Myra Keller

Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy.

Background: Parabens are suspected endocrine disruptors and ubiquitous preservatives used in personal care products, pharmaceuticals, and foods. No studies have assessed the variability of parabens in women, including during pregnancy. Objective: We evaluated predictors and variability of urinary paraben concentrations. Methods: We measured urinary concentrations of methyl (MP), propyl (PP), and butyl paraben (BP) among couples from a fertility center. Mixed-effects regression models were fit to examine demographic predictors of paraben concentrations and to calculate intraclass correlation coefficients (ICCs). Results: Between 2005 and 2010, we collected 2,721 spot urine samples from 245 men and 408 women. The median concentrations were 112 µg/L (MP), 24.2 µg/L (PP), and 0.70 µg/L (BP). Urinary MP and PP concentrations were 4.6 and 7.8 times higher in women than men, respectively, and concentrations of both MP and PP were 3.8 times higher in African Americans than Caucasians. MP and PP concentrations we CI re slightly more variable in women (ICC = 0.42, 0.43) than men (ICC = 0.54, 0.51), and were weakly correlated between partners (r = 0.27–0.32). Among 129 pregnant women, urinary paraben concentrations were 25–45% lower during pregnancy than before pregnancy, and MP and PP concentrations were more variable (ICCs of 0.38 and 0.36 compared with 0.46 and 0.44, respectively). Conclusions: Urinary paraben concentrations were more variable in women compared with men, and during pregnancy compared with before pregnancy. However, results for this study population suggest that a single urine sample may reasonably represent an individual’s exposure over several months, and that a single sample collected during pregnancy may reasonably classify gestational exposure.

Trans–fatty acid levels in sperm are associated with sperm concentration among men from an infertility clinic

We measured the sperm fatty acid composition using gas chromatography in anonymized semen samples of 33 men undergoing infertility evaluation at an academic medical center. Trans-fatty acids were present in human sperm and were related inversely to sperm concentration (r = -0.44).

Serum 25-hydroxyvitamin D concentrations and treatment outcomes of women undergoing assisted reproduction

BACKGROUND Vitamin D deficiency impairs fertility in animal models, but the role of vitamin D in human fertility or treatment of infertility is less clear. OBJECTIVE We examined the association between circulating 25-hydroxyvitamin D [25(OH)D] concentrations and the outcome in women undergoing assisted reproduction technologies (ARTs). DESIGN We randomly selected 100 women undergoing infertility treatment with ART enrolled in an ongoing prospective cohort study who underwent 168 treatment cycles. Serum 25(OH)D concentrations were measured in samples collected from women between days 3 and 9 of gonadotropin treatment. Generalized linear mixed models were used to evaluate the association of 25(OH)D concentrations with ART outcomes while adjusting for potential confounders and accounting for repeated treatment cycles per woman. RESULTS Median (range) serum 25(OH)D concentrations were 86.5 (33.5-155.5) nmol/L. Ninety-one percent of participants consumed multivitamins. Serum 25(OH)D concentrations were positively related to fertilization rate. The adjusted fertilization rate for women in increasing quartiles of serum 25(OH)D were 0.62 (95% CI: 0.51, 0.72), 0.53 (95% CI: 0.43, 0.63), 0.67 (95% CI: 0.56, 0.76), and 0.73 (95% CI: 0.63, 0.80), respectively (P-trend = 0.03). This association persisted when analyses were restricted to women with serum 25(OH)D between 50 and 125 nmol/L when models were further adjusted for season of blood draw and when analyses were restricted to the first treatment cycle. However, 25(OH)D concentrations were unrelated to probability of pregnancy (P-trend = 0.83) or live birth after ART (P-trend = 0.47). CONCLUSION Vitamin D may be associated with higher fertilization rates, but this apparent benefit does not translate into higher probability of pregnancy or live birth. This trial was registered at www.clinicaltrials.gov as NCT00011713.

Trimester-Specific Urinary Bisphenol A Concentrations and Blood Glucose Levels Among Pregnant Women From a Fertility Clinic

