Search

Background: Identifying the impact of environmental mixtures on human health is an important topic. However, such studies face challenges when exposure measurements lie below limit of detection (LOD). While various approaches for accommodating a single exposure subject to LOD have been used, their impact on mixture analysis has not been thoroughly investigated. Our study aims to understand the impact of five popular LOD accommodation approaches on mixture analysis results with multiple exposures subject to LOD, including omitting subjects with any exposures below LOD (complete case analysis); single imputations by LOD/ 2 , and by estimates from a censored accelerated failure time (AFT) model; and multiple imputation (MI) with or without truncation based on LOD., Methods: In extensive simulation studies with high-dimensional and highly correlated exposures and a continuous health outcome, we examined the performance of each LOD approach on three mixture analysis methods: elastic net regression, weighted quantile sum regression (WQS) and Bayesian kernel machine regression (BKMR). We further analyzed data from the National Health and Nutrition Examination Survey (NHANES) on how persistent organic pollutants (POPs) influenced leukocyte telomere length (LTL)., Results: Complete case analysis was inefficient and could result in severe bias for some mixture methods. Imputation by LOD/ 2 showed unstable performance across mixture methods. Conventional MI was associated with consistent mild biases, which can be reduced by using a truncated distribution for imputation. Estimating censored values by AFT models had a minimal impact on the results. In the NHANES analysis, imputation by LOD/ 2 , truncated MI and censored AFT models performed similarly, with a positive overall effect of POPs on LTL while PCB126, PCB169 and furan 2,3,4,7,8-pncdf being the most important exposures., Conclusions: Our study favored using truncated MI and censored AFT models to accommodate values below LOD for the stability of downstream mixture analysis., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: A few endocrine disrupting chemicals (EDCs) have been associated with pregnancy loss often as reported by women, though there has been no study of EDC mixtures and pregnancy loss in keeping with the nature of human exposure., Objectives: To investigate preconception exposure to a mixture of EDCs to identify important drivers and inform multi-pollutant models of EDCs in relation to incident human gonadrophin chorionic (hCG) pregnancy loss., Methods: A cohort of 501 couples were recruited from the general population and prospectively followed until a hCG-confirmed pregnancy or 12 months of trying to become pregnant. Pregnant (n = 344; 69%) women were followed daily through seven weeks post-conception then monthly until delivery. Loss was defined as conversion to negative pregnancy test or a clinical diagnosis. Preconception exposure assessment of EDCs included sixty-three serum chemicals and three blood metals. EDCs were measured using isotope dilution gas chromatography-high resolution mass spectrometry or high-performance liquid chromatography-tandem mass spectrometry, and inductively coupled plasma-mass spectrometry, respectively. Using elastic net variable selection to identify important factors from the exposure mixture, EDC levels and covariates were then included in Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of time-to-pregnancy loss in multi-pollutant models., Results: Incidence of hCG pregnancy loss was 28%. Nine EDCs of the sixty-six chemical mixture were associated with pregnancy loss; HRs were elevated for polychlorinated biphenyl 194, 2-(N-methyl-perfluorooctane sulfonamido) acetate, polybrominated diphenyl ether 28, and cadmium, even in sensitivity models adjusting for male partners' EDC concentrations. In final multivariable multi-pollutant Cox proportional hazard models, female partners'polybrominated diphenyl ether 28 (aHR = 1.16, 95% CI: 1.02, 1.31) and cadmium (aHR = 1.23, 95% CI: 1.07, 1.40) remained associated with hCG pregnancy loss. Female partners' preconception serum polychlorinated biphenyl 194 and 2-(N-methyl-perfluorooctane sulfonamido) acetate concentrations were consistently inversely associated with loss [(aHR = 0.72, 95% CI: 0.56, 0.92) and (aHR = 0.79, 95% CI: 0.65, 0.95), respectively]., Conclusion: Assessing exposure to a mixture of 66 persistent EDCs, females' preconception concentrations of polybrominated diphenyl ether 28 and cadmium were positively associated with incident hCG pregnancy loss in a cohort of couples from the general population trying for pregnancy., (Copyright © 2021. Published by Elsevier Ltd.)

