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Author(s): Ulla Sovio [sup.1] [sup.2] , Neil Goulding [sup.3] [sup.4] [sup.5] , Nancy McBride [sup.3] [sup.4] [sup.5] , Emma Cook [sup.1] , Francesca Gaccioli [sup.1] [sup.2] , D. Stephen Charnock-Jones [...], Fetal growth restriction (FGR) is the major single cause of stillbirth.sup.1 and is also associated with neonatal morbidity and mortality.sup.2,3, impaired health and educational achievement in childhood.sup.4,5 and with a range of diseases in later life.sup.6. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) metabolomics on maternal serum at 12, 20 and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the Pregnancy Outcome Prediction (POP) study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC (P-18:0/18:1) and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5[alpha]-androstan-3[alpha],17[alpha]-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker.sup.7, the soluble fms-like tyrosine kinase 1:placental growth factor (sFLT1:PlGF) ratio (AUC 0.78 versus 0.64, P = 0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford (BiB), conducted in Bradford, UK (P = 0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor. The relative concentrations of four metabolites in maternal blood at 36 weeks of gestation predict fetal growth restriction in infants subsequently born at term, enabling enhanced fetal monitoring in pregnancies at risk.

Author(s): Sanjiv Risal [sup.1] , Yu Pei [sup.1] [sup.2] , Haojiang Lu [sup.1] , Maria Manti [sup.1] , Romina Fornes [sup.1] , Han-Pin Pui [sup.1] , Zhiyi Zhao [sup.1] [sup.3] [...], How obesity and elevated androgen levels in women with polycystic ovary syndrome (PCOS) affect their offspring is unclear. In a Swedish nationwide register-based cohort and a clinical case-control study from Chile, we found that daughters of mothers with PCOS were more likely to be diagnosed with PCOS. Furthermore, female mice (F.sub.0) with PCOS-like traits induced by late-gestation injection of dihydrotestosterone, with and without obesity, produced female F.sub.1-F.sub.3 offspring with PCOS-like reproductive and metabolic phenotypes. Sequencing of single metaphase II oocytes from F.sub.1-F.sub.3 offspring revealed common and unique altered gene expression across all generations. Notably, four genes were also differentially expressed in serum samples from daughters in the case-control study and unrelated women with PCOS. Our findings provide evidence of transgenerational effects in female offspring of mothers with PCOS and identify possible candidate genes for the prediction of a PCOS phenotype in future generations. Prenatal androgen exposure causes transgenerational increases in offspring susceptibility to polycystic ovary syndrome in adulthood.

INTRODUCTION Vitamin D deficiency is related to various adverse health outcomes in early and later life. (1-4) An accumulating body of evidence suggests that vitamin D status during pregnancy may [...], BACKGROUND/OBJECTIVES: Maternal vitamin D deficiency during pregnancy may influence offspring kidney health. We aimed to examine the associations of 25-hydroxyvitamin D (25(OH)D) blood levels during fetal life with kidney outcomes at school age. SUBJECTS/METHODS: This study was embedded in a population-based prospective cohort study among 4212 mother-child pairs. We measured maternal second trimester (18-25 weeks) and fetal cord blood (at birth) 25(OH)D levels. At a median age of 6.0 years, we measured children's combined kidney volume, glomerular filtration rate (eGFR) from creatinine and cystatin C serum levels, and microalbuminuria from albumin and creatinine urine levels. RESULTS: Of all mothers, 21.9% had severely deficient levels (25(OH)D < 25.0 nmol/l), 25.7% had deficient levels (25.0-49.9 nmol/l), 25% had sufficient levels (50.0-74.9 nmol/l) and 27.4% had optimal levels (≥ 75.0 nmol/l). Maternal 25(OH)D levels were not consistently associated with childhood combined kidney volume. Higher maternal 25(OH)D levels were associated with lower childhood eGFR (difference -0.94 ml/min per 1.73 [m.sup.2] (95% confidence interval, -1.73;-0.15) per 1 standard deviation (s.d.) increase in 25(OH)D). Maternal 25(OH)D levels were not associated with microalbuminuria. Cord blood 25(OH)D levels were not associated with childhood kidney outcomes. The associations of maternal 25(OH)D levels with childhood eGFR were partly explained by childhood vitamin D status. CONCLUSIONS: Our findings suggest that maternal 25(OH)D levels during pregnancy may influence childhood kidney outcomes. These results should be considered hypothesis generating. Further studies are needed to replicate the observations, to examine the underlying mechanisms and to identify the long-term clinical consequences. European Journal of Clinical Nutrition (2016) 70, 629-634; doi: 10.1038/ejcn.2015.216; published online 23 December 2015

