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BACKGROUND: The association between obesity (body mass index (BMI) ≥ 30 kg/m(2)) and pattern of medication use during pregnancy in the United States is not well-studied. Higher prepregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation. OBJECTIVES: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status. METHODS: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery. RESULTS: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19–29.9 kg/m(2)), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively (p > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity. CONCLUSION: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.

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.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.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.Screen time in early childhood did not displace reported time spent reading, but did displace reported peer play time.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.

OBJECTIVE This study aimed to describe the overall quantity and type of supplements and medications used during pregnancy in a low-risk cohort and to examine any racial/ethnic differences in intake. STUDY DESIGN We used data from 2,164 racially/ethnically diverse, nonobese, and low-risk pregnant women participating without pre-pregnancy chronic conditions in a prospective cohort study at 12 sites across the United States. Medication data were self-reported as free text in enrollment, follow-up visit questionnaires, and abstracted from medical records at delivery. Supplements and medications data were mapped to their active ingredients and categorized into corresponding classes using the Slone Drug Dictionary. The total number and classes of supplements and medications consumed during pregnancy were calculated. Modified Poisson regression models were used to estimate the racial/ethnic differences in supplements and medications intake. All models were adjusted for maternal sociodemographic factors and study site. RESULTS 98% of women took at least one supplement during pregnancy, with prenatal vitamins/multivitamins being most common. While only 31% reported taking no medications during pregnancy, 23% took one, 18% took two, and 28% took three or more. The percentage of women taking at least one medication during pregnancy was highest among non-Hispanic white women and lowest among Asians (84 vs. 55%, p

Background Epigenetic mechanisms may underlie associations between maternal caffeine consumption and adverse childhood metabolic outcomes. However, limited studies have examined neonate DNA methylation (DNAm) patterns in the context of preconception or prenatal exposure to caffeine metabolites. Objective We examined preconception and pregnancy caffeine exposure with DNAm alterations in neonate cord blood (n = 378). Design In a secondary analysis of the Effects of Aspirin in Gestation and Reproduction Trial (EAGeR), we measured maternal caffeine, paraxanthine, and theobromine concentrations from stored serum collected preconception (on average 2 months before pregnancy) and at 8 weeks of gestation. In parallel, self-reported caffeinated beverage intake was captured via administration of questionnaires and daily diaries. We profiled DNAm from the cord blood buffy coat of singletons using the MethylationEPIC BeadChip. We assessed associations of maternal caffeine exposure and methylation β-values using multivariable robust linear regression. A false discovery rate (FDR) correction was applied using the Benjamini-Hochberg method. Results In preconception the majority of women reported consuming one or fewer servings/day on average and caffeine and paraxanthine metabolite levels were 88 and 36 µmol/L, respectively. Preconception serum caffeine metabolites were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine was associated with DNAm at cg09460369 near RAB2A (β = 0.028; SE = 0.005; FDR P = 0.012). Preconception self-reported caffeinated beverage intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (β = -0.013; SE = 0.002; FDR P = 0.036). No associations with self-reported intake during pregnancy were found. Conclusions Few effects of maternal caffeine exposure on neonate methylation differences in leukocytes were identified in this relatively low caffeine consumption population.Clinical Trial Registry: #NCT00467363.

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.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.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.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.

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 (

Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain.The objective of the study was to examine whether male infants increase the risk of maternal mortality.This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project (CPP). Collaborative Perinatal Project records were linked to the National Death Index and the Social Security Master Death File to ascertain deaths until 2016. Foetal sex was determined by infant sex at birth, defined as the total number of male or female infants in pregnancies prior to or during enrolment in the CPP. In secondary analyses, exposure was defined as infant sex at the last CPP delivery. Outcomes included all-cause and underlying causes of mortality. We used Cox proportional hazards models weighted by the number of prior live births and stratified our models by parity and race/ethnicity.Among 48,188 women, 50.8% had a male infant at their last registered CPP pregnancy and 39.0% had a recorded death after a mean follow-up of 47.8 years (SD 10.5 years). No linear association was found between the number of liveborn males and all-cause mortality (primipara women: HR 1.02, 95% CI 0.95, 1.09, multipara women, 1 prior live birth: HR 0.96, 95% CI 0.89, 1.03, multipara women, ≥2 prior live births: HR 0.97, 95% CI 0.85, 1.11). A similar trend was noted for cardiovascular- and cancer-related mortality. At the last delivery, women with a male infant did not have an increased risk of all-cause or cause-specific mortality compared to women with a female infant. These findings were consistent across racial/ethnic groups.Women who give birth to male infants, regardless of number, are not at increased risk of all-cause and cause-specific mortality. These findings suggest that giving birth to male infants may not independently influence the long-term health of women.

Background Preterm birth is associated with lower neurocognitive performance. However, whether children’s neurodevelopment improves with longer gestations within the full-term range (37–41 weeks) is unclear. Given the high rate of obstetric intervention in the USA, it is critical to determine whether long-term outcomes differ for children delivered at each week of term. Methods This secondary analysis included 39 199 live-born singleton children of women who were admitted to the hospital in spontaneous labour from the US Collaborative Perinatal Project (1959–76). At each week of term gestation, we evaluated development at 8 months using the Bayley Scales of Infant Development, 4 years using the Stanford–Binet IQ (SBIQ) domains and 7 years using the Wechsler Intelligence Scales for Children (WISC) and Wide-Range Achievement Tests (WRAT). Results Children’s neurocognitive performance improved with each week of gestation from 37 weeks, peaking at 40 or 41 weeks. Relative to those delivered at 40 weeks, children had lower neurocognitive scores at 37 and 38 weeks for all assessments except SBIQ and WISC Performance IQ. Children delivered at 39 weeks had lower Bayley Mental (β = −1.18; confidence interval −1.77, −0.58) and Psychomotor (β = −1.18; confidence interval −1.90, −0.46) scores. Results were similar for within-family analyses comparing siblings, with the addition of lower WRAT scores at 39 weeks. Conclusions The improvement in development scores across assessment periods indicates that each week up to 40 or 41 weeks of gestation is important for short- and long-term cognitive development, suggesting 40–41 weeks may be the ideal delivery window for optimal neurodevelopmental outcomes.

