by providing the necessary evidence to improve care for women and children affected by these substances.

Hepatotoxicity of Statins as Determined by Serum Alanine Aminotransferase in a Pediatric Cohort With Dyslipidemia.

OBJECTIVE: The aim of the study was to evaluate the hepatotoxicity of statins, as determined by serum alanine aminotransferase (ALT), in children and adolescents with dyslipidemia in real-world clinical practice. STUDY DESIGN: Clinical and laboratory data were prospectively collected between September 2010 and March 2014. We compared ALT levels between patients prescribed versus not prescribed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), and then compared ALT before and after initiation of statins. RESULTS: Over the 3.5-year observation period, there were 2704 ALT measurements among 943 patients. The mean age was 14 years; 54% were boys, 47% obese, and 208 patients were treated with statins. Median follow-up after first ALT was 18 months. The mean (SD) ALT in statin and non-statin users was 23 (20) U/L and 28 (28) U/L, respectively. In models adjusted for age, sex, and race, ALT was 2.1 U/L (95% CI 0.1 to 4.4; P = 0.04) lower among statin users, which was attenuated after adjustment for weight category. Patients started on statins during the observation period did not demonstrate an increase in ALT over time (ALT 0.9 U/L [95% confidence interval -5.2 to 3.4] increase per year; P = 0.7). CONCLUSIONS: In our study population, we did not observe a higher burden of ALT elevations among pediatric patients on statins as compared to those with dyslipidemia who are not on statins, supporting the hepatic safety of statin use in childhood.

Seasonal and weather variation of sleep and physical activity in 12-14-year-old children.

Background: Understanding variation in physical activity (PA) and sleep is necessary to develop novel intervention strategies targeting adolescents' health behaviors. We examined the extent to which PA and sleep vary by aspects of the physical environment. Participants: We performed a cross-sectional analysis of 669 adolescents in the Project Viva cohort. Methods: We estimated total PA, sleep duration, sleep efficiency, and sleep midpoint timing from wrist accelerometers. We used multivariable linear regression models and generalized estimated equations to assess associations of PA and sleep with season and daily weather conditions obtained from the National Oceanic and Atmospheric Administration archive. Results: Mean age was 12.9 (SD 0.6) years; 51% were female and 68% were white. Mean sleep duration was 466 (SD 42) min per night and total PA was 1,652 (SD 431) counts per min per day. Sleep midpoint time was 41 (95% CI: 27 to 54) min later in summer, 28 (95% CI: -41 to -14) min earlier in spring, and 29 (95% CI: -43 to -15) min earlier in autumn compared to winter. Higher temperature and longer day length both were associated with small reductions of nightly sleep duration. Adolescents were less physically active during winter and on rainy and short sunlight days. There was an inverse U-shaped relationship between PA and mean temperature. Conclusions: Season was associated with large changes in sleep timing, and smaller changes in other sleep and PA measurements. Given the importance of sleep and circadian alignment, future health behavioral interventions may benefit by targeting "season-specific" interventions.

What cervical screening is appropriate for women who have been vaccinated against high risk HPV? A simulation study.

Women vaccinated against HPV16/18 are approaching the age for cervical screening; however, an updated screening algorithm has not been agreed. We use a microsimulation model calibrated to real published data to determine the appropriate screening intensity for vaccinated women. Natural histories in the absence of vaccination were simulated for 300,000 women using 10,000 sets of transition probabilities. Vaccination with (i) 100% efficacy against HPV16/18, (ii) 15% cross-protection, (iii) 22% cross-protection, (iv) waning vaccine efficacy and (v) 100% efficacy against HPV16/18/31/33/45/52/58 was added, as were a range of screening scenarios appropriate to the UK. To benchmark cost-benefits of screening for vaccinated women, we evaluated the proportion of cancers prevented per additional screen (incremental benefit) of current cytology and likely HPV screening scenarios in unvaccinated women. Slightly more cancers are prevented through vaccination with no screening (70.3%, 95% CR: 65.1-75.5) than realistic compliance to the current UK screening programme in the absence of vaccination (64.3%, 95% CR: 61.3-66.8). In unvaccinated women, when switching to HPV primary testing, there is no loss in effectiveness when doubling the screening interval. Benchmarking supports screening scenarios with incremental benefits of ≥2.0%, and rejects scenarios with incremental benefits ≤0.9%. In HPV16/18-vaccinated women, the incremental benefit of offering a third lifetime screen was at most 3.3% (95% CR: 2.2-4.5), with an incremental benefit of 1.3% (-0.3-2.8) for a fourth screen. For HPV16/18/31/33/45/52/58-vaccinated women, two lifetime screens are supported. It is important to know women's vaccination status; in these simulations, HPV16/18-vaccinated women require three lifetime screens, HPV16/18/31/33/45/52/58-vaccinated women require two lifetime screens, yet unvaccinated women require seven lifetime screens.