Author(s): Matias C. Vieira 1,2, Sophie Relph 1, Martina Persson 3, Paul T. Seed 1, Dharmintra Pasupathy 1,* Introduction Infants with abnormal fetal growth have an increased risk of adverse [...], Background Although many studies have compared birth-weight charts to determine which better identify infants at risk of adverse perinatal outcomes, less attention has been given to the threshold used to define small or large for gestational age (SGA or LGA) infants. Our aim was to explore different thresholds associated with increased risk of adverse perinatal outcomes using population, customised, and Intergrowth centile charts. Methods and findings This is a population-based cohort study (Swedish Medical Birth Registry), which included term singleton births between 2006 and 2015 from women with available data on first-trimester screening. Population, customised, and Intergrowth charts were studied. Outcomes included cesarean section, postpartum haemorrhage, severe perineal tear, Apgar score at 5 minutes, neonatal morbidity, and perinatal mortality. Odds for each outcome were assessed in intervals of 5 centiles of birth weight (reference being 40th-60th centiles) using logistic regression. Intervals of 5% of the population were also explored. Sensitivity for fixed false-positive rates (FPRs) was reported for neonatal outcomes. Data from 212,101 births were analysed. Mean age was 33 ± 5 years, 48% of women were nulliparous, and 80% were born in Sweden. Prevalence of SGA (90th centile) was 10.0%, 8.2%, and 25.1%, assessed using population, customised, and Intergrowth charts, respectively. In small infants, the risk of perinatal mortality was consistently increased below the 15th, 10th, and 35th birth-weight centiles for the respective charts (odds ratio [OR] 1.59, 95% confidence interval [CI] 1.05-2.39, p = 0.03 for 10th-15th population centile; OR 2.54, 95% CI 1.74-3.71, p < 0.001 for 5th-10th customised centile; OR 1.81, 95% CI 1.07-3.04, p = 0.03 for 30th-35th Intergrowth centile). The strength of association with adverse perinatal outcomes was different between infants below the 5th birth-weight centile for each chart (OR 4.47, 95% CI 3.30-6.04, p < 0.001 for the population chart; OR 5.78, 95% CI 4.22-7.91, p < 0.001 for the customised chart; OR 10.74, 95% CI 7.32-15.77, p < 0.001 for the Intergrowth chart) but similar in the smallest 5% of the population (OR 4.34, 95% CI 3.22-5.86, p < 0.001 for the population chart; OR 5.23, 95% CI 3.85-7.11, p < 0.001 for the customised chart; OR 4.69, 95% CI 3.47-6.34, p < 0.001 for the Intergrowth chart). For a fixed FPR of 10%, different thresholds for each chart achieved similar sensitivity for perinatal mortality in small infants (29% for all charts). Similar behaviour of different thresholds and similar risk/sensitivity for fixed FPR were observed in relation to other outcomes and for LGA infants. Limitations of this study include the relative homogeneity of the Swedish population, which limits generalisability to other populations; customised centiles may perform differently in populations with increased heterogeneity of ethnic background. Conclusions The risk of adverse outcomes was consistent across proportions of the population but did not reflect fixed thresholds, such as the 10th or 90th centiles, across different growth charts. Chart-specific thresholds for the population should be considered in clinical practice.

