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The associations between urinary phenol concentrations and markers of thyroid function and autoimmunity among potentially susceptible subgroups, such as subfertile women, have been understudied, especially when considering chemical mixtures. We evaluated cross-sectional associations of urinary phenol concentrations, individually and as a mixture, with serum markers of thyroid function and autoimmunity. We included 339 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2009–2015). We quantified four phenols in urine using isotope dilution high-performance liquid chromatography–tandem mass spectrometry, and biomarkers of thyroid function (thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4), and triiodothyronine (fT3, TT3)), and autoimmunity (thyroid peroxidase (TPO) and thyroglobulin (Tg) antibodies (Ab)) in serum using electrochemoluminescence assays. We fit linear and additive models to investigate the association between urinary phenols—both individually and as a mixture—and serum thyroid function and autoimmunity, adjusted for confounders. As a sensitivity analysis, we also applied Bayesian Kernel Machine Regression (BKMR) to investigate non-linear and non-additive interactions. Urinary bisphenol A was associated with thyroid function, in particular, fT3 (mean difference for a 1 log unit increase in concentration: −0.088; 95% CI [−0.151, −0.025]) and TT3 (−0.066; 95% CI [−0.112, −0.020]). Urinary methylparaben and triclosan were also associated with several thyroid hormones. The overall mixture was negatively associated with serum fT3 concentrations (mean difference comparing all four mixture components at their 75th vs. 25th percentiles: −0.19, 95% CI [−0.35, −0.03]). We found no evidence of non-linearity or interactions. These results add to the current literature on phenol exposures and thyroid function in women, suggesting that some phenols may alter the thyroid system.

OBJECTIVE: To examine the association between dietary folate intake and antral follicle count (AFC) among women seeing treatment for infertility. DESIGN: Cohort study SETTING: Academic fertility center PATIENTS: 552 women attending the Massachusetts General Hospital Fertility Center (2007-2019) who participated in the Environment and Reproductive Health Study. INTERVENTION(S): None. Folate intake was measured using a validated food frequency questionnaire at study entry. Multivariable Poisson regression models with robust standard errors were used to estimate the association of folate intake with AFC adjusting for calorie intake, age, BMI, physical activity, education, smoking status, year of AFC, and intakes of vitamin B12, iron, and vitamin D. Non-linearity was assessed with restricted cubic splines. MAIN OUTCOME MEASURES: AFC as measured with transvaginal ultrasonography as part of routine care. RESULTS: Among the 552 women (median age 35.0 years, median folate intake 1,005 μg/day), total and supplemental folate intake had a significant non-linear relationship with AFC (P for non-linearity 0.05 and 0.02, respectively). There was a positive linear association with AFC up to approximately 1200 μg/day for total folate intake and up to 800 μg/day for supplemental folate intake; however, there was no additional benefit of higher folate intakes. The magnitude of association was modest – for example, the predicted adjusted difference in AFC between a woman consuming 400 versus 800 μg/day of supplemental folate was approximately 1.5 follicles. CONCLUSIONS: Higher intake of folate, particularly from supplements, was associated with modestly higher ovarian reserve as measured by AFC among women attending a fertility center. TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov as NCT00011713

Objective To examine the impact of men’s diet on outcomes of infertility treatment with assisted reproductive technology (ART) using an empirical score representing the relation of diet with semen quality. Design Prospective cohort study. Setting Fertility center at an academic medical center. Patient(s) We included 296 men (688 semen samples) to identify an empirical dietary pattern and 231 couples (406 ART cycles) to investigate the association of this diet pattern with ART outcomes. Intervention(s) Men’s diet was assessed at baseline using a validated questionnaire. An empirical dietary pattern reflecting the overall relation of diet with semen quality was identified using reduced rank regression. Main Outcome Measure(s) The primary outcome was live birth per treatment cycle. The secondary outcomes were fertilization, implantation, and clinical pregnancy. Result(s) Men had a median baseline age and body mass index of 36.8 years and 26.9 kg/m2, respectively. Although the empirical diet pattern was significantly associated with all semen parameters, the empirical diet score was not related to any clinical outcome of infertility treatment after ART. The adjusted probabilities of relevant clinical outcomes in the lowest and highest quartiles of the empirical score were 0.62 (0.50–0.73) and 0.55 (0.45–0.66) for implantation, 0.57 (0.46–0.69) and 0.50 (0.40–0.61) for clinical pregnancy, and 0.49 (0.37–0.62) and 0.36 (0.25–0.48) for live birth. Analyses excluding couples with a diagnosis of male factor infertility and, separately, excluding intracytoplasmic sperm injection cycles yielded similar results. Conclusion(s) A dietary score representing the overall association of diet with semen quality parameters was not associated with ART outcomes.

PURPOSE(S): To evaluate the relationship of men’s dietary patterns with outcomes of in vitro fertilization (IVF). METHODS: This is a prospective cohort study including 231 couples with 407 IVF cycles, presented at an academic fertility center from April 2007 to April 2018. We assessed diet with a validated food frequency questionnaire and identified Dietary Pattern 1 and Dietary Pattern 2 using principal component analysis. We evaluated adjusted probability of IVF outcomes across the quartiles of the adherence to two dietary patterns by generalized linear mixed models. RESULTS: Men had a median age of 36.8 years and BMI of 26.9 kg/m(2). Women’s median age and BMI were 35.0 years and 23.1 kg/m(2), respectively. Adherence to Dietary Pattern 1 (r(Pearson)=0.44) and Dietary Pattern 2 (r(Pearson)=0.54) was positively correlated within couples. Adherence to Dietary Pattern 1 was positively associated with sperm concentration. A 1-unit increase in this pattern was associated with a 13.33 (0.71–25.96) million/mL higher sperm concentration. However, neither Dietary Pattern 1 nor Dietary Pattern 2 was associated with fertilization, implantation, clinical pregnancy, or live birth probabilities. CONCLUSIONS: Data-derived dietary patterns were associated with semen quality but unrelated to the probability of successful IVF outcomes. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02251-9.

To investigate whether history of comorbidities is associated with markers of ovarian reserve among subfertile women.This observational study includes 645 women seeking fertility care at the Massachusetts General Hospital who enrolled in the Environment and Reproductive Health (EARTH) study (2005-2019). Women completed a comprehensive questionnaire including medical diagnosis of comorbidities. Ovarian reserve markers including antral follicle count (AFC), assessed by transvaginal ultrasound, and circulating serum levels of day 3 FSH and AMH, are assessed by immunoassays. We fit linear regression models to evaluate the association between history of comorbidities and markers of ovarian reserve while adjusting for confounders.Self-reported history of hypertension, cancer, and neurological disorders was negatively associated with AFC in unadjusted models and in adjusted models for age, smoking, physical activity, comorbidity count, and BMI. Adjusted mean AFC (95% CI) was lower among women with history of hypertension, compared to women with no self-reported history of hypertension (11.5 vs 15.6, p value 0.0001). In contrast, day 3 FSH levels were positively related to history of eating disorders in both unadjusted and adjusted models (10.8 vs. 7.43 IU/L, p value ≤ 0.0001). Self-reported history of other comorbidities was unrelated to AFC, day 3 FSH, and AMH levels.History of hypertension, cancer, and neurological disorders was negatively associated with AFC, and eating disorders were positively related to day 3 FSH levels. The prevention of common comorbidities among women in reproductive age may help increase women's fertility given the declining birth rates and increasing use of assisted reproductive technologies in the past years.