Early-Pregnancy Plasma Concentrations of Perfluoroalkyl Substances and Birth Outcomes in Project Viva: Confounded by Pregnancy Hemodynamics?

Associations of prenatal exposure to perfluoroalkyl substances (PFAS), ubiquitous chemicals used in stain- and water-resistant products, with adverse birth outcomes may be confounded by pregnancy hemodynamics. We measured plasma concentrations of 4 PFAS in early pregnancy (median length of gestation, 9 weeks) among 1,645 women in Project Viva, a study of a birth cohort recruited during 1999-2002 in eastern Massachusetts. We fitted multivariable models to estimate associations of PFAS with birth weight-for-gestational age z score and length of gestation, adjusting for sociodemographic confounders and 2 hemodynamic markers: 1) plasma albumin concentration, a measure of plasma volume expansion, and 2) plasma creatinine concentration, used to estimate glomerular filtration rate. Perfluorooctane sulfonate (PFOS) and perfluorononanoate (PFNA) were weakly inversely associated with birth weight-for-gestational age z scores (adjusted ß = -0.04 (95% confidence interval (CI): -0.08, 0.01) and adjusted ß = -0.06 (95% CI: -0.11, -0.01) per interquartile-range increase, respectively). PFOS and PFNA were also associated with higher odds of preterm birth (e.g., for highest PFOS quartile vs. lowest, adjusted odds ratio = 2.4, 95% CI: 1.3, 4.4). Adjusting for markers of pregnancy hemodynamics (glomerular filtration rate and plasma albumin), to the extent that they accurately reflect underlying pregnancy physiology, did not materially affect associations. These results suggest that pregnancy hemodynamics may not confound associations with birth outcomes when PFAS are measured early in pregnancy.

Associations of Early to Mid-Childhood Adiposity with Elevated Mid-Childhood Alanine Aminotransferase Levels in the Project Viva Cohort.

OBJECTIVES: To examine the longitudinal relationship of early to mid-childhood adiposity measures with mid-childhood alanine aminotransferase (ALT) levels. STUDY DESIGN: We studied 635 children in the Project Viva cohort. Research staff measured weight, height, skinfolds thicknesses, and waist and hip circumferences at early (median 3.2 years) and mid-childhood (median 7.7 years) visits. At mid-childhood, we collected blood for ALT analysis. We used established sex-specific ALT cut-offs to define elevated ALT. In multivariable linear and logistic regression models, we assessed the association of adiposity measures from early to mid-childhood with mid-childhood ALT level, adjusting for confounders. RESULTS: Children were 48% female, 59% white, 21% black, 6% Hispanic/Latino, and 3% Asian. At early childhood, 29% had overweight/obesity and mean waist circumference was 51.5 (SD 3.8) cm. At mid-childhood, mean ALT was 20.3 (SD 7.3) units/L, and 23% had an elevated ALT. In multivariable-adjusted regression models, each additional 10-cm greater waist circumference at early childhood was associated with 1.99 (95% CI 1.19-3.33) greater odds of elevated ALT at mid-childhood. Greater increases from early to mid-childhood in body mass index z score, sum of subscapular and triceps skinfold thicknesses, waist circumference, and hip circumference were associated with greater ALT at mid-childhood. CONCLUSIONS: In this prospective cohort, greater waist circumference at early childhood and greater increases in adiposity measures from early to mid-childhood were associated with greater ALT levels at mid-childhood.