INTRODUCTION The clinical importance of fetal and pediatric body composition merits re-emphasizing. Although it is still widely underused in the clinical setting, pediatric body composition can aid the clinician in [...], Fetal body composition is an important determinant of body composition at birth, and it is likely to be an important determinant at later stages in life. The purpose of this work is to provide a comprehensive overview by presenting data from previously published studies that report on body composition during fetal development in newborns and the infant/child through 5 years of age. Understanding the changes in body composition that occur both in utero and during infancy and childhood, and how they may be related, may help inform evidence-based practice during pregnancy and childhood. We describe body composition measurement techniques from the in utero period to 5 years of age, and identify gaps in knowledge to direct future research efforts. Available literature on chemical and cadaver analyses of fetal studies during gestation is presented to show the timing and accretion rates of adipose and lean tissues. Quantitative and qualitative aspects of fetal lean and fat mass accretion could be especially useful in the clinical setting for diagnostic purposes. The practicality of different pediatric body composition measurement methods in the clinical setting is discussed by presenting the assumptions and limitations associated with each method that may assist the clinician in characterizing the health and nutritional status of the fetus, infant and child. It is our hope that this review will help guide future research efforts directed at increasing the understanding of how body composition in early development may be associated with chronic diseases in later life. European Journal of Clinical Nutrition (2015) 69, 1279-1289; doi: 10.1038/ejcn.2015.117; published online 5 August 2015

Author(s): Jonas F. Ludvigsson 1,2,3,4,*, Donghao Lu 1,5, Lennart Hammarström 6, Sven Cnattingius 7, Fang Fang 1 Introduction The Barker hypothesis proposes that intrauterine growth restriction may cause cardiovascular disease [...], Background Small for gestational age (SGA) has been associated with increased risks of stillbirth and neonatal mortality, but data on long-term childhood mortality are scarce. Maternal antenatal care, including globally reducing the risk of SGA birth, may be key to achieving the Millennium Development Goal of reducing under-5 mortality. We therefore aimed to examine the association between SGA and mortality from 28 days to Methods and findings In a Swedish population study, we identified 3,795,603 non-malformed singleton live births and 2,781,464 full siblings born from January 1, 1973, to December 31, 2012. We examined the associations of severe ( Conclusions We found that SGA, especially severe SGA, was associated with an increased risk of childhood death beyond the neonatal period, with the highest risk estimates for death from infection and neurologic disease. The similar results obtained between the population- and sibling-based analyses argue against strong confounding by factors shared within families.

Introduction In the United States, ~ 11% of all pregnancies result in preterm birth (PTB; birth prior to 37 wk gestation) (March of Dimes 2014). Although the reasons for this [...], Background: Epidemiological studies associate inhalation of fine-sized particulate matter ([PM.sub.2.5]) during pregnancy with preterm birth (PTB) and low birth weight (LBW) but disagree over which time frames are most sensitive, or if effects are cumulative. Objectives: Our objective was to provide experimental plausibility for epidemiological observations by testing the hypothesis that exposure to [PM.sub.2.5] during discrete periods of pregnancy results in PTB and LBW. Methods: For the first study, timed-pregnant B6C3[F.sub.1] mice were exposed to concentrated ambient [PM.sub.2.5] (CAPs) or filtered air (FA) throughout pregnancy [6 h/d from gestational day (GD) 0.5 through GD16.5]. A follow-up study examined the effects of CAPs exposure during discrete gestational periods (1: GD0.5-5.5; 2: GD6.5-14.5; 3: GD14.5-16.5; 4: GD0.5-16.5) aligning to milestones during human development. Results: In the first experiment, exposure to 160 [micro]g CAPs/[m.sup.3] throughout pregnancy decreased gestational term by 0.5 d (~ 1.1 wk decrease for humans) and birth weight by 11.4% compared with FA. The follow-up experiment investigated timing of CAPs exposure (mean concentrations at 178, 193, 171, and 173 [micro]g/[m.sup.3] for periods 1-4, respectively). Pregnancy was significantly shortened (vs. FA) by ~ 0.4d when exposure occurred during gestational periods 2 and 4, and by ~ 0.5d if exposure occurred during period 3. Exposure during periods 1, 2, and 4 reduced birth weight by ~ 10% compared with FA, and placental weight was reduced (~ 8%) on GD17.5 if exposure occurred only during period 3. Conclusions: Adverse [PM.sub.2.5]-induced outcomes such as PTB and LBW are dependent upon the periods of maternal exposure. The results of these experimental studies could contribute significantly to air pollution policy decisions in the future. https://doi.org/10.1289/EHP1029