Importance: Prenatal exposure to persistent organic pollutants (POPs) has been associated with birth size, but data on fetal growth and among racially/ethnically diverse pregnant women remain scarce., Objectives: To assess the association between maternal plasma POPs in early pregnancy and fetal growth and by infant sex and maternal race/ethnicity., Design, Setting, and Participants: This cohort study used the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, which recruited nonobese, low-risk pregnant women before 14 weeks' gestation between July 1, 2009, and January 31, 2013, in 12 community-based clinics throughout the United States. Participants self-identified their race/ethnicity, self-reported their behavioral risk factors, and were followed up throughout their pregnancy. Data were analyzed from July 31, 2018, to June 3, 2019., Exposures: Levels of 76 POPs in early gestation plasma were measured: 11 perfluoroalkyl and polyfluoroalkyl substances, 1 polybrominated biphenyl, 9 polybrominated diphenyl ethers (PBDEs), 44 polychlorinated biphenyls (PCBs), and 11 organochlorine pesticides (OCPs). The bayesian kernel machine regression method was used to examine chemical class mixtures, and generalized additive mixed model was used to analyze individual chemicals., Main Outcomes and Measures: Fourteen fetal biometrics were measured, including head circumference, abdominal circumference, and femur length, within 5 ultrasonography appointments., Results: A total of 2284 low-risk pregnant women were included: 606 women (26.5%) self-identified as white with a mean (SD) age of 30.3 (4.4) years, 589 (25.8%) as black with a mean (SD) age of 25.5 (5.5) years, 635 (27.8%) as Hispanic with a mean (SD) age of 27.1 (5.5) years, and 454 (19.9%) as Asian with a mean (SD) age of 30.5 (4.5) years. A comparison between the 75th and 25th percentile of exposure revealed that the OCP mixture was negatively associated with most fetal growth measures, with a reduction of 4.7 mm (95% CI, -6.7 to -2.8 mm) in head circumference, 3.5 mm (95% CI, -4.7 to -2.2 mm) in abdominal circumference, and 0.6 mm (95% CI, -1.1 to -0.2 mm) in femur length. Higher exposure to the PBDE mixture was associated with reduced abdominal circumference (-2.4 mm; 95% CI, -4.0 to -0.5 mm) and femur length (-0.5 mm; 95% CI, -1.0 to -0.1 mm), and the dioxin-like PCB mixture was associated with reduced head circumference (-6.4 mm; 95% CI, -8.4 to -4.3 mm) and abdominal circumference (-2.4 mm; 95% CI, -3.9 to -0.8 mm). Associations with individual chemicals were less consistent. There were some interactions by fetal sex, although most of the results did not vary by maternal race/ethnicity. For example, oxychlordane (-0.98 mm; 95% CI, -1.60 to -0.36 mm; P for interaction <.001), trans-nonachlor (-0.31 mm; 95% CI, -0.54 to -0.08 mm; P for interaction = .005), and p,p'-dichlorodiphenyldichloroethylene (-0.19 mm; 95% CI, -0.22 to -0.09 mm; P for interaction = .006) were associated with shorter femur length among boys only., Conclusions and Relevance: This study found that, among pregnant women with low POP levels, a mixture of OCPs was negatively associated with most fetal growth measures and that mixtures of PBDEs and dioxin-like PCBs were associated with reduced abdominal circumference. These findings suggested that, although exposures may be low, associations with fetal growth are apparent.

Background: Polybrominated diphenyl ethers (PBDEs) have not been studied in relation to incident pregnancy loss in human populations, despite their ubiquitous exposure and purported reproductive toxicity., Objectives: To investigate the association between preconception serum PBDE concentrations and incident pregnancy loss., Methods: A preconception cohort of 501 couples was followed while trying to become pregnant, and for whom serum concentrations of 10 PBDE congeners were measured using gas chromatography-high resolution mass spectrometry. Pregnancy was prospectively identified as a positive home pregnancy test on the day of expected menstruation. Incident pregnancy loss was defined for 344 singleton pregnancies as a conversion to a negative home pregnancy test, menses, or clinical diagnosis depending upon gestational age. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for individual and summed PBDEs and incident pregnancy loss, adjusting for relevant covariates and male partners' information. In sensitivity analyses, inverse probability weighting was used to account for couples not becoming pregnant and, thereby, not at risk for loss., Results: The incidence of prospectively observed pregnancy loss was 28%, and the serum concentrations of PBDE congeners in females were consistently associated with a higher hazard of incident pregnancy loss. Specifically, statistically significant hazard ratios (HRs) for incident pregnancy loss were observed for lower brominated PBDE congeners: 17 (HR 1.23; CI: 1.07-1.42), 28 (HR 1.25; CI: 1.03-1.52), 66 (HR 1.23; CI: 1.07-1.42), and homolog triBDE (HR: 1.25; CI: 1.05-1.49). Findings were robust to various model specifications explored in sensitivity analyses., Conclusions: Maternal preconception serum concentrations of specific PBDE congeners may increase the hazard of incident pregnancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Intrauterine exposure to endocrine disrupting chemicals (EDCs) has been equivocally associated with birth weight, length and head circumference with limited attention to anthropometric endpoints such as umbilical circumference and limb lengths., Objective: To explore 76 prenatal maternal plasma EDC concentrations in a healthy obstetric cohort and 7 neonatal anthropometric endpoints by maternal race/ethnicity., Methods: The study cohort comprised 2106 (564 White, 549 Black, 590 Hispanic, 403 Asian) healthy pregnant women recruited from 12 U.S. clinical sites between 2009 and 2012 who were followed through delivery. Neonates underwent standardized anthropometric assessment (weight, length, head and umbilical circumference, and mid- upper arm and thigh length). Plasma EDC concentrations were quantified using high resolution gas chromatography-high resolution mass spectrometry and liquid chromatography-tandem mass spectrometry. EDCs were log-transformed and rescaled by their deviations (SD) when modeled relative to neonatal endpoints using linear regression adjusting for age, education, pre-pregnancy body mass index (BMI), serum cotinine, serum lipids for lipophilic chemicals, and a race/ethnicity interaction term; p-values had false discovery rate correction (<0.05)., Results: The cohort comprised women aged 28 (SD = 5) years with normal BMIs (23.6 kg/m 2 , SD = 3). Maternal EDC concentrations varied by self-identified race/ethnicity and neonatal outcomes, though no specific EDC was consistently associated with neonatal anthropometric outcomes across racial/ethnic groups. For the overall cohort, perfluorooctanoic acid was negatively associated with birth length per SD increase in concentration (β = -0.23 cm; 95% CI -0.35, -0.10), while perfluorohexanesulfonic acid was negatively associated with umbilical circumference (β = -0.26 cm; 95% CI -0.40, -0.13), perfluorodecanoic acid with arm length (-0.09 cm; 95% CI -0.14, -0.04), and PCBs congeners 118/106 (-0.12 cm; 95% CI -0.20, -0.04) and 146/161 (-0.14 cm; 95% CI -0.23, -0.05) with thigh length, as were 7 other poly-and-perfluorinated alkyl substances (PFASs)., Conclusions: Among healthy pregnant women with low risk antenatal profiles and relatively low EDC concentrations, reductions in umbilical circumference and bone lengths may be a sensitive marker of intrauterine EDC exposure, particularly for PFAS., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Environmental exposure to metals and metalloids is associated with pregnancy loss in some but not all studies. We assessed arsenic, cadmium, mercury, and lead concentrations in 501 couples upon trying for pregnancy and followed them throughout pregnancy to estimate the risk of incident pregnancy loss. Using Cox proportional hazard models, we estimated hazard ratios (HR) and 95% confidence intervals (CIs) for pregnancy loss after covariate adjustment for each partner modeled individually then we jointly modeled both partners' concentrations. Incidence of pregnancy loss was 28%. In individual partner models, the highest adjusted HRs were observed for female and male blood cadmium (HR=1.08; CI 0.81, 1.44; HR=1.09; 95% CI 0.84, 1.41, respectively). In couple based models, neither partner's blood cadmium concentrations were associated with loss (HR=1.01; 95% CI 0.75, 1.37; HR=0.92; CI 0.68, 1.25, respectively). We observed no evidence of a significant relation between metal(loids) at these environmentally relevant concentrations and pregnancy loss., (Published by Elsevier Inc.)

