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Objective Design Setting Population Methods Main outcome measures Results Conclusions To evaluate the associations of plasma polybrominated diphenyl ether (PBDE) concentrations in early pregnancy with gestational weight gain (GWG).Prospective cohort study.US‐based, multicentre cohort of pregnant women.We used data from 2052 women without obesity and 397 women with obesity participating in the NICHD Fetal Growth Studies – Singleton Cohort, with first‐trimester plasma PBDE concentrations and weight measurements throughout pregnancy.We applied generalised linear models and Bayesian kernel machine regression (BKMR) to evaluate both the individual and joint associations of PBDEs with measures of GWG, adjusting for potential confounders.Total GWG (kg), total and trimester‐specific GWG velocities (kg/week), and GWG categories and trajectory groups.Mean pre‐pregnancy BMIs were 23.6 and 34.5 kg/m2 for women without and with obesity, respectively. Among women without obesity, there were no associations of PBDEs with any GWG measure. Among women with obesity, one standard deviation increase in log‐transformed PBDE 47 was associated with a 1.87 kg higher total GWG (95% CI 0.39–3.35) and a 0.05 kg/week higher total GWG velocity (95% CI 0.01–0.09). Similar associations were found for PBDE 47 in BKMR among women with obesity, and PBDE 47, 99 and 100 were associated with lower odds of being in the low GWG trajectory group.PBDEs were not associated with GWG among individuals without obesity. Among those with obesity, only PBDE 47 showed consistent positive associations with GWG measures across multiple statistical methods. Further research is needed to validate this association and explore potential mechanisms. [ABSTRACT FROM AUTHOR]

Introduction: Studies have reported a higher risk of suboptimal neurodevelopment among children who are HIV‐exposed uninfected (HEU) compared to children HIV‐unexposed uninfected (HUU). Actual academic performance among school‐aged children by HIV exposure status has not been studied. Methods: Academic performance in Mathematics, Science, English, Setswana and overall among children enrolled in the Botswana‐based FLOURISH study who were attending public primary school and ranging in age from 7.1 to 14.6 years were compared by HIV exposure status using a Cochran‐Mantel‐Haenszel test. Lower academic performance was defined as a grade of "C" or lower (≤60%). Unadjusted and adjusted logistic regression models were fit to assess for an association between HIV exposure and lower academic performance. Results: Between April 2021 and December 2022, 398 children attending public primary school enrolled in the FLOURSH study, 307 (77%) were HEU. Median age was 9.4 years (IQR 8.9–10.2). Only 17.9% of children HEU were breastfeed versus 100% of children HUU. Among children HEU, 80.3% had foetal exposure to three‐drug antiretroviral treatment, 18.7% to zidovudine only and 1.0% had no antiretroviral exposure. Caregivers of children HEU were older compared to caregivers of children HUU (median 42 vs. 36 years) and more likely to have no or primary education only (15.0% vs. 1.1%). In unadjusted analyses, children HEU were more likely to have lower overall academic performance compared to their children HUU (odds ratio [OR]: 1.96 [95% confidence interval (CI): 1.16, 3.30]), and lower performance in Mathematics, Science and English. The association was attenuated after adjustment for maternal education, caregiver income, breastfeeding, low birth weight and child sex (aOR: 1.86 [95% CI: 0.78, 4.43]). Conclusions: In this Botswana‐based cohort, primary school academic performance was lower among children HEU compared to children HUU. Biological and socio‐demographic factors, including child sex, appear to contribute to this difference. Further research is needed to identify modifiable contributors, develop screening tools to identify the risk of poor academic performance and design interventions to mitigate risk. [ABSTRACT FROM AUTHOR]

There has been heightened interest in identifying critical windows of exposure for adverse health outcomes; that is, time points during which exposures have the greatest impact on a person's health. Multiple informant models implemented using generalized estimating equations (MIM GEEs) have been applied to address this research question because they enable statistical comparisons of differences in associations across exposure windows. As interest rises in using MIMs, the feasibility and appropriateness of their application under settings of correlated exposures and partially missing exposure measurements requires further examination. We evaluated the impact of correlation between exposure measurements and missing exposure data on the power and differences in association estimated by the MIM GEE and an inverse probability weighted extension to account for informatively missing exposures. We assessed these operating characteristics under a variety of correlation structures, sample sizes, and missing data mechanisms considering various exposure‐outcome scenarios. We showed that applying MIM GEEs maintains higher power when there is a single critical window of exposure and exposure measures are not highly correlated, but may result in low power and bias under other settings. We applied these methods to a study of pregnant women living with HIV to explore differences in association between trimester‐specific viral load and infant neurodevelopment. [ABSTRACT FROM AUTHOR]

