Reproductive Outcomes of Patients Undergoing Uterine Artery Embolization for Uterine Fibroids: Proceedings from The Dr. James B. Spies Summit for Uterine Fibroid Research-A Society of Interventional Radiology Foundation Research Consensus Panel.

Reproductive outcomes after uterine artery embolization (UAE) for the treatment of uterine fibroids are challenging to study, leaving several unanswered questions surrounding the future fertility of patients undergoing the procedure. Subject matter experts from interventional radiology, diagnostic radiology, obstetrics and gynecology, and reproductive medicine participated in a Society of Interventional Radiology (SIR) Foundation Research Consensus Panel to discuss and prioritize critical research topics focusing on fertility and reproductive outcomes in patients undergoing UAE for symptomatic uterine fibroids. After presentations and discussion of research ideas, the panelists prioritized the following topics for further investigation: (a) a prospective study of factors that influence implantation and gene expression in patients undergoing UAE or myomectomy over 1 year; (b) refinement of a classification system for uterine fibroids that can allow for more focused study design, which may include burden of fibroid disease; and (c) conjoint analysis/discrete choice experiments to better characterize those patients for whom fertility preservation is a high priority.

Predictors of Serum Per- and Polyfluoroalkyl Substances Concentrations among U.S. Couples Attending a Fertility Clinic.

Previous studies have examined the predictors of PFAS concentrations among pregnant women and children. However, no study has explored the predictors of preconception PFAS concentrations among couples in the United States. This study included 572 females and 279 males (249 couples) who attended a U.S. fertility clinic between 2005 and 2019. Questionnaire information on demographics, reproductive history, and lifestyles and serum samples quantified for PFAS concentrations were collected at study enrollment. We examined the PFAS distribution and correlation within couples. We used Ridge regressions to predict the serum concentration of each PFAS in females and males using data of (1) socio-demographic and reproductive history, (2) diet, (3) behavioral factors, and (4) all factors included in (1) to (3) after accounting for temporal exposure trends. We used general linear models for univariate association of each factor with the PFAS concentration. We found moderate to high correlations for PFAS concentrations within couples. Among all examined factors, diet explained more of the variation in PFAS concentrations (1-48%), while behavioral factors explained the least (0-4%). Individuals reporting White race, with a higher body mass index, and nulliparous women had higher PFAS concentrations than others. Fish and shellfish consumption was positively associated with PFAS concentrations among both females and males, while intake of beans (females), peas (male), kale (females), and tortilla (both) was inversely associated with PFAS concentrations. Our findings provide important data for identifying sources of couples' PFAS exposure and informing interventions to reduce PFAS exposure in the preconception period.

Maternal and Paternal Preconception Serum Concentrations of Per and Polyfluoroalkyl Substances in Relation to Birth Outcomes.

Prenatal per and polyfluoroalkyl substances (PFAS) exposure is associated with adverse birth outcomes. There is an absence of evidence on the relationship between maternal and paternal preconception PFAS exposure and birth outcomes. This study included 312 mothers and 145 fathers with a singleton live birth from a preconception cohort of subfertile couples seeking fertility treatment at a U.S. clinic. PFAS were quantified in serum samples collected before conception. Gestational age (GA) and birthweight (BW) were abstracted from delivery records. We also assessed low birthweight (BW < 2500 g) and preterm birth (GA < 37 completed weeks). We utilized multivariable linear regression, logistic regression, and quantile-based g computation to examine maternal or paternal serum concentrations of individual PFAS and mixture with birth outcomes. Maternal serum concentrations of perfluorooctanesulfonate (PFOS), perfluorohexanesulfonate (PFHxS), and the total PFAS mixture were inversely associated with birthweight. Maternal PFOS concentration was associated with a higher risk of low birthweight. Conversely, paternal PFOS and PFHxS concentrations were imprecisely associated with higher birthweight. No associations were found for gestational age or preterm birth. The findings have important implications for preconception care. Future research with larger sample sizes would assist in validating these findings.

Long-term health-related quality of life and symptom severity following hysterectomy, myomectomy, or uterine artery embolization for the treatment of symptomatic uterine fibroids.