Context Women with a history of infertility are at increased risk of impaired glucose tolerance during pregnancy. Studies suggest higher urinary bisphenol A (BPA) concentrations are associated with diabetes in nonpregnant populations, but the association between BPA and glucose levels among pregnant women is unclear. Objective To assess trimester-specific urinary BPA concentrations in relation to blood glucose levels among subfertile women. Design Environment and Reproductive Health Study, an ongoing prospective cohort study. Setting A fertility center in a teaching hospital. Patients A total of 245 women contributed at least one urine sample during first and/or second trimesters, delivered a singleton or twin pregnancy, and had available blood glucose data (2005 to 2015). Main Outcome Measure Blood glucose levels after a nonfasting 50-g glucose challenge test at 24 to 28 weeks of gestation. Results The specific gravity-adjusted geometric mean urinary BPA concentrations during first and second trimesters were 1.39 and 1.27 µg/L, respectively. Second-trimester BPA concentrations were positively associated with blood glucose (P, trend = 0.01). Specifically, the adjusted mean glucose levels (95% confidence interval) for women in the highest quartile of second-trimester BPA concentrations was 119 (112, 126) mg/dL compared with 106 (100, 112) mg/dL for women in the lowest quartile. No associations were observed between first-trimester BPA concentrations and glucose levels. Conclusions BPA exposure during the second trimester may have adverse effect on blood glucose levels among subfertile women. As the findings represent the first report suggesting a potential etiologically relevant window for BPA and glucose in humans, further studies are needed.

The Environment and Reproductive Health (EARTH) Study: A Prospective Preconception Cohort

Abstract STUDY QUESTION Do environmental exposures, diet and lifestyle factors impact reproductive and pregnancy outcomes among subfertile couples attending a fertility clinic? SUMMARY ANSWER Environmental chemicals exposure in men and women were associated with reduced fertility and a higher risk of adverse outcomes, whereas some dietary factors improved the probability of successful reproductive outcomes. WHAT IS KNOWN ALREADY Accumulating epidemiologic evidence has shown associations of environmental chemicals and nutritional factors with reproductive and pregnancy outcomes. However, few studies have been designed to assess these factors simultaneously, and even fewer have collected such data among both men and women in the preconception period. Furthermore, early and sensitive reproductive endpoints (e.g. fertilization, implantation, biochemical pregnancy loss) are largely unobservable in population-based designs. STUDY DESIGN SIZE, DURATION The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional and lifestyle factors in both women and men on fertility and pregnancy outcomes. The study has been ongoing since 2004 and has recruited 799 women and 487 men (447 couples; 40 men joined without female partners) as of June 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS The study recruits women aged 18–45 years and men aged 18–55 years seeking fertility evaluation and treatment at a large academic hospital fertility center. Women and men are eligible to join either independently or as a couple. Participants are followed from study entry throughout each fertility treatment cycle, once per trimester of pregnancy (for those achieving pregnancy), and up to labor and delivery, or until they discontinue treatment or withdraw from the study. The study prospectively collects a combination of biological samples (e.g. blood, urine, semen), self-reported questionnaire data (including a validated food frequency questionnaire) and medical information abstracted from fertility clinic and hospital records. MAIN RESULTS AND THE ROLE OF CHANCE Among women in this cohort, higher urinary concentrations of some phthalate metabolites were associated with reduced oocyte yields, lower likelihood of clinical pregnancy, increased risk of pregnancy loss and lower likelihood of live birth following infertility treatment. Certain urinary phthalate metabolite concentrations among men was also associated with decreased odds of implantation and live birth. Maternal soy and folate intake significantly modified the association between bisphenol A (BPA) and IVF outcomes in women. While the EARTH Study has tested many a priori hypotheses, multiple comparisons were undertaken, and we cannot rule out the possibility that some of findings may be spurious or due to chance. LIMITATIONS REASONS FOR CAUTION While the fertility clinic setting provides the opportunity to measure environmental exposures, diet and lifestyle factors across different windows of vulnerability and to evaluate their potential effect on critical early fertility, pregnancy and delivery outcomes, the findings may be less generalizable to naturally conceived pregnancies. WIDER IMPLICATIONS OF THE FINDINGS The EARTH Study is one of the few cohorts designed to examine multiple windows of vulnerability, including the paternal and maternal preconception windows and the periconception and prenatal windows, in pregnancy. It is also one of the few human studies that has assessed potential interactions between environmental exposures and dietary factors. STUDY FUNDING/COMPETING INTEREST(S) The EARTH Study has been funded by the National Institute of Environmental Health Sciences since its inception in 2004. The authors declare no competing interests. TRIAL REGISTRATION NUMBER n/a.

Maternal physical and sedentary activities in relation to reproductive outcomes following IVF

Physical activity could benefit reproductive function through its ability to regulate energy balance and improve insulin sensitivity, but its association with IVF outcomes remains unclear. The aim of this study was to evaluate whether pre-treatment physical and sedentary activity is associated with outcomes of IVF. The Environment and Reproductive Health Study is an ongoing prospective cohort study that enrols subfertile couples at Massachusetts General Hospital Fertility Center. Time spent in physical and sedentary activities in the year before IVF treatment is self-reported using a validated questionnaire. This analysis included 273 women who underwent 427 IVF cycles. Women engaged in a median of 2.8 h per week of moderate-to-vigorous activities. Time spent in moderate-to-vigorous physical activities and total metabolic equivalent task hours before IVF were not associated with probability of implantation, clinical pregnancy or live birth. Of the specific physical activities, only greater time spent in aerobics, rowing, and on the ski or stair machine was associated with higher probability of live birth. Time spent in total and specific sedentary activities were not associated with clinical outcomes of IVF. Physical activity is unlikely to have a deleterious effect on IVF success and certain forms of vigorous activity may be beneficial.