Background: Perfluoroalkyl substances have been associated with changes in menstrual cycle characteristics and fecundity, when modeled separately. However, these outcomes are biologically related, and we evaluate their joint association with exposure to perfluoroalkyl substances., Methods: We recruited 501 couples from Michigan and Texas in 2005-2009 upon their discontinuing contraception and followed them until pregnancy or 12 months of trying. Female partners provided a serum sample on enrollment and completed daily journals on menstruation, intercourse, and pregnancy test results. We measured seven perfluoroalkyl substances in serum using liquid chromatography-tandem mass spectrometry. We assessed the association between perfluoroalkyl substances and menstrual cycle length using accelerated failure time models and between perfluoroalkyl substances and fecundity using a Bayesian joint modeling approach to incorporate cycle length., Results: Menstrual cycles were 3% longer comparing women in the second versus first tertile of perfluorodecanoate (PFDeA; acceleration factor [AF] = 1.03, 95% credible interval [CrI] = [1.00, 1.05]), but 2% shorter for women in the highest versus lowest tertile of perfluorooctanoic acid (PFOA; AF = 0.98, 95% CrI = [0.96, 1.00]). When accounting for cycle length, relevant covariates, and remaining perfluoroalkyl substances, the probability of pregnancy was lower for women in second versus first tertile of perfluorononanoate (PFNA; odds ratio [OR] = 0.6, 95% CrI = [0.4, 1.0]) although not when comparing the highest versus lowest (OR = 0.7, 95% CrI = [0.3, 1.1]) tertile., Conclusions: In this prospective cohort study, we observed associations between two perfluoroalkyl substances and menstrual cycle length changes, and between select perfluoroalkyl substances and diminished fecundity at some (but not all) concentrations. See video abstract at, http://links.lww.com/EDE/B136.

Equivocal findings are reported for perfluoroalkyl and polyfluoroalkyl substances (PFASs) and self-reported pregnancy loss. We prospectively assessed PFASs and pregnancy loss in a cohort comprising 501 couples recruited preconception and followed daily through 7 post-conception weeks. Seven PFASs were quantified: 2-N-ethyl-perfluorooctane sulfonamide acetate (Et-PFOSA-AcOH); 2-N-methyl-perfluorooctane sulfonamido acetate (Me-PFOSA-AcOH); perfluorodecanoate (PFDeA); perfluorononanoate (PFNA); perfluorooctane sulfonamide (PFOSA); perfluorooctane sulfonate (PFOS); and perfluorooctanoate (PFOA). Women used home pregnancy test kits. Loss denoted conversion from a positive to a negative pregnancy test, onset of menses or clinical confirmation (n=98; 28%). Chemicals were log transformed and rescaled by their standard deviations to estimate adjusted hazard ratios (HRs) and 95% confidence intervals. No significantly elevated HRs were observed for any PFASs suggesting no association with loss: Et-PFOSA-AcOH (1.04; 0.87, 1.23), Me-PFOSA-AcOH (0.79; 0.61, 1.00; p<0.05), PFDeA (0.83; 0.66, 1.04), PFNA (0.86; 0.70, 1.06), PFOSA (0.74; 0.50, 1.09), PFOS (0.81; 0.65, 1.00), and PFOA (0.93; 0.75, 1.16)., (Published by Elsevier Inc.)