US adolescents at risk for not meeting physical activity recommendations by season.

BACKGROUND: We sought to identify regional and seasonal variation in not meeting physical activity (PA) recommendations of ≥60 min a day of moderate-to-vigorous PA (MVPA) and 3 h of vigorous PA per week (VPA) in a longitudinal cohort of United States (US) adolescents. METHODS: Participants in the Growing Up Today Study 2, a prospective study of 10,918 adolescents, self-reported season-specific weekly hours of MVPA and VPA from 2004 through 2011. To assess variation in PA by climate, we grouped the contiguous US into nine climatically consistent geographic regions. We also examined MVPA and VPA by season, sex, ethnicity, weight status, and age group. RESULTS: The majority (85%) of adolescents did not meet the MVPA recommendation, and 91% did not meet the VPA recommendation, for one or more seasons over the four study years. Across all climate regions, adolescents were two times more likely to not meet the MVPA recommendation during the winter compared to summer (odds ratio 2.02, 95% confidence interval: 1.96-2.08). CONCLUSION: Regardless of climate region, gender, ethnicity, or age group, adolescents were more likely not to meet MVPA or VPA recommendations in the winter than the summer. Adolescents may benefit from interventions aimed at increasing PA in the winter.

Supporting healthful lifestyles during pregnancy: a health coach intervention pilot study.

BACKGROUND: Excessive gestational weight gain (GWG) is associated with adverse health outcomes in both the mother and child. Many previous lifestyle interventions in women with excess weight during pregnancy encouraging appropriate GWG have been unsuccessful, and there remains no consensus about the content, format, or theoretical framework of GWG interventions. We assessed the feasibility and acceptability of a remote health coach intervention to promote healthful lifestyle behaviors and appropriate GWG among overweight pregnant women. METHODS: At one northeastern US clinic, we enrolled 30 overweight (pre-pregnancy BMI ≥ 25 kg/m2) pregnant women at a median gestation of 12.5 weeks (IQR: 11-15) into a one-arm trial. We connected participants with a health coach to provide behavioral support to help participants adopt healthful lifestyles during pregnancy. Health coaches contacted participants by phone every 2-3 weeks to monitor goals, and sent emails and text messages between calls. Participants completed baseline (N = 30) and follow-up (N = 26) surveys at the end of the intervention (36 weeks gestation), as well as follow-up phone interviews (N = 18). RESULTS: Among 30 participants, median age was 32 years (IQR: 28-33), median self-reported pre-pregnancy BMI was 27.3 kg/m2 (IQR: 25.7-31.1), and 17/30 were white, 9/30 African-American, and 3/30 Asian. Three-quarters (22/29) of participants completed at least a college degree. Although 25/30 participants reported in baseline surveys that they worried about being able to lose the weight postpartum that they expected to gain during pregnancy, just 12/26 participants reported the same at follow-up (P < 0.001). In follow-up surveys, 21/26 participants reported that health coaches were helpful in keeping them motivated, and 22/26 thought the phone conversations helped them face problems and find solutions. Based on qualitative assessment, several themes emerged in follow-up interviews about the quality of the intervention including accountability and support from health coaches. Participants also expressed desire for more visual resources and integration with standard clinical care to improve the intervention. CONCLUSIONS: We demonstrated feasibility and high participant satisfaction with our remote health coach intervention during pregnancy. We identified areas in which we could refine the intervention for inclusion in a full-scale RCT, such as integration with clinical care and additional visual resources. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov ( NCT03080064 , 3/14/2017).

Development and testing of a novel survey to assess Stakeholder-driven Community Diffusion of childhood obesity prevention efforts.

