J.C. Petrozza

Temporal Variability and Predictors of Urinary Bisphenol A Concentrations in Men and Women

Background Bisphenol A (BPA) is used to manufacture polymeric materials, such as polycarbonate plastics, and is found in a variety of consumer products. Recent data show widespread BPA exposure among the U.S. population. Objective Our goal in the present study was to determine the temporal variability and predictors of BPA exposure. Methods We measured urinary concentrations of BPA among male and female patients from the Massachusetts General Hospital Fertility Center. Results Between 2004 and 2006, 217 urine samples were collected from 82 subjects: 45 women (145 samples) and 37 men (72 samples). Of these, 24 women and men were partners and contributed 42 pairs of samples collected on the same day. Ten women became pregnant during the follow-up period. Among the 217 urine samples, the median BPA concentration was 1.20 μg/L, ranging from below the limit of detection (0.4 μg/L) to 42.6 μg/L. Age, body mass index, and sex were not significant predictors of urinary BPA concentrations. BPA urinary concentrations among pregnant women were 26% higher (–26%, +115%) than those among the same women when not pregnant (p > 0.05). The urinary BPA concentrations of the female and male partner on the same day were correlated (r = 0.36; p = 0.02). The sensitivity of classifying a subject in the highest tertile using a single urine sample was 0.64. Conclusion We found a nonsignificant increase in urinary BPA concentrations in women while pregnant compared with nonpregnant samples from the same women. Samples collected from partners on the same day were correlated, suggesting shared sources of exposure. Finally, a single urine sample showed moderate sensitivity for predicting a subject’s tertile categorization.

Urinary bisphenol A concentrations and ovarian response among women undergoing IVF

Bisphenol A (BPA) is a synthetic chemical used in the manufacture of materials present in many common consumer products. In experimental animals, BPA caused oocyte aneuploidy and reduced production of oestradiol. In a prospective cohort study, we investigated the association between urinary BPA concentrations and ovarian response among women undergoing in vitro fertilization (IVF) at the Massachusetts General Hospital (MGH) Fertility Center. The geometric mean of two specific-gravity (SG) adjusted urinary BPA concentrations collected during each IVF cycle was used as the cycle-specific BPA exposure level. BPA concentrations were measured using online solid phase extraction coupled to isotope dilution-high-performance liquid chromatography-tandem mass spectrometry. Peak serum oestradiol was measured using the Elecsys Estradiol II immunoassay kit. Multivariable mixed effect models and Poisson regression models adjusting for correlation between multiple IVF cycles in the same woman were used to evaluate the association between urinary BPA concentrations and ovarian response, adjusting for age, BMI and day 3 follicle stimulating hormone (FSH) levels, a clinical measure of ovarian reserve. Urinary BPA concentrations were measured in 84 women (mean age 35.6 years) undergoing 112 IVF cycles; 23 women (27%) contributed more than one IVF cycle. BPA concentrations ranged from <0.4 to 25.5 microg/L (geometric mean 2.52 +/- SD 3.2); 15% of urine samples had concentrations <0.4 microg/L. Peak serum oestradiol levels correlated with the total number of oocytes retrieved per cycle (r = 0.65, p < 0.001). For each log unit increase in SG-BPA, there was an average decrease of 12% (95% CI: 4, 23%; p = 0.007) in the number of oocytes retrieved and an average decrease of 213 pg/ml (95% CI: -407, -20; p = 0.03) in peak oestradiol. BPA was detected in the urine of the majority of women undergoing IVF, and was inversely associated with number of oocytes retrieved and peak oestradiol levels.

Urinary bisphenol A concentrations and early reproductive health outcomes among women undergoing IVF