Persistent organic pollutants (POPs) have been implicated in the development of obesity in non-pregnant adults. However, few studies have explored the association of POPs with gestational weight gain (GWG), an important predictor of future risk of obesity in both the mother and offspring. We estimated the association of maternal pre-pregnancy levels of 63 POPs with GWG. Data are from women (18-40 years; n = 218) participating in a prospective cohort study. POPs were assessed using established protocols in pre-pregnancy, non-fasting blood samples. GWG was assessed using three techniques: (1) total GWG (difference between measured pre-pregnancy weight and final self-reported pre-delivery weight); (2) category based on pre-pregnancy body mass index (BMI)-specific Institute of Medicine (IOM) recommendations; and (3) area under the GWG curve (AUC). In an exploratory analysis, effects were estimated separately for women with BMI < 25 kg/m² versus BMI ≥ 25 kg/m². Multivariable polytomous logistic regression and linear regression were used to estimate the association between each chemical or congener and the three GWG outcomes. p,p'-dichlorodiphenyl trichloroethane (p,p'-DDT) was significantly inversely associated with AUC after adjustment for lipids and pre-pregnancy BMI: beta {95% confidence interval (CI)}, -378.03 (-724.02, -32.05). Perfluorooctane sulfonate (PFOS) was significantly positively associated with AUC after adjustment for lipids among women with a BMI < 25 kg/m² {beta (95% CI), 280.29 (13.71, 546.86)}, but not among women with a BMI ≥ 25 kg/m² {beta (95% CI), 56.99 (-328.36, 442.34)}. In summary, pre-pregnancy levels of select POPs, namely, p,p'-DDT and PFOS, were moderately associated with GWG. The association between POPs and weight gain during pregnancy may be more complex than previously thought, and adiposity prior to pregnancy may be an important effect modifier., Competing Interests: The authors declare no conflict of interest.

We sought to investigate the relationship between maternal preconception exposures to persistent organic pollutants (POPs) and pregnancy complications, gestational diabetes (GDM) and gestational hypertension. Data from 258 (51%) women with human chorionic gonadotropin (hCG) confirmed pregnancies reaching ≥24weeks gestation, from a prospective cohort of 501 couples who discontinued contraception to attempt pregnancy, were analyzed. Preconception concentrations of 9 organochlorine pesticides (OCPs) and 10 polybrominated diphenyl ethers (PBDEs) were quantified in serum. In separate multiple logistic regression models of self-reported physician diagnosed outcomes: GDM (11%) and gestational hypertension (10%), chemicals were natural log-transformed and rescaled by their standard deviation (SD). Models were adjusted for serum lipids, and then adjusted for age, body mass index, race, and smoking. Models were additionally adjusted for the sum of the remaining POPs in each chemical class. Women's serum concentration of PBDE congener 153 (PBDE-153) was positively associated with an increased odds of GDM per SD increase in log-transformed concentration, for unadjusted (OR=1.36, 95%CI: 1.02-1.81), a priori adjusted (OR=1.38, 95% CI: 1.03-1.86) and with the sum of remaining PBDEs (OR=1.79, 95% CI: 1.18, 2.74) models. Our findings suggest that at environmentally relevant concentrations, maternal exposure to POPs prior to conception may contribute to increased chance of developing GDM., (Published by Elsevier B.V.)

Background: While several studies have shown an association between environmental pollutants and diabetes among non-pregnant adults, few studies have prospectively assessed the association among pregnant women. We estimated the association between maternal pre-pregnancy levels of a polybrominated biphenyl (PBB 153) and 36 polychlorinated biphenyls (PCBs) with gestational diabetes (GDM)., Methods: Data are from women (18-40 years) participating in a prospective cohort who achieved pregnancy lasting ≥24 weeks gestation and completed monthly pregnancy journals (n = 258). Women were recruited between 2005 and 2007 from 16 counties in Michigan and Texas. Women who ever reported a physician diagnosis of high blood glucose in monthly pregnancy journals were categorized as having gestational diabetes (n = 28; 10.9 %). Multivariable binary logistic regression was used to estimate odds ratios (OR) and 95 % confidence intervals (CIs)., Results: There was no association between PBB 153 and GDM or any of the PCB congeners and GDM in unadjusted models. All associations remained non-significant with stepwise adjustment for age and waist-to-height ratio. Only with further adjustment for total serum lipids did the associations become significant, with lower levels of nine PCB congeners associated with GDM: 138, 153, 156, 167, 170, 172, 178, 180, and 194. The adjusted ORs for PCBs 170 and 180 were the strongest: 0.40 (0.18, 0.88) and 0.41 (0.19, 0.87), respectively., Conclusions: Pre-pregnancy levels of PCBs were not consistently associated with development of GDM in this prospective cohort of U.S. women. Interestingly, we found that although women with GDM had higher mean pre-pregnancy circulating lipid levels compared to women without GDM, they had lower wet weight circulating levels of many PCBs. More research is needed to understand the dynamic fluctuations of PCBs and other persistent organic pollutants between lipid compartments in women preparing to conceive and throughout pregnancy.

Background: Bisphenol A (BPA) and phthalates are ubiquitous non-persistent endocrine disrupting chemicals whose relation with infant birth size is not clearly understood., Methods: We examined associations between maternal and paternal preconception urinary concentrations of total BPA and 14 phthalate metabolites and birth size for 233 infants. Multiple linear regression models were used to estimate parental quartiles of BPA and phthalates in relation to birth weight, length, head circumference, and ponderal index with separate models run for each parent adjusting for age, smoking, body mass index, education, alcohol, parity, and creatinine. Models also included an interaction term for each chemical and infant sex and were further adjusted to include the other partner's chemical concentrations., Results: In maternal models adjusted for partner's exposure and covariates, reductions in birth weight (range: 178-215 g; p < 0.05) were observed for the 2nd quartile of maternal monomethyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate and mono-n-octyl phthalate when compared with the 1st quartiles. The 3rd quartile of monoethylhexyl phthalate (mEHP) was also associated with a 200.16 g (95 % CI: -386.90, -13.42) reduction. Similar reductions in birth weight were observed for the 2(nd) quartile of paternal mEHP (β = -191.93 g; 95 % CI: -381.61, -2.25). Additionally, select maternal urinary metabolites were associated with decreased head circumference, birth length and gestational age. However, paternal concentrations were generally associated with increased birth length and gestational age., Conclusions: We observed some suggestion that preconception maternal and paternal urinary concentration of BPA and specific phthalate metabolites may be associated with smaller birth size and increased gestational age, though the findings appeared to be parent and chemical specific.

