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Background: Single-pollutant models have linked prenatal PM 2.5 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 PM 2.5 , PM 10 , NO X , SO 2 , 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 PM 2.5 exposure (IQR: 3.3 µg/m 3 ) from the median during this window correlated with a 34 g decrement in birthweight (95 % CI: -54, -14), followed by SO 2 (IQR: 2.0 ppb; β: -31), PM 10 (IQR: 4.6 µg/m 3 ; β: -29), CO (IQR: 60.8 ppb; β: -27), and NO X (IQR: 7.9 ppb; β: -26). Multi-pollutant BKMR models revealed that PM 2.5 , NO X , 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 PM 2.5 , 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

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 <32, 32-34, 35-36, 37, 38, and 40 weeks of gestational age were 5.32 (3.42-8.28), 2.43 (1.60-3.69), 1.38 (1.00-1.90), 1.37 (0.98-1.90), 1.29 (0.99-1.67), 0.73 (0.55-0.96), and 0.51 (0.32-0.82). Similar risks of being eligible for Early Intervention Program services were observed (aOR: 4.19, 2.10, 1.29, 1.20, 1.01, 1.00 [ref], 0.92, and 0.78 respectively for <32, 32-34, 37, 38, 39 [ref], 40, and 41 weeks)., 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., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To study the associations between maternal polycystic ovary syndrome (PCOS) and hirsutism with offspring attention-deficit/hyperactivity disorder (ADHD), anxiety, conduct disorder, and behavioral problems., Design: Prospective birth cohort study., Setting: Not applicable., Patient(s): A total of 1,915 mother-child dyads., Intervention(s): None., Main Outcome Measure(s): Maternal report of offspring ADHD, anxiety, or conduct disorder diagnosis at 7 to 8 years; emotional symptoms, behavioral problems (including peer relationship, conduct, hyperactivity/inattention), and prosocial problems measured with the Strengths and Difficulties Questionnaire (SDQ) at 7 years., Result(s): Prevalence of PCOS and hirsutism were 12.0% and 3.9%; 84% of women with hirsutism had PCOS. After adjustment for sociodemographic covariates, prepregnancy body mass index, and parental history of affective disorders, children born to mothers with PCOS had higher risk of anxiety (adjusted risk ratio [aRR] 1.62; 95% confidence interval [CI], 1.02-2.57) and borderline emotional symptoms (aRR 1.66; 95% CI, 1.18-2.33) compared with children born to mothers without PCOS. The associations between maternal PCOS and offspring ADHD were positive but imprecise. Maternal hirsutism was related to a higher risk of children's ADHD (aRR 2.33; 95% CI, 1.28-4.24), conduct disorder (aRR 2.54; 95% CI 1.18-5.47), borderline emotional symptoms, peer relationship problems, and conduct problems (aRRs 2.61; 95% CI, 1.69-4.05; 1.92; 95% CI, 1.16-3.17; and 2.22; 95% CI, 1.30-3.79, respectively)., Conclusion(s): Maternal PCOS was associated with offspring anxiety, and hirsutism was related to other offspring behavioral problems. These findings should be interpreted with caution as replication is needed in prospective cohort studies that assess PCOS and hirsutism diagnoses using medical records., (Published by Elsevier Inc.)

