Prenatal exposure to air pollutant mixtures and birthweight in the upstate KIDS cohort.

BACKGROUND: Single-pollutant models have linked prenatal PM2.5 exposure to lower birthweight. However, analyzing air pollutant mixtures better captures pollutant interactions and total effects. Unfortunately, strong correlations between pollutants restrict traditional methods. OBJECTIVES: We explored the association between exposure to a mixture of air pollutants during different gestational age windows of pregnancy and birthweight. METHODS: We included 4,635 mother-infant dyads from a New York State birth cohort born 2008-2010. Air pollution data were sourced from the EPA's Community Multiscale Air Quality model and matched to the census tract centroid of each maternal home address. Birthweight and gestational age were extracted from vital records. We applied linear regression to study the association between prenatal exposure to PM2.5, PM10, NOX, SO2, and CO and birthweight during six sensitive windows. We then utilized Bayesian kernel machine regression to examine the non-linear effects and interactions within this five-pollutant mixture. Final models adjusted for maternal socio-demographics, infant characteristics, and seasonality. RESULTS: Single-pollutant linear regression models indicated that most pollutants were associated with a decrement in birthweight, specifically during the two-week window before birth. An interquartile range increase in PM2.5 exposure (IQR: 3.3 µg/m3) from the median during this window correlated with a 34 g decrement in birthweight (95 % CI: -54, -14), followed by SO2 (IQR: 2.0 ppb; ß: -31), PM10 (IQR: 4.6 µg/m3; ß: -29), CO (IQR: 60.8 ppb; ß: -27), and NOX (IQR: 7.9 ppb; ß: -26). Multi-pollutant BKMR models revealed that PM2.5, NOX, and CO exposure were negatively and non-linearly linked with birthweight. As the five-pollutant mixture increased, birthweight decreased until the median level of exposure. DISCUSSION: Prenatal exposure to air pollutants, notably PM2.5, during the final two weeks of pregnancy may negatively impact birthweight. The non-linear relationships between air pollution and birthweight highlight the importance of studying pollutant mixtures and their interactions.

Place-Based Child Opportunity at Birth and Child Development from Infancy to Age 4.

OBJECTIVE: The objective of this study was to evaluate whether the children's neighborhood quality, as a measure of place-based social determinants of health, is associated with the odds of developmental delay and developmental performance up to the age of 4 years. STUDY DESIGN: Mothers of 5702 children from the Upstate KIDS Study, a longitudinal population-based cohort of children born from 2008 through 2010, provided questionnaire data and a subset of 573 children participated in a clinic visit. The Child Opportunity Index 2.0 was linked to home census tract at birth. Probable developmental delays were assessed by the Ages and Stages Questionnaire up to 7 times between 4 and 36 months, and developmental performance was assessed via the Battelle Developmental Inventory at the age of 4 years. RESULTS: In unadjusted models, higher neighborhood opportunity was protective against developmental delays and was associated with slightly higher development scores at age 4. After adjusting for family-level confounding variables, 10-point higher Child Opportunity Index (on a 100-point scale) remained associated with a lower odds of any developmental delay (OR = .966, 95% CI = .940-.992), and specifically delays in the personal-social domain (OR = .921, 95% CI = .886-.958), as well as better development performance in motor (B = 0.79, 95% CI = 0.11-1.48), personal-social (B = 0.64, 95% CI = 0.003-1.28), and adaptive (B = 0.69, 95% CI = 0.04-1.34) domains at age 4. CONCLUSIONS: Community-level opportunities are associated with some aspects of child development prior to school entry. Pediatric providers may find it helpful to use neighborhood quality as an indicator to inform targeted developmental screening.

Longitudinal Child Growth Patterns in Twins and Singletons in the Upstate KIDS Cohort.