BACKGROUND: Few studies have directly compared different surgical procedures for uterine fibroids with respect to long-term health-related quality of life outcomes and symptom improvement. OBJECTIVE: We examined differences in change from baseline to 1-, 2-, and 3-year follow-up in health-related quality of life and symptom severity among patients who underwent abdominal myomectomy, laparoscopic or robotic myomectomy, abdominal hysterectomy, laparoscopic or robotic hysterectomy, or uterine artery embolization. STUDY DESIGN: The COMPARE-UF registry is a multiinstitutional prospective observational cohort study of women undergoing treatment for uterine fibroids. A subset of 1384 women aged 31 to 45 years who underwent either abdominal myomectomy (n=237), laparoscopic myomectomy (n=272), abdominal hysterectomy (n=177), laparoscopic hysterectomy (n=522), or uterine artery embolization (n=176) were included in this analysis. We obtained demographics, fibroid history, and symptoms by questionnaires at enrollment and at 1, 2, and 3 years posttreatment. We used the UFS-QoL (Uterine Fibroid Symptom and Quality of Life) questionnaire to ascertain symptom severity and health-related quality of life scores among participants. To account for potential baseline differences across treatment groups, a propensity score model was used to derive overlap weights and compare total health-related quality of life and symptom severity scores after enrollment with a repeated measures model. For this health-related quality of life tool, a specific minimal clinically important difference has not been determined, but on the basis of previous research, a difference of 10 points was considered as a reasonable estimate. Use of this difference was agreed upon by the Steering Committee at the time when the analysis was planned. RESULTS: At baseline, women undergoing hysterectomy and uterine artery embolization reported the lowest health-related quality of life scores and highest symptom severity scores compared with those undergoing abdominal myomectomy or laparoscopic myomectomy (P<.001). Those undergoing hysterectomy and uterine artery embolization reported the longest duration of fibroid symptoms with a mean of 6.3 years (standard deviation, 6.7; P<.001). The most common fibroid symptoms were menorrhagia (75.3%), bulk symptoms (74.2%), and bloating (73.2%). More than half (54.9%) of participants reported anemia, and 9.4% women reported a history of blood transfusion. Across all modalities, total health-related quality of life and symptom severity score markedly improved from baseline to 1-year with the largest improvement in the laparoscopic hysterectomy group (Uterine Fibroids Symptom and Quality of Life: delta= [+] 49.2; symptom severity: delta= [-] 51.3). Those undergoing abdominal myomectomy, laparoscopic myomectomy, and uterine artery embolization also demonstrated significant improvement in health-related quality of life (delta= [+]43.9, [+]32.9, [+]40.7, respectively) and symptom severity (delta= [-]41.4, [-] 31.5, [-] 38.5, respectively) at 1 year, and the improvement persisted from baseline for uterine-sparing procedures during second (Uterine Fibroids Symptom and Quality of Life: delta= [+]40.7, [+]37.4, [+]39.3 SS: delta= [-] 38.5, [-] 32.0, [-] 37.7 and third year (Uterine Fibroids Symptom and Quality of Life: delta= [+] 40.9, [+]39.9, [+]41.1 and SS: delta= [-] 33.9, [-]36.5, [-] 33.0, respectively), posttreatment intervals, however with a trend toward decline in degree of improvement from years 1 and 2. Differences from baseline were greatest for hysterectomy; however, this may reflect the relative importance of bleeding in the Uterine Fibroids Symptom and Quality of Life, rather than clinically meaningful symptom recurrence among women undergoing uterus-sparing treatments. CONCLUSION: All treatment modalities were associated with significant improvements in health-related quality of life and symptom severity reduction 1-year posttreatment. However, abdominal myomectomy, laparoscopic myomectomy and uterine artery embolization indicated a gradual decline in symptom improvement and health-related quality of life by third year after the procedure.

