Yin Hsiu Chen

Longitudinal Profiling of Inflammatory Cytokines and C‐reactive Protein during Uncomplicated and Preterm Pregnancy

Previous studies have investigated the utility of inflammation markers as predictors of preterm birth, but none have compared trends in levels between uncomplicated and preterm pregnancy.

Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis.

Background Phthalate exposure occurs readily in the environment and has been associated with an array of health end points, including adverse birth outcomes. Some of these may be mediated by oxidative stress, a proposed mechanism for phthalate action. Objectives In the present study, we explored the associations between phthalate metabolites and biomarkers of oxidative stress measured in urine samples from multiple time points during pregnancy. Methods Women were participants in a nested case–control study of preterm birth (n = 130 cases, n = 352 controls). Each was recruited early in pregnancy and followed until delivery, providing urine samples at up to four visits. Nine phthalate metabolites were measured to assess exposure, and 8-hydroxydeoxyguanosine and 8-isoprostane were also measured in urine as markers of oxidative stress. Associations were assessed using linear mixed models to account for intraindividual correlation, with inverse selection probability weightings based on case status to allow for greater generalizability. Results Interquartile range increases in phthalate metabolites were associated with significantly higher concentrations of both biomarkers. Estimated differences were greater in association with monobenzyl phthalate (MBzP), mono-n-butyl phthalate (MBP), and monoisobutyl phthalate (MiBP), compared with di(2-ethylhexyl) phthalate (DEHP) metabolites. Conclusions Urinary phthalate metabolites were associated with increased oxidative stress biomarkers in our study population of pregnant women. These relationships may be particularly relevant to the study of birth outcomes linked to phthalate exposure. Although replication is necessary in other populations, these results may also be of great importance for a range of other health outcomes associated with phthalates. Citation Ferguson KK, McElrath TF, Chen YH, Mukherjee B, Meeker JD. 2015. Urinary phthalate metabolites and biomarkers of oxidative stress in pregnant women: a repeated measures analysis. Environ Health Perspect 123:210–216; http://dx.doi.org/10.1289/ehp.1307996

Repeated measures of urinary oxidative stress biomarkers during pregnancy and preterm birth.

OBJECTIVE The purpose of this study was to investigate oxidative stress as a mechanism of preterm birth in human subjects; we examined associations between urinary biomarkers of oxidative stress that were measured at multiple time points during pregnancy and preterm birth. STUDY DESIGN This nested case-control study included 130 mothers who delivered preterm and 352 mothers who delivered term who were originally recruited as part of an ongoing prospective birth cohort at Brigham and Womens Hospital. Two biomarkers that included 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane were measured in urine samples that were collected at up to 4 time points (median 10, 18, 26, and 35 weeks) during gestation. RESULTS Urinary concentrations of 8-isoprostane and 8-OHdG decreased and increased, respectively, as pregnancy progressed. Average levels of 8-isoprostane across pregnancy were associated with increased odds of spontaneous preterm birth (adjusted odds ratio, 6.25; 95% confidence interval, 2.86-13.7), and associations were strongest with levels measured later in pregnancy. Average levels of 8-OHdG were protective against overall preterm birth (adjusted odds ratio, 0.19; 95% confidence interval, 0.10-0.34), and there were no apparent differences in the protective effect in cases of spontaneous preterm birth compared with cases of placental origin. Odds ratios for overall preterm birth were more protective in association with urinary 8-OHdG concentrations that were measured early in pregnancy. CONCLUSION Maternal oxidative stress may be an important contributor to preterm birth, regardless of subtype and timing of exposure during pregnancy. The 2 biomarkers that were measured in the present study had opposite associations with preterm birth; an improved understanding of what each represents may help to identify more precisely important mechanisms in the pathway to preterm birth.

Statistical methods for modeling repeated measures of maternal environmental exposure biomarkers during pregnancy in association with preterm birth