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co‐exposures on the mediator, (2) the co‐exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure‐mediator and exposure‐mediator‐outcome relationships are complex, BKMR‐Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co‐exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its 75th percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment. [ABSTRACT FROM AUTHOR]

Introduction: Antiretrovirals such as dolutegravir (DTG) and tenofovir alafenamide (TAF) have been associated with excessive weight gain. The objective of this study was to understand the potential impact of ART‐associated weight gain on pregnancy outcomes among women living with HIV. Methods: Using data from the Tsepamo birth outcomes surveillance study in Botswana, we evaluated the relationship between maternal weight (and weight gain) and severe birth outcomes (very preterm delivery <32 weeks, very small for gestational age (SGA) <3rd percentile, perinatal death), macrosomia (birthweight > 4000 g) and maternal hypertension. We estimated the relative risk of each outcome by baseline weight (first weight in pregnancy <24 weeks) and second trimester average weekly weight gain (kg/week from 12 ± 2 to 24 ± 2 weeks) using log binomial regression and evaluated effect modification by ART regimen (DTG vs. Efavirenz (EFV)). Results: Of 22,828 women on ART at conception with singleton deliveries between August 2014 and April 2020, 16,300 (71.4%) had a weight measured <24 weeks' gestation (baseline weight) and 4437 (19.2%) had weight measured both at 12 (±2) weeks and 24 (±2) weeks, allowing second trimester weight gain calculation. Compared to women with baseline weight 60 to 70 kg, low baseline weight (<50 kg) was associated with increased risk of very preterm delivery (aRR 1.30, 95% CI 1.03, 1.65) and very SGA (aRR1.96, 95% CI 1.69, 2.28). High baseline weight (>90 kg) was associated with increased risk of macrosomia (aRR 3.24, 95% CI 2.36, 4.44) and maternal hypertension (aRR 1.79, 95% CI 1.62, 1.97). Baseline weight was not associated with stillbirth or early neonatal death. For all outcomes, second trimester weight gain showed weaker associations than did baseline weight. Duration of pre‐pregnancy ART (years) was associated with higher baseline weight for DTG but not for EFV, and the risk of maternal hypertension by baseline weight category was higher for DTG than EFV for all strata. Conclusions: ART regimens associated with weight gain may reduce the number of women at risk for certain severe adverse pregnancy outcomes associated with low weight but increase the number at risk of macrosomia and maternal hypertension. Further research could determine whether weight‐based ART treatment strategies improve maternal and child health. [ABSTRACT FROM AUTHOR]

Introduction: Preterm delivery (<37 weeks) predicts later cardiovascular disease risk in mothers, even among normotensive deliveries. However, development of subclinical cardiovascular risk before and after preterm delivery is not well understood. We sought to investigate differences in life course cardiovascular risk factor trajectories based on preterm delivery history. Material and methods: The HUNT Study (1984‐2008) linked with the Medical Birth Registry of Norway (1967‐2012) yielded clinical measurements and pregnancy outcomes for 19 806 parous women with normotensive first deliveries. Women had up to three measurements of body mass index, waist‐to‐hip ratio, blood pressure, lipids, non‐fasting glucose, and C‐reactive protein during follow up between 21 years before to 41 years after first delivery. Using mixed effects models, we compared risk factor trajectories for women with preterm vs term/postterm first deliveries. Results: Trajectories overlapped for women with preterm compared with term/postterm first deliveries for all cardiovascular risk factors examined. For instance, the mean difference in systolic blood pressure in women with preterm first deliveries compared with those with term deliveries was 0.2 mm Hg (95% CI −1.8 to 2.3) at age 20 and 1.5 mm Hg (95% CI −0.5 to 3.6) at age 60. Conclusions: A history of preterm delivery was not associated with different life course trajectories of common cardiovascular risk factors in our study population. This suggests that the robust association between preterm delivery and cardiovascular end points in Norway or similar contexts is not explained by one or more commonly measured cardiovascular risk factors. Overall, we did not find evidence for a single cardiovascular disease prevention strategy that would reduce risk among the majority of women who had preterm delivery. [ABSTRACT FROM AUTHOR]