The epidemiologic literature on associations between urinary phenol concentrations and lipid profiles during pregnancy is limited. We examined whether urinary concentrations of phenol and phenol replacement biomarkers were associated with serum lipid levels among pregnant women. This cross-sectional study included 175 women attending the Massachusetts General Hospital Fertility Center who enrolled in the Environment and Reproductive Health (EARTH) Study between 2005 and 2017 and had data available on urinary phenol biomarkers and serum lipids during pregnancy. We used linear regression models to assess the relationship between groups of urinary phenol and phenol replacement biomarkers and serum lipid levels [total cholesterol, high density lipoprotein (HDL), non-HDL, low-density lipoprotein (LDL) cholesterol, and triglycerides], while adjusting for age at sample collection, pre-pregnancy BMI, education, race, infertility diagnosis, cycle type, number of fetuses, trimester and specific gravity. In adjusted models, pregnant women with urinary propylparaben concentrations in the highest tertile had 10% [22 (95% CI = 5, 40) mg/dL], 12% [19 (95% CI = 2, 36) mg/dL] and 16% [19 (95% CI = 3, 35) mg/dL] higher mean total, non-HDL and LDL cholesterol, respectively, compared to women with concentrations in the lowest tertile. Similar elevations were observed for urinary bisphenol A concentrations. Urinary bisphenol S, benzophenone-3, triclosan, methylparaben, ethylparaben, and butylparaben were unrelated to serum lipids. Among pregnant women, urinary concentrations of bisphenol A and propylparaben were associated with higher serum levels of total, non-HDL and LDL cholesterol.

PURPOSE: To enhance the understanding of the clinical significance of anti-Müllerian hormone (AMH) in follicular fluid, we aimed to determine the variability of AMH concentrations in follicular fluid within and across IVF cycles and whether high follicular fluid AMH concentrations are associated with improved clinical IVF outcomes. METHODS: This was a retrospective cohort study of companion follicular fluid and serum samples from 162 women enrolled in the Environment and Reproductive Health (EARTH) Study between 2010 and 2016. AMH concentrations were quantified using a sandwich enzyme-linked immunosorbent assay. Spearman correlation and intra-class correlation (ICC) were calculated to assess variability of follicular fluid AMH, and generalized linear mixed models were used to evaluate the associations of FF AMH with IVF outcomes. RESULTS: The median (interquartile range, IQR) age of the 162 women was 34.0 years (32.0, 37.0). Follicular fluid AMH concentrations were highly correlated between follicles within each IVF cycle (Spearman r = 0.78 to 0.86) and across cycles for each woman (ICC 0.87 (95% CI 0.81 to 0.92)). Compared with women in the highest tertile of FF AMH (mean AMH = 2.3 ng/ml), women in the lowest tertile (mean AMH = 0.2 ng/ml) had lower serum AMH (T1 = 0.1 ng/ml vs. T3 = 0.6 ng/ml, p

STUDY QUESTION Are serum concentrations of polybrominated diphenyl ethers (PBDEs) and hydroxylated brominated diphenyl ethers (OH-BDEs) associated with IVF endpoints? SUMMARY ANSWER Positive associations were observed for BDE153 and several OH-BDEs with IVF endpoints. WHAT IS KNOWN ALREADY PBDEs have been voluntarily phased out of production in the USA and EU due to their persistence and toxicity to humans and ecosystems. PBDEs have been associated with implantation failure among women undergoing IVF, yet some animal studies suggest greater toxicity from their metabolites, OH-BDEs. STUDY DESIGN, SIZE, DURATION We evaluated a subset of 215 women (contributing 330 IVF cycles) enrolled between 2005 and 2016 in a longitudinal cohort based at Massachusetts General Hospital Fertility Center. PARTICIPANTS/MATERIALS, SETTING, METHODS The following PBDEs were quantified: 47, 99, 100, 153 and 154 and the following OH-BDEs: 3-OH-BDE47, 5-OH-BDE47, 6-OH-BDE47 and 4-OH-BDE49. Clinical endpoints of IVF treatments were abstracted from electronic medical records. Associations of log-transformed PBDEs and OH-BDEs with IVF outcomes were assessed using multivariable generalized mixed models and cluster weighted generalized estimating equation models adjusted for lipids, age, BMI, race, year of sample collection, IVF protocol and FSH levels. Outcomes were adjusted to represent a percent change in outcome with an increase equal to the magnitude of the difference between the 75th and 25th percentiles for each specific compound (interquartile range (IQR) increase). MAIN RESULTS AND THE ROLE OF CHANCE Detection frequencies were highest for congeners 47 and 153 (82% ≥ method detection limit (MDL)) and metabolites 3 and 5-OH-BDE47 and 4-OH-BDE49 (92% > MDL). PBDE and OH-BDE geometric mean concentrations declined by up to 80% between participants recruited in 2005 and those recruited in 2016. An IQR increase of BDE153 was associated with an increase in the probability of implantation (relative risk (RR) = 1.26, 95% CI: 1.16, 1.36), clinical pregnancy (RR = 1.32, 95% CI: 1.19, 1.46) and live birth (RR = 1.34; 95% CI: 1.15, 1.54). An IQR increase in 3 and 5-OH-BDE47 was associated with increased probabilities of implantation (RR = 1.52; 95% CI: 1.11, 2.09), clinical pregnancy (RR = 1.66; 95% CI: 1.17, 2.36), and live birth (RR = 1.61; 95% CI: 1.07, 2.40). When models were stratified by race (White (86%)/Other race (14%)), associations remained positive for White women, yet inverse associations were observed for Other race women. An IQR increase in BDE47 was associated with a 46% decreased probability of clinical pregnancy (95% CI: 0.31, 0.95) for Other race women. LIMITATIONS, REASONS FOR CAUTION Despite the long half-lives of PBDEs and OH-BDEs, exposure misclassification is possible for women who underwent multiple treatment cycles over several months or years. It is also possible another medium, such as follicular fluid would be optimal to characterize exposure. We also tested associations for multiple congeners and metabolites with multiple outcomes. WIDER IMPLICATIONS OF THE FINDINGS Detections of serum concentrations of PBDEs and OH-BDEs were highest in the early years of the study and suggests that the phase-out of these compounds has contributed to a decrease in exposure. The negative associations found for PBDEs and IVF outcomes among other race women suggests the potential for racial disparity. Potential racial disparities in PBDE exposure and exploration of alternative flame retardants with reproductive health outcomes should be the focus of future investigations. STUDY FUNDING/COMPETING INTEREST(S) Funding for this research was supported by the National Institutes of Environmental Health Sciences (NIEHS) [R01 ES009718, ES022955, ES000002 and 009718T32ES007069]. The authors have no conflicts of interest.