BackgroundIt is of critical importance to evaluate the role of environmental chemical exposures in premature birth. While a number of studies investigate this relationship, most utilize single exposure measurements during pregnancy in association with the outcome. The studies with repeated measures of exposure during pregnancy employ primarily cross-sectional analyses that may not be fully leveraging the power and additional information that the data provide.MethodsWe examine 9 statistical methods that may be utilized to estimate the relationship between a longitudinal exposure and a binary, non-time-varying outcome. To exemplify these methods we utilized data from a nested case–control study examining repeated measures of urinary phthalate metabolites during pregnancy in association with preterm birth.ResultsThe methods summarized may be useful for: 1) Examining sensitive windows of exposure in association with an outcome; 2) Summarizing repeated measures to estimate the relationship between average exposure and an outcome; 3) Identifying acute exposures that may be relevant to the outcome; and 4) Understanding the contribution of temporal patterns in exposure levels to the outcome of interest. In the study of phthalates, changes in urinary metabolites over pregnancy did not appear to contribute significantly to preterm birth, making summary of average exposure across gestation optimal given the current design.ConclusionsThe methods exemplified may be of great use in future epidemiologic research projects intended to: 1) Elucidate the complex relationships between environmental chemical exposures and preterm birth; 2) Investigate biological mechanisms in prematurity using repeated measures of maternal factors throughout pregnancy; and 3) More generally, address the relationship between a longitudinal predictor and a binary, non-time-varying outcome.

Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy

Background: Mediation analysis is useful for understanding mechanisms and has been used minimally in the study of the environment and disease. Objective: We examined mediation of the association between phthalate exposure during pregnancy and preterm birth by oxidative stress. Methods: This nested case–control study of preterm birth (n = 130 cases, 352 controls) included women who delivered in Boston, Massachusestts, from 2006 through 2008. Phthalate metabolites and 8-isoprostane, an oxidative stress biomarker, were measured in urine from three visits in pregnancy. We applied four counterfactual mediation methods: method 1, utilizing exposure and mediator averages; method 2, using averages but allowing for an exposure–mediator interaction; method 3, incorporating longitudinal measurements of the exposure and mediator; and method 4, using longitudinal measurements and allowing for an exposure–mediator interaction. Results: We observed mediation of the associations between phthalate metabolites and all preterm birth by 8-isoprostane, with the greatest estimated proportion mediated observed for spontaneous preterm births specifically. Fully utilizing repeated measures of the exposure and mediator improved precision of indirect (i.e., mediated) effect estimates, and including an exposure–mediator interaction increased the estimated proportion mediated. For example, for mono(2-ethyl-carboxy-propyl) phthalate (MECPP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), the percent of the total effect mediated by 8-isoprostane increased from 47% to 60% with inclusion of an exposure–mediator interaction term, in reference to a total adjusted odds ratio of 1.67 or 1.48, respectively. Conclusions: This demonstrates mediation of the phthalate–preterm birth relationship by oxidative stress, and the utility of complex regression models in capturing mediated associations when repeated measures of exposure and mediator are available and an exposure–mediator interaction may exist. Citation: Ferguson KK, Chen YH, VanderWeele TJ, McElrath TF, Meeker JD, Mukherjee B. 2017. Mediation of the relationship between maternal phthalate exposure and preterm birth by oxidative stress with repeated measurements across pregnancy. Environ Health Perspect 125:488–494; http://dx.doi.org/10.1289/EHP282

Utilizing Longitudinal Measures of Fetal Growth to Create a Standard Method to Assess the Impacts of Maternal Disease and Environmental Exposure

Impaired or suboptimal fetal growth is associated with an increased risk of perinatal morbidity and mortality. By utilizing readily available clinical data on the relative size of the fetus at multiple points in pregnancy, including delivery, future epidemiological research can improve our understanding of the impacts of maternal, fetal, and environmental factors on fetal growth at different windows during pregnancy. This study presents mean and standard deviation ultrasound measurements from a clinically representative US population that can be utilized for creating Z-scores to this end. Between 2006 and 2012, 18, 904 non-anomalous pregnancies that received prenatal care, first and second trimester ultrasound evaluations, and ultimately delivered singleton newborns at Brigham and Women’s hospital in Boston were used to create the standard population. To illustrate the utility of this standard, we created Z-scores for ultrasound and delivery measurements for a cohort study population and examined associations with factors known to be associated with fetal growth. In addition to cross-sectional regression models, we created linear mixed models and generalized additive mixed models to illustrate how these scores can be utilized longitudinally and for the identification of windows of susceptibility. After adjustment for a priori confounders, maternal BMI was positively associated with increased fetal size beginning in the second trimester in cross-sectional models. Female infants and maternal smoking were associated with consistently reduced fetal size in the longitudinal models. Maternal age had a non-significant association with increased size in the first trimester that was attenuated as gestation progressed. As the growth measurements examined here are widely available in contemporary obstetrical practice, these data may be abstracted from medical records by investigators and standardized with the population means presented here. This will enable easy extension of clinical data to epidemiologic studies investigating novel maternal, fetal, and environmental factors that may impact fetal growth.