Evidence suggests that trace exposures to select elements may increase the risk for adverse birth outcomes. To investigate further, we used multiple regression to assess associations between preconception parental exposures to Pb, Cd, and total Hg in blood, and 21 elements in urine, with n=235 singleton birth outcomes, adjusted for confounders and partner's exposure. Earlier gestational age at delivery (GA) was associated with higher tertiles of urine maternal W (-1.22 days) and paternal U (-1.07 days), but GA was later for higher tertiles of maternal (+1.11 days) and paternal (+1.30 days) blood Hg. Additional analysis indicated shorter GA associated with higher paternal urine Ba, W, and U, and with higher maternal blood Pb for boys, but GA was longer in association with higher maternal urine Cr. Birth weight (BW) was lower for higher tertiles of paternal urine Cs (-237.85g), U (-187.34g), and Zn (-209.08g), and for higher continuous Cr (P=0.021). In contrast, BW was higher for higher tertiles of paternal urine As (+194.71g) and counterintuitively for maternal blood Cd (+178.52g). Birth length (BL) was shorter for higher tertiles of urine maternal W (-1.22cm) and paternal U (-1.10cm). Yet, higher tertiles of maternal (+1.11cm) and paternal (+1.30) blood Hg were associated with longer BL. Head circumference at delivery was lower for higher tertiles of paternal urine U (-0.83cm), and for higher continuous Mo in boys (-0.57cm). Overall, associations were most consistently indicated for GA and measures of birth size with urine W and U, and paternal exposures were more frequently associated than maternal. Though limited by several factors, ours is the largest multi-element investigation of prospective couple-level trace exposures and birth outcomes to date; the novel observations for W and U merit further investigation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The relation between persistent environmental chemicals and semen quality is evolving, although limited data exist for men recruited from general populations., Objectives: We examined the relation between perfluorinated chemicals (PFCs) and semen quality among 501 male partners of couples planning pregnancy., Methods: Using population-based sampling strategies, we recruited 501 couples discontinuing contraception from two U.S. geographic regions from 2005 through 2009. Baseline interviews and anthropometric assessments were conducted, followed by blood collection for the quantification of seven serum PFCs (perfluorosulfonates, perfluorocarboxylates, and perfluorosulfonamides) using tandem mass spectrometry. Men collected a baseline semen sample and another approximately 1 month later. Semen samples were shipped with freezer packs, and analyses were performed on the day after collection. We used linear regression to estimate the difference in each semen parameter associated with a one unit increase in the natural log-transformed PFC concentration after adjusting for confounders and modeling repeated semen samples. Sensitivity analyses included optimal Box-Cox transformation of semen quality end points., Results: Six PFCs [2-(N-methyl-perfluorooctane sulfonamido) acetate (Me-PFOSA-AcOH), perfluorodecanoate (PFDeA), perfluorononanoate (PFNA), perfluorooctane sulfonamide (PFOSA), perfluorooctane sulfonate (PFOS), and perfluorooctanoic acid (PFOA)] were associated with 17 semen quality end points before Box-Cox transformation. PFOSA was associated with smaller sperm head area and perimeter, a lower percentage of DNA stainability, and a higher percentage of bicephalic and immature sperm. PFDeA, PFNA, PFOA, and PFOS were associated with a lower percentage of sperm with coiled tails., Conclusions: Select PFCs were associated with certain semen end points, with the most significant associations observed for PFOSA but with results in varying directions.

Objective: To examine preconception serum concentrations of perfluorooctanoic acid (PFOA) and six other PFCs in relation to gestational diabetes (GDM) risk., Design: Prospective cohort with longitudinal follow-up., Setting: Not applicable., Patient(s): Among 501 women recruited upon discontinuing contraception for the purpose of becoming pregnant, 258 (51%) became pregnant and were eligible for the study, of which 28 (11%) reported having physician-diagnosed GDM during follow-up., Intervention(s): None., Main Outcome Measure(s): The odds ratios (ORs) and 95% confidence intervals (CIs) of GDM associated with each standard deviation (SD) increment of preconception serum PFOA concentration (ng/mL, log-transformed) and six other PFCs were estimated with the use of logistic regression after adjusting for age, prepregnancy body mass index, smoking, and parity conditional on gravidity., Result(s): Preconception geometric mean (95% CI) PFOA concentrations (in ng/mL) were higher for women with than without GDM (3.94 [3.15-4.93] vs. 3.07 [2.83-3.12], respectively). Each SD increment in PFOA was associated with a 1.87-fold increased GDM risk (adjusted OR 1.86 [95% CI 1.14-3.02]). A slightly increased risk associated with each SD increment for the six other PFCs was observed as well (all ORs >1.0, range 1.06-1.27), although the associations were not statistically significant., Conclusion(s): Our findings suggested that higher environmentally relevant concentrations of PFOA were significantly associated with an increased risk of GDM. If corroborated, these findings may be suggestive of a possible environmental etiology for GDM., (Published by Elsevier Inc.)