OBJECTIVES: To investigate childhood growth patterns in twins and to determine whether they show the same signs of excess growth as singletons born small-for-gestational age (SGA), which may confer future cardiometabolic risk. STUDY DESIGN: In the Upstate KIDS cohort of infants delivered from 2008 through 2010, we compared height, weight, and body mass index (BMI) z-scores at 0-3 and 7-9 years of age, as well as risk of rapid weight gain (RWG) in infancy and overweight/obesity beginning at 2 years, among appropriate-for-gestational age (AGA) twins (n = 1121), AGA singletons (n = 2684), and two groups of SGA twins: uncertain SGA twins (<10th percentile for birthweight by a singleton reference but >10th% by a population-based twin birthweight reference; n = 319) and true SGA twins (<10th% by a population-based twin reference; n = 144). RESULTS: Compared with AGA twins, both SGA twin groups had lower weight and BMI z-scores at both time points. By 7-9 years, both groups caught up in height with AGA twins. Compared with AGA singletons, z-score differences decreased between 0-3 and 7-9 years for uncertain SGA and true SGA twins, though true SGA twins had the lowest z-scores for all measures. During infancy, twins were more likely to display RWG compared with AGA singletons (RR = 2.06 to 2.67), which may reflect normal catch-up growth, as no twin group had higher prevalence of overweight/obesity at either time point. CONCLUSIONS: Though twins had lower height, weight, and BMI z-scores at birth and into toddlerhood, differences were reduced by 7-9 years, with no evidence of pathological growth and no group of twins showing elevated risk of overweight/obesity.

Indoor air pollution exposure and early childhood development in the Upstate KIDS Study.

BACKGROUND: Limited human studies have investigated the impact of indoor air pollution on early childhood neurodevelopment among the US population. We aimed to examine the associations between prenatal and postnatal indoor air pollution exposure and early childhood development in a population-based birth cohort. METHODS: This analysis included 4735 mother-child pairs enrolled between 2008 and 2010 in the Upstate KIDS Study. Indoor air pollution exposure from cooking fuels, heating fuels, and passive smoke during pregnancy, and at 12 and 36 months after birth were assessed by questionnaires. Five domains of child development were assessed by the Ages and Stages Questionnaire at 4, 8, 12, 18, 24, 30, and 36 months. Generalized estimating equations were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for potential confounders. RESULTS: Exposure to unclean cooking fuels (natural gas, propane, or wood) throughout the study period was associated with increased odds of failing any development domain (OR = 1.28, 95% CI 1.07, 1.53), the gross motor domain (OR = 1.52, 95% CI: 1.09, 2.13), and the personal-social domain (OR = 1.36, 95% CI: 1.00, 1.85), respectively. Passive smoke exposure throughout the study period increased the odds of failing the problem-solving domain by 71% (OR = 1.71, 95% CI 1.01, 2.91) among children of non-smoking mothers. No association was found between heating fuel use and failing any or specific domains. CONCLUSION: Unclean cooking fuel use and passive smoke exposure during pregnancy and early life were associated with developmental delays in this large prospective birth cohort.

Determinants of maternal and neonatal PFAS concentrations: a review.

Per- and polyfluoroalkyl substances (PFAS) are used for their properties such as stain and water resistance. The substances have been associated with adverse health outcomes in both pregnant mothers and infants, including pre-eclampsia and low birthweight. A growing body of research suggests that PFAS are transferred from mother to fetus through the placenta, leading to in utero exposure. A systematic review was performed using the PubMed database to search for studies evaluating determinants of PFAS concentrations in blood matrices of pregnant mothers and neonates shortly after birth. Studies were included in this review if an observational study design was utilized, exposure to at least one PFAS analyte was measured, PFAS were measured in maternal or neonatal matrices, at least one determinant of PFAS concentrations was assessed, and results such as beta estimates were provided. We identified 35 studies for inclusion in the review and evaluated the PFAS and determinant relationships among the factors collected in these studies. Parity, breastfeeding history, maternal race and country of origin, and household income had the strongest and most consistent evidence to support their roles as determinants of certain PFAS concentrations in pregnant mothers. Reported study findings on smoking status, alcohol consumption, and pre-pregnancy body mass index (BMI) suggest that these factors are not important determinants of PFAS concentrations in pregnant mothers or neonates. Further study into informative factors such as consumer product use, detailed dietary information, and consumed water sources as potential determinants of maternal or neonatal PFAS concentrations is needed. Research on determinants of maternal or neonatal PFAS concentrations is critical to estimate past PFAS exposure, build improved exposure models, and further our understanding on dose-response relationships, which can influence epidemiological studies and risk assessment evaluations. Given the potential for adverse outcomes in pregnant mothers and neonates exposed to PFAS, it is important to identify and understand determinants of maternal and neonatal PFAS concentrations to better implement public health interventions in these populations.