OBJECTIVE: To investigate whether men's adherence to dietary patterns promoted for the prevention of cardiovascular disease is associated with semen parameters and couples’ ART outcomes. DESIGN: Prospective cohort study. SETTING: Fertility center at an academic medical center. PATIENTS: A total of 245 men and their female partners, who underwent 438 assisted reproductive technology (ART) cycles from 2007 to 2020. INTERVENTION: Male pre-treatment diet intake was assessed with a 131-item food-frequency questionnaire from which we calculated eight a-priori defined scores: Trichopoulou Mediterranean, Alternate Mediterranean, Panagiotakos Mediterranean, Healthy Eating Index, Alternative Healthy Eating Index, American Heart Association, Dietary Approaches to Stop Hypertension, and Plant-based. MAIN OUTCOME MEASURES: The primary outcome was live birth per treatment cycle. Secondary outcomes were fertilization, implantation, and clinical pregnancy and seminogram parameters. RESULTS: There was an inverse association of greater men’s adherence to the Panagiotakos Mediterranean diet (P-trend=0.016) and the American Heart Association dietary pattern (P-trend=0.033) with lower fertilization rate. However, there was no significant association of men’s adherence to any of the analyzed dietary pattern with probabilities of implantation, clinical pregnancy, or live birth in multivariable-adjusted models. No significant differences in any of the semen parameters were found between participants of the lowest quartile and those of the higher quartile of the eight dietary patterns. CONCLUSIONS: These findings suggest that men’s adherence to several a-priori defined dietary scores with documented cardiovascular benefits is not related to major outcomes of infertility treatment with ART or semen quality.

Long-chain omega-3 fatty acids and their food sources have garnered interest as a potential nutrient with wide-range health benefits, including fertility.This study aimed to investigate the association of women's and men's intake of omega-3 fatty acids and omega-3 rich-foods with semen quality and outcomes of infertility treatment with assisted reproductive technologies.Couples presenting to the Massachusetts General Hospital were invited to enroll in a prospective cohort study (2007-2020). Male and female diets were assessed using a validated 131-item food frequency questionnaire. The primary outcomes were implantation, clinical pregnancy, and live birth probabilities. The secondary outcomes included total and clinical pregnancy loss and conventional semen parameters, for males only. We estimated the relationship between intakes of omega-3 fatty acids, nuts, and fish and the probability (95% confidence interval) of study outcomes using generalized linear mixed models to account for repeated treatment cycles per participant while simultaneously adjusting for age, body mass index, smoking status, education, dietary patterns, total energy intake, and male partner diet.A total of 229 couples and 410 assisted reproductive technology cycles were analyzed for primary and secondary outcomes. Of note, 343 men contributing 896 semen samples were included in analyses for semen quality measures. Women's docosahexaenoic acid + eicosapentaenoic acid intake was positively associated with live birth. The multivariable-adjusted probabilities of live birth for women in the bottom and top quartiles of eicosapentaenoic acid + docosahexaenoic acid intake were 0.36 (95% confidence interval, 0.26-0.48) and 0.54 (95% confidence interval, 0.42-0.66) (P trend=.02). Eicosapentaenoic acid + docosahexaenoic acid intake was inversely related to the risk of pregnancy loss, which was 0.53 among women in the lowest quartile of eicosapentaenoic acid + docosahexaenoic acid intake and 0.05 among women in the highest quartile (P trend=.01). Men's intake of total omega-3 fatty acids was positively related to sperm count, concentration, and motility, but unrelated to any assisted reproductive technology outcomes. Similar associations were observed when evaluating the intake of primary food sources of these fatty acids.Women's consumption of omega-3 fatty acids and omega-3-rich foods may improve the probability of conception by decreasing the risk of pregnancy loss. In addition, men's intake of omega-3 fatty acids may influence semen quality.

BACKGROUND: Air pollution exposure has been linked with diminished fertility. Identifying the metabolic changes induced by periconception air pollution exposure among women could enhance our understanding of the potential biological pathways underlying air pollution’s reproductive toxicity. OBJECTIVE: To identify serum metabolites associated with periconception air pollution exposure and evaluate the extent to which these metabolites mediate the association between air pollution and live birth. METHODS: We included 200 women undergoing a fresh assisted reproductive technology (ART) cycle at Massachusetts General Hospital Fertility Center (2005–2015). A serum sample was collected during stimulation, and untargeted metabolic profiling was conducted using liquid chromatography with ultra-high-resolution mass spectrometry. Exposure to nitrogen dioxide (NO(2)), ozone (O(3)), fine particulate matter

Study question Is men’s adherence to the Mediterranean diet (MD) associated with sperm parameters and couples’ outcomes of assisted reproductive technologies (ART)? Summary answer Higher men’s adherence to the MD was associated with an increased probability of clinical pregnancy and live birth among couples undergoing ART. What is known already There is growing literature supporting the hypothesis that some nutrients, foods, and dietary patterns may be related to sperm quality and fertility. However, no previous studies analyzed the relationship of men’s adherence to the Mediterranean diet with sperm parameters and ART outcomes in the same cohort. Study design, size, duration The Environmental and Reproductive Health (EARTH) Study is a prospective preconception cohort of couples seeking fertility treatment at the Massachusetts General Hospital Fertility Center (Boston, USA). This analysis includes 314 men and their female partner, who underwent 791 ART cycles (2007–2020). Diet intake was measured by a validated semi-quantitative food frequency questionnaire completed prior to ART. Men’s adherence to the MD was estimated using the Trichopoulou score. Participants/materials, setting, methods Primary outcomes included: conventional sperm parameters (volume, sperm count, concentration, motility, and morphology), and ART outcomes (implantation, clinical pregnancy, and live birth). We estimated the marginal means and 95% confidence interval (95%CI) for semen parameters and the probability of ART (95%CI) by employing generalized linear mixed models while adjusting for several potential confounders. Sensitivity analyses by changing the cut-off points of adherence to the MD were tested. Main results and the role of chance At baseline, men had a median (IQR) age of 35.6 (32.6, 38.8) years and a BMI of 26.7 (24.0, 29.4) kg/m2. Female partner age median (IQR) was 35.0 years (32.0, 38.0) and BMI 23.3 (21.3, 26.6) kg/m2. Couples were mostly white and had never smoked. Men’s adherence to the MD was not associated with seminal parameters in the multivariable-adjusted models but it was related to a higher probability of clinical pregnancy and live birth. The predicted marginal proportions and confidence intervals among men in the lowest compared with the highest quartile of adherence to the MD were 0.25 (0.14, 0.40), 0.55 (0.41, 0.68) for clinical pregnancy (P-trend=0.005), and 0.19 (0.10, 0.32), 0.42 (0.30, 0.55) for live birth (P-trend=0.014). Male partner MD dietary pattern scores were unrelated to the probability of implantation. Sensitivity analyses using tertiles and quintiles of men’s adherence to the MD showed similar associations. Limitations, reasons for caution Although we have adjusted our models by several potential confounding factors, residual confounding cannot be ruled out, and therefore our results should be interpreted with caution. The findings may not be generalizable to other populations or couples attempting conception without ART. Wider implications of the findings: According to our knowledge, this is the first study suggesting that adherence to MD could be suitable dietary guidance for men whose partners are undergoing infertility treatment. Trial registration number Not applicable