Background: Risk factors for birth defects are frequently investigated using data limited to liveborn infants. By conditioning on survival, results of such studies may be distorted by selection bias, also described as "livebirth bias." However, the implications of livebirth bias on risk estimation remain poorly understood.Objectives: We sought to quantify livebirth bias and to investigate the conditions under which it arose.Methods: We used data on 3994 birth defects cases and 11 829 controls enrolled in the National Birth Defects Prevention Study to compare odds ratio (OR) estimates of the relationship between three established risk factors (antiepileptic drug use, smoking, and multifetal pregnancy) and four birth defects (anencephaly, spina bifida, omphalocele, and cleft palate) when restricted to livebirths as compared to among livebirths, stillbirths, and elective terminations. Exposures and birth defects represented varying strengths of association with livebirth; all controls were liveborn. We performed a quantitative bias analysis to evaluate the sensitivity of our results to excluding terminated and stillborn controls.Results: Cases ranged from 33% liveborn (anencephaly) to 99% (cleft palate). Smoking and multifetal pregnancy were associated with livebirth among anencephaly (crude OR [cOR] 0.61 and cOR 3.15, respectively) and omphalocele cases (cOR 2.22 and cOR 5.22, respectively). For analyses of the association between exposures and birth defects, restricting to livebirths produced negligible differences in estimates except for anencephaly and multifetal pregnancy, which was twofold higher among livebirths (adjusted OR [aOR] 4.93) as among all pregnancy outcomes (aOR 2.44). Within tested scenarios, bias analyses suggested that results were not sensitive to the restriction to liveborn controls.Conclusions: Selection bias was generally limited except for high mortality defects in the context of exposures strongly associated with livebirth. Findings indicate that substantial livebirth bias is unlikely to affect studies of risk factors for most birth defects. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to test the extent to which pregnancy per- and polyfluoroalkyl substance (PFAS) concentrations were associated with gestational weight gain and postpartum weight changes.Methods: This study was composed of 1,614 women recruited between 1999 and 2002 via the Project Viva cohort with pregnancy plasma concentrations of six PFAS, including perfluorooctanesulfonic acid, perfluorooctanoic acid (PFOA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid. Gestational weight gain was defined as the difference between last pregnancy weight and prepregnancy weight, 1-year postpartum weight retention as the difference between 1-year postpartum weight and prepregnancy weight, and 3-year postpartum weight change as the difference between 3-year postpartum weight and prepregnancy weight.Results: During pregnancy, women gained 0.37 kg (95% CI: 0.11-0.62) more weight per doubling of 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid. At 1 year post partum, women retained 0.55 kg (95% CI: 0.07-1.04) more weight per doubling of PFOA. At 3 years post partum, women gained 0.91 kg (95% CI: 0.25-1.56) more weight per doubling in PFOA. Findings were similar after adjustment for all PFAS. Other PFAS were not associated with weight changes. Postpartum associations were stronger among women with higher prepregnancy BMI. Models were adjusted for demographics.Conclusions: Pregnancy PFAS were associated with greater gestational weight gain, weight retention, and weight gain years after pregnancy. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusion Epidemiologic studies of the effects of parental preconception paraben exposures on child behavior are limited despite emerging evidence suggesting that such exposures may affect offspring neurodevelopment.We investigated whether maternal and paternal preconception and maternal pregnancy urinary concentrations of parabens were associated with child behavior.We analyzed data from the Preconception Environmental exposure And Childhood health Effects Study, an ongoing prospective cohort of children aged 6–13 years and their parents. We estimated covariate‐adjusted associations of loge‐transformed urinary methyl, propyl, and butyl paraben concentrations (individually using linear regression models and as a mixture using quantile g‐computation) collected prior to conception and during pregnancy with Behavioral Assessment System for Children‐3 and Behavior Rating Inventory of Executive Function T‐scores (higher scores indicate more problem behaviors).This analysis included 140 mothers, 81 fathers, and 171 children (25 sets of twins); parents were predominantly non‐Hispanic white (88% for both mothers and fathers). In single paraben models, higher paternal preconception urinary propyl and methyl paraben concentrations were associated with higher Internalizing Problem T‐scores (propyl paraben β$\beta \;$= 1.7; 95% confidence interval: 0.6, 2.8, methyl paraben β$\beta \;$= 2.2; 95% confidence interval: 0.5, 3.9) and higher Behavioral Symptom Index T‐scores (propyl paraben β$\beta \;$= 1.4; 95% confidence interval: 0.3, 2.5, methyl paraben β$\beta \;$= 1.6; 95% confidence interval: ‐0.1, 3.3). Each quantile increase in the paternal mixture of three parabens was associated with a 3.4 (95% confidence interval: 0.67, 6.1) and 2.5 (95% confidence interval: 0.01, 5.0) increased internalizing problem and Behavioral Symptom Index T‐scores respectively. Higher paternal preconception (β$\beta \;$= 1.0; 95% confidence interval: 0.04, 1.9) and maternal preconception (β$\beta \;$= 1.1 95% confidence interval: ‐0.1, 2.2) concentrations of propyl paraben were associated with higher Behavior Rating Inventory of Executive Function Metacognition Index T‐scores in children, but the paraben mixtures was not.In this cohort, paternal preconception urinary concentrations of propyl and methyl paraben were associated with worse parent‐reported child behaviors. [ABSTRACT FROM AUTHOR]