Prenatal omega-3 fatty acid supplementation, particularly docosahexaenoic acid and eicosapentaenoic acid, has been associated with greater birthweight in clinical trials; however, its effect on fetal growth throughout gestation is unknown.This study aimed to examine the association between first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation and growth trajectories of estimated fetal weight and specific fetal biometrics measured longitudinally from the second trimester of pregnancy to delivery.In a multisite, prospective cohort of racially diverse, low-risk pregnant women, we used secondary data analysis to examine fetal growth trajectories in relation to self-reported (yes or no) first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation. Fetal ultrasonographic measurements, including abdominal circumference, biparietal diameter, femur length, head circumference, and humerus length, were measured at enrollment (8-13 weeks) and up to 5 follow-up visits. Estimated fetal weight and head circumference-to-abdominal circumference ratio (a measure of growth symmetry) were calculated. Fetal growth trajectories were modeled for each measure using a linear mixed model with cubic splines. If significant differences in fetal growth trajectories between groups were observed (global P.05), weekly comparisons were performed to determine when in gestation these differences emerged. Analyses were adjusted for maternal sociodemographics, parity, infant sex, total energy consumption, and diet quality score. All analyses were repeated using dietary docosahexaenoic acid and eicosapentaenoic acid intake, dichotomized at the recommended cutoff for pregnant and lactating women (≥0.25 vs0.25 g/d), among women who did not report supplement intake in the first trimester of pregnancy were repeated.Among 1535 women, 143 (9%) reported docosahexaenoic acid and eicosapentaenoic acid supplementation in the first trimester of pregnancy. Overall, first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation was associated with statistically significant differences (P-value.05) in fetal growth trajectories during pregnancy. Specifically, estimated fetal weight was larger among women with docosahexaenoic acid and eicosapentaenoic acid supplementation than among those without supplementation (global P=.028) with significant weekly differences in median estimated fetal weight most apparent between 38 to 41 weeks of gestation (median estimated fetal weight difference at 40 weeks of gestation, 114 g). Differences in fetal growth trajectories for abdominal circumference (P=.003), head circumference (P=.003), and head circumference-to-abdominal circumference ratio (P=.0004) were also identified by supplementation status. In weekly comparisons, docosahexaenoic acid and eicosapentaenoic acid supplement use was associated with larger median abdominal circumference (changed from 2 to 9 mm) in midpregnancy onward (19 to 41 weeks), larger median head circumference between 30 to 33 weeks of gestation, and smaller median head circumference-to-abdominal circumference ratio in the second and third trimesters of pregnancy. There was no specific weekly difference in fetal femur length or humerus length by docosahexaenoic acid and eicosapentaenoic acid supplementation. First-trimester dietary sources of docosahexaenoic acid and eicosapentaenoic acid among women with no first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation (n=1392) were associated with differences in fetal biparietal diameter (P=.043), but not other metrics of fetal growth. At the recommended dietary docosahexaenoic acid and eicosapentaenoic acid levels compared with below-recommended levels, biparietal diameter was larger between 38 to 41 weeks of gestation.In this racially diverse pregnancy cohort, first-trimester docosahexaenoic acid and eicosapentaenoic acid supplementation was associated with significant increases in fetal growth, specifically greater estimated fetal abdominal circumference in the second and third trimesters of pregnancy.

Objective This study examined the extent to which maternal immune activity during pregnancy is associated with childhood adiposity, and if so, whether associations at birth differ from those in infancy and childhood. Sex-specific associations were also examined. Methods Participants were 1,366 singleton pregnancies from the Collaborative Perinatal Project (1959-1966). Interleukin-1β (IL-1β), IL-6, TNF-α, IL-8, and IL-10 in maternal sera were assayed repeatedly during pregnancy. Children's BMI was calculated repeatedly from birth through age 8 and derived age- and sex-normalized BMI z scores (BMIz). Linear mixed models were used to estimate the cumulative concentration of each cytokine in the second and third trimesters and then related this concentration to child BMIz. Results Children exposed to higher IL-1β, IL-6, IL-8, and IL-10 concentrations had lower BMIz at birth but higher BMIz during childhood. Higher concentrations of IL-8 and IL-1β were also associated with higher BMIz during infancy (B per log increase in IL-8 = 0.04; 95% CI: 0.02 to 0.07; B per log increase in IL-1β = 0.03; 95% CI: 0.001 to 0.06). The associations between TNF-α and BMIz were in opposing directions in boys (B = -0.13; 95% CI: -0.31 to 0.04) and girls (B = 0.14; 95% CI: 0.02 to 0.26) during childhood. Conclusions Maternal prenatal inflammation contributes to the age- and sex-specific programming of obesity risk in childhood.

PURPOSE OF REVIEW: Technological advances have allowed dried blood spots (DBS) to be utilized for various measurements, helpful in population-based studies. The following is a review of the literature highlighting the advantages and disadvantages of DBS and describing their use in multiple areas of research. RECENT FINDINGS: DBS can track pollutant exposure to understand their impact on health. DBS can also be used for (epi-)genetic studies, to measure clinical biomarkers, and to monitor drug adherence. Advantages of DBS include being minimally invasive, requiring low blood volume, and being cost-effective to collect, transport, and store. Disadvantages of DBS include the hematocrit effect, which is related to the viscosity of the blood affecting its spread on to the filter paper, causing a major source of error when assessing concentrations, and the possibility of low DNA volume. SUMMARY: Numerous uses for DBS makes them an important source of biomaterial but they require additional validation for accuracy and reproducibility.