Experimental studies suggest that prenatal exposure to endocrine disrupting chemicals interferes with developmental processes in the fetal brain. Yet, epidemiological evidence is inconclusive. In a birth cohort (2008-2010, upstate New York), we quantified concentrations of perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and bisphenol A (BPA) in stored newborn dried blood spots using liquid chromatography/tandem mass spectrometry. Mothers reported on children's behavior using the Strengths and Difficulties Questionnaire at age 7 (650 singletons and 138 twins). Difficulties in total behavior (i.e., emotional, conduct, hyperactivity, and peer problems) and prosocial behavior were classified using validated cut-offs. We used logistic regression with generalized estimating equations to estimate the odds of having difficulties per exposure category. In total, 111 children (12.1%) had total behavioral difficulties and 60 (6.5%) had difficulties in prosocial behavior. The median (interquartile range) of PFOS, PFOA, and BPA were 1.74 ng/ml (1.33), 1.12 ng/ml (0.96), and 7.93 ng/ml (10.79), respectively. Higher PFOS levels were associated with increased odds of having behavioral difficulties (OR per SD of log PFOS = 1.30, 95%CI: 1.03-1.65). We observed associations between PFOS in the highest relative to the lowest quartile and behavioral difficulties (OR for PFOS 1.14-1.74  = 1.65, 95%CI: 0.84-3.34; PFOS 1.75-2.47  = 1.73, 95%CI: 0.87-3.43; and PFOS >2.47  = 2.47, 95%CI: 1.29-4.72 compared to PFOS <1.41 ). The associations between higher concentrations of PFOS and behavioral difficulties at age 7 years were driven by problems in conduct and emotional symptoms. Higher PFOA levels were associated with difficulties in prosocial behavior (OR = 1.35, 95%CI: 1.03-1.75). There was an inverse association between BPA concentrations and difficulties in prosocial behavior but only in the 2nd and 4th quartiles. We found no interactions between sex and chemical concentrations. Increasing prenatal exposure to PFOS and PFOA, as reflected in neonatal concentrations, may pose risk for child behavioral difficulties., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Novel methodologies to quantify infant exposures to endocrine disrupting chemicals (EDCs) for population-based studies are needed., Objectives: We used newborn dried blood spots to quantify three EDCs and their associations with infant outcomes in the Upstate KIDS Cohort., Methods: We measured bisphenol A (BPA), perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in 2071 singleton and 1040 twin infants born to mothers in New York State. We log transformed concentrations after rescaling by their standard deviations and modeled each in relation to gestational age, birthweight, length, head circumference and Ponderal Index (PI) using linear regression techniques. All models were adjusted for maternal age, body mass index, education, infertility treatment and parity. Generalized estimating equations with robust standard errors were used to assess the associations for twins., Results: Chemicals were largely quantified above the limits of detection (>99% for PFOS and PFOA; 90% for BPA). Overall, we observed no significant associations between PFASs and birth size irrespective of plurality of birth. However, among twins, BPA was associated with decreases in gestational age (adjusted β = -0.09 weeks; 95% Confidence Interval (CI): -0.16, -0.02) and birthweight (adjusted β = -32.52 g; 95% CI: -60.99, -4.05), head circumference (adjusted β = -0.18 cm; 95% CI: -0.38, -0.02) and increased PI in singletons (adjusted β = 0.02 cm; 95% CI: 0.004, 0.04)., Conclusion: We observed negative associations between BPA and birth size in twins. Our findings demonstrate the feasibility of newborn dried blood spots for quantifying neonatal exposure at the population level., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Polycystic ovarian syndrome (PCOS) is the most common cause of female infertility and is associated with higher levels of circulating androgens. Exposure to higher levels of androgens in utero may be a risk factor for obesity among children of women with PCOS., Methods: We examined whether maternal PCOS was associated with differences in offspring growth and obesity in the Upstate KIDS study, a prospective cohort study of infants born in New York State (excluding New York City) oversampled for fertility treatments and multiple births. Measurements of offspring length/height and weight were recorded at doctor's visits through 3 years of age. PCOS diagnosis was