Intake of full-fat dairy has been linked to lower semen quality but whether this leads to decreased fertility is unknown. To address this question, we prospectively evaluated the association of men's dairy intake with treatment outcomes of subfertile couples undergoing assisted reproductive technology ( ART). We followed 142 men from couples undergoing infertility treatment with ART at an academic fertility centre between 2007 and 2014. Couples completed dietary assessments prior to treatment, and the female partners underwent a total of 248 ART cycles. Multivariable generalized linear mixed models were used to examine the association of dairy intake with fertilization, implantation, clinical pregnancy and live birth rates adjusting for age, body mass index, smoking status, total exercise time, dietary patterns, alcohol, caffeine, total energy intake, and female dairy intake. Intake of dairy foods, regardless of their fat content, was not associated with fertilization, implantation, clinical pregnancy or live birth rates. The adjusted live birth rates (95% confidence interval) for couples in increasing quartiles of men's dairy intake were 0.42 (0.25, 0.60), 0.25 (0.13, 0.42), 0.26 (0.15, 0.41), and 0.44 (0.27, 0.63) ( p linear trend = 0.73). Results remained similar after adjustment for female partner intake of dairy foods. Overall, men's dairy intake was not associated with treatment outcomes of couples undergoing ART. [ABSTRACT FROM AUTHOR]

In vitro fertilization (IVF) is an increasingly common method of assisted reproductive technology. Because of the careful observation and follow-up required as part of the procedure, IVF studies provide an ideal opportunity to identify and assess clinical and demographic factors along with environmental exposures that may impact successful reproduction. A major challenge in analyzing data from IVF studies is handling the complexity and multiplicity of outcome, resulting from both multiple opportunities for pregnancy loss within a single IVF cycle in addition to multiple IVF cycles. To date, most evaluations of IVF studies do not make use of full data because of its complex structure. In this paper, we develop statistical methodology for analysis of IVF data with multiple cycles and possibly multiple failure types observed for each individual. We develop a general analysis framework based on a generalized linear modeling formulation that allows implementation of various types of models including shared frailty models, failure-specific frailty models, and transitional models, using standard software. We apply our methodology to data from an IVF study conducted at the Brigham and Women's Hospital, Massachusetts. We also summarize the performance of our proposed methods on the basis of a simulation study. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives: Maternal periodontal diseases have been associated with increased risk of preterm birth and restricted fetal growth among relatively low socioeconomic groups. Whether the association can be generalized to middle-class populations remains uncertain. We evaluated periodontitis in relation to preterm birth (<37 weeks’ gestation) and small-for-gestational-age (SGA, birth weight below the 10th percentile of birth weight for gestational age) among a group of medically insured women. Methods: We conducted a prospective study among participants of Project Viva, a US cohort study of pregnant women and their offspring from 1999 to 2002. Pregnancy outcomes were obtained from medical records. Self-reported periodontitis was assessed during the second trimester of pregnancy, and validated against radiographs. Logistic regression analyses were employed to evaluate the association of periodontitis with pregnancy outcomes adjusted for age, race/ethnicity, smoking status, income, frequency of dental check-ups, prepregnancy body mass index, pregnancy weight gain, gravidity, prior history of preterm birth and history of genitourinary infection. Results: Of the 1635 women, 72.7% were Caucasian, 65.0% had annual household income >$70 000, 3.8% reported having periodontitis, 6.4% delivered preterm, 5.4% delivered SGA babies, and 11.0% had poor pregnancy outcome (either preterm birth or SGA). The odds ratio (OR) associated with periodontitis was 1.74 (95% CI 0.65–4.66) for preterm delivery and 2.11 (95% CI 0.76–5.86) for SGA individually. When preterm delivery and/or SGA were combined, the OR was 2.26 (95% CI 1.05–4.85) relating periodontitis with poor pregnancy outcome. Conclusion: Within the limitations of the study, the results suggest that periodontitis is an independent risk factor for poor pregnancy outcome among middle-class women. [ABSTRACT FROM AUTHOR]