Study question Is men’s diet associated with assisted reproductive technology (ART) outcomes? Summary answer An empirical dietary score representing the overall effect of men’s diet on semen quality was unrelated to ART outcomes. What is known already Multiple studies have related various aspects of men’s diet to semen quality. Generally, healthier foods, such as fish, vegetables, and fruits, have been related to better semen quality, whereas unhealthy foods, like processed and red meats, have had the opposite relationship. Nevertheless, while bulk semen parameters are important biomarkers of male fertility and a diagnostic cornerstone for male factor infertility, they are imperfect predictors of a couple’s fertility. Study design, size, duration Couples presenting to the Massachusetts General Hospital Fertility Center between April 2007 and April 2018 were invited to participate in the Environment and Reproductive Health (EARTH) study, a prospective cohort study. Men’s diet was assessed with a previously validated food frequency questionnaire. A dietary score reflecting the overall relation of men’s food intake with semen quality parameters was empirically derived using reduced rank regression (RRR). The resulting dietary score was related to ART outcomes. Participants/materials, setting, methods We used information from 349 men (908 semen samples) to derive the empirical diet pattern and data from 231 couples (407 ART cycles). The primary outcome was the probability of live birth per treatment cycle; secondary outcomes were semen quality, and fertilization, implantation, and clinical pregnancy rates. We evaluated the association between the dietary score and these outcomes using logistic generalized linear mixed models to account for repeated cycles while adjusting for confounders. Main results and the role of chance Men had a median baseline age and BMI of 36.8 years and 26.9 kg/m2, respectively. The empirical diet pattern was significantly associated with all semen parameters. One standard deviation increase in the empirical diet pattern was associated with lower volume (–0.10 standard units [95% CI: –0.17 to –0.04]) and to higher sperm total sperm count (0.13 standard units [0.06 to 0.20]), concentration (0.17 standard units [0.10 to 0.24]), total motility (0.14 standard units [0.07 to 0.20]), progressive motility (0.08 standard units [0.01 to 0.15]), and normal morphology (0.18 standard units [0.11 to 0.25]). Couples with men in the lowest quartile of the empirical score were more likely to have a diagnosis of male infertility than couples with men in the highest quartile (49% vs 24%). Despite the association with semen parameters, the empirical diet score was not related to any clinical outcome of infertility treatment with ART. The adjusted probabilities of implantation, clinical pregnancy and live birth in the lowest and highest quartile of the empirical score were 0.62 (0.50–0.73) and 0.55 (0.45–0.66), 0.57 (0.46–0.69) and 0.50 (0.40–0.61), and 0.49 (0.37–0.62) and 0.36 (0.25–0.48), respectively. Analyses excluding couples with a diagnosis of male factor infertility yielded similar results. Limitations, reasons for caution We evaluated the relationship only among couples presenting to a fertility center and therefore it is unclear whether findings can be generalized to couples trying to conceive without ART. Wider implications of the findings: Given ART is a robust intervention including stringent sperm selection procedures, any effect that empirical diet may have on a couple’s chances of conceiving through assisted reproduction is unlikely to reflect the effect of these factors on bulk semen quality parameters. Trial registration number The project was funded by ES009718, ES022955, ES026648, and ES000002 from the National Institute of Environmental Health Sciences, and P30DK46200 from the National Institute of Diabetes and Digestive and Kidney Diseases

Study question Which methodological approaches are most appropriate for analyzing IVF data with multiple cycles in the context of a binary outcome? Summary answer Both mixed effect models and generalized estimating equation (GEE) modeling approaches can account for multiple IVF cycles and may reduce bias over first-cycle only approaches, but CIs were narrowest with cluster-weighted generalized estimating equation models (CWGEE). What is known already There is a lack of consensus among investigators regarding how to best incorporate data from multiple cycles and whether to present odds or risks in the analysis of IVF data. Failure to account for correlated outcomes within individuals and informative cluster size may lead to invalid CIs and biased estimates. Study design, size, duration The Environment and Reproductive Health (EARTH) Study is an ongoing prospective cohort study of subfertile couples conducted at an academic medical center. This cohort was established in 2004 and follows couples seeking treatment for infertility throughout the course of their treatment and pregnancy. Participants/materials, setting, methods Women aged 18-46 years enrolled in the EARTH Study from 2004 to 2017 who initiated at least one IVF cycle were eligible. Cycle initiation was defined as beginning ovulation induction with the intent to progress through an IVF or ICSI cycle. This analysis included 442 women undergoing 642 cycles who met the study inclusion criteria. We compared the results and interpretations of log-binomial and logistic models restricting to the first cycle, as well as mixed effects models, unweighted GEE models, and CWGEE models including all cycles. This analysis was conducted for two distinct exposures: maternal age at cycle initiation, and maternal preconception urinary concentrations of di(2-ethylhexyl) phthalate (DEHP) metabolites (previously reported to be associated with a decreased probability of live birth). Main results and the role of chance In general, the CIs were widest for mixed effects models and narrowest for CWGEE models. Further, in models evaluating the sum of urinary concentrations of DEHP metabolites (∑DEHP, available for 91% of women), the point estimates were surprisingly different between the first-cycle and multiple-cycle models. We observed significant associations between maternal age and live birth in all models. However, we observed no associations between ∑DEHP and live birth. Limitations, reasons for caution This analysis was limited to an example dataset in which the true effect of any exposure is unknown. While this allows us to observe model performance in the context of real data, future analyses should be conducted within simulated datasets under various assumptions to further evaluate the appropriateness of each approach. In addition, we did not address differential loss to follow-up in our statistical approaches. Wider implications of the findings The use of CWGEE models should be more widely considered in the analysis of IVF data with multiple cycles per woman. The CWGEE approach is computationally simple, addresses non-ignorable (informative) cluster size, and is robust against mis-specification of the underlying covariance structure. Among the methods compared in this analysis, CWGEE models generally yielded the narrowest CIs, possibly indicating the most precise estimates. We also stress the importance of estimating risks rather than odds in the analysis of IVF data. Study funding/competing interest(s) The project was funded by Grants (R01ES022955, R01ES009718, and P30ES000002) from the National Institutes of Health. None of the authors has any conflicts of interest to declare.