Background: Persistent organic pollutants (POPs) are developmental toxicants, but the impact of both maternal and paternal exposures on offspring birth size is largely unexplored., Objective: We examined associations between maternal and paternal serum concentrations of 63 POPs, comprising five major classes of pollutants, with birth size measures., Methods: Parental serum concentrations of 9 organochlorine pesticides, 1 polybrominated biphenyl (PBB), 7 perfluoroalkyl chemicals (PFCs), 10 polybrominated diphenyl ethers (PBDEs), and 36 polychlorinated biphenyls (PCBs) were measured before conception for 234 couples. Differences in birth weight, length, head circumference, and ponderal index were estimated using multiple linear regression per 1-SD increase in natural log-transformed (ln-transformed) chemicals. Models were estimated separately for each parent and adjusted for maternal age, maternal prepregnancy body mass index (kilograms per meter squared) and other confounders, and all models included an interaction term between infant sex and each chemical., Results: Among girls (n = 117), birth weight was significantly lower (range, 84-195 g) in association with a 1-SD increase in ln-transformed maternal serum concentrations of DDT, PBDE congeners 28 and 183, and paternal serum concentrations of PBDE-183 and PCB-167. Among boys (n = 113), maternal (PCBs 138, 153, 167, 170, 195, and 209 and perfluorooctane sulfonamide) and paternal (PCBs 172 and 195) serum concentrations of several POPs were statistically associated with lower birth weight (range, 98-170 g), whereas paternal concentrations of PBDEs (66, 99) were associated with higher birth weight. Differences in offspring head circumference, length, and ponderal index were also associated with parental exposures., Conclusions: Preconceptional maternal and paternal concentrations of several POPs were associated with statistically significant differences in birth size among offspring.

Objective: To assess the relationship between environmental chemicals and couple fecundity or time to pregnancy (TTP)., Design: Prospective cohort., Setting: Communities of targeted populations with reported exposure., Patient(s): 501 couples recruited upon discontinuing contraception to become pregnant, 2005-2009., Intervention(s): None., Main Outcome Measure(s): Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) estimated for each partner's chemical concentrations adjusted for age, body mass index, cotinine, creatinine, and research site while accounting for time off contraception., Result(s): Couples completed interviews and anthropometric assessments and provided the urine specimens for quantification of bisphenol A (BPA) and 14 phthalate metabolites, which were measured using high-performance liquid chromatography with electrospray triple-quadrupole mass spectrometer. Women recorded menstruation and pregnancy test results in daily journals. Couples were evaluated until a positive human-chorionic gonadotropin pregnancy test or 12 cycles without pregnancy. Neither female nor male BPA concentration was associated with TTP (FOR 0.98; 95% CI, 0.86, 1.13 and FOR 1.04; 95% CI, 0.91, 1.18, respectively). Men's urinary concentrations of monomethyl, mono-n-butyl, and monobenzyl phthalates were associated with a longer TTP (FOR 0.80; 95% CI, 0.70, 0.93; FOR 0.82, 95% CI, 0.70, 0.97; and FOR 0.77, 95% CI, 0.65 0.92, respectively)., Conclusion(s): Select male but not female phthalate exposures were associated with an approximately 20% reduction in fecundity, underscoring the importance of assessing both partners' exposure to minimize erroneous conclusions., (Published by Elsevier Inc.)

There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18-44 years were recruited into an operative cohort, along with 131 similarly aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (aOR) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR=0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR=1.97; 95% CI: 1.21, 3.19; aOR=2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research., (Published by Elsevier Inc.)

Objective: To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis., Design: Matched cohort design., Setting: Fourteen clinical centers., Patient(s): The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131 women matched on age and residence., Intervention(s): None., Main Outcome Measure(s): Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts, respectively., Result(s): Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index, and creatinine. In the population cohort, six phthalate metabolites-mono-n-butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate-were significantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (monooctyl phthalate; OR 1.38; 95% CI 1.10-1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03-1.78]., Conclusion(s): Select phthalates were associated with higher odds of an endometriosis diagnosis for women with magnetic resonance imaging-diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggesting that persistent environmental pollutants may be reproductive toxicants underscores the need for prospective studies of couples for whom exposures are measured., Objectives: We examined the relationship between selected persistent pollutants and couple fecundity as measured by time to pregnancy., Methods: A cohort of 501 couples who discontinued contraception to become pregnant was prospectively followed for 12 months of trying to conceive or until a human chorionic gonadotrophin (hCG) test confirmed pregnancy. Couples completed daily journals on lifestyle and provided biospecimens for the quantification of 9 organochlorine pesticides, 1 polybrominated biphenyl, 10 polybrominated diphenyl ethers, 36 polychlorinated biphenyls (PCBs), and 7 perfluorochemicals (PFCs) in serum. Using Cox models for discrete time, we estimated fecundability odds ratios (FORs) and 95% CIs separately for each partner's concentrations adjusting for age, body mass index, serum cotinine, serum lipids (except for PFCs), and study site (Michigan or Texas); sensitivity models were further adjusted for left truncation or time off of contraception (≤ 2 months) before enrollment., Results: The adjusted reduction in fecundability associated with standard deviation increases in log-transformed serum concentrations ranged between 18% and 21% for PCB congeners 118, 167, 209, and perfluorooctane sulfonamide in females; and between 17% and 29% for p,p´-DDE and PCB congeners 138, 156, 157, 167, 170, 172, and 209 in males. The strongest associations were observed for PCB 167 (FOR 0.79; 95% CI: 0.64, 0.97) in females and PCB 138 (FOR = 0.71; 95% CI: 0.52, 0.98) in males., Conclusions: In this couple-based prospective cohort study with preconception enrollment and quantification of exposures in both female and male partners, we observed that a subset of persistent environmental chemicals were associated with reduced fecundity.