Effects on neonatal immunoglobulin concentrations by infant mode of delivery in the upstate KIDS study (2008-2010).

PROBLEM: Previous studies document an association between mode of delivery (MOD) and allergic conditions in children. Immunoglobulin (Ig) concentrations at birth may play a role. The goal of this study is to assess the impact of MOD on Ig concentrations at delivery from newborn dried blood spots (DBS). METHOD OF STUDY: The Upstate KIDS Study (2008-2010) is a prospective cohort of mother-child pairs recruited from New York State, excluding New York City. Ig subtypes IgA, IgE, IgG1 , IgG2 , IgG3 , IgG4 , and IgM were measured in residual NDBS from the Newborn Screening Program (N = 3274 infants). MOD was categorized as vaginal delivery (VD), emergency cesarean delivery (ECD) or planned cesarean delivery (PCD). Associations between MOD and Ig levels were assessed using ANOVA and multiple regression, with models adjusted for gestational age, birth weight, maternal race, plurality, and smoking status. RESULTS: IgA, and the IgG subtypes IgG3 and IgG4 were found to be significantly lower in PCD neonates relative to VD neonates in adjusted regression models: 3.57 mg/ml, (95% CI: 3.51, 3.63) compared to 3.64 mg/ml (95% CI: 3.59, 3.69); 8.95 ng/ml (95% CI: 8.88,9.03) compared to 9.03 ng/ml (95% CI: 8.98, 9.08) and 8.05 ng/ml (95% CI: 7.91, 8.20) compared to 8.22 ng/ml (95% CI: 7.91,8.20), respectively. CONCLUSIONS: MOD may thus be related to neonatal immune profile. Results were found to be robust to sensitivity testing based on maternal complications and indication for CD. Clinical implications are unclear given the small levels of association found in newborns, but the result suggests greater susceptibility to infection, and further study is warranted.

Maternal antenatal depression's effects on child developmental delays: Gestational age, postnatal depressive symptoms, and breastfeeding as mediators.

BACKGROUND: Maternal antenatal depression experienced around conception or during pregnancy may adversely affect child development. This study explores three potential mechanisms of the effects of antenatal depression on children's developmental delays at 2-3 years: gestational age of the child, continued depressive symptoms postnatally, and interrupted breastfeeding practices. METHODS: Mothers (N = 2888) of 3450 children, including 2303 singletons and 1147 multiples from the Upstate KIDS cohort provided data. Linked hospital discharge data was combined with mothers' reports to identify women with moderate to severe antenatal depression. Gestational age was extracted from birth certificates. Mothers completed a depression screener at 4 months postpartum, reported about their breastfeeding practices from 4 to 12 months postpartum, and completed a developmental delay screener when children were 24, 30, and 36 months. RESULTS: In unadjusted path analysis models, mothers with antenatal depression had more postnatal depressive symptoms and breastfed fewer months, which translated into children being more likely to have developmental delays. Gestational age was not a mediator. Effects were similar across girls and boys and singletons and twins, and largely held when adjusting for covariates. LIMITATIONS: Main limitations were the relatively advantaged sample and reliance on maternal report. CONCLUSIONS: Maternal antenatal depression may impact child development through continued depressive symptoms in the postpartum period and through reduced breastfeeding duration suggesting additional targets for intervention.