Introduction Birth weight (BW) is an indicator of cumulative fetal growth that has been closely related to health risk later in life (Barker and Thornburg 2013). Rates of low BW [...], Background: Reduced fetal growth increases the risk for adverse health outcomes. Growing evidence suggests that metal exposures contribute to reduced fetal growth, but little is known about the effects of complex metal mixtures. Objectives: We investigated the impact of a complex mixture of metals on birth weight for gestational age (BW for GA) in the Maternal and Developmental Risks from Environmental and Social Stressors study, a predominately lower-income Hispanic pregnancy cohort in Los Angeles, California. Methods: Cadmium (Cd), cobalt (Co), mercury (Hg), nickel (Ni), molybdenum (Mo), lead (Pb), antimony (Sb), tin (Sn), and thallium (Tl) were measured by inductively coupled plasma mass spectrometry (ICP-MS) in maternal urine samples collected in early pregnancy (median GA: 13.1 wk). Speciated urinary arsenic (As) (inorganic+monomethyl+dimethyl As) was measured by high-performance liquid chromatography coupled to ICPMS. Primary analyses focused on a mixture of seven metals that have previously been associated individually with fetal growth (i.e., As, Cd, Co, Hg, Ni, Pb, Tl) (n = 262). In exploratory analyses, we additionally examined three metals that have been less studied in relation to fetal growth (i.e., Mo, Sb, Sn). Covariate-adjusted Bayesian kernel machine regression was used to investigate metal mixture associations with BW for GA z-scores. Results: In primary analyses, Hg and Ni ranked highest as predictors of BW for GA. An inverse linear association was estimated for Hg, whereas a positive association was estimated for Ni at low-to-moderate concentrations. A potential interaction between Hg and Ni was also identified. In our exploratory analysis, Sb ranked highest as a predictor of BW for GA, followed by Hg and Ni. Conclusions: Our findings suggest that in this understudied population, Hg may reduce fetal growth, whereas Ni may promote fetal growth. We also identified Sb as a potential metal of concern for this population, which merits additional investigation.

Author(s): Sarah J. Stock 1,2,*, Jenny Myers 3 Appropriate fetal growth and development in utero is essential for newborn health and lifelong well-being. Both fetal growth restriction (in which the [...]

Introduction There is increasing recognition that modifiable environmental factors play an important role in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASD) (Hallmayer et al. 2011). Traits [...], Background: Prenatal exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment and behaviors related to autism spectrum disorders (ASD) in previous studies, including in the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a birth cohort living in the agricultural Salinas Valley in California. Objectives: To investigate the association of prenatal exposure to OP pesticides with traits related to ASD, in childhood and adolescents in CHAMACOS. Methods: We assessed OP exposure during pregnancy with measurements of dialkyl phosphates (DAP) metabolites in urine, and residential proximity to OP use during pregnancy using California&apos;s Pesticide Use Reporting (PUR) data and estimated associations with ASD- related traits using linear regression models. We measured traits reported by parents and teachers as well as the child&apos;s performance on tests that evaluate the ability to use facial expressions to recognize the mental state of others at 7, 10 1/2, and 14 years of age. Results: Prenatal DAPs were associated with poorer parent and teacher reported social behavior [e.g., a 10-fold DAP increase was associated with a 2.7-point increase (95% confidence interval (CI): 0.9, 4.5) in parent-reported Social Responsiveness Scale, Version 2, T-scores at age 14]. We did not find clear evidence of associations between residential proximity to OP use during pregnancy and ASD-related traits. Conclusions: These findings contribute mixed evidence linking OP pesticide exposures with traits related to developmental disorders like ASD. Subtle pesticide-related effects on ASD-related traits among a population with ubiquitous exposure could result in a rise in cases of clinically diagnosed disorders like ASD. https://doi.org/10.1289/EHP2580