Background Few epidemiologic studies have evaluated the impact of paternal environmental exposures, particularly as mixtures, on couples’ pregnancy outcomes. Objective We investigated whether mixtures of paternal urinary bisphenol A (BPA), paraben, and phthalates were associated with pregnancy outcomes among couples attending a fertility center. Methods We included 210 couples undergoing 300 in vitro fertilization (IVF) between 2004 and 2017 in this prospective analysis. We quantified paternal urinary biomarker concentrations in one sample per cycle using isotope-dilution tandem mass spectrometry. We used principal component analysis (PCA) to identify correlations of biomarker concentrations and multivariable Cox proportional hazards models for discrete survival time to estimate the hazard ratios (HRs) and 95% CIs for the associations between PCA-derived factor scores and probability of failing to achieve a live birth. Interactions were also included in the models to examine strength of associations over three vulnerable periods [embryo transfer to implantation, implantation to clinical pregnancy, and clinical pregnancy to live birth]. Models were adjusted for paternal and maternal ages and body mass indexes, urinary dilution (specific gravity) and year of collection, infertility diagnosis, and other PCA factor scores. Sensitivity analyses with further adjustment for maternal PCA factor scores were performed. Results We identified three factors, representing di-2-ethylhexyl phthalate (DEHP) metabolites, BPA and non-DEHP metabolites, and parabens, accounting for 56%, 15% and 10%, respectively, of the total variance explained. An interquartile range (25th and 75th percentiles) increase in the DEHP-related factor score was associated with elevated probability of failing prior to live birth (HR = 1.41, 95% CI: 1.08, 1.81) and the association was stronger between implantation and clinical pregnancy as well as between clinical pregnancy and live birth compared to before implantation. The overall HRs of failure for the BPA/non-DEHP-related and paraben-related factor scores were HR = 1.24 (95% CI: 0.97, 1.59) and HR = 0.99 (95% CI: 0.80, 1.24). We found similar HRs when additionally adjusting for maternal PCA factor scores. Conclusion Paternal mixtures of urinary concentrations of DEHP metabolites were related to higher infertility treatment failure.

Objective To assess for the first time the potential relationships of personal exposure to magnetic fields (MF) with pregnancy outcomes among a cohort of women from a fertility clinic, addressing, through study design, some of the primary limitations of previous studies on this topic. Design Longitudinal preconception prospective cohort. Setting Fertility center. Patient(s) Our analysis included 119 women recruited from 2012 to 2018, who underwent in vitro fertilization (IVF) (n = 163 cycles) and/or intrauterine insemination (IUI) (n = 123 cycles). Intervention(s) Women wore personal exposure monitors continuously for up to three consecutive 24-hour time periods separated by several weeks. Main Outcome Measure(s) Implantation, clinical pregnancy, live birth, and pregnancy loss. Result(s) The median and maximum of the overall daily mean (daily peak) MF exposure levels were 1.10 mG (2.14 mG) and 15.54 mG (58.73 mG), respectively. MF exposure metrics were highest among women who changed environments four or more times per day. Overall, no statistically significant associations between MF exposure metrics and fertility treatment or pregnancy outcomes were observed in crude or adjusted models. Effect estimates, both positive and negative, varied by outcome and the exposure metric, including the way in which exposure was modeled. Conclusion(s) Personal MF exposures were not associated with fertility treatment outcomes or pregnancy outcomes. Despite its limited size, strengths of the study include a longitudinal repeated-measures design, the collection of personal MF exposure data across multiple days, and carefully documented outcome and covariate information among a potentially susceptible study population.

Background Exposure to endocrine disrupting chemicals (EDC), such as phthalates and phenols, during pregnancy may be associated with excessive gestational weight gain (GWG), an important predictor of future health of the mother and the offspring. There is however a paucity of literature examining this association, and no study has accounted for the complex nature of EDCs exposure as a time-varying mixture of chemicals. Objective We examined the association between trimester-specific EDCs mixture and GWG in pregnant women attending a fertility clinic, to identify windows of susceptibility to such exposures, and assess the individual contribution of each chemical over pregnancy. Methods We included 243 pregnant women from the Environment and Reproductive Health (EARTH) Study, who provided up to 3 urine samples (one per trimester), and with available data on GWG. Urinary concentrations of 7 phthalate metabolites, bisphenol A, and 2 parabens, corrected for specific gravity, were included in the analysis. The association between trimester-specific EDCs mixture and GWG was evaluated using multiple regression models – categorizing exposures into concentration quartiles– and with Bayesian Kernel Machine Regression (BKMR), while adjusting for potential confounders. Hierarchical BKMR (hBKMR) was used to account for the time-varying nature of chemical concentrations over pregnancy, identifying the most important trimester and most important EDC within each trimester. Results During 1st trimester, higher GWG was observed at higher sum of metabolites of di (2-ethylhexyl) phthalate (ΣDEHP) from both multiple regression (e.g. comparing the 4th quartile with the 1st: β = 2.36 kg, 95% CI: 0.47, 5.19) and BKMR. During 2nd and 3rd trimesters, positive associations with mono-n-butyl phthalate and propylparaben, and negative with ΣDEHP and methylparaben were observed. When evaluating exposures as a time-varying mixture with hBKMR, 1st trimester was the most important exposure window when evaluating prenatal urinary EDCs in relation to GWG. Within the 1st trimester, urinary ΣDEHP, mono-isobutyl phthalate and propylparaben had the highest contribution in the positive association between the mixture and GWG. Conclusion We observed positive associations between urinary EDCs during pregnancy, especially DEHP metabolites, and GWG. Our results suggest the 1st trimester of pregnancy as the time window of highest susceptibility to the effects of EDCs on GWG, with potential indication for the design of public health interventions, informing prevention strategies for reducing sources of exposure at specific time points.