Displacement of peer play by screen time: associations with toddler development.

BACKGROUND: Young children's digital media use may adversely affect child development, but the mechanisms of this association are unclear. We evaluated whether screen time displaces reading and peer play time, which are subsequently associated with child development. METHODS: When children were 12, 18, 24, 30, and 36 months, mothers (n = 3894) reported the time their children spent on screens, being read to by an adult, and playing with other children. At 36 months, mothers completed the Ages and Stages Questionnaire©, an assessment of their child's developmental status. RESULTS: In unadjusted models, screen time from 12 to 36 months was not associated with reading but was associated with less time engaging in play with peers. In adjusted models accounting for developmental delay at 12 months, family and child characteristics, screen time was not directly associated with developmental delay. More peer play time was associated with a lower likelihood of developmental delay, and having higher screen time increased the likelihood of developmental delay indirectly through reduced peer play time. Results were similar for developmental delays in fine and gross motor, communication, and personal-social domains. CONCLUSIONS: Screen time in early childhood did not displace reported time spent reading, but did displace reported peer play time. IMPACT: Among children 1-3 years of age, more screen time was associated with less time engaged in peer play but not less reading with an adult. Having higher screen time from 1 to 3 years increased the odds of developmental delay indirectly through reduced peer play time. Ensuring that children engage in adequate time playing with peers may offset the negative associations between screen time and child development.

Interaction of maternal medication use with ambient heat exposure on congenital heart defects in the National Birth Defects Prevention Study.

BACKGROUND: Maternal exposure to weather-related extreme heat events (EHEs) has been associated with congenital heart defects (CHDs) in offspring. Certain medications may affect an individual's physiologic responses to EHEs. We evaluated whether thermoregulation-related medications modified associations between maternal EHE exposure and CHDs. METHODS: We linked geocoded residence data from the U.S. National Birth Defects Prevention Study, a population-based case-control study, to summertime EHE exposures. An EHE was defined using the 90th percentile of daily maximum temperature (EHE90) for each of six climate regions during postconceptional weeks 3-8. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for associations between EHE90 and the risk of CHDs were estimated by strata of maternal thermoregulation-related medication use and climate region. Interaction effects were evaluated on multiplicative and additive scales. RESULTS: Over 45% of participants reported thermoregulation-related medication use during the critical period of cardiogenesis. Overall, these medications did not significantly modify the association between EHEs and CHDs. Still, medications that alter central thermoregulation increased aORs (95% CI) of EHE90 from 0.73 (0.41, 1.30) among non-users to 5.09 (1.20, 21.67) among users in the Southwest region, U.S. This effect modification was statistically significant on the multiplicative (P = 0.03) and additive scales, with an interaction contrast ratio (95% CI) of 1.64 (0.26, 3.02). CONCLUSION: No significant interaction was found for the maternal use of thermoregulation-related medications with EHEs on CHDs in general, while medications altering central thermoregulation significantly modified the association between EHEs and CHDs in Southwest U.S. This finding deserves further research.

Exposure to perfluoroalkyl substances and neonatal immunoglobulin profiles in the upstate KIDS study (2008-2010).