STUDY QUESTION In women undergoing IVF, are urinary bisphenol A (BPA) concentrations associated with ovarian response and early reproductive outcomes, including oocyte maturation and fertilization, Day 3 embryo quality and blastocyst formation? SUMMARY ANSWER Higher urinary BPA concentrations were found to be associated with decreased ovarian response, number of fertilized oocytes and decreased blastocyst formation. WHAT IS KNOWN ALREADY Experimental animal and in vitro studies have reported associations between BPA exposure and adverse reproductive outcomes. We previously reported an association between urinary BPA and decreased ovarian response [peak serum estradiol (E(2)) and oocyte count at the time of retrieval] in women undergoing IVF; however, there are limited human data on reproductive health outcomes, such as fertilization and embryo development. STUDY DESIGN, SIZE AND DURATION Prospective preconception cohort study. One hundred and seventy-four women aged 18-45 years and undergoing 237 IVF cycles were recruited at the Massachusetts General Hospital Fertility Center, Boston, MA, USA, between November 2004 and August 2010. These women were followed until they either had a live birth or discontinued treatment. Cryothaw and donor egg cycles were not included in the analysis. PARTICIPANTS/MATERIALS, SETTING AND METHODS Urinary BPA concentrations were measured by online solid-phase extraction-high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Mixed effect models, poisson regression and multivariate logistic regression models were used wherever appropriate to evaluate the association between cycle-specific urinary BPA concentrations and measures of ovarian response, oocyte maturation (metaphase II), fertilization, embryo quality and cleavage rate. We accounted for correlation among multiple IVF cycles in the same woman using generalized estimating equations. MAIN RESULTS AND THE ROLE OF CHANCE The geometric mean (SD) for urinary BPA concentrations was 1.50 (2.22) µg/l. After adjustment for age and other potential confounders (Day 3 serum FSH, smoking, BMI), there was a significant linear dose-response association between increased urinary BPA concentrations and decreased number of oocytes (overall and mature), decreased number of normally fertilized oocytes and decreased E(2) levels (mean decreases of 40, 253 and 471 pg/ml for urinary BPA quartiles 2, 3 and 4, when compared with the lowest quartile, respectively; P-value for trend = 0.001). The mean number of oocytes and normally fertilized oocytes decreased by 24 and 27%, respectively, for the highest versus the lowest quartile of urinary BPA (trend test P < 0.001 and 0.002, respectively). Women with urinary BPA above the lowest quartile had decreased blastocyst formation (trend test P-value = 0.08). LIMITATIONS AND REASONS FOR CAUTION Potential limitations include exposure misclassification due to the very short half-life of BPA and its high variability over time; uncertainty about the generalizability of the results to the general population of women conceiving naturally and limited sample. WIDER IMPLICATIONS OF THE FINDINGS The results from this extended study, using IVF as a model to study early reproductive health outcomes in humans, indicate a negative dose-response association between urinary BPA concentrations and serum peak E(2) and oocyte yield, confirming our previous findings. In addition, we found significantly decreased metaphase II oocyte count and number of normally fertilizing oocytes and a suggestive association between BPA urinary concentrations and decreased blastocyst formation, thus indicating that BPA may alter reproductive function in susceptible women undergoing IVF. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants ES009718 and ES000002 from the National Institute of Environmental Health Sciences and grant OH008578 from the National Institute for Occupational Safety and Health. None of the authors has actual or potential competing financial interests. DISCLAIMER The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Urinary Bisphenol A Concentrations and Implantation Failure among Women Undergoing in Vitro Fertilization

Background: Bisphenol A (BPA) is a synthetic chemical widely used in the production of polycarbonate plastic and epoxy resins found in numerous consumer products. In experimental animals, BPA increases embryo implantation failure and reduces litter size. Objective: We evaluated the association of urinary BPA concentrations with implantation failure among women undergoing in vitro fertilization (IVF). Methods: We used online solid phase extraction–high performance liquid chromatography–isotope dilution tandem mass spectrometry to measure urinary BPA concentrations in 137 women in a prospective cohort study among women undergoing IVF at the Massachusetts General Hospital Fertility Center in Boston, Massachusetts. We used logistic regression to evaluate the association of cycle-specific urinary BPA concentrations with implantation failure, accounting for correlation among multiple IVF cycles in the same woman using generalized estimating equations. Implantation failure was defined as a negative serum β-human chorionic gonadotropin test (β-hCG < 6 IU/L) 17 days after egg retrieval. Results: Among 137 women undergoing 180 IVF cycles, urinary BPA concentrations had a geometric mean (SD) of 1.53 (2.22) µg/L. Overall, 42% (n = 75) of the IVF cycles resulted in implantation failure. In adjusted models, there was an increased odds of implantation failure with higher quartiles of urinary BPA concentrations {odds ratio (OR) 1.02 [95% confidence interval (CI): 0.35, 2.95}, 1.60 (95% CI: 0.70, 3.78), and 2.11 (95% CI: 0.84, 5.31) for quartiles 2, 3, and 4, respectively, compared with the lowest quartile (p-trend = 0.06). Conclusion: There was a positive linear dose–response association between BPA urinary concentrations and implantation failure.