Summary Objective Obesity has become a major, worldwide public health issue and is associated with a greater risk of adverse pregnancy outcomes. Leptin, a hormone produced by adipocytes, is elevated in individuals with obesity and may mediate the association between obesity and pregnancy outcomes. Though leptin levels during pregnancy have been associated with pregnancy outcomes, less is understood regarding preconception levels. Therefore, the objective of this study was to evaluate associations between preconception leptin levels and adverse pregnancy outcomes. Methods This was a prospective cohort study nested within a large randomized controlled trial conducted at four medical centres in the United States. A total of 1078 women completed the parent study; this analysis involved women who became pregnant during that study (n = 776). Patients were healthy women, ages 18 to 40, attempting to conceive, with 1 to 2 prior pregnancy losses. Participants were followed for less than or equal to 6 cycles while trying to conceive and throughout pregnancy if they conceived. Preconception leptin concentrations were measured in serum collected at baseline then categorized by tertiles (using the lowest as reference group). Weighted log‐binomial regression estimated risk ratios (RR) and 95% confidence intervals (CIs) for pregnancy loss, preterm delivery (PTD), gestational diabetes (GDM), and hypertensive disorders in pregnancy, adjusting for age, waist‐to‐hip ratio (WHR), and body mass index (BMI). Results The mean (SD) BMI in this cohort was 25.4 ± 6.0. GDM (RR 18.37; 95% CI, 2.39‐141.55) and hypertensive disorders of pregnancy (RR 2.35; 95% CI, 1.20‐4.61) risks were higher among women in the high tertile after adjusting for age and WHR. The associated risk persisted when adjusting for BMI for GDM but was attenuated for hypertensive disorders in pregnancy. Leptin levels were not associated with risk of pregnancy loss or PTD. Conclusions Women with higher baseline preconception leptin levels had a higher likelihood of experiencing some adverse pregnancy outcomes including GDM and hypertensive disorders of pregnancy. These findings warrant further evaluation, especially in light of the association between leptin and obesity.

Objective The aim of this study is to model the association between gestational age at birth and early child development through 3 years of age. Study Design Development of 5,868 children in Upstate KIDS (New York State; 2008–2014) was assessed at 7 time points using the Ages and Stages Questionnaire (ASQ). The ASQ was implemented using gestational age corrected dates of birth at 4, 8, 12, 18, 24, 30, and 36 months. Whether children were eligible for developmental services from the Early Intervention Program was determined through linkage. Gestational age was based on vital records. Statistical models adjusted for covariates including sociodemographic factors, maternal smoking, and plurality. Results Compared with gestational age of 39 weeks, adjusted odds ratios (aOR) and 95% confidence intervals of failing the ASQ for children delivered at Conclusion Gestational age was inversely associated with developmental delays for all gestational ages. Evidence from our study is potentially informative for low-risk deliveries at 39 weeks, but it is notable that deliveries at 40 weeks exhibited further lower risk.

STUDY QUESTION Are toddlers conceived by fertility treatment at higher risk of failing a screening tool for autism spectrum disorders (ASD) than toddlers not conceived by treatment? SUMMARY ANSWER Compared with children not conceived by infertility treatment, children conceived by any infertility treatment, ovulation induction with or without intrauterine insemination (OI/IUI), or assisted reproductive technologies (ART) appeared to have had higher odds of failing an ASD screening; however, results were inconclusive and need replication. WHAT IS KNOWN ALREADY Although most of the studies which have examined risk of ASD after ART show no association, the results are mixed. Thus, further studies are needed to clarify this association. STUDY DESIGN SIZE, DURATION The Upstate KIDS Study is a population-based, prospective cohort study of children born in New York State between 2008 and 2010. Children were screened for ASD using the Modified Checklist for Autism in Toddlers (M-CHAT) at ages 18 and 24 months. PARTICIPANTS/MATERIALS, SETTING, AND METHODS The New York State live-birth registry was used to identify newborns conceived with and without fertility treatment with a 1:3 ratio, frequency matched on region of birth. At 18 and 24 months, 3183 and 3063 mothers, respectively, completed the M-CHAT questionnaire. The current analysis included 2586 singletons and 1296 twins with M-CHAT information at 18 and/or 24 months. Multivariable logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (aOR) and 95% confidence intervals (CI) after adjustment for covariates such as maternal age, education and plurality. MAIN RESULTS AND THE ROLE OF CHANCE We found that 200 (5.2%) and 115 (3.0%) children failed the M-CHAT at 18 and 24 months, respectively. The associations between use of infertility treatment and failing the M-CHAT at 18 and/or 24 months were positive but inconclusive as they failed to exclude no association (18 months aOR 1.71, 95% CI: 0.81–3.61; 24 months aOR 1.78, 95% CI: 0.66–4.81; and both 18 and 24 months aOR 1.53, 95% CI: 0.78–2.99). The relationships between OI/IUI and ART with M-CHAT failure at 18 and/or 24 months were similar to those of using any fertility treatment. In vitro fertilization with intracytoplasmic sperm injection was not consistently positively or inversely associated with M-CHAT failure at each time point (18 months aOR 1.20, 95% CI: 0.51–2.83; 24 months aOR 0.93, 95% CI: 0.37–2.31; and both 18 and 24 months aOR 1.09, 95% CI: 0.50–2.60). LIMITATIONS REASONS FOR CAUTION The M-CHAT is a screening tool used for ASD risk assessment, and therefore, M-CHAT failure does not indicate ASD diagnosis. In addition, we did not have power to detect associations of small magnitude. Finally, non-response to follow-up may bias the results. WIDER IMPLICATIONS OF THE FINDINGS Despite lack of precision, the positive associations between ART and M-CHAT failure suggest that larger population-based studies with longer follow-up are needed. STUDY FUNDING/COMPETING INTEREST(S) Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, HHSN267200700019C). The sponsor played no role in the study design, data collection, data analysis or interpretation, writing of the manuscript or decision to submit the article for publication. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable.