Infant exposure to per/polyfluoroalkyl compounds is associated with immune disruption. We examined associations between neonatal concentrations of perflurooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) and immunoglobulin (Ig) isotype profiles in a prospective cohort of infants. We measured Ig isotypes, including IgA, IgE, IgM and the IgG subclasses IgG1, IgG2, IgG3, and IgG4, and PFOA and PFOS in newborn dried bloodspots from N = 3175 infants in the Upstate KIDS Study (2008-2010). We examined the association between newborn Ig isotype levels and individual PFOS and PFOA concentrations using mixed effects regression models with a random intercept to account for twins among study participants. We assessed the joint effect PFOA and PFOS with quantile-based g-computation on all singletons and one randomly selected twin (N = 2901), with Ig categorized as above or below median value. Models were adjusted for infant sex, and maternal pre-pregnancy body mass index, race, parity, age and infertility treatment. In adjusted models, PFOA was inversely associated with IgE (coefficient = -0.12 per unit increase in PFOA, 95% CI: -0.065, -0.17), whereas IgG2, IgM, and IgA were positively associated with PFOA (coefficient for IgG2 = 0.22, 95% CI: 0.15, 0.27; coefficient for IgM = 0.11, 95% CI: 0.08, 0.15; and coefficient for IgA = 0.15, 95% CI: 0.07, 0.18). There was no relation between PFOS and Ig isotypes. Analysis of the joint effect of PFOA and PFOS showed an OR of 1.2 (95% CI: 1.04, 1.36) for IgA and OR of 1.12 (95% CI: 1.00, 1.24) for IgG2 levels above the median for every quartile increase. PFOA levels were significantly associated with elevated IgA, IgM, IgG2, and reduced levels of IgE in single-pollutant models. A small but significant joint effect of PFOA and PFOS was observed. Our results suggest that early exposure to PFOA and PFOS may disrupt neonatal immunoglobulin levels.

Modeling Collective Invasion and Single-Cell Mesenchymal Invasion in Three-Dimensional Matrigel-Collagen I Cultures.

Understanding the modes and mechanisms of tumor cell invasion is key to developing targeted therapies against metastatic disease. In vitro assays modeling tumor progression have primarily been optimized for studying classical single-cell migration through an epithelial-mesenchymal transition (EMT). Although experimental and clinical histopathological evidence has revealed that tumor invasion is plastic and that epithelial carcinomas can invade by a range of modes that vary from single, mesenchyme-like cells, all the way to cohesive, collective units, few in vitro assays have been designed to assess these modes specifically. Thus, we have developed a Matrigel-Collagen I overlay assay that is suitable for identifying and quantifying both collective and mesenchymal invasion. This three-dimensional (3D) culture assay utilizes the features of Matrigel and Collagen I to mimic the laminin-rich basement membrane and the stiff, fibrillar Collagen I tumor microenvironment allowing for spheroid invasion to be assessed at the interface between these two matrix components.

Maternal obesity, gestational weight gain, and offspring asthma and atopy.

BACKGROUND: Maternal obesity may affect offspring asthma and atopic disease risk by altering fetal immune system development. However, few studies evaluate gestational weight gain (GWG). OBJECTIVE: To evaluate relationships between maternal body mass index (BMI), GWG, and persistent wheeze, eczema, allergy, and asthma risk in offspring through middle childhood. METHODS: A total of 5939 children from Upstate KIDS, a population-based longitudinal cohort of children born in upstate New York (2008-2019) were included in the analysis. Persistent wheeze or asthma, eczema, and allergy were maternally reported at multiple study time points throughout early and middle childhood. Poisson regression models with robust SEs were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CIs) for offspring atopic outcomes by maternal prepregnancy BMI and GWG. RESULTS: Prepregnancy BMI was associated with increased risk of persistent wheeze by 3 years of age even after adjustments for maternal atopy (class I obesity: aRR, 1.58; 95% CI, 1.13-2.20; class II or III obesity: aRR, 1.69; 95% CI, 1.22-2.35). Associations with reported asthma in middle childhood did not reach statistical significance. Furthermore, no associations were found between prepregnancy BMI and atopic outcomes in either early or middle childhood. GWG was not associated with higher risk of early childhood persistent wheeze or middle childhood asthma. CONCLUSION: Maternal prepregnancy BMI was associated with increased risk of offspring wheeze, whereas excessive GWG was generally not associated with childhood asthma or atopy.

Targeting a Tumor-Specific Epitope on Podocalyxin Increases Survival in Human Tumor Preclinical Models.