Ultrasound gel as an unrecognized source of exposure to phthalates and phenols among pregnant women undergoing routine scan

BACKGROUND Systemic absorption of phthalates and parabens has been demonstrated after dermal application of body lotion, and medical devices such as intravenous bags and tubing have been identified as a source of exposure to di(2-ethylhexyl) phthalate (DEHP). However, use of products during medical procedures such as aqueous gel applied during obstetrical ultrasound in pregnancy has not been investigated as a potential source of endocrine disrupting chemical (EDC) exposure. Human studies have associated EDCs with various adverse pregnancy outcomes. There is a need to identify sources of inadvertent exposure to EDCs especially during vulnerable developmental periods such as pregnancy. OBJECTIVES We conducted a pilot study to determine whether use of gel during routine obstetrical ultrasound increased urinary concentrations of phthalate and phenol biomarkers. METHODS We recruited 13 women from the Massachusetts General Hospital who provided spot urine samples at the time of their second trimester anatomic survey. The first sample was collected prior to the procedure (pre-exposure, time 1), and two additional samples were obtained at approximately 1-2h (time 2) and 7-12h (time 3) post-exposure following the scan. RESULTS Urinary concentrations of several DEHP metabolites and metabolite of diisononyl cyclohexane-1,2-dicarboxylate (DINCH) increased across time. For example, the geometric mean concentrations of mono(2-ethyl-5-hydroxyhexyl) phthalate increased from 3.1ng/ml to 7.1ng/ml (p-value=0.03) between time 1 and time 3. We also observed significant differences in concentrations of metabolites of butylbenzyl phthalate (BBzP), di-n-butyl phthalate (DnBP), and di-isobutyl phthalate (DiBP). For example, mono-n-butyl phthalate (metabolite of DnBP) decreased from 3.5ng/ml to 1.8ng/ml (p-value=0.04) between time 1 and time 2, but then increased to 6.6ng/ml (p-value=0.002) at time 3. Propylparaben concentrations increased from 8.9ng/ml to 33.6ng/ml between time 1 and time 2 (p-value=0.005), followed by a decrease to 12.9ng/ml at time 3 (p-value=0.01). However, we cannot rule out the possibility that some of the observed differences are due to other sources of exposure to these compounds. CONCLUSIONS While additional research is needed, this pilot study potentially identifies a previously unknown source of phthalate and paraben exposure among pregnant women undergoing routine ultrasound examination.

Urinary concentrations of parabens mixture and pregnancy glucose levels among women from a fertility clinic

Background: A number of endocrine disrupting chemicals (EDC) have been associated with gestational diabetes (GDM) risk factors. However, no human study has investigated the association between pregnancy exposure to parabens, a class of EDCs, and pregnancy glucose levels, a risk factor for GDM. Furthermore, little is known about this association in subfertile women—a group at high risk of GDM. Methods: A total of 241 women from the Environment and Reproductive Health Study had data available on 1st and/or 2nd trimester urinary methylparaben, propylparaben, and butylparaben concentrations, and blood glucose levels after the glucose loading test (GLT), a non‐fasting 50 g glucose loading test taken at late 2nd trimester. Trimester‐specific associations between specific gravity adjusted methylparaben, butylparaben, and propylparaben with adjusted mean of pregnancy glucose levels were evaluated in linear regression models, using quartiles of each parabens distribution, and as a paraben mixture, using mutual adjustment and Bayesian kernel machine regression (BKMR), a recently proposed method for investigating chemical mixtures that flexibly models the joint effect of chemicals. Results: Investigating parabens one at the time did not provide any significant results. When investigating parabens as a chemical mixture with both multiple regression and BKMR, we observed positive associations of butylparaben (e.g comparing the 4th and 1st quartiles) with glucose levels, for both the 1st trimester (adjusted difference=12.5 mg/dL; 95% CI: 0.9, 24.2) and 2nd trimester (adjusted difference=11.2 mg/dL; 95% CI: 0.2, 22.3), and a negative association between 1st trimester propylparaben and glucose (adjusted difference=−22.3 mg/dL; 95% CI: −43.2, −1.4). Conclusions: We found 1st trimester butylparaben and propylparaben urinary concentrations to be associated with glucose levels in a pregnancy cohort of women at high risk of GDM, even after adjusting for potential confounders. Because exposure to parabens is widespread, these findings may suggest further investigating the effects of this chemical class on pregnancy health.