Background Subfertile women have higher risk of glucose intolerance during pregnancy. Studies suggest associations between several endocrine disrupting chemicals (EDCs) and pregnancy glucose levels. However, the association between benzophenone-3 (BP-3), an EDC widely found in sunscreen, and pregnancy glucose levels remains unclear. We aimed to assess the association between perinatal exposures to BP-3 and pregnancy glucose levels in subfertile women. Methods We evaluated 217 women from a prospective cohort based at a fertility clinic who had urinary BP-3 concentrations measured during 3-month preconception, first and/or second trimesters, and blood glucose measured at glucose load tests (GLTs) during late pregnancy. Multivariable linear and logistic regression models were used to assess associations between time-specific BP-3 in quartiles (Q1 – Q4) and mean glucose levels, as well as odds of abnormal GLT (glucose level ≥ 140 mg/dL), adjusting for potential confounders. Effect modification was assessed by age, season, BMI, infertility diagnosis, sex of fetus (es) and physical activity. Results Women with higher first trimester BP-3 concentrations had lower mean glucose levels [mean glucose (95% CI) for Q4 vs Q1 = 103.4 (95.0, 112.5) vs. 114.6 (105.8, 124.2) mg/dL]. Women with higher second trimester BP-3 concentrations had lower odds of abnormal GLT [OR (95% CI) for Q3 vs. Q1 = 0.12 (0.01, 0.94)]. The associations between BP-3 and glucose levels were modified by several factors: women with female-factor infertility, urine collected during summer, older age, lower BMI, or carried female fetus (es) had the strongest inverse associations between BP-3 and glucose levels, while no associations were observed in the remaining subgroups. Conclusions Time-specific inverse associations between BP-3 and pregnancy glucose levels existed in subfertile women, and especially among certain subgroups of this high-risk-population.

Key Points Question Are paternal and maternal preconception urinary metabolite concentrations of phthalates and phthalate substitutes associated with singleton preterm birth? Findings In this preconception cohort study of 420 singleton infants, maternal preconception urinary concentrations of di-(2-ethylhexyl) phthalate and di(isononyl)cyclohexane-1,2-dicarboxylate (a nonphthalate plasticizer substitute) were associated with an increased risk of preterm birth. Fathers’ preconception concentrations of these biomarkers were not associated with preterm birth in offspring. Meaning Female exposure to select plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes., Importance Although phthalate exposure during pregnancy has been associated with preterm birth, the association of preconception exposure in either parent with preterm birth constitutes a knowledge gap. Objective To examine the association of paternal and maternal preconception urinary concentrations of biomarkers of phthalates and phthalate substitutes with singleton preterm birth. Design, Setting, and Participants This study, conducted at an academic fertility center in Boston, Massachusetts, included a prospective preconception cohort of subfertile couples comprising 419 mothers and 229 fathers and their 420 live-born singleton offspring born between January 1, 2005, and December 31, 2018. Statistical analysis was performed from August 1 to October 31, 2019. Exposures Urinary concentrations of metabolites of phthalates and phthalate substitutes obtained before conception. Main Outcomes and Measures Gestational age was abstracted from delivery records and validated using the American College of Obstetricians and Gynecologists guidelines for births after medically assisted reproduction. The risk ratio (RR) of preterm birth (live birth before 37 completed weeks’ gestation) was estimated in association with urinary concentrations of 11 individual phthalate metabolites, the molar sum of 4 di-(2-ethylhexyl) phthalate (ΣDEHP) metabolites, and 2 metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH, a nonphthalate plasticizer substitute) using modified Poisson regression models adjusted for covariates. Results The mean (SD) age of the 419 mothers was 34.7 (4.0) years, the mean (SD) age of the 229 fathers was 36.0 (4.5) years, and the mean (SD) gestational age of the 420 singleton children (217 boys) was 39.3 (1.7) weeks, with 34 (8%) born preterm. In adjusted models, maternal preconception ΣDEHP concentrations (RR, 1.50; 95% CI, 1.09-2.06; P = .01) and cyclohexane-1,2-dicarboxylic acid monohydroxy isononyl ester (MHiNCH, a metabolite of DINCH) concentrations (RR, 1.70; 95% CI, 0.89-3.24; P = .11) were associated with an increased risk of preterm birth. After additional adjustment for prenatal ΣDEHP or MHiNCH concentrations, the association of maternal preconception exposure to ΣDEHP and preterm birth remained robust (RR, 1.69; 95% CI, 1.17-2.44; P = .006), while the association of maternal preconception exposure to MHiNCH and preterm birth was attenuated (RR, 1.17; 95% CI, 0.49-2.81; P = .72). The remaining urinary metabolites examined in either parent showed no association with preterm birth. Conclusions and Relevance In this prospective cohort of subfertile couples, maternal preconception exposure to ΣDEHP metabolites was associated with an increased risk of preterm birth. The results suggest that female exposure to select phthalate plasticizers during the preconception period may be a potential risk factor for adverse pregnancy outcomes, which may need to be considered in preconception care strategies., This cohort study examines the association of paternal and maternal preconception urinary concentrations of biomarkers of phthalates and phthalate substitutes with singleton preterm birth.

Background: Phenol exposure during pregnancy has been associated with preterm birth, but the potential effect of preconception exposure in either parent is unknown. There is a growing body of evidence to suggest that the preconception period is a critical window of vulnerability for adverse pregnancy outcomes. Objective: We examined whether maternal and paternal preconception urinary concentrations of select phenols were associated with the risk of preterm birth among couples attending fertility care. Methods: The analysis included 417 female and 229 male participants of the Environment and Reproductive Health (EARTH) Study who gave birth to 418 singleton infants between 2005 and 2018 and for whom we had phenol biomarkers quantified in at least one urine sample collected before conception. Mothers and fathers provided an average of 4 and 3 urine samples during the preconception period, respectively. We calculated the geometric mean of bisphenol A (BPA), bisphenol S (BPS), benzophenone-3, triclosan, and the molar sum of parabens (ΣParabens) urinary concentrations to estimate each participant’s preconception exposure. Risk ratios (RRs) of preterm birth (live birth before 37 completed weeks’ gestation) were estimated using modified Poisson regression models adjusted for covariates. Results: The mean (SD) gestational age among singletons was 39.3 (1.7) weeks with 8% born preterm. A natural log-unit increase in maternal preconception BPA (RR 1.94; 95% CI: 1.20, 3.14) and BPS (RR 2.42; 95% CI: 1.01, 5.77) concentration was associated with an increased risk of preterm birth. These associations remained after further adjustment for maternal prenatal and paternal preconception biomarker concentrations. Paternal preconception ΣParabens concentrations showed a possible elevated risk of preterm birth (RR 1.36; 95% CI: 0.94, 1.96). No consistent pattern of association was observed for benzophenone-3 or triclosan biomarkers in either parent. Discussion: Maternal preconception urinary BPA and BPS concentrations, as well as paternal preconception urinary parabens concentrations were prospectively associated with a higher risk of preterm birth. Subfertile couples’ exposure to select phenols during the preconception period may be an unrecognized risk factor for adverse pregnancy outcomes. Keywords: Bisphenol, Paraben, Triclosan, Benzophenone, Preconception, Preterm birth