Despite research indicating that sleep disorders influence reproductive health, the effects of sleep on reproductive hormone concentrations are poorly characterized. We prospectively followed 259 regularly menstruating women across one to two menstrual cycles (the BioCycle Study, 2005–2007), measuring fasting serum hormone concentrations up to eight times per cycle. Women provided information about daily sleep in diaries and chronotype and night/shift work on a baseline questionnaire. We evaluated percent differences in mean hormone concentrations, the magnitude of shifts in the timing and amplitude of hormone peaks, and the risk for sporadic anovulation associated with self-reported sleep patterns and night/shift work. We estimated chronotype scores – categorizing women below and above the interquartile range (IQR) as “morning” and “evening” chronotypes, respectively. For every hour increase in daily sleep duration, mean estradiol concentrations increased by 3.9% (95% confidence interval [CI] 2.0, 5.9%) and luteal phase progesterone by 9.4% (CI 4.0, 15.2%). Receiving less than 7 hours of sleep per day was associated with slightly earlier rises in peak levels for several hormones. Women reporting night/shift work (n = 77) had lower testosterone relative to women employed without night/shift work (percent difference: −9.9%, CI −18.4, −0.4%). Women with morning chronotypes (n = 47) had earlier rises in estradiol during their cycles and potentially an earlier rise in luteinizing hormone. Compared to those who had intermediate chronotypes, women with evening chronotypes (n = 42) had a later luteinizing hormone peak of borderline statistical significance. A reduced risk for sporadic anovulation was suggested, but imprecise, for increasing hours of daily sleep leading up to ovulation (risk ratio 0.79, CI 0.59, 1.06), while an imprecise increased risk was observed for women with morning chronotypes (risk ratio 2.50, CI 0.93, 6.77). Sleep-related hormonal changes may not greatly alter ovarian function in healthy women, but have the potential to influence gynecologic health.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may be associated with obesogenic effects in offspring. Our study is the first to investigate associations between concentrations of POPs from newborn dried blood spots (DBS) and birth characteristics. METHODS: Concentrations of 10 polychlorinated biphenyl congeners (PCBs), polybrominated diphenyl ether-47 (PBDE-47), and p,p´-dichlorodiphenyldichloroethylene (p,p´-DDE) were measured from DBSs collected at birth from 2065 singleton infants. DBS samples were pooled in groups of five and assayed together in order to reach limits of detection. Differences in risk of large for gestational age (LGA, defined as >90(th) percentile of birthweight for sex and gestational age), small for gestational age (SGA

Pregnancy loss is a common reproductive complication, but its association with long-term mortality and whether this varies by maternal race/ethnicity is not well understood. Data from a racially diverse cohort of pregnant women enrolled in the Collaborative Perinatal Project (CPP) from 1959 to 1966 were used for this study. CPP records were linked to the National Death Index and the Social Security Death Master File to identify deaths and underlying cause (until 2016). Pregnancy loss comprised self-reported losses, including abortions, stillbirths, and ectopic pregnancies. Among 48,188 women (46.0% White, 45.8% Black, 8.2% other race/ethnicity), 25.6% reported at least 1 pregnancy loss and 39% died. Pregnancy loss was associated with a higher absolute risk of all-cause mortality (risk difference, 4.0 per 100 women, 95% confidence interval: 1.4, 6.5) and cardiovascular mortality (risk difference, 2.2 per 100 women, 95% confidence interval: 0.8, 3.5). Stratified by race/ethnicity, a higher risk of mortality persisted in White, but not Black, women. Women with recurrent losses are at increased risk of death, both overall and across all race/ethnicity groups. Pregnancy loss is associated with death; however, it does not confer an excess risk above the observed baseline risk in Black women. These findings support the need to assess reproductive history as part of routine screening in women.

ObjectivesTo evaluate the individual and combined associations of five modifiable risk factors with risk of type 2 diabetes among women with a history of gestational diabetes mellitus and examine whether these associations differ by obesity and genetic predisposition to type 2 diabetes.DesignProspective cohort study.SettingNurses’ Health Study II, US.Participants4275 women with a history of gestational diabetes mellitus, with repeated measurements of weight and lifestyle factors and followed up between 1991 and 2009.Main outcome measureSelf-reported, clinically diagnosed type 2 diabetes. Five modifiable risk factors were assessed, including not being overweight or obese (body mass index of the modified Alternate Healthy Eating Index), regular exercise (≥150 min/week of moderate intensity or ≥75 min/week of vigorous intensity), moderate alcohol consumption (5.0-14.9 g/day), and no current smoking. Genetic susceptibility for type 2 diabetes was characterised by a genetic risk score based on 59 single nucleotide polymorphisms associated with type 2 diabetes in a subset of participants (n=1372).ResultsOver a median 27.9 years of follow-up, 924 women developed type 2 diabetes. Compared with participants who did not have optimal levels of any of the risk factors for the development of type 2 diabetes, those who had optimal levels of all five factors had >90% lower risk of the disorder. Hazard ratios of type 2 diabetes for those with one, two, three, four, and five optimal levels of modifiable factors compared with none was 0.94 (95% confidence interval 0.59 to 1.49), 0.61 (0.38 to 0.96), 0.32 (0.20 to 0.51), 0.15 (0.09 to 0.26), and 0.08 (0.03 to 0.23), respectively (PtrendtrendConclusionsAmong women with a history of gestational diabetes mellitus, each additional optimal modifiable factor was associated with an incrementally lower risk of type 2 diabetes. These associations were seen even among individuals who were overweight/obese or were at greater genetic susceptibility.