Background: Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues., Methods: We formulated two samples. The first was an operative sample comprising 495 women aged 18-44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007-2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity., Results: Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17-3.06]) and perfluorononanoic acid (2.20 [1.02-4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99-2.66] and 1.99 [0.91-4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05-3.30]) and PFOA (2.58 [1.18-5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively)., Conclusions: Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.

The effect of heavy metals at environmentally relevant concentrations on couple fecundity has received limited study despite ubiquitous exposure. In 2005-2009, couples (n=501) desiring pregnancy and discontinuing contraception were recruited and asked to complete interviews and to provide blood specimens for the quantification of cadmium (μg L(-1)), lead (μg dL(-1)) and mercury (μg L(-1)) using inductively coupled plasma-mass spectrometry. Couples completed daily journals on lifestyle and intercourse along with menstruation and pregnancy testing for women. Couples were followed for 12 months or until pregnant. Fecundability odds ratios (FORs) and 95% confidence intervals (CIs) were estimated adjusting for age, body mass index, cotinine, and serum lipids in relation to female then male exposures. FORs <1 denote a longer time to pregnancy. In adjusted models, reduced FORs were observed for both female cadmium (0.78; 95% CI 0.63-0.97) and male lead (0.85; 95% CI 0.73-0.98) concentrations. When jointly modeling couples' exposures, only male lead concentration significantly reduced the FOR (0.82; 95% CI 0.68, 0.97), though the FOR remained <1 for female cadmium (0.80; 95% CI 0.64, 1.00). This prospective couple based cohort with longitudinal capture of time to pregnancy is suggestive of cadmium and lead's reproductive toxicity at environmentally relevant concentrations., (Published by Elsevier Ltd.)

Background: An equivocal literature exists regarding the relation between persistent organochlorine pollutants (POPs) and endometriosis in women, with differences attributed to methodologies., Objectives: We assessed the association between POPs and the odds of an endometriosis diagnosis and the consistency of findings by biological medium and study cohort., Methods: Using a matched cohort design, we assembled an operative cohort of women 18-44 years of age undergoing laparoscopy or laparotomy at 14 participating clinical centers from 2007 to 2009 and a population-based cohort matched on age and residence within a 50-mile catchment area of the clinical centers. Endometriosis was defined as visualized disease in the operative cohort and as diagnosed by magnetic resonance imaging in the population cohort. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each POP in relation to an endometriosis diagnosis, with separate models run for each medium (omental fat in the operative cohort, serum in both cohorts) and cohort. Adjusted models included age, body mass index, breast-feeding conditional on parity, cotinine, and lipids., Results: Concentrations were higher in omental fat than in serum for all POPs. In the operative cohort, γ-hexachlorocyclohexane (γ-HCH) was the only POP with a significant positive association with endometriosis [per 1-SD increase in log-transformed γ-HCH: adjusted OR (AOR) = 1.27; 95% CI: 1.01, 1.59]; β-HCH was the only significant predictor in the population cohort (per 1-SD increase in log-transformed β-HCH: AOR = 1.72; 95% CI: 1.09, 2.72)., Conclusions: Using a matched cohort design, we found that cohort-specific and biological-medium-specific POPs were associated with endometriosis, underscoring the importance of methodological considerations when interpreting findings.

Benzophenone (BP)-type UV filters are widely used in a variety of personal care products for the protection of skin and hair from UV irradiation. Despite the estrogenic potencies of BP derivatives, few studies have examined the occurrence of these compounds in human matrices. Furthermore, associations among exposure to these compounds and estrogen-dependent diseases (such as endometriosis) have not been examined previously. In this study, we determined the concentrations of five BP derivatives, 2-hydroxy-4-methoxybenzophenone (2OH-4MeO-BP), 2,4-dihydroxybenzophenone (2,4OH-BP), 2,2'-dihydroxy-4-methoxybenzophenone (2,2'OH-4MeO-BP), 2,2',4,4'-tetrahydroxybenzophenone (2,2',4,4'OH-BP), and 4-hydroxybenzophenone (4OH-BP), in urine collected from 625 women in Utah and California, using liquid chromatography (LC)-tandem mass spectrometry (MS/MS). The association of urinary concentrations of BP derivatives with an increase in the odds of a diagnosis of endometriosis was examined in 600 women who underwent laparoscopy/laparotomy (n = 473: operative cohort) or pelvic magnetic resonance imaging (n = 127: population cohort), during 2007-2009. 2OH-4MeO-BP, 2,4OH-BP, and 4OH-BP respectively were detected in 99.0%, 93.3%, and 83.8% of the urine samples analyzed, whereas the detection rates for 2,2',4,4'OH-BP and 2,2'OH-4MeO-BP were below 6.0%. Significant regional differences (higher concentrations in California) and monthly variations (higher concentrations in July and August) were found for urinary concentrations of 2OH-4MeO-BP and 2,4OH-BP. In addition, urinary concentrations of 2OH-4MeO-BP and 2,4OH-BP tended to be higher in more affluent, older, and leaner women. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for the urinary concentrations of BP derivatives and the odds of an endometriosis diagnosis; ORs increased across quartiles of 2OH-4MeO-BP and 2,4OH-BP concentrations, but a significant trend was observed only between 2,4OH-BP and the odds of an endometriosis diagnosis in the operative cohort (OR = 1.19; 95% CI = 1.01, 1.41). When women in the highest quartile of 2,4OH-BP concentrations were compared with women in the first three quartiles, the OR increased considerably (OR = 1.65; 95% CI = 1.07, 2.53). Given that 2,4OH-BP possesses an estrogenic activity higher than that of 2OH-4MeO-BP, our results invite the speculation that exposure to elevated 2,4OH-BP levels may be associated with endometriosis.