Supplemental Digital Content is available in the text., Background: Epidemiologic studies suggest that prenatal urinary bisphenol A (BPA) concentrations are associated with childhood behavior problems, but there is limited research on prenatal paraben concentrations. In rodent offspring, preconception maternal BPA exposure caused behavioral problems and paraben exposure impacted sperm quality. However, the effects of parental preconception and prenatal BPA and paraben exposure on children’s neurodevelopment are unknown. Methods: The Environment and Reproductive Health (EARTH) Study is a prospective cohort of couples from a fertility clinic at Massachusetts General Hospital. The Centers for Disease Control and Prevention (CDC) quantified BPA, butylparaben, ethylparaben, methylparaben, and propylparaben concentrations in multiple urine samples collected before conception and during pregnancy. From the eligible parents (N = 220), we enrolled 158 children between 2 and 9 years of age. The parents completed the Behavior-Assessment-System-for-Children-2 (BASC-2). We estimated covariate-adjusted associations of average parental preconception and prenatal ln-transformed urinary BPA and sum of paraben concentrations (∑paraben) with BASC-2 scores using linear regression with generalized estimating equations. Results: Median urinary BPA and Σparaben concentrations were 1.2 and 189 μg/L in mothers preconception and 1.7 and 25 μg/L in fathers preconception, respectively. Among all children, parental BPA and ∑paraben concentrations were not associated with BASC-2 behavioral symptoms index, internalizing, or externalizing problems scores. Point estimates ranged from −1.5 to 1.4 with wide 95% confidence intervals that included the null value. Conclusion: In this fertility clinic cohort, parental preconception and maternal prenatal BPA and paraben concentrations were not associated with problem behaviors among children. However, our small sample sizes reduced the precision of our results.

Background: Although previous epidemiological studies have explored associations of phthalate metabolites with thyroid function, no studies to date have assessed associations of mixtures with thyroid function and autoimmunity among potentially susceptible subgroups such as subfertile women. Objective: We aimed to explore associations of mixtures of urinary phthalate metabolites with serum markers of thyroid function and autoimmunity. Methods: This cross-sectional study included 558 women attending a fertility center who provided one spot urine and one blood sample at enrollment (2005–2015). We quantified urinary concentrations of eight phthalate metabolites using mass spectrometry, and biomarkers of thyroid function [thyroid-stimulating hormone (TSH), free and total thyroxine (fT4, TT4) and triiodothyronine (fT3, TT3), and autoimmunity [thyroid peroxidase and thyroglobulin antibodies (TPOAb and TgAb, respectively)] in serum using electrochemiluminescence assays. We applied principal component analysis (PCA) and Bayesian kernel machine regression (BKMR) to identify the main patterns of urinary phthalate metabolites. We used linear mixed models to assess the association between PCA-derived factor scores in quintiles and serum thyroid function and autoimmunity, adjusting for age, body mass index (BMI), specific gravity (SG), and, for the PCA, other factor scores. Results: We observed two factors using PCA, one representing the di(2-ethylhexyl) (DEHP) and another non-DEHP metabolites. Compared to women in the lowest quintile of the DEHP factor scores, women in the highest quintile had significantly lower serum concentrations of fT4, TT4, fT3, and TT3 [absolute difference: −0.62; 95% confidence interval (CI): −0.12, −0.01; p=0.04; absolute difference: −8.31; 95% CI: −13.8, −2.85; p=0.003; absolute difference: −0.37; 95% CI: 0.54, −0.19; p

Background Subfertile women are at increased risk of glucose intolerance in pregnancy. Based on epidemiologic studies, exposure to certain phthalates is associated with diabetes, elevated glucose, and increased insulin resistance. Objectives To evaluate the association between urinary phthalate metabolites and pregnancy glucose levels in women seeking medically assisted reproduction. Methods We evaluated 245 women participating in a prospective cohort study based at a large fertility clinic who delivered live births and had data on pregnancy urinary phthalate metabolite concentrations and blood glucose levels. Urinary phthalate metabolite concentrations were from single spot urine samples collected in 1st and 2nd trimesters. Blood glucose data was abstracted from medical records for non-fasting 50-g glucose challenge tests at 24–28 weeks gestation. Multivariable linear regression models were used to evaluate associations between 7 urinary phthalate metabolites in quartiles and mean glucose adjusted for potential confounders. Results Eighteen percent of women had glucose levels ≥ 140 mg/dL. Second trimester monoethyl phthalate (MEP) concentrations were positively associated with glucose levels, with adjusted mean (95%CI) glucose levels of 121 mg/dl (114, 128) vs. 109 mg/dL (103, 116) for women in highest and lowest quartiles, respectively. Women in the highest quartile of second trimester mono-isobutyl phthalate (MiBP) concentrations had a mean glucose level 14 mg/dL lower compared to women in the lowest quartile. No other urinary phthalate metabolites were associated with glucose levels. Conclusions MEP and MiBP—metabolites of diethyl phthalate and dibutyl phthalate, respectively—were associated with higher pregnancy glucose in subfertile women—a population at high risk of glucose intolerance in pregnancy. Electronic supplementary material The online version of this article (10.1186/s12940-018-0399-5) contains supplementary material, which is available to authorized users.

Background: Emerging data from animal and human studies suggest that traffic-related air pollution adversely affects early pregnancy outcomes; however evidence is limited. Objective: We examined whether residential proximity to major roadways and traffic, as proxies for traffic-related air pollution, are associated with in vitro fertilization (IVF) outcomes. Methods: This analysis included 423 women enrolled in the Environment and Reproductive Health (EARTH) Study, a prospective cohort study, who underwent 726 IVF cycles (2004–2017). Using geocoded residential addresses collected at study entry, we calculated the distance to nearest major roadway and the traffic density within a 100 m radius. IVF outcomes were abstracted from electronic medical records. We used multivariable generalized linear mixed models to evaluate the associations between residential proximity to major roadways and traffic density and IVF outcomes adjusting for maternal age, body mass index, race, education level, smoking status, and census tract median income. Results: Closer residential proximity to major roadways was statistically significantly associated with lower probability of implantation and live birth following IVF. The adjusted percentage of IVF cycles resulting in live birth for women living ≥400 m from a major roadway was 46% (95% CI 36, 56%) compared to 33% (95% CI 26, 40%) for women living