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 IgG

OBJECTIVES: Prior research has suggested that epigenetic mechanisms may underly associations between maternal caffeine intake and adverse childhood metabolic outcomes. We examined preconception and early pregnancy maternal caffeine exposure with DNA methylation (DNAm) patterns in the cord blood of 378 neonates. METHODS: DNAm was profiled by the Infinium MethylationEPIC BeadChip in women enrolled in the EAGeR Trial. Maternal serum was collected 1–2 cycles preconception and at 8 weeks gestation as was self-reported caffeinated beverage intake through standardized questionnaires or daily diaries. Serum caffeine, paraxanthine, and theobromine were measured by liquid chromatography mass spectrometry. We performed multivariable robust linear regression to assess associations between maternal caffeine and methylation β-values and Ingenuity Pathway Analysis to evaluate biologic implications. RESULTS: Preconceptionally, 65%, 21% and 7% reported any soda, coffee or tea intake, respectively with the majority consuming on average ≤ 1 serving/day. Preconception self-reported intake compared to no intake was associated with DNAm at cg09002832 near GLIS3 (false discovery rate [FDR] p = 0.036). No associations with self-reported intake were found during pregnancy. Preconception serum markers were not associated with individual CpG sites (FDR > 5%), though pregnancy theobromine (tertile 2 vs 1) was associated with DNAm at cg09460369 near RAB2A (FDR p = 0.012). Overlapping pathways for the top 100 CpG sites identified in the preconception intake and pregnancy theobromine analyses elucidated cell cycle and lipid metabolism processes. CONCLUSIONS: Few differences in DNAm were identified in association with maternal caffeine intake in this low consumption population. DNAm changes from preconception caffeine or pregnancy theobromine exposure may be linked to signaling networks involving lipid metabolism, but further research among women with higher caffeine and theobromine exposure is warranted. FUNDING SOURCES: Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

OBJECTIVES: Physical activity (PA) prior to and during pregnancy may influence offspring health through epigenetic modifications in the placenta. Prior studies had a single PA assessment in pregnancy limiting the ability to account for PA changes during pregnancy. We hypothesized that timing of PA may be associated with differential methylation and evaluated associations between multiple assessments of PA and genome-wide methylation changes in the placenta. METHODS: Placental tissues were obtained at delivery and DNA methylation was measured using the Illumina Human Methylation450 Beadchip for 301 mothers in the NICHD Fetal Growth Studies–Singleton cohort. Total PA (metabolic equivalent minutes/week) was assessed using the Pregnancy PA Questionnaire targeted for 8–13 (visit 0), 16–22 (visit 1), 24–29 (visit 2), 30–33 (visit 3), 34–37 (visit 4), 38–41 (visit 5) weeks’ gestation. For associations of PA at each visit with methylation, we conducted linear regression adjusting for potential confounders such as maternal age, race/ethnicity, pre-pregnancy body mass index. Genes annotating significant CpG sites (false discovery rate adjusted P

Background: Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. Objectives: The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. Population: A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. Design: The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. Methods: Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. Preliminary results: Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. Conclusions: The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.

Context With the increase of obesity, it is imperative to understand the neuroendocrine mechanisms, including the neuroendocrine hormone leptin, by which obese or overweight women are at increased risk for subfertility and infertility. Objective The objective was to examine associations between preconception serum leptin concentrations, fecundability, pregnancy, and live birth. Design Secondary analysis of a prospective cohort among women with prior pregnancy losses. Setting The study was conducted at four US medical centers (2006 to 2012). Intervention Not available. Materials and Methods Preconception serum leptin concentrations were measured at baseline, and women were followed for up to six menstrual cycles, and throughout pregnancy if they conceived. Discrete Cox proportional hazard regression models were used to assess fecundability odds ratios (FORs) and log-binomial regression to estimate risk ratios (RRs) for pregnancy and live birth. Models were adjusted for age, physical activity, treatment arm, and adiposity, either by measured waist-to-hip ratio or body mass index (BMI). Results High leptin concentrations were associated with decreased fecundability (FOR 0.72, 95% CI 0.58, 0.90), reduced risk of pregnancy (RR 0.87, 95% CI 0.78, 0.96) and live birth (RR 0.76, 95% CI 0.65, 0.89) comparing the upper to the lower tertile. However, adjustment for BMI in lieu of waist-to-hip ratio nullified observed associations. Conclusions In women with a history of pregnancy loss, relations between higher preconception leptin and fecundability were attenuated after adjustment for BMI, although not after adjustment for other markers of adiposity. Leptin may serve as a complementary marker of adiposity for assessment of obesity and reproductive outcomes.

Aim: We examined maternal prepregnancy anthropometry and cord blood DNA methylation. Methods: Associations between maternal measures (i.e., weight, height, waist circumference, hip circumference, skinfolds, leptin) and methylation β-values at each CpG (measured by the Infinium MethylationEPIC BeadChip) were estimated among 391 singletons. Results: Total of 18% of mothers were obese (body mass index ≥ 30) and 27% centrally obese (waist-to-hip ratio ≥ 0.85). One Bonferroni significant CpG with respect to obesity (cg02975187) and two with central obesity (cg12053563, cg12549355) were identified (p -8). A suggestive association (p -6) was observed at SFRS8 with increasing body mass index. SFRS8 was previously identified with propensity for weight gain in adults. Conclusion: While associations identified with multiple measures related to maternal adiposity suggest different pathways, methylation differences were small in magnitude.

OBJECTIVE The goal of this study was to determine whether newborn concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and bisphenol A (BPA) are associated with early childhood growth. METHODS A total of 1,954 singletons and 966 twins from the Upstate KIDS Study (born 2008-2010) were included in this study. Newborn dried blood spot concentrations of PFOS, PFOA, and BPA were quantified by liquid chromatography tandem mass spectrometry. Children's weight and height were reported from birth through 3 years of age. Repeated measures were modeled using generalized linear mixed models. RESULTS PFOS and PFOA were associated with lower BMI (-0.078 kg/m2 [-0.12 to -0.038] and -0.076 kg/m2 [-0.17 to -0.051] per 1 standard deviation increase in log PFOS and PFOA, respectively) and not with early obesity among singletons. Inconsistent associations were observed for twins. BPA levels were higher among neonates with a neonatal intensive care unit stay (P

We examined whether cesarean delivery (CD) increased the risk of wheeze or food allergy in early childhood compared with vaginal delivery and whether these associations were mediated by breastfeeding. The study population was the Upstate KIDS cohort (2008-2010) of mothers and infants from the State of New York (excluding New York City). Infant's wheeze was reported by questionnaire every 4-6 months until 3 years of age, as were food allergies beginning at 8 months. Modified Poisson regression was used to compare risks of the outcomes according to mode of delivery (MOD). Potential confounders were identified a priori using directed acyclic graphs. Emergency CD (n = 1,356) was associated with elevated risk of wheeze, adjusting for pregnancy complications, maternal atopy, gestational age, birth weight, and smoking during pregnancy (risk ratio = 2.47, 95% confidence interval: 1.31, 4.66), and an increased risk of food allergy, adjusting for maternal atopy, prepregnancy body mass index, smoking during pregnancy, and parity (risk ratio = 3.02, 95% confidence interval: 1.26, 7.25). Neither outcome was significantly associated with planned CD (n = 1,565 infants). Breastfeeding mediated the association between MOD and wheeze but not food allergy. Other factors not associated with early-life microbial transfer, but relating to the development of the outcomes, might contribute to the association between MOD and wheeze/food allergy.