An evolving body of evidence suggests an adverse relation between persistent organochlorine pollutants (POPs) and menstruation, though prospective longitudinal measurement of menses is limited and served as the impetus for study. We prospectively assessed the relation between a mixture of persistent organochlorine compounds and menstrual cycle length and duration of bleeding in a cohort of women attempting to become pregnant. Eighty-three (83%) women contributing 447 cycles for analysis provided a blood specimen for the quantification of 76 polychlorinated biphenyls and seven organochlorine pesticides, and completed daily diaries on menstruation until a human chorionic gonadotropin confirmed pregnancy or 12 menstrual cycles without conception. Gas chromatography with electron capture detection was used to quantify concentrations (ng g(-1)serum); enzymatic methods were used to quantify serum lipids (mg dL(-1)). A linear regression model with a mixture distribution was used to identify chemicals grouped by purported biologic activity that significantly affected menstrual cycle length and duration of bleeding adjusting for age at menarche and enrollment, body mass index, and cigarette smoking. A significant 3-d increase in cycle length was observed for women in the highest tertile of estrogenic PCB congeners relative to the lowest tertile (β=3.20; 95% CI 0.36, 6.04). A significant reduction in bleeding (<1 d) was observed among women in the highest versus lowest tertile of aromatic fungicide exposure (γ=-0.15; 95% CI -0.29, -0.00). Select POPs were associated with changes in menstruation underscoring the importance of assessing chemical mixtures for female fecundity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy; obtaining environmental data across sensitive windows of reproduction and development; home-based biospecimen collection; and development of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e., fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424,423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, ∼ 85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility monitors for identifying ovulation and home pregnancy test kits. Couples can be recruited for preconception cohorts and will comply with intensive data collection across sensitive windows. However, appropriately sized sampling frameworks are critical, given the small percentage of couples contacted found eligible and reportedly planning pregnancy at any point in time., (© Published 2011. This article is a US Government work and is in the public domain in the USA.)

Background: Prenatal and postnatal polychlorinated biphenyl (PCBs) exposure has been associated with decrements in fetal and infant growth and development, although exposures during the preconception window have not been examined despite recent evidence suggesting that this window may correspond with the highest serum concentrations., Objectives: We assessed maternal serum PCB concentrations at two sensitive developmental windows in relation to birth weight., Methods: Serum samples were collected from 99 women as they began trying to become pregnant (preconception) and after a positive pregnancy test (prenatal); 52 (53%) women gave birth and represent the study cohort. Using daily diaries, women recorded sexual intercourse, menstruation, and home pregnancy test results until pregnant or up to 12 menstrual cycles with intercourse during the estimated fertile window. With gas chromatography with electron capture, 76 PCB congeners were quantified (nanograms per gram serum) and subsequently categorized by purported biologic activity. Serum PCBs were log-transformed and entered both as continuous and categorized exposures along with birth weight (grams) and covariates [smoking (yes/no), height (inches), and infant sex (male/female)] into linear regression., Results: A substantial reduction in birth weight (grams) was observed for women in the highest versus the lowest tertile of preconception antiestrogenic PCB concentration (beta; = 429.3 g, p = 0.038) even after adjusting for covariates (beta; = 470.8, p = 0.04)., Conclusions: These data reflect the potential developmental toxicity of antiestrogenic PCBs, particularly during the sensitive preconception critical window among women with environmentally relevant chemical exposures, and underscore the importance of PCB congener-specific investigation.

ObjectiveTo explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis.DesignMatched cohort design.SettingFourteen clinical centers.Patient(s)The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, whereas the population cohort comprised 131 women matched on age and residence.Intervention(s)None.Main outcome measure(s)Surgically visualized or pelvic magnetic resonance imaging diagnosed endometriosis in the two cohorts, respectively.Result(s)Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index, and creatinine. In the population cohort, six phthalate metabolites-mono-n-butyl phthalate, mono-[(2-carboxymethyl) hexyl] phthalate, mono (2-ethyl-5-carboxyphentyl) phthalate, mono (2-ethylhexyl) phthalate, mono (2-ethyl-5-hydroxyhexyl) phthalate, and mono (2-ethyl-5-oxohexyl) phthalate-were significantly associated with an approximately twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (monooctyl phthalate; OR 1.38; 95% CI 1.10-1.72) or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis [mono (2-ethylhexyl) phthalate; OR 1.35; 95% CI 1.03-1.78].Conclusion(s)Select phthalates were associated with higher odds of an endometriosis diagnosis for women with magnetic resonance imaging-diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings.

BackgroundEnvironmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues.MethodsWe formulated two samples. The first was an operative sample comprising 495 women aged 18-44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007-2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity.ResultsSerum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17-3.06]) and perfluorononanoic acid (2.20 [1.02-4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99-2.66] and 1.99 [0.91-4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05-3.30]) and PFOA (2.58 [1.18-5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively).ConclusionsSelect PFCs were associated with an endometriosis diagnosis. These associations await corroboration.