Objectives: We applied three statistical approaches for evaluating associations between prenatal urinary concentrations of a mixture of phthalate metabolites and birth weight. Methods: We included 300 women who provided 732 urine samples during pregnancy and delivered a singleton infant. We measured urinary concentrations of metabolites of di(2-ethylhexyl)-phthalate, di-isobutyl-, di-n-butyl-, butylbenzyl-, and diethyl phthalates. We applied 1) linear regressions; 2) classification methods [principal component analysis (PCA) and structural equation models (SEM)]; and 3) Bayesian kernel machine regression (BKMR), to evaluate associations between phthalate metabolite mixtures and birth weight adjusting for potential confounders. Data were presented as mean differences (95% CI) in birth weight (grams) as each phthalate increased from the 10th to the 90th percentile. Results: When analyzing individual phthalate metabolites using linear regressions, each metabolite demonstrated a modest inverse association with birth weight [from −93 (−206, 21) to −49 (−164, 65)]. When simultaneously including all metabolites in a multivariable model, inflation of the estimates and standard errors were noted. PCA identified two principal components, both inversely associated with birth weight [−23 (−68, 22), −27 (−71, 17), respectively]. These inverse associations were confirmed when applying SEM. BKMR further identified that monoethyl and mono(2-ethylhexyl) phthalate and phthalate concentrations were linearly related to lower birth weight [−51(−164, 63) and −122 (−311, 67), respectively], and suggested no evidence of interaction between metabolites. Conclusions: While none of the methods produced significant results, we demonstrated the potential issues arising using linear regression models in the context of correlated exposures. Among the other selected approaches, classification techniques identified common sources of exposures with implications for interventions, while BKMR further identified specific contributions of individual metabolites. Keywords: Chemical mixtures, Principal component analysis, Structural equation models, Bayesian Kernel Machine Regression

Background: Use of organophosphate flame retardants (PFRs) has increased over the past decade following the phase out of some brominated flame retardants, leading to increased human exposure. We recently reported that increasing maternal PFR exposure is associated with poorer pregnancy outcomes among women from a fertility clinic. Because a small epidemiologic study previously reported an inverse association between male PFR exposures and sperm motility, we sought to examine associations of paternal urinary concentrations of PFR metabolites and their partner's pregnancy outcomes. Methods: This analysis included 201 couples enrolled in the Environment and Reproductive Health (EARTH) prospective cohort study (2005–2015) who provided one or two urine samples per IVF cycle. In both the male and female partner, we measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP) and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). The sum of the molar concentrations of the urinary PFR metabolites was calculated. We used multivariable generalized linear mixed models to evaluate the association of urinary concentrations of paternal PFR metabolites with IVF outcomes, accounting for multiple in vitro fertilization (IVF) cycles per couple. Models were adjusted for year of IVF treatment cycle, primary infertility diagnosis, and maternal urinary PFR metabolites as well as paternal and maternal age, body mass index, and race/ethnicity. Results: Detection rates were high for paternal urinary concentrations of BDCIPP (84%), DPHP (87%) and ip-PPP (76%) but low for tb-PPP (12%) and zero for BCIPP (0%). We observed a significant 12% decline in the proportion of fertilized oocytes from the first to second quartile of male urinary ΣPFR and a 47% decline in the number of best quality embryos from the first to third quartile of male urinary BDCIPP in our adjusted models. An 8% decline in fertilization was observed for the highest compared to lowest quartile of urinary BDCIPP concentrations (95% CI: 0.01, 0.12, p-trend=0.06). Conclusions: Using IVF as a model to investigate human reproduction and pregnancy outcomes, we found that paternal urinary concentrations of BDCIPP were associated with reduced fertilization. In contrast to previously reported findings for the female partners, the paternal urinary PFR metabolites were not associated with the proportion of cycles resulting in successful implantation, clinical pregnancy, and live birth. These results indicate that paternal preconception exposure to TDCIPP may adversely impact successful oocyte fertilization, whereas female preconception exposure to ΣPFRs may be more relevant to adverse pregnancy outcomes. Keywords: Endocrine disruption, Epidemiology, Fertility, Flame retardants, Reproductive health

Objective To investigate the association of hair mercury (Hg) levels with antral follicle count (AFC), as a marker of ovarian reserve, and evaluate whether this relationship differed among women with high vs. low total intake of long chain omega-3 polyunsaturated fatty acids (n3PUFA) from foods and supplements. Design We included 353 women attending an academic fertility center (2007–2019) who had data on hair Hg levels, total n3PUFA intake, and AFC. Methods Hair Hg levels were assessed using a Direct Mercury Analyser, total n3PUFA intake was estimated using an extensively validated food frequency questionnaire, and AFC was assessed by transvaginal ultrasonography. Poisson regression models adjusted for potential confounders were used to evaluate the association of hair Hg levels (divided into tertiles, and as above vs below EPA reference (1 ppm)) with AFC. Associations were also evaluated after stratification by median n3PUFA intake (≤0.124% vs. >0.125% calories/week). Results Women's median hair Hg level was 0.60 ppm (range = 0.001–8.60 ppm), with more than 30% > 1 ppm (EPA reference level). Hair Hg was positively related to AFC after adjusting for age, BMI, smoking status, infertility diagnosis, and alcohol intake. However, associations became attenuated after adjustment for intake of total n3PUFA. The positive associations of hair Hg and AFC were observed only among women above the median total n3PUFA intake. Specifically, women who consumed >0.125% calories/week of total n3PUFA had mean AFCs of 11.9, 13.2 and 14.1, respectively, across increasing tertiles of hair Hg (p,trend = 0.004). Similar results were found when hair Hg was divided above vs below EPA reference (mean AFC = 12.7 vs. 14.1, p = 0.008). Conclusions In these women, positive associations of hair Hg with AFC may be reflective of beneficial effects of n3PUFA on ovarian reserve rather than a beneficial effect of Hg per se. Our findings highlight the importance of considering diet when exploring Hg effects on women's reproductive health in urban settings.

Objective To investigate the association between urinary triclosan concentrations and antral follicle count (AFC), a well-accepted marker of ovarian reserve, among women from a fertility center. Design Prospective cohort study. Setting Hospital fertility center. Patient(s) A total of 109 women. Intervention(s) Urinary triclosan concentrations quantified by online solid phase extraction-high performance liquid chromatography-isotope dilution tandem mass spectrometry. Main Outcome Measure(s) AFC through transvaginal ultrasonography on the third day of an unstimulated menstrual cycle or on the third day of a progesterone withdrawal bleed. Result(s) The geometric mean of the specific gravity–adjusted urinary triclosan concentrations for the 225 samples provided by the 109 women was 13.0 μg/L (95% confidence interval [CI], 8.9, 19.1). Women had median (with interquartile range) AFC of 13 (8, 18). The specific gravity–adjusted urinary triclosan concentrations were inversely associated with AFC (−4%; 95% CI, −7%, −1%). Women with triclosan concentrations above the median had lower AFC compared with those whose triclosan concentrations were equal to or below the median, with an adjusted difference of −3.2 (95% CI, −3.9, −1.6) among those with a body mass index 2 and −1.8 (95% CI, −3.2, −0.3) among those who were Conclusion(s) Specific gravity–adjusted urinary triclosan concentrations were inversely associated with AFC in women seeking care at a fertility center. This association was modified by age and body mass index, with the younger and leaner women showing larger decreases in AFC.