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.Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment.New York State (excluding New York City).This analysis included 855 newborns and 152 children at approximately 9 years of age.None.DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted.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.ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.

OBJECTIVES: To identify homogenous depressive symptom trajectories over the postpartum period and the demographic and perinatal factors linked to different trajectories. METHODS: Mothers (N = 4866) were recruited for Upstate KIDS, a population-based birth cohort study, and provided assessments of depressive symptoms at 4, 12, 24, and 36 months postpartum. Maternal demographic and perinatal conditions were obtained from vital records and/or maternal report. RESULTS: Four depression trajectories were identified: low-stable (74.7%), characterized by low symptoms at all waves; low-increasing (8.2%), characterized by initially low but increasing symptoms; medium-decreasing (12.6%), characterized by initially moderate but remitting symptoms; and high-persistent (4.5%), characterized by high symptoms at all waves. Compared with the high-persistent group, older mothers (maximum odds ratio [OR] of the 3 comparisons: 1.10; 95% confidence interval [CI]: 1.05 to 1.15) or those with college education (maximum OR: 2.52; 95% CI: 1.36 to 4.68) were more likely to be in all other symptom groups, and mothers who had a history of mood disorder (minimum OR: 0.07; 95% CI: 0.04 to 0.10) or gestational diabetes mellitus diagnosis (minimum OR: 0.23; 95% CI: 0.08 to 0.68) were less likely to be in other symptom groups. Infertility treatment, multiple births, prepregnancy BMI, gestational hypertension, and infant sex were not differentially associated with depressive symptom trajectories. CONCLUSIONS: One-quarter of mothers in a population-based birth cohort had elevated depressive symptoms in 3 years postpartum. Screening for maternal depression beyond the postpartum period may be warranted, particularly after mood and diabetic disorders.

OBJECTIVE: To determine if feeding problems are an indicator of developmental delay. STUDY DESIGN: In this prospective longitudinal cohort study, mothers of 3,597 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 18, 24, and 30 months of age. Average scores of feeding problems were computed at each age, as well as a categorical score indicating persistently high feeding problems ≥90(th) percentile across time. The Battelle Developmental Inventory (BDI-2) assessed 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 six ASQ domains from 18 months (Odds Ratios (ORs) ranged from 1.30 to 1.98) to 24 months (ORs = 2.07 – 2.69) to 30 months (ORs = 3.90 – 5.64). Compared with children who never experienced feeding problems, children who experienced high feeding problems at one or two time points were more than twice as likely to have a delay on all ASQ domains (ORs = 2.10 – 2.50), and children who experienced high feeding problems at all three time points were four or more times as likely to have a delay on all ASQ domains (ORs = 3.94 – 5.05). Children with one-point higher feeding problems at 30 months scored 3-4 points lower on 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.

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are persistent organic pollutants which may alter prenatal development, potentially through epigenetic modifications. Prior studies examining PFOS/PFOA and DNA methylation have relatively few subjects (n90(th) percentile was related to DNA methylation at cg15557840, near SCRT2, SRXN1; PFOS>90(th) percentile was related to 2 CpG sites in a sex-specific manner (cg19039925 in GVIN1 in boys and cg05754408 in ZNF26 in girls). When analysis was restricted to CoRSIVs, log-scaled, continuous PFOS concentration was related to DNA methylation at cg03278866 within PTBP1. In conclusion, there was limited evidence of an association between high concentrations of PFOA/PFOS and DNA methylation in newborn DBS in the Upstate KIDS cohort. These findings merit replication in populations with a higher median concentration of PFOA/PFOS.

Background: Women with a history of GDM are at exceptionally high risk of T2D but adopting a healthy lifestyle may mitigate this risk. Methods: We analyzed 4,287 women with a prior clinician diagnosis of GDM from the Nurses’ Health Study II cohort as part of the Diabetes and Women’s Health Study. Healthy lifestyle factors, which were assessed every 2-4 years, included no current smoking, normal body mass index (500 MET-min/week), high-quality diet (above median for the Alternative Healthy Eating Index), and moderate alcohol consumption (>0-15 g/day). Self-reported incident T2D was confirmed via validated supplementary questionnaire (98% concordance with medical records). Multivariate-adjusted Cox models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI), adjusting for demographic, reproductive, and clinical characteristics. Results: We ascertained 835 incident T2D cases during a median 27.9 years of follow-up. Compared to women reporting no healthy lifestyle factors, HR (95% CI) for risk of T2D among those with 1, 2, 3, 4, or 5 factors were 0.91 (0.64, 1.30), 0.62 (0.44, 0.87), 0.45 (0.31, 0.64), 0.33 (0.22, 0.48), and 0.13 (0.06, 0.28), respectively (P86% (population attributable risk [PAR]%: 86.3%; 95% CI: 70.6%, 93.7%) of T2D cases were theoretically preventable if participants had adherence to all 5 healthy lifestyle factors. Conclusion: Adherence to healthy lifestyle factors was associated with a substantially lower likelihood of progressing to T2D in women with a history of GDM, and strategies to improve long-term adherence are warranted. Disclosure F. Qian: None. J.E. Chavarro: None. S.H. Ley: None. D. Tobias: None. E. Yeung: None. M. Li: None. A. Liu: None. J. Mills: None. Q. Sun: None. F. Hu: None. C. Zhang: None.