BACKGROUND: Involving groups of community stakeholders (e.g., steering committees) to lead community-wide health interventions appears to support multiple outcomes ranging from policy and systems change to individual biology. While numerous tools are available to measure stakeholder characteristics, many lack detail on reliability and validity, are not context specific, and may not be sensitive enough to capture change over time. This study describes the development and reliability of a novel survey to measure Stakeholder-driven Community Diffusion via assessment of stakeholders' social networks, knowledge, and engagement about childhood obesity prevention. METHODS: This study was completed in three phases. Phase 1 included conceptualization and online survey development through literature reviews and expert input. Phase 2 included a retrospective study with stakeholders from two completed whole-of-community interventions. Between May-October 2015, 21 stakeholders from the Shape Up Somerville and Romp & Chomp interventions recalled their social networks, knowledge, and engagement pre-post intervention. We also assessed one-week test-retest reliability of knowledge and engagement survey modules among Shape Up Somerville respondents. Phase 3 included survey modifications and a second prospective reliability assessment. Test-retest reliability was assessed in May 2016 among 13 stakeholders involved in ongoing interventions in Victoria, Australia. RESULTS: In Phase 1, we developed a survey with 7, 20 and 50 items for the social networks, knowledge, and engagement survey modules, respectively. In the Phase 2 retrospective study, Shape Up Somerville and Romp & Chomp networks included 99 and 54 individuals. Pre-post Shape Up Somerville and Romp & Chomp mean knowledge scores increased by 3.5 points (95% CI: 0.35-6.72) and (- 0.42-7.42). Engagement scores did not change significantly (Shape Up Somerville: 1.1 points (- 0.55-2.73); Romp & Chomp: 0.7 points (- 0.43-1.73)). Intraclass correlation coefficients (ICCs) for knowledge and engagement were 0.88 (0.67-0.97) and 0.97 (0.89-0.99). In Phase 3, the modified knowledge and engagement survey modules included 18 and 25 items, respectively. Knowledge and engagement ICCs were 0.84 (0.62-0.95) and 0.58 (0.23-0.86). CONCLUSIONS: The survey measures upstream stakeholder properties-social networks, knowledge, and engagement-with good test-retest reliability. Future research related to Stakeholder-driven Community Diffusion should focus on prospective change and survey validation for intervention effectiveness.

Some utilities to help produce Rich Text Files from Stata.

Producing RTF files from Stata can be difficult and somewhat cryptic. Utilities are introduced to simplify this process; one builds up a table row-by-row, another inserts a PNG image file into an RTF document, and the others start and finish the RTF document.

Evaluating the Relationship Between Birth Weight for Gestational Age and Adult Blood Pressure Using Participants From a Cohort of Same-Sex Siblings, Discordant on Birth Weight Percentile.

Many studies have described an inverse relationship between birth weight and blood pressure (BP). Debate continues, however, over the magnitude and validity of the association. This analysis draws on the Early Determinants of Adult Health study (2005-2008), a cohort of 393 US adults (mean age 43 years; 47% male), including 114 same-sex sibling pairs deliberately sampled to be discordant on sex-specific birth weight for gestational age (BW/GA) in order to minimize confounding in studies of fetal growth and midlife health outcomes. Every quintile increment in BW/GA percentile was associated with a 1.04-mm Hg decrement in adult systolic BP (95% confidence interval (CI): -2.14, 0.06) and a 0.63-mm Hg decrement in diastolic BP (95% CI: -1.35, 0.09), controlling for sex, age, site, smoking, and race/ethnicity. The relationship was strongest among those in the lowest decile of BW/GA. Adding adult body mass index to the models attenuated the estimates (e.g., to -0.90 mm Hg (95% CI: -1.94, 0.14) for systolic BP). In the sibling-pair subgroup, associations were slightly stronger but with wider confidence intervals (e.g., -1.22 mm Hg (95% CI: -5.20, 2.75) for systolic BP). In conclusion, we found a small inverse relationship between BW/GA and BP in cohort and sibling-pair analyses, but the clinical or public health significance is likely limited.

The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial.

BACKGROUND: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. METHODS: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1ß, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. RESULTS: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. CONCLUSIONS: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ; Date Registered 09/03/2007).

Infant Nutritional Status and Markers of Environmental Enteric Dysfunction are Associated with Midchildhood Anthropometry and Blood Pressure in Tanzania.