Podocalyxin (Podxl) is a CD34-related cell surface sialomucin that is normally highly expressed by adult vascular endothelia and kidney podocytes where it plays a key role in blocking adhesion. Importantly, it is also frequently upregulated on a wide array of human tumors and its expression often correlates with poor prognosis. We previously showed that, in xenograft studies, Podxl plays a key role in metastatic disease by making tumor initiating cells more mobile and invasive. Recently, we developed a novel antibody, PODO447, which shows exquisite specificity for a tumor-restricted glycoform of Podxl but does not react with Podxl expressed by normal adult tissue. Here we utilized an array of glycosylation defective cell lines to further define the PODO447 reactive epitope and reveal it as an O-linked core 1 glycan presented in the context of the Podxl peptide backbone. Further, we show that when coupled to monomethyl auristatin E (MMAE) toxic payload, PODO447 functions as a highly specific and effective antibody drug conjugate (ADC) in killing ovarian, pancreatic, glioblastoma and leukemia cell lines in vitro. Finally, we demonstrate PODO447-ADCs are highly effective in targeting human pancreatic and ovarian tumors in xenografted NSG and Nude mouse models. These data reveal PODO447-ADCs as exquisitely tumor-specific and highly efficacious immunotherapeutic reagents for the targeting of human tumors. Thus, PODO447 exhibits the appropriate characteristics for further development as a targeted clinical immunotherapy.

Age of Juice Introduction and Child Anthropometry at 2-3 and 7-9 Years.

OBJECTIVES: To assess the association between age of juice introduction and child anthropometry after the American Academy of Pediatrics changed their guidelines in 2017 to recommend delaying juice introduction until at least 12 months of age (previously 6 months), citing concerns of weight gain. STUDY DESIGN: Upstate KIDS is a prospective birth cohort with follow-up through 9 years of age. Juice introduction was assessed on parental questionnaires at 4-18 months and categorized as <6, 6-<12, and ≥12 months. Child height and weight were recorded at 2-3 and 7-9 years of age. Weight-, height-, and body mass index (BMI)-for-age and sex z scores were calculated using the Centers for Disease Control and Prevention reference. Overweight/obese and obese status were categorized as BMI-for-age z score ≥85th and ≥95th percentiles. Controlling for sociodemographic characteristics and parental BMI, we assessed the associations of age of juice introduction with child anthropometry. RESULTS: Prevalence of childhood obesity was 16.4% at 2-3 (n = 1713) and 22.8% at 7-9 years of age (n = 1283). Juice introduction at <6 vs ≥12 months was associated with higher weight-for-age z score at 2-3 years of age (mean difference = 0.21; 95% CI 0.04-0.37). At 7-9 years of age, juice introduction at <6 vs ≥12 months was related to higher BMI-for-age (0.38; 0.12-0.64) and weight-for-age z scores (0.27; 0.06-0.49). Risk of developing overweight/obesity and obesity was 1.54 (0.99-2.38) and 2.17 (1.11-4.23) times higher among children with juice introduced at <6 months. No associations were found with juice introduced at 6-<12 vs ≥12 months. CONCLUSIONS: Risk of developing overweight/obesity or obesity is higher among children introduced to juice before 6 months of age compared with ≥12 months.

Associations of toddler mechanical/distress feeding problems with psychopathology symptoms five years later.

BACKGROUND: Feeding problems are common in early childhood, and some evidence suggests that feeding problems may be associated with psychopathology. Few prospective studies have explored whether toddler feeding problems predict later psychopathology. METHODS: Mothers of 1,136 children from the Upstate KIDS cohort study provided data when children were 2.5 and 8 years of age. Food refusal (picky eating) and mechanical/distress feeding problems and developmental delays were assessed at 2.5 years. Child eating behaviors (enjoyment of food, food fussiness, and emotional under and overeating) and child psychopathology (attention-deficit/hyperactivity (ADHD), oppositional-defiant (OD), conduct disorder (CD), and anxiety/depression) symptoms were assessed at 8 years. RESULTS: Mechanical/distress feeding problems at age 2.5, but not food refusal problems, were associated with ADHD, problematic behavior (OD/CD), and anxiety/depression symptoms at 8 years in models adjusting for eating behaviors at 8 years and child and family covariates. Associations with mechanical/distress feeding problems were larger for ADHD and problematic behavior than anxiety/depression symptoms, though all were modest. Model estimates were similar for boys and girls. CONCLUSIONS: Much of the research on feeding problems focuses on picky eating. This study suggests that early mechanical and mealtime distress problems may serve as better predictors of later psychopathology than food refusal. Parents and pediatricians could monitor children with mechanical/distress feeding problems for signs of developing psychopathology.