Background: Women with a history of gestational diabetes mellitus (GDM) are at increased risk for cardiovascular disease (CVD). Whether healthy lifestyle practices can mitigate this risk is unclear. Aims: To prospectively assess associations of healthy lifestyle factors with CVD risk in women with a history of GDM. Methods: We included 4,372 women from the Nurses’ Health Study II with a prior clinician diagnosis of GDM who were free of cancer or CVD at the time of the index pregnancy. Healthy lifestyle factors, which were updated every 2-4 years, included non-current smoking, body mass index2 , regular physical activity (>500 MET-min/week), high-quality diet (above median on the Alternative Healthy Eating Index), and moderate alcohol consumption (>0-15 g/day). A composite outcome of CVD was defined as the combination of nonfatal/fatal myocardial infarction (MI), stroke, angiographically confirmed angina, and coronary artery bypass surgery or angioplasty/stenting. Multivariate-adjusted Cox models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: During a median 28 years of follow-up, 179 incident CVD events were ascertained. Compared to women with 0 or 1 healthy lifestyle factor, HR (95% CI) for risk of CVD among those who had 2, 3, and ≥4 factors were 1.02 (0.68, 1.53), 0.45 (0.28, 0.74), and 0.32 (0.18, 0.60), respectively ( P trend < 0.001) ( Table 1 ). Similar results were observed for clinical CVD events (nonfatal/fatal MI or stroke) and total MI. When modeled continuously, each additional healthy lifestyle factor was associated with a lower risk of the composite outcome, HR (95% CI): 0.67 (0.57, 0.80); clinical CVD, HR (95% CI): 0.74 (0.58, 0.94); and MI, HR (95% CI): 0.61 (0.43, 0.86). We estimated that 62.5% (95% CI: 34.9%, 79.0%) of the CVD risk in this population was potentially avoidable with adherence to ≥4 healthy lifestyle factors. Conclusion: Greater adherence to healthy lifestyle factors was associated with a significant reduction in CVD risk in women with a history of GDM.

Background Studies linking large pregnancy cohorts with mortality data can address critical questions about long-term implications of gravid health, yet relevant US data are scant. We examined the feasibility of linking the Collaborative Perinatal Project, a large multiracial U.S. cohort study of pregnant women (n = 48,197; 1959-1966), to death records. Methods We abstracted essential National Death Index (NDI) (1979-2016) (n = 46,428). We performed a linkage to the Social Security Administration Death Master File through 2016 (n = 46,450). Genealogists manually searched vital status in 2016 for a random sample of women (n = 1,249). We conducted agreement analyses for women with abstracted data among the three sources. As proof of concept, we calculated adjusted associations between mortality and smoking and other sociodemographic factors using Cox proportional hazards regression. Results We successfully abstracted identifying information for most of the cohort (97%). National Death Index identified the greatest proportion of participants deceased (35%), followed by genealogists (31%) and Death Master File (23%). Estimates of agreement (κ [95% confidence interval]) between National Death Index and Death Master File were lower (0.52 [0.51, 0.53]) than for National Death Index and genealogist (0.66 [0.61, 0.70]). As expected, compared with nonsmokers, smoking ≥1 pack per day was associated with elevated mortality for all vital sources and was strongest for National Death Index. Conclusions Linking this historic cohort with mortality records was feasible and agreed reasonably on vital status when compared with other data sources. Such linkage enables future examination of pregnancy conditions in relation to mortality in a diverse U.S. cohort.

OBJECTIVES: To assess relations of pre-pregnancy maternal and paternal obesity with offspring behavioral problems and psychiatric symptoms at 7–8 years in the Upstate KIDS study, a prospective cohort study. STUDY DESIGN: Maternal body mass index (BMI) was calculated from pre-pregnancy height and weight provided in vital records or self-report at 4 months post-partum. Mothers reported paternal height and weight. At 7–8 years, mothers indicated if their children had been diagnosed with ADHD or anxiety (n=1915). Additionally, children’s behavior was measured with the Strengths and Difficulties Questionnaire (SDQ) at 7 years (n=1386) and the Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS) at 8 years (n=1484). Based on SDQ scores, we identified children with borderline behavioral problems. Adjusted risk ratios (aRR) and 95% confidence intervals (CIs) were estimated with robust multivariable Poisson regression. RESULTS: Compared with children of mothers with BMI

OBJECTIVE: To study the development of children conceived from non-IVF infertility treatments consisting of gonadotropins, clomiphene or letrozole. DESIGN: Prospective cohort study SETTING: U.S Academic Health Centers PATIENTS: Children of women with PCOS who conceived with Letrozole(LTZ) or Clomiphene(CC) in PPCOS II study, or women with unexplained infertility(AMIGOS study) who conceived with LTZ, CC or gonadotropin(GN). INTERVENTIONS: Longitudinal annual follow up from birth to Age 3 of the children. MAIN OUTCOME MEASURES: Scores from Ages and Stages Developmental Questionnaire(ASQ), MacArthur-Bates Communicative Development Inventor(MCDI) and annual growth. RESULTS: 185 children from 160 families participated in at least one follow-up evaluation from the two infertility trials. Most multiple gestation families in follow-up study resulted from GN treatment(N=14) followed by CC(N=6) followed by LTZ(N=3). There were no significant differences among the 3 groups at any time point with respect to abnormal scores on the ASQ. On the MCDI Words and Gestures, the LTZ group scored significantly higher than the GN group for all items(phrases p=0.02, words understood p=0.04, words produced p=0.04, early gestures p=0.01, later gestures p