OBJECTIVE: To assess whether growth and biomarkers of environmental enteric dysfunction in infancy are related to health outcomes in midchildhood in Tanzania. STUDY DESIGN: Children who participated in 2 randomized trials of micronutrient supplements in infancy were followed up in midchildhood (4.6-9.8 years of age). Anthropometry was measured at age 6 and 52 weeks in both trials, and blood samples were available from children at 6 weeks and 6 months from 1 trial. Linear regression was used for height-for-age z-score, body mass index-for-age z-score, and weight for age z-score, and blood pressure analyses; log-binomial models were used to estimate risk of overweight, obesity, and stunting in midchildhood. RESULTS: One hundred thirteen children were followed-up. Length-for-age z-score at 6 weeks and delta length-for-age z-score from 6 to 52 weeks were associated independently and positively with height-for-age z-score and inversely associated with stunting in midchildhood. Delta weight-for-length and weight-for-age z-score were also positively associated with midchildhood height-for-age z-score. The 6-week and delta weight-for-length z-scores were associated independently and positively with midchildhood body mass index-for-age z-score and overweight, as was the 6-week and delta weight-for-age z-score. Delta length-for-age z-score was also associated with an increased risk of overweight in midchildhood. Body mass index-for-age z-score in midchildhood was associated positively with systolic blood pressure. Serum anti-flagellin IgA concentration at 6 weeks was also associated with increased blood pressure in midchildhood. CONCLUSIONS: Anthropometry at 6 weeks and growth in infancy independently predict size in midchildhood, while anti-flagellin IgA, a biomarker of environmental enteric dysfunction, in early infancy is associated with increased blood pressure in midchildhood. Interventions in early life should focus on optimizing linear growth while minimizing excess weight gain and environmental enteric dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730 and NCT00421668.

Higher Maternal Protein Intake during Pregnancy Is Associated with Lower Cord Blood Concentrations of Insulin-like Growth Factor (IGF)-II, IGF Binding Protein 3, and Insulin, but Not IGF-I, in a Cohort of Women with High Protein Intake.

Background: Prenatal exposure to dietary protein may program growth-regulating hormones, consequently influencing early-life growth patterns and later risk of associated chronic diseases. The insulin-like growth factor (IGF) axis is of particular interest in this context given its influence on pre- and postnatal growth and its sensitivity to the early nutritional environment.Objective: Our objective was to examine associations of maternal protein intake during pregnancy with cord blood concentrations of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3), and insulin.Methods: We studied 938 mother-child pairs from early pregnancy through delivery in the Project Viva cohort. Using multivariable linear regression models adjusted for maternal race/ethnicity, education, income, smoking, parity, height, and gestational weight gain and for child sex, we examined associations of second-trimester maternal protein intake [grams per kilogram (weight before pregnancy) per day], as reported on a food frequency questionnaire, with IGF-I, IGF-II, IGFBP-3, and insulin concentrations in cord blood. We also examined how these associations may differ by child sex and parity.Results: Mothers were predominantly white (71%), college-educated (64%), and nonsmokers (67%). Mean ± SD protein intake was 1.35 ± 0.35 g ⋅ kg-1 ⋅ d-1 Each 1-SD increment in second-trimester protein intake corresponded to a change of -0.50 ng/mL (95% CI: -2.26, 1.26 ng/mL) in IGF-I and -0.91 µU/mL (95% CI: -1.45, -0.37 µU/mL) in insulin. Child sex and parity modified associations of maternal protein intake with IGF-II and IGFBP-3: protein intake was inversely associated with IGF-II in girls (P-interaction = 0.04) and multiparous mothers (P-interaction = 0.05), and with IGFBP-3 in multiparous mothers (P-interaction = 0.04).Conclusions: In a cohort of pregnant women with relatively high mean protein intakes, higher intake was associated with lower concentrations of growth-promoting hormones in cord blood, suggesting a pathway that may link higher protein intake to lower fetal growth. This trial was registered at clinicaltrials.gov as NCT02820402.