Endometriosis Classification Systems: An International Survey to Map Current Knowledge and Uptake.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed, but do clinicians routinely use these classification systems, which system do they use and what are the clinicians' motivations? DATA SOURCES: A cross-sectional study was performed to gather data on the current use of endometriosis classification systems, problems encountered and interest in a new simple surgical descriptive system for endometriosis. Of particular focus were three systems most commonly used: the Revised American Society for Reproductive Medicine (rASRM) classification, the Endometriosis Fertility Index (EFI), and the ENZIAN classification. Data were analysed by SPSS. A survey was designed using the online SurveyMonkey tool consisting of 11 questions concerning three domains-participants background, existing classification systems and intentions with regards to a new classification system for endometriosis. Replies were collected between 15 May and 1 July 2020. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: The final dataset included the replies of 1178 clinicians, including surgeons, gynecologists, reproductive endocrinologists, fertility specialists and sonographers, all managing women with endometriosis in their clinical practice. Overall, 75.5% of the professionals indicate that they currently use a classification system for endometriosis. The rASRM classification system was the best known and used system, the EFI system and ENZIAN system were known by a majority of the professionals but used by only a minority. The lack of clinical relevance was most often selected as a problem with using any system. The findings of the survey suggest that clinicians worldwide are open to using a new classification system for endometriosis that can achieve standardized reporting, and is clinically relevant and simple. The findings therefore support future initiatives for the development of a new descriptive system for endometriosis and provide information on user expectations and conditions for universal uptake of such a system. CONCLUSION: Even with a high uptake of the existing endometriosis classification systems (rASRM, ENZIAN and EFI), most clinicians managing endometriosis would like a new simple surgical descriptive system for endometriosis.

Identifying windows of susceptibility to endocrine disrupting chemicals in relation to gestational weight gain among pregnant women attending a fertility clinic.

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: ß = 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.

An International Terminology for Endometriosis, 2021.

OBJECTIVE: Different classification systems have been developed for endometriosis, using different definitions for the disease, the different subtypes, symptoms and treatments. In addition, an International Glossary on Infertility and Fertility Care has been published in 2017 by the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) in collaboration with other organisations. An international working group convened over the development of a classification or descriptive system for endometriosis. As a basis for such system, a terminology for endometriosis was considered a condition sine qua non. The aim of the current study was to develop a set of terms and definitions be prepared on endometriosis that would be the basis for standardization in disease description, classification and research. DATA SOURCES: The working group listed a number of terms relevant to be included in the terminology, documented currently used and published definitions, and discussed and adapted them until consensus was reached within the working group. Following stakeholder review, further terms were added, and definitions further clarified. Although definitions were collected through published literature, the final set of terms and definitions is to be considered consensus-based. After finalization of the first draft, the members of the international societies and other stakeholders were consulted for feedback and comments, which lead to further adaptations. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION, AND RESULTS: A list of 49 terms and definitions in the field of endometriosis is presented, including a definition for endometriosis and its subtypes, different locations, interventions, symptoms and outcomes. Endometriosis is defined as a disease characterized by the presence of endometrium-like epithelium and/or stroma outside the endometrium and myometrium, usually with an associated inflammatory process. CONCLUSION: The current paper outlines a list of 49 terms and definitions in the field of endometriosis. The application of the defined terms aims to facilitate harmonization in endometriosis research and clinical practice. Future research may require further refinement of the presented definitions.

Endometriosis Classification, Staging and Reporting Systems: A Review on the Road to a Universally Accepted Endometriosis Classification.

OBJECTIVE: In the field of endometriosis, several classification, staging and reporting systems have been developed. Which endometriosis classification, staging and reporting systems have been published and validated for use in clinical practice? DATA SOURCES: A systematic PUBMED literature search was performed. Data were extracted and summarized. METHODS OF STUDY SELECTION: na TABULATION, INTEGRATION AND RESULTS: Twenty-two endometriosis classification, staging and reporting systems have been published between 1973 and 2021, each developed for specific, and different, purposes. There still is no international agreement on how to describe the disease. Studies evaluating the different systems are summarized showing a discrepancy between the intended and the evaluated purpose, and a general lack of validation data confirming a correlation with pain symptoms or quality of life for any of the current systems. A few studies confirm the value of the ENZIAN system for surgical description of deep endometriosis. With regards to infertility, the endometriosis fertility index has been confirmed valid for its intended purpose. CONCLUSION: Of the 22 endometriosis classification, staging and reporting systems identified in this historical overview, only a few have been evaluated for the purpose for which they were developed. The literature search was limited to PUBMED. Unpublished classification, staging or reporting systems, or those published in books were not considered. It can be concluded that there is no international agreement on how to describe endometriosis or how to classify it, and that most classification/staging systems show no or very little correlation with patient outcomes. This overview of existing systems is a first step in working towards a universally accepted endometriosis classification.