Urinary phthalate metabolite and bisphenol A associations with ultrasound and delivery indices of fetal growth

Growth of the fetus is highly sensitive to environmental perturbations, and disruption can lead to problems in pregnancy as well as later in life. This study investigates the relationship between maternal exposure to common plasticizers in pregnancy and fetal growth. Participants from a longitudinal birth cohort in Boston were recruited early in gestation and followed until delivery. Urine samples were collected at up to four time points and analyzed for concentrations of phthalate metabolites and bisphenol A (BPA). Ultrasound scans were performed at four time points during pregnancy for estimation of growth parameters, and birthweight was recorded at delivery. Growth measures were standardized to a larger population. For the present analysis we examined cross-sectional and repeated measures associations between exposure biomarkers and growth estimates in 482 non-anomalous singleton pregnancies. Cross-sectional associations between urinary phthalate metabolites or BPA and growth indices were imprecise. However, in repeated measures models, we observed significant inverse associations between di-2-ethylhexyl phthalate (DEHP) metabolites and estimated or actual fetal weight. An interquartile range increase in summed DEHP metabolites was associated with a 0.13 standard deviation decrease in estimated or actual fetal weight (95% confidence interval=-0.23, -0.03). Associations were consistent across different growth parameters (e.g., head circumference, femur length), and by fetal sex. No consistent associations were observed for other phthalate metabolites or BPA. Maternal exposure to DEHP during pregnancy was associated with decreased fetal growth, which could have repercussive effects.

Incretin-based therapy in type 2 diabetes: An evidence based systematic review and meta-analysis

Incretin based therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) are increasingly used for the treatment of Type 2 diabetes mellitus. In clinical practice and in previously performed clinical trials, these agents are often used in combination with other oral anti-diabetic agents (OADs) and Insulin. Prior meta-analytic reviews however do not adequately address the impact of background therapy and active comparator arms. Accordingly, we aimed to further investigate the efficacy of incretin based therapies by updating existing reviews by including clinical trial evidence after 2008; estimating the pooled effect of incretin therapies on glycemic efficacy and weight-loss, stratified by comparator therapy (placebo, mono-therapy, etc.), estimating the impact of background OADs and within class (GLP-1Ra or DPP-4i) comparative efficacy, on glycemia control. 82 randomized controlled trials after 2008 with glycemic control and weight loss as primary end-points were included. Both DPP-4i and GLP-1Ra reduced HbA1c, but only GLP-1Ra caused weight loss when compared to either active comparator drugs or placebo. GLP-1Ra were more effective than DPP-4i in glycemia lowering. Long acting GLP-1Ra were more effective in HbA1c lowering than short-acting agents but with similar weight loss effect. The effect of DPP-4i incretin glycemic efficacy was not modified by background therapy used in the study.

A new variance component score test for testing distributed lag functions with applications in time series analysis

We propose to test a given constrained distributed lag model (DLM) of the form β = Cθ against an unconstrained alternative using a variance component score test (VCST) and show that VCST is more powerful than the standard likelihood ratio test in a simulation study.

Mediation Formula for a Binary Outcome and a Time-Varying Exposure and Mediator, Accounting for Possible Exposure-Mediator Interaction

Valeri and VanderWeele [1] used the counterfactual framework to extend formulas from Baron and Kenny [2] to account for exposure-mediator interaction in mediation analysis. The results are also extended to the case when the outcome is binary. VanderWeele and Tchetgen Tchetgen [3] identified the randomized interventional analogues of the natural direct and indirect effects in longitudinal settings in presence of time-varying exposure, time-varying mediator, and possibly time-varying confounders where the outcome is continuous. We synthesize the ideas in these two papers to derive expressions for natural direct and indirect effects when the outcome is binary but the exposure, mediator and potential confounders are time-varying. Let Y denote the binary outcome, A(t) denote the exposure measured at time t, M(t) denote the mediator at time t, L(t) denote the potentially time-varying confounders at time t, and V denote the set of time-invariant baseline covariates for t = 1, 2, ..., T . Let Ā(t) = (A(1), ..., A(t)), M̄(t) = (M(1), ...,M(t)), and L̄(t) = (L(1), ..., L(t)) and let Ā ≡ Ā(T ), M̄ ≡ M̄(T ), and L̄ ≡ L̄(T ). The corresponding lower-case letters refer to the realizations of the random variates. With initial baseline covariates V and subsequent temporal order A(t), L(t),M(t), the relationships among A(t), L(t), M(t), Y , and V can be depicted as