Congenital absence of the uterus and vagina is not commonly transmitted as a dominant genetic trait: Outcomes of surrogate pregnancies

OBJECTIVE To determine the inheritance pattern of congenital absence of the uterus and vagina in affected women undergoing surrogacy IVF with this disorder. DESIGN Retrospective study. SETTING A hospital-based reproductive endocrinology and infertility center. PATIENT(S) Women diagnosed with congenital absence of the uterus and vagina undergoing IVF with subsequent transfer of embryos to a surrogate uterus. INTERVENTION(S) Questionnaires were sent to all infertility treatment centers performing surrogate procedures. MAIN OUTCOME MEASURE(S) Number, gender, and frequency of congenital anomalies in progeny. RESULT(S) Thirty-two of 53 surveyed programs responded (60%). One hundred sixty-two IVF cycles were performed, and 34 liveborn children were delivered (half female). No congenital anomalies were found, except for one male child with a middle ear defect and hearing loss. CONCLUSION(S) These results strongly suggest that congenital absence of the uterus and vagina, if genetically transmitted, is not inherited commonly in a dominant fashion.

Body mass index and short-term weight change in relation to treatment outcomes in women undergoing assisted reproduction

OBJECTIVE To assess the relation between body mass index (BMI) and short-term weight change with assisted reproductive technology (ART) outcomes. DESIGN Prospective cohort study. SETTING Fertility center. PATIENT(S) A total of 170 women undergoing 233 ART cycles. INTERVENTION(S) Baseline BMI and short-term weight change were related to ART outcomes. Regression models accounting for repeated observations were used to adjust data for potential confounders. MAIN OUTCOME MEASURE(S) Peak E2 levels, oocyte yield, MII yield, fertilization rate, embryo quality, postive [beta]-hCH, clinical pregnancy and live birth rates. RESULT(S) Overweight and obesity were associated with lower live birth rates. The adjusted live birth rate (95% confidence interval) was 42% (28%-58%) among women with a BMI between 20 and 22.4 kg/m(2) and 23% (14%-36%) among overweight or obese women. Short-term weight loss was associated with a higher proportion of metaphase II (MII) oocytes retrieved. The adjusted proportion of MII eggs was 91% (87%-94%) for women who lost 3 kg or more and 86% (81%-89%) for women whose weight remained stable. This association was stronger among women who were overweight or obese at baseline. Short-term weight loss was unrelated to positive β-hCG, clinical pregnancy, or live birth rates. CONCLUSION(S) Overweight and obesity were related to lower live birth rates in women undergoing ART. Short-term weight loss was related to higher MII yield, particularly among overweight and obese women, but unrelated to clinical outcomes.

Women, weight, and fertility: the effect of body mass index on the outcome of superovulation/intrauterine insemination cycles.

OBJECTIVE To determine the fecundity of overweight and obese infertile women treated with gonadotropins and undergoing intrauterine insemination (IUI). DESIGN Retrospective study. SETTING Academic infertility clinic. PATIENT(S) Four hundred seventy-seven women undergoing 1,189 ovulation induction (OI)/IUI cycles stratified by body mass index (BMI). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) BMI groups were compared regarding the following: gonadotropin dose, duration of treatment, peak E(2), number of follicles (total, large, and medium size), E(2)/follicle, endometrial thickness, spontaneous abortion, and clinical and multiple pregnancy rates. RESULT(S) There was a significant trend toward higher medication requirements and lower E(2) levels with increasing BMI. BMI was inversely associated with [1] the E(2) level per produced preovulatory follicle and [2] the number of medium-size follicles. Furthermore, BMI was inversely associated with the number of medium, large, and total follicles divided by total FSH dose, suggesting that women with a higher BMI develop a lower number of medium and/or large follicles at a given total FSH dose. BMI was positively associated with endometrial thickness, and endometrial thickness was positively associated with pregnancy. Mean number of cycles required to conceive, clinical pregnancy, and spontaneous abortion rates did not differ significantly among the different BMI categories. CONCLUSION(S) Obese women require higher doses of medication and produce fewer follicles for a given dose, but once medication and response are adjusted to overcome the weight effect, the success of the treatment cycle is comparable to that of normal weight women.

Transcatheter Endovascular Techniques for Management of Obstetrical and Gynecologic Emergencies

Since the initial description of selective uterine artery embolization for the treatment of postpartum hemorrhage in 1979, transcatheter embolization and other endovascular techniques have become the second-line therapeutic option for the management of intractable obstetrical and gynecologic bleeding. Advances in catheter-based techniques, as well as recognition of the effectiveness of minimally invasive treatment options, have expanded the role of interventional radiology in the management of hemorrhage for a variety of indications, such as postpartum hemorrhage, menorrhagia, and postmenopausal bleeding. Transcatheter interventions include the following: (1) prophylactic selective catheterization of the internal iliac arteries, with either temporary balloon occlusion or embolotherapy; (2) selective embolization of collateral pelvic vessels in the setting of surgical ligation of the internal iliac arteries and/or delivery-related injuries to the genital tract; (3) transarterial embolization for the management of abnormal placentation; and (4) massive bleeding secondary to uterine leiomyomas (fibroids) and/or arteriovenous malformations. Transcatheter embolization is a fast, safe, and effective minimally invasive alternative to hysterectomy, when medical treatment fails to control uterine bleeding. Moreover, it preserves the uterus with little or no significant impact on future pregnancies and fertility. This article reviews the transcatheter endovascular techniques that are used in a variety of clinical scenarios for the management of obstetrical and gynecologic emergencies.

Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic

STUDY QUESTION Is consumption of fruits and vegetables with high levels of pesticide residues associated with lower semen quality? SUMMARY ANSWER Consumption of fruits and vegetables with high levels of pesticide residues was associated with a lower total sperm count and a lower percentage of morphologically normal sperm among men presenting to a fertility clinic. WHAT IS KNOWN ALREADY Occupational and environmental exposure to pesticides is associated with lower semen quality. Whether the same is true for exposure through diet is unknown. STUDY DESIGN, SIZE, DURATION Men enrolled in the Environment and Reproductive Health (EARTH) Study, an ongoing prospective cohort at an academic medical fertility center. Male partners (n = 155) in subfertile couples provided 338 semen samples during 2007-2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Semen samples were collected over an 18-month period following diet assessment. Sperm concentration and motility were evaluated by computer-aided semen analysis (CASA). Fruits and vegetables were categorized as containing high or low-to-moderate pesticide residues based on data from the annual United States Department of Agriculture Pesticide Data Program. Linear mixed models were used to analyze the association of fruit and vegetable intake with sperm parameters accounting for within-person correlations across repeat samples while adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE Total fruit and vegetable intake was unrelated to semen quality parameters. High pesticide residue fruit and vegetable intake, however, was associated with poorer semen quality. On average, men in highest quartile of high pesticide residue fruit and vegetable intake (≥1.5 servings/day) had 49% (95% confidence interval (CI): 31%, 63%) lower total sperm count and 32% (95% CI: 7%, 58%) lower percentage of morphologically normal sperm than men in the lowest quartile of intake (<0.5 servings/day) (P, trend = 0.003 and 0.02, respectively). Low-to-moderate pesticide residue fruit and vegetable intake was associated with a higher percentage of morphologically normal sperm (P, trend = 0.04). LIMITATIONS, REASONS FOR CAUTION Surveillance data, rather than individual pesticide assessment, was used to assess the pesticide residue status of fruits and vegetables. CASA is a useful method for clinical evaluation but may be considered less favorable for accurate semen analysis in the research setting. Owing to the observational nature of the study, confirmation is required by interventional studies as well. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the first report on the consumption of fruits and vegetables with high levels of pesticide residue in relation to semen quality. Further confirmation of these findings is warranted. STUDY FUNDING/COMPETING INTERESTS Supported by National Institutes of Health grants ES009718, ES022955, ES000002, P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16. None of the authors has any conflicts of interest to declare.

Increased frequency of occult fragile X-associated primary ovarian insufficiency in infertile women with evidence of impaired ovarian function

BACKGROUND The FMR1 premutation is associated with overt primary ovarian insufficiency (POI). However, its prevalence in women with occult POI (i.e. menstrual cycles, but impaired ovarian response) has not been examined. We hypothesized that both the FMR1 premutation and intermediate allele is more frequent in infertile women with occult POI than in controls, and that a repeat length cutoff might predict occult POI. METHODS All subjects were menstruating women <42 years old and with no family history of unexplained mental retardation, autism or fragile X syndrome. Cases had occult POI defined by elevated FSH or poor response to gonadotrophin therapy (n = 535). Control subjects (n = 521) had infertility from other causes or were oocyte donors. Prevalence of the FMR1 premutation and intermediate alleles was examined and allele length was compared between controls and women with occult POI. RESULTS The frequency of the premutation (7/535 versus 1/521; P< 0.05) and intermediate alleles (17/535 versus 7/521; P< 0.05) was higher in women with occult POI than in controls. The allele with the greatest number of CGG repeats was longer in women with occult POI compared with controls (32.7 ± 7.1 versus 31.6 ± 4.3; P < 0.01). A receiver operating characteristic curve examining repeat length as a test for occult POI had an area of 0.56 ± 0.02 (P < 0.01). A repeat cutoff of 45 had a specificity of 98%, but a sensitivity of only 5% to identify occult POI. The positive predictive value was only 21% for a fertility population that has ∼ 22% of its patients with occult POI. CONCLUSIONS The data suggest that FMR1 premutations and intermediate alleles are increased in women with occult POI. Thus, FMR1 testing should be performed in these women as some will have fragileX-associated POI. Although the FMR1 repeat lengths were longer in women with occult POI, the data do not support the use of a repeat length cutoff to predict occult POI.