Perinatal urinary benzophenone-3 concentrations and glucose levels among women from a fertility clinic.

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.

Marijuana smoking and markers of testicular function among men from a fertility centre.

STUDY QUESTION: Is marijuana smoking associated with semen quality, sperm DNA integrity or serum concentrations of reproductive hormones among subfertile men? SUMMARY ANSWER: Men who had ever smoked marijuana had higher sperm concentration and count and lower serum FSH concentrations than men who had never smoked marijuana; no differences were observed between current and past marijuana smokers. WHAT IS KNOWN ALREADY: Studies of marijuana abuse in humans and animal models of exposure to marijuana suggest that marijuana smoking adversely impacts spermatogenesis. Data is less clear for moderate consumption levels and multiple studies have found higher serum testosterone concentrations among marijuana consumers. STUDY DESIGN, SIZE, DURATION: This longitudinal study included 662 subfertile men enroled at the Massachusetts General Hospital Fertility Center between 2000 and 2017. The men provided a total of 1143 semen samples; 317 men also provided blood samples in which we measured reproductive hormones. PARTICIPANTS/MATERIALS, SETTING, METHODS: Use of marijuana and other drugs was self-reported at baseline. Standard protocols were followed for measuring semen quality, sex hormones and DNA integrity. We used linear mixed effect models with a random intercept to evaluate the associations of self-reported marijuana smoking at enrolment with semen parameters from subsequently collected samples, and linear regression models for sperm DNA integrity and serum reproductive hormones, while adjusting for confounders including smoking and cocaine use. MAIN RESULTS AND THE ROLE OF CHANCE: Men who had ever smoked marijuana (N = 365) had significantly higher sperm concentration (62.7 (95% confidence interval: 56.0, 70.3) million/mL) than men who had never smoked marijuana (N = 297) (45.4 (38.6, 53.3) million/mL) after adjusting for potential confounders (P = 0.0003). There were no significant differences in sperm concentration between current (N = 74) (59.5 (47.3, 74.8) million/mL) and past marijuana smokers (N = 291) (63.5 (56.1, 72.0) million/mL; P = 0.60). A similar pattern was observed for total sperm count. Furthermore, the adjusted prevalence of sperm concentration and total sperm motility below WHO reference values among marijuana smokers was less than half that of never marijuana smokers. Marijuana smokers had significantly lower follicle stimulating hormone (FSH) concentrations than never marijuana smokers (-16% (-27%, -4%)) and there were no significant differences between current and past marijuana smokers (P = 0.53). Marijuana smoking was not associated with other semen parameters, with markers of sperm DNA integrity or with reproductive hormones other than FSH. Chance findings cannot be excluded due to the multiple comparisons. LIMITATIONS, REASONS FOR CAUTION: Our results may not be generalisable to men from the general population. Marijuana smoking was self-reported and there may be misclassification of the exposure. WIDER IMPLICATIONS OF THE FINDINGS: These findings are not consistent with a deleterious effect of marijuana on testicular function. Whether these findings are reflective of the previously described role of the endocannabinoid system in spermatogenesis or a spurious association requires confirmation in further studies. STUDY FUNDING/COMPETING INTEREST(S): The project was funded by grants R01ES009718 and P30ES000002 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Marijuana smoking and outcomes of infertility treatment with assisted reproductive technologies.