Feeding Problems as an Indicator of Developmental Delay in Early Childhood.

OBJECTIVE: To determine whether feeding problems are indicators of developmental delay. STUDY DESIGN: In this prospective longitudinal cohort study, mothers of 3597 children (49% female, 35% multiples) reported on their children's feeding problems and developmental delays (using the Ages and Stages Questionnaire [ASQ]) when children were age 18, 24, and 30 months. Average scores of feeding problems were computed at each age, as well as a categorical score indicating a persistently high number of feeding problems ≥90th percentile across time. The Battelle Developmental Inventory, Second Edition (BDI-2) was used to assess development in 5 domains for a subset of children at 4 years. RESULTS: In adjusted analyses, feeding problems (per point increase) were increasingly associated with 6 ASQ domains from 18 months (OR, 1.30-1.98) to 24 months (OR, 2.07-2.69) to 30 months (OR, 3.90-5.64). Compared with children who never experienced feeding problems, children who experienced a high number of feeding problems at 1 or 2 time points were more than twice as likely to have a delay on all ASQ domains (OR, 2.10-2.50), and children who experienced a high number of feeding problems at all 3 time points were ≥4-fold more likely to have a delay on all ASQ domains (OR, 3.94-5.05). Children with 1-point higher feeding problems at 30 months scored 3-4 points lower in all BDI-2 domains at 4 years. CONCLUSIONS: Frequent feeding problems, especially those that persist into the third year, could be used to identify children at risk for developmental delay for more targeted screening.

Predictors of Age at Juice Introduction and Associations with Subsequent Beverage Intake in Early and Middle Childhood.

BACKGROUND: The American Academy of Pediatrics recommends that if parents choose to introduce juice, they wait until ≥12 months, citing concerns of obesity and dental caries. OBJECTIVES: We sought to identify correlates of early juice introduction (<6 months) and determine whether early introduction establishes a pattern of sugary beverage intake in childhood. METHODS: Upstate KIDS is a prospective birth cohort study with follow-up through 7 years (n = 4989). The age of juice introduction was assessed from responses on periodic questionnaires from 4-18 months and categorized as <6,  6 to <12, and ≥12 months. Sociodemographic information was reported using vital records or maternal questionnaires. At 24, 30, and 36 months and 7 years, mothers reported their child's regular juice, soda, water, and milk intakes. The analysis was restricted to singletons and 1 randomly selected twin from each pair with information on juice introduction (n = 4067). We assessed associations of sociodemographic correlates with juice introduction using Cox proportional hazard models. The relations of juice introduction with beverage intake were evaluated using Poisson or logistic regression for adjusted risk ratios (aRR) or ORs, adjusting for sociodemographic covariates and total beverage intake. RESULTS: Of the mothers, 25% and 74% introduced juice prior to 6 and 12 months, respectively. Younger maternal age; black or Hispanic race/ethnicity; lower educational attainment; Special Supplemental Nutrition Program for Women, Infants, and Children participation (yes); smoking during pregnancy; a higher pre-pregnancy BMI; a lower household income; and living in a townhouse/condominium or mobile home were associated with earlier juice introduction. Earlier juice introduction was related to a higher childhood juice intake, any soda intake, and lower water intake, holding total beverage intake constant [aRR, 1.5 (95% CI: 1.3-1.7; P-trend < 0.0001); adjusted OR 1.6 (95% CI: 1.0-2.4; P-trend = 0.01); aRR 0.9 (95% CI: 0.8-0.9; P-trend < 0.0001), respectively]. CONCLUSIONS: Markers of lower socioeconomic status are strongly associated with earlier juice introduction, which, in turn, relates to sugary beverage intake in childhood, potentially replacing water.