Introduction The World Health Organization (WHO) reported that there were 214 million cases of malaria in 2015, resulting in about 438,000 deaths, with most deaths occurring in children under 5 [...], Background: Although indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) and pyrethroids effectively controls malaria, it potentially increases human exposure to these insecticides. Previous studies suggest that prenatal exposure to these insecticides may impact human neurodevelopment. OBJECTIVES: We aimed to estimate the effects of maternal insecticide exposure and neurodevelopment of toddlers living in a malaria-endemic region currently using IRS. Methods: The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort of 752 mother-child pairs in Limpopo, South Africa. We measured maternal exposure to DDT and its breakdown product, dichlorodiphenyldichloroethylene (DDE), in maternal serum, and measured pyrethroid metabolites in maternal urine. We assessed children&apos;s neurodevelopment at 1 and 2 y of age using the Bayley Scales of Infant Development, third edition (BSID-III), and examined associations with maternal exposure. Results: DDT and DDE were not associated with significantly lower scores for any BSID-III scale. In contrast, each 10-fold increase in cis-DCCA, trans-DCCA, and 3-phenoxybenzoic acid were associated, respectively, with a -0.63 (95% CI: -1.14, -0.12), -0.48 (95% CI: -0.92, -0.05), and -0.58 (-1.11, -0.06) decrement in Social-Emotional scores at 1 y of age. In addition, each 10-fold increase in maternal cis-DBCA levels was associated with significant decrements at 2 y of age in Language Composite scores and Expressive Communication scores [[beta] = - 1.74 (95% CI: -3.34, -0.13) and [beta] = - 0.40 (95% CI: -0.77, -0.04), respectively, for a 10-fold increase]. Significant differences by sex were estimated for pyrethroid metabolites and motor function scores at 2 y of age, with higher scores for boys and lower scores for girls. Conclusions: Prenatal exposure to pyrethroids may be associated at 1 y of age with poorer social-emotional development. At 2 y of age, poorer language development was observed with higher prenatal pyrethroid levels. Considering the widespread use of pyrethroids, these findings deserve further investigation. https://doi.org/10.1289/EHP2129

Introduction Intrauterine growth restriction (IUGR) is an adverse pregnancy outcome defined by Peleg et al. (1998) as a reduction in fetal weight (below the 10th percentile for gestational age) with [...], Background: Epidemiological studies suggest that increased ozone exposure during gestation may compromise fetal growth. In particular, the implantation stage of pregnancy is considered a key window of susceptibility for this outcome. Objectives: The main goals of this study were to investigate the effects of short-term ozone inhalation during implantation on fetal growth outcomes and to explore the potential for alterations in uterine arterial flow as a contributing mechanism. Methods: Pregnant Long-Evans rats were exposed to filtered air, 0.4 ppm ozone, or 0.8 ppm ozone for 4 h/d during implantation, on gestation days (GD) 5 and 6. Tail cuff blood pressure and uterine artery Doppler ultrasound were measured on GD 15, 19, and 21. To assess whether peri-implantation ozone exposure resulted in sustained pulmonary or systemic health effects, bronchoalveolar lavage fluid, serum metabolic and inflammatory end points, and kidney histopathology were evaluated in dams at GD 21. Growth parameters assessed in GD 21 offspring included fetal weight, length, and body composition. Results: Measures of maternal uterine arterial flow, including resistance index and mean velocity, indicated that resistance increased between GD 15 and GD 21 in 0.8 ppm dams but decreased in controls, although absolute values were similar in both groups on GD 21. Ozone-exposed dams also had lower serum glucose and higher free fatty acid concentrations than controls on GD 21. On GD 21, both male and female offspring had lower body weight than controls, and pooled subsets of 3 male and 3 female fetuses from litters exposed to 0.8 ppm ozone had lower lean mass and fat mass than pooled control offspring. Conclusions: Findings from our experimental model suggest that the offspring of dams exposed to ozone during implantation had reduced growth compared with controls, possibly as a consequence of ozone-induced vascular dysfunction. https://doi.org/10.1289/EHP2019