STUDY QUESTION: What is the association of female and male partner marijuana smoking with infertility treatment outcomes with ART? SUMMARY ANSWER: Women who were marijuana smokers at enrollment had a significantly higher adjusted probability of pregnancy loss during infertility treatment with ART whereas, unexpectedly, there was a suggestion of more favorable treatment outcomes in couples where the man was a marijuana smoker at enrollment. WHAT IS KNOWN ALREADY: Data on the relation of female and male partner marijuana use with outcomes of infertility treatment is scarce despite increased use and legalization worldwide. STUDY DESIGN, SIZE, DURATION: We followed 421 women who underwent 730 ART cycles while participating in a prospective cohort (the Environment and Reproductive Health Study) at a fertility center between 2004 and 2017. Among them, 200 women (368 cycles) were part of a couple in which their male partner also enrolled in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants self-reported marijuana smoking at baseline. Clinical endpoints were abstracted from electronic medical records. We used generalized linear mixed models with empirical standard errors to evaluate the association of baseline marijuana smoking with ART outcomes adjusting for participants' age, race, BMI, tobacco smoking, coffee and alcohol consumption, and cocaine use. We estimated the adjusted probability of implantation, clinical pregnancy, and live birth per ART cycle, as well as the probability of pregnancy loss among those with a positive B-hCG. MAIN RESULTS AND THE ROLE OF CHANCE: The 44% of the women and 61% of the men had ever smoked marijuana; 3% and 12% were marijuana smokers at enrollment, respectively. Among 317 women (395 cycles) with a positive B-hCG, those who were marijuana smokers at enrollment (N = 9, cycles = 16) had more than double the adjusted probability of pregnancy loss than those who were past marijuana smokers or had never smoked marijuana (N = 308, 379 cycles) (54% vs 26%; P = 0.0003). This estimate was based on sparse data. However, couples in which the male partner was a marijuana smoker at enrollment (N = 23, 41 cycles) had a significantly higher adjusted probability of live birth than couples in which the male partner was a past marijuana smoker or had never smoked marijuana (N= 177, 327 cycles) (48% vs 29%; P = 0.04), independently of the women's marijuana smoking status. Treatment outcomes of past marijuana smokers, male and female, did not differ significantly from those who had never smoked marijuana. LIMITATIONS, REASONS FOR CAUTION: Marijuana smoking was self-reported with possible exposure misclassification. Chance findings cannot be excluded due to the small number of exposed cases. The results may not be generalizable to couples from the general population. WIDER IMPLICATIONS OF THE FINDINGS: Even though marijuana smoking has not been found in past studies to impact the ability to become pregnant among pregnancy planners in the general population, it may increase the risk of pregnancy loss among couples undergoing infertility treatment. Marijuana smoking by females and males may have opposing effects on outcomes of infertility treatment with ART. STUDY FUNDING/COMPETING INTEREST(S): The project was financed by grants R01ES009718, P30ES000002, and K99ES026648 from the National Institute of Environmental Health Sciences (NIEHS). None of the authors has any conflicts of interest to declare.

Men's Intake of Vitamin C and ß-Carotene Is Positively Related to Fertilization Rate but Not to Live Birth Rate in Couples Undergoing Infertility Treatment.

BACKGROUND: Randomized clinical trials show that men's use of antioxidant supplements during infertility treatment may improve clinical outcomes. However, important limitations in the design of most trials make it difficult to draw firm conclusions on their findings. OBJECTIVE: We examined whether men's intake of antioxidants and biologically related compounds without direct antioxidant capacity is associated with outcomes of assisted reproductive technologies (ARTs). METHODS: We conducted a prospective cohort study of men in couples who underwent infertility treatment with ART using their own gametes between 2007 and 2017. We followed 171 couples who presented at Massachusetts General Hospital Fertility Center and underwent 294 autologous ART cycles for infertility treatment. Diet was assessed in both partners using an FFQ. The primary study outcome was the probability of achieving a live birth as a result of infertility treatment. Secondary outcomes were fertilization, implantation, and clinical pregnancy rates. Generalized linear mixed models with random intercepts were fitted to account for multiple ART cycles per woman while adjusting for confounding. RESULTS: Men's vitamin C intake was positively associated with fertilization rate. The adjusted fertilization rate (95% CI) for couples in the lowest and highest quartiles of men's vitamin C intake were 69% (61-76%) and 81% (74-86%) (P-trend = 0.02). Men's ß-carotene intake was positively associated with fertilization rate in intracytoplasmic sperm injection cycles but not in conventional in