Developmental outcomes in small-for-gestational age twins using a singleton vs twin birthweight reference.

BACKGROUND: Limited data exist about the potential developmental delays in appropriately grown twins; furthermore, twins may be at higher risk of developmental delay than singletons. Small-for-gestational age is a risk factor for developmental delay and is based on singleton birthweight references, which may misclassify small-for-gestational age in a subset of appropriately grown twins. OBJECTIVE: This study aimed to evaluate the risk of developmental delay in twins classified as small-for-gestational age according to the twin and singleton birthweight references (<10th percentile). STUDY DESIGN: In a birth cohort (2008-2010) of twins (n=1790) and singletons (n=3829) where parents completed Ages & Stages Questionnaires for child development between 4 and 36 months, we used a US population-based birthweight reference to categorize singletons and twins as small-for-gestational age. Uncertain small-for-gestational age twins were defined as small-for-gestational age by a singleton reference (<10th percentile) and not by a twin reference, and twin-reference small-for-gestational age twins were defined as small-for-gestational age by a twin reference. Adjusted generalized linear mixed-effects models were used to estimate the odds of failure on any Ages & Stages Questionnaires domain and on each of the 5 domains (fine motor, gross motor, communication, personal-social, and problem-solving domains); random intercepts accounted for repeated measures and twin clustering. RESULTS: Compared with non-small-for-gestational age twins (>10th percentile), uncertain small-for-gestational age twins did not have higher odds of Ages & Stages Questionnaires failure (adjusted odds ratio, 1.28; 95% confidence interval, 0.91-1.80). Compared with non-small-for-gestational age singletons, both twin-reference and uncertain small-for-gestational age twins had higher odds of Ages & Stages Questionnaires failure, with the highest risk conferred to twin-reference small-for-gestational age twins (twin-reference adjusted odds ratio, 3.14 [95% confidence interval, 1.94-5.10]; uncertain adjusted odds ratio, 2.35 [95% confidence interval, 1.69-3.26]; P<.01 for trend). Results remained consistent when limiting analyses to term births (≥37 weeks' gestation). CONCLUSION: Although a singleton reference may overestimate small-for-gestational age in twins, the findings indicated that a singleton birthweight reference may be appropriate for twins because it identifies more twins at risk of developmental delay than a twin reference.

Conception by fertility treatment and offspring deoxyribonucleic acid methylation.

OBJECTIVE: To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment. DESIGN: Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment. SETTING: New York State (excluding New York City). PATIENT(S): This analysis included 855 newborns and 152 children at approximately 9 years of age. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted. RESULT(S): Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction. CONCLUSION(S): ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.

Exposure, health effects, sensing, and remediation of the emerging PFAS contaminants - Scientific challenges and potential research directions.

Per- and polyfluoroalkyl substances (PFAS) make up a large group of persistent anthropogenic chemicals which are difficult to degrade and/or destroy. PFAS are an emerging class of contaminants, but little is known about the long-term health effects related to exposure. In addition, technologies to identify levels of contamination in the environment and to remediate contaminated sites are currently inadequate. In this opinion-type discussion paper, a team of researchers from the University of Connecticut and the University at Albany discuss the scientific challenges in their specific but intertwined PFAS research areas, including rapid and low-cost detection, energy-saving remediation, the role of T helper cells in immunotoxicity, and the biochemical and molecular effects of PFAS among community residents with measurable PFAS concentrations. Potential research directions that may be employed to address those challenges and improve the understanding of sensing, remediation, exposure to, and health effects of PFAS are then presented. We hope our account of emerging problems related to PFAS contamination will encourage a broad range of scientific experts to bring these research initiatives addressing PFAS into play on a national scale.