BACKGROUND: Preconception nutrition sets the stage for a healthy pregnancy. Maternal fatty acids (FAs) are related to beneficial neonatal outcomes with DNA methylation proposed as a mechanism; however, few studies have investigated this association and none with preconception FAs. OBJECTIVES: We examined the relations of maternal plasma FA concentrations at preconception (n = 346) and 8 weeks of gestation (n = 374) with newborn DNA methylation. METHODS: The Effects of Aspirin in Gestation and Reproduction Trial (2006–2012) randomly assigned women with previous pregnancy loss to low dose aspirin or placebo prior to conception. We measured maternal plasma phospholipid FA concentration at preconception (on average 4 mo before pregnancy) and 8 weeks of gestation. Cord blood DNA from singletons was measured using the MethylationEPIC BeadChip. We used robust linear regression to test the associations of FA concentration with methylation β-values of each CpG site, adjusting for estimated cell count using a cord blood reference, sample plate, maternal sociodemographic characteristics, cholesterol, infant sex, and epigenetic-derived ancestry. False discovery rate correction was used for multiple testing. RESULTS: Mean ± SD concentrations of preconception marine (20:5n–3+22:6n–3+22:5n–3) and ω-6 PUFAs, SFAs, MUFAs, and trans FAs were 4.7 ± 1.2, 38.0 ± 2.0, 39.4 ± 1.8, 11.6 ± 1.1, and 1.0 ± 0.4 % of total FA, respectively; concentrations at 8 weeks of gestation were similar. Preconception marine PUFA concentration was associated with higher methylation at GRAMD2 (P = 1.1 × 10(−8)), LOXL1 (P = 5.5 × 10(−8)), SIK3 (P = 1.6 × 10(−7)), HTR1B (P = 1.9 × 10(−7)), and MCC (P = 2.1 × 10(−7)) genes. Preconception SFA concentration was associated with higher methylation at KIF25-AS1 and lower methylation at SLC39A14; other associations exhibited sensitivity to outliers. The trans FA concentration was related to lower methylation at 3 sites and higher methylation at 1 site. FAs at 8 weeks of gestation were largely unrelated to DNA methylation. CONCLUSIONS: Maternal preconception FAs are related to newborn DNA methylation of specific CpG sites, highlighting the importance of examining nutritional exposures preconceptionally. This trial was registered at clinicaltrials.gov as NCT00467363.

BACKGROUND: Gestational diabetes mellitus (GDM) is a common pregnancy complication which has substantial short- and long-term adverse health implications for women and their children. However, large-scale studies on genetic risk loci for GDM remain sparse. METHODS: We conducted a case-control study among 2,636 GDM cases and 6,086 non GDM controls from the Nurses’ Health Study II (NHSII) and the Danish National Birth Cohort (DNBC). One hundred and twelve susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes (T2D) were selected and measured. A weighted genetic risk score (GRS) was created based on variants that were significantly associated with risk of GDM after correcting for false discovery rate (FDR). RESULTS: For the first time, we identified eight variants associated with GDM, namely rs7957197 (HNF1A), rs10814916 (GLIS3), rs3802177 (SLC30A8), rs9379084 (RREB1), rs34872471 (TCF7L2), rs7903146 (TCF7L2), rs11787792 (GPSM1), and rs7041847 (GLIS3). Additionally, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B), and rs4506565 (TCF7L2), that were previously significantly associated with GDM risk. Furthermore, compared to participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the odds ratios of GDM were 1.07 (95% CI: 0.93, 1.22), 1.23 (95% CI 1.07, 1.41), and 1.53 (95% CI 1.34, 1.74) in the second, third, and fourth (highest) quartile, respectively. The significant positive associations between the weighted GRS and risk of GDM persisted across most of the strata of major risk factors for GDM including family history of type 2 diabetes, smoking status, body mass index, and age. CONCLUSION: In this large-scale case-control study with women from two independent populations, eight novel GDM SNPs were identified, which offers potential to improve our understanding on GDM etiology, particularly biological mechanisms related to beta cell function.

Background While adipokines can regulate satiety and energy metabolism, whether they are associated with childhood growth is unclear. Objective To evaluate whether adipokine levels at birth are associated with growth. Methods A total of 2264 singletons and 1144 twins from Upstate KIDS (born 2008-2010) had adiponectin, leptin, resistin and complement factor D measured in newborn blood spots. Parents reported anthropometry from paediatric visits via questionnaires every 4-6 months. Generalized linear mixed effects models were used to estimate growth trajectories through 3 years of age. Results Among singletons, resistin and leptin were associated with greater weight-for-age (0.12 z-score units (95%CI: 0.04, 0.20) [p = 0.003] and 0.15 (0.06, 0.24) [p = 0.001], respectively) and BMI z-score (0.11; 0.02, 0.20 [p = 0.02] and 0.18; 0.07, 0.28 [p = 0.002], respectively). After adjusting for birthweight, resistin and a ratio of resistin-to-adiponectin remained associated with weight through 3 years of age and odds of being overweight at 3 years of age in a subgroup of singletons. Among twins, adiponectin was associated with increased weight-for-age and length-for-age z-scores even after adjusting for birthweight (0.18; 0.08, 0.28 [p = 0.0006]; 0.20; 0.07, 0.33 [p = 0.003], respectively). Conclusions Levels of adipokines were associated with early childhood growth in small magnitudes. Resistin may be relevant for further examination in paediatric obesity.

Concerns remain about the health of children conceived by infertility treatment. Studies to date have predominantly not identified substantial long-term health effects after accounting for plurality, which is reassuring given the increasing numbers of children conceived by infertility treatment worldwide. However, as technological advances in treatment arise, ongoing studies remain critical for monitoring health effects. To study whether the techniques used in infertility treatment cause health differences, however, remains challenging due to identification of an appropriate comparison group, heterogeneous treatment, and confounding by the underlying causes of infertility. In fact, the factors that are associated with underlying infertility, including parental obesity and other specific male and female factors, may be important independent factors to consider. This review will summarize key methodological considerations in studying children conceived by infertility treatment including the evidence of associations between underlying infertility factors and child health.

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.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).In a birth cohort (2008-2010) of twins (n=1790) and singletons (n=3829) where parents completed AgesStages 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 AgesStages 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.Compared with non-small-for-gestational age twins (10th percentile), uncertain small-for-gestational age twins did not have higher odds of AgesStages 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 AgesStages 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).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.