Background: Periodontitis has been associated with increased risk of adverse pregnancy outcomes and elevated C-reactive protein (CRP) concentrations in non-pregnant adults. We examined the relationship between periodontitis and CRP among women who provided dental radiographs and had blood collected during early pregnancy, excluding smokers and diabetic patients.Methods: From Project Viva, an ongoing cohort study, we measured plasma CRP in 35 subjects with periodontitis (i.e., at least one site with > or =3 mm of alveolar bone loss) and a random sample of 66 periodontally healthy subjects matched on age and race/ethnicity. We performed linear regression analysis with log-transformed CRP levels as the outcome.Results: The mean (+/- SE) CRP level was 65% higher (95% confidence interval: -2%, 180%; P = 0.06) in women with periodontitis (2.46 +/- 0.52 mg/l) than in controls (1.49 +/- 0.22 mg/l), adjusting for factors related to CRP levels, including age, race/ethnicity, pre-pregnancy body mass index, alcohol intake, education, income, and gestational age at blood collection.Conclusions: These findings suggest that periodontitis may increase CRP levels in pregnancy. CRP could potentially mediate the association of periodontitis with adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Background Confounding by indication is a common problem in pharmacoepidemiology, where predictors of treatment also have prognostic value for the outcome of interest. The tools available to the epidemiologist that can be used to mitigate the effects of confounding by indication often have limits with respect to the number of variables that can be simultaneously incorporated as components of the confounding. This constraint becomes particularly apparent in the context of a rich data source (such as administrative claims data), applied to the study of an outcome that occurs infrequently. In such settings, there will typically be many more variables available for control as potential confounders than traditional epidemiologic techniques will allow. Methods One tool that can indirectly permit control of a large number of variables is the propensity score approach. This paper illustrates the application of the propensity score to a study conducted in an administrative database, and raises critical issues to be addressed in such an analysis. In this example, the effect of statin therapy on the occurrence of myocardial infarction was examined, and numerous potential confounders of this association were adjusted simultaneously using a propensity score to form matched cohorts of statin initiators and non-initiators. Results The incidence of myocardial infarction observed in the statin treated cohort was lower than the incidence in the untreated cohort, and the magnitude of this effect was consistent with results from randomized placebo controlled clinical trials of statin therapy. Conclusions This example illustrates how confounding by indication can be mitigated by the propensity score matching technique. Concerns remain over the generalizability of estimates obtained from such a study, and how to know when propensity scores are removing bias, since apparent balance between compared groups on measured variables could leave variables not included in the propensity score unbalanced and lead to confounded effect estimates. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Standard experimental designs for conducting developmental toxicity studies typically include three- or four-dose levels in addition to a control group. Some researchers have suggested that designs with more exposure groups would improve dose-response characterization and risk estimation. Such proposals have not, however, been supported by the results of simulation studies, which instead back the use of fewer dose levels. This discrepancy is partly due to using a known dose-response pattern to generate data, making model choice obvious. While the carcinogenicity literature has explored implications of different study designs, little attention has been given to the role of design in developmental toxicity risk assessment (or noncancer toxicology in general). In this research, we explore the implications of various experimental designs for developmental toxicity by resampling data from a large study of 2,4,5-trichlorophenoxyacetic acid in mice. We compare the properties of benchmark dose (BMD) estimation for different design strategies by randomly selecting animals within particular dose groups from the entire 2,4,5-T database of over 77,000 birth outcomes to create smaller "pseudo-studies" that are representative of standard bioassay sample sizes. Our results show that experimental designs which include more dose levels have advantages in terms of risk characterization and estimation. KEY WORDS: Benchmark dose; design; developmental toxicology; dose-response modeling; risk assessment. [ABSTRACT FROM AUTHOR]

In the assessment of developmental and reproductive effects, the timing and duration of exposures to chemical compounds or other environmental contaminants are of particular interest, as the gestational cycle is known to have periods of increased sensitivity. The goal of this research is to identify optimal experimental designs for conducting developmental toxicity studies when the effects of both exposure level and duration of exposure are of interest. The elements of the study design considered in this evaluation are the allocation of animals to dose-duration exposure groups and the determination of the most efficient intermediate exposure levels. The optimality of various designs is assessed via the accuracy of the estimated excess risk as well as testing criteria. Simulation studies are conducted to compare these criteria and determine optimal design strategies under various underlying dose-response patterns. Asymptotic results are also derived to lend support to the simulation studies. [ABSTRACT FROM AUTHOR]