self-reported by mothers at baseline. We used linear mixed models with robust SEs to estimate differences in growth by maternal PCOS exposure. We used logistic regression to examine whether infants experienced rapid weight gain at 4, 9 and 12 months. Growth measures were reported by 4098 mothers for 4949 children (1745 twins). Of these, 435 mothers (10.6%) had a diagnosis of PCOS., Results: Compared with children born to mothers without PCOS, children of mothers with PCOS did not have significant differences in weight (4.81 g, 95% CI -95.1 to 104.7), length/height (0.18 cm, 95% CI -0.16 to 0.52) and body mass index (-0.14 kg/m 2 , 95% CI -0.30 to 0.01) through 3 years of age. We also observed no association between maternal PCOS and offspring rapid weight gain., Conclusions: Overall, we found little evidence to suggest that maternal PCOS influences early childhood growth in this large, prospective cohort study., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Evidence shows cytokine dysregulation in children with developmental disabilities. The association between immune activity during the perinatal period and child development is less clear., Methods: We examined the relationship between newborn concentrations of immune markers and child development. Within Upstate KIDS, a population-based birth cohort (2008-2010, upstate New York), we assayed immune markers, which are postulated to have neuro-modulatory effects, in newborn dried blood spots (NDBS, n = 3038). Mothers completed the Ages & Stages Questionnaire© (ASQ) for their children repeatedly through age 36 months. At 30 and 36 months, mothers also reported whether their children received any developmental services. We used generalised linear mixed models adjusted for maternal and child characteristics to test associations., Results: Sixteen immune markers were associated with failing ASQ in unadjusted models. After full adjustment (for gestational age, mode of delivery, parity, pregnancy smoking, etc.), we observed that higher levels of 4 markers, including platelet-derived growth factor-AA (PDGF-AA, OR 0.77, 95% CI 0.67, 0.89), plasminogen activator inhibitor-1 (OR 0.80, 95% CI 0.68, 0.94), stromal cell derived factor-1 (OR 0.85, 95% CI 0.73, 0.98), and macrophage inflammatory protein-1beta (OR 0.87, 95% CI 0.77, 0.98) were associated with lower odds of ASQ failure. The associations did not exist if correction for multiple comparisons was performed, except for PDGF-AA. Analyses with developmental service use revealed similar null findings., Conclusions: Immune marker concentrations in NDBS may not be associated with developmental delay in the general population. Newborn concentrations of growth factor PDGF-AA may be protective of developmental delay in childhood., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To identify associations between fertility treatment use (assisted reproductive technologies, ovulation induction, and artificial insemination) and subsequent infant feeding practices., Design: The Upstate KIDS population-based cohort enrolled mothers who delivered live births in New York (2008-2010), sampling on fertility treatment and plurality., Setting: Not applicable., Patient(s): Data regarding singletons and one randomly selected infant between twins were used., Intervention(s): Not applicable., Main Outcome Measure(s): Mothers reported breast feeding and formula feeding practices at 4, 8, and 12 months postpartum. Modified Poisson regression was used to compare risks for feeding practices by mode of conception. Marginal structural models were used to estimate the controlled direct effects of fertility treatment on feeding, independent of preterm birth., Result(s): Among 4,591 mothers, 1,361 (30%) conceived with the use of fertility treatments. Mothers who used fertility treatments were less likely to breast feed to 12 months after birth and were more likely to provide formula, solids, and juice by 4 months than mothers who did not conceive with treatments. Fertility treatment remained associated with breast feeding cessation and formula feeding in mediation analyses, suggesting that preterm birth does not fully explain these associations., Conclusion(s): Women who conceived with the use of fertility treatments were less likely to breast feed later in infancy and were more likely to provide formula, solids, and juice earlier in infancy. Our analyses accounted for confounding and preterm birth, but other contributing factors may include difficulties feeding twins or workplace breast feeding accommodations., (Published by Elsevier Inc.)

Importance: An increasing percentage of births are conceived with assisted reproductive technology (ART) and other infertility treatment. Despite findings that such treatments may be associated with diminished gestation and birth size, scarce data exist regarding infertility treatments and children's development in the United States., Objective: To assess the use and type of infertility treatment in relation to children's development through age 36 months., Design, Setting, and Participants: Prospective cohort study (conducted 2008-2014) that sampled based on infertility treatment and plurality. Included in the study were infants born between 2008 and 2010 in New York state (excluding New York City) whose parents completed developmental screening instruments through 36 months of age. A total of 4824 mothers (97% of 4989) completed 1 or more developmental screening instruments for 5841 children, including 1830 conceived with infertility treatment and 2074 twins., Exposures: Maternal self-report of any infertility treatment was further categorized into ART and ovulation induction/intrauterine insemination. Assisted reproductive technology use was previously validated by linkage with the Society for Assisted Reproductive Technology-Clinical Outcome Reporting System., Main Outcomes and Measures: Five developmental domains (fine motor, gross motor, communication, personal-social functioning, and problem-solving ability), as measured by the parental completion of the Ages and Stages Questionnaires at 4, 8, 12, 18, 24, 30, and 36 months of age. Generalized linear mixed modeling techniques estimated adjusted odds ratios (aORs) and 95% CIs for use and type of infertility treatment in relation to failing a developmental domain. Data were stratified by plurality and weighted for the sampling scheme., Results: There were 1422 mothers (29.5%; mean [SD], age, 34.1 [5.2] years) who underwent infertility treatment. Infertility treatment was not associated with risk of their children failing any developmental domain (aOR, 1.33; 95% CI, 0.94-1.89). Assisted reproductive technology was associated with increased risk for failing any developmental domain but only when singletons and twins were evaluated together (aOR, 1.81; 95% CI, 1.21-2.72). Adjustment for birth weight further attenuated this estimate (aOR, 1.26; 95% CI, 0.82-1.93). After stratifying by plurality, type of treatment also was not significantly associated with failing any developmental domain for ovulation induction/intrauterine insemination (aOR, 1.00; 95% CI, 0.57-1.77 for singletons and aOR, 1.30; 95% CI, 0.76-2.21 for twins) or ART (aOR, 1.38; 95% CI, 0.78-2.43 for singletons and aOR, 1.58; 95% CI, 0.94-2.65 for twins)., Conclusions and Relevance: After considering plurality, children's development through age 3 years was similar irrespective of infertility treatment or specific type. To our knowledge, these findings are among the first to focus on non-ART treatments in the United States., Competing Interests: Disclosures: None reported.

Objective: To assess the validity of maternally reported assisted reproductive technologies (ART) use and to identify predictors of reporting errors., Design: Linkage study., Setting: Not applicable., Patient(s): A total of 5,034 (27%) mothers enrolled, from whom 4,886 (97%) self-reported information about use of infertility treatment, including ART, for the index birth., Intervention(s): None., Main Outcome Measure(s): Four measures of validity (sensitivity, specificity, positive and negative predictive values) and use of net reclassification improvement (NRI) methods to identify predictors associated with concordant/discordant maternal reporting., Result(s): The Upstate New York Infant Development Screening Program (Update KIDS Study) was linked with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) using a defined algorithm for 2008-2010. The sensitivity, specificity, positive and negative predictive values were high (0.93, 0.99, 0.80, and 1.00, respectively). The validity of maternal report was high, reflecting few differences by participant characteristics except for maternal age dichotomized at 29 years as identified with NRI methods., Conclusion(s): Maternally reported ART is valid, with little variation across various characteristics. No strong predictors of discordant reporting were found, supporting the utility of population-based research with SART CORS linkage., (Published by Elsevier Inc.)

Background/aims: We sought to investigate the association between preconception serum lipids and their daily rate of change in relation to length of gestation., Methods: In a cohort of 70 women, 61 (87%) became pregnant, resulting in 48 (69%) live births. Serum lipid measurements (in milligrams per deciliter) included total cholesterol, free cholesterol, triglycerides and phospholipids at preconception, upon human chorionic gonadotropin-confirmed pregnancy and following pregnancy loss (<14 weeks) or post partum. Pregnancy outcome (loss, preterm and term delivery) and gestational length were modeled relative to daily rate of change in lipids using multinomial regression and Cox proportional hazards models, respectively, adjusting for body mass index and smoking., Results: A rate of triglyceride change below the median was associated with an increased risk for pregnancy loss compared with term birth (adjusted odds ratio: 9.02; 95% CI: 1.62-50.30). A rate of triglyceride change of ≤0.01 mg/dl per day versus above the median was associated with a trend for increased risk of pregnancy loss or preterm (<37 weeks) birth (adjusted hazard ratio: 1.77; 95% CI: 0.94-3.33)., Conclusion: A low rate of triglyceride change during early pregnancy may be a signal of risk of pregnancy loss or preterm birth. Lipids offer promise for identifying pregnancies at risk for adverse outcomes.

Understanding conception probabilities is important not only for helping couples to achieve pregnancy but also in identifying acute or chronic reproductive toxicants that affect the highly timed and interrelated processes underlying hormonal profiles, ovulation, libido, and conception during menstrual cycles. Currently, 2 statistical approaches are available for estimating conception probabilities depending upon the research question and extent of data collection during the menstrual cycle: a survival approach when interested in modeling time-to-pregnancy (TTP) in relation to women or couples' purported exposure(s), or a hierarchical Bayesian approach when one is interested in modeling day-specific conception probabilities during the estimated fertile window. We propose a biologically valid discrete survival model that unifies the above 2 approaches while relaxing some assumptions that may not be consistent with human reproduction or behavior. This approach combines both the survival and the hierarchical models allowing investigators to obtain the distribution of TTP and day-specific probabilities during the fertile window in a single model. Our model allows for the consideration of covariate effects at both the cycle and the daily level while accounting for daily variation in conception. We conduct extensive simulations and utilize the New York State Angler Prospective Pregnancy Cohort Study to illustrate our approach. We also provide the code to implement the model in R software in the supplemental section of the supplementary material available at Biostatistics online.

Trace exposures to metals may affect female reproductive health. To assess the relation between trace concentrations of blood metals and female fecundity, 99 non-pregnant women discontinuing contraception for the purpose of becoming pregnant were prospectively followed. Participants completed a baseline interview and daily diaries until pregnant, or up to 12 menstrual cycles at risk for pregnancy; home pregnancy test kits were used. For 80 women, whole blood specimens were analyzed for arsenic, cadmium, lead, magnesium, nickel, selenium and zinc using inductively coupled plasma mass spectrometry (ICP-MS). Time to pregnancy was estimated using Cox proportional hazards models for discrete time. Metal concentrations were generally within population reference intervals. Adjusted models suggest a 51.5% increase in the probability for pregnancy per 3.60 μg/L increase in Mg (P=0.062), and a 27.7% decrease per 0.54 μg/L increase in Zn (P=0.114). Findings indicate that Mg and Zn may impact female fecundity, but in varying directions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Human fecundability is defined as the probability of conception during a menstrual cycle among couples at risk for pregnancy. It is highly relevant for understanding human reproduction and represents a series of highly interrelated and timed processes. The statistical literature has recognized the need to incorporate both biological and behavioral factors (Barrett and Marshall, 1969; Dunson and Stanford, 2005) when modeling conception probabilities, given that intercourse during the fertile window is a necessary but not sufficient criterion for conception. The heterogeneity of behaviors such as the timing and frequency of intercourse in a menstrual cycle needs to be considered when estimating conception. Here we propose a joint model of intercourse behavior and human fecundability through a classic conception probability model and a structural equation model (SEM) to accommodate intercourse during the menstrual cycle. The SEM part of the proposed model allows the dependency between intercourse behaviors on consecutive days in a menstrual cycle to vary across days. Consequently, the proposed model can accommodate not only a broad variety of intercourse patterns and dependency structures but also general covariate effects. Finally, we present a detailed analysis of the New York State Angler Cohort Prospective Pregnancy Study to illustrate the proposed methodology.

Background: The reliability of retrospective time to pregnancy (TTP) has been established, but its validity has been assessed in only 1 study, which had a short follow-up., Methods: Ninety-nine women enrolled a decade earlier in a prospective TTP study were queried by means of mailed questionnaires about the duration of time they had required to become pregnant. Their responses were compared with their earlier data from daily diaries (gold standard)., Results: One-third of women could not recall their earlier TTP either in menstrual cycles or calendar months. Only 17%-19% of women recalled their TTP exactly. Agreement increased to 41%-51%, 65%-72%, and 72%-77% when defined as +/-1, +/-2, and +/-3 months, respectively. Women with longer observed TTPs or previous pregnancies were more likely to under-report their TTP., Conclusions: The findings raise questions about the commonly assumed validity of self-reported TTP. Recalled TTP may introduce error when estimating fecundability or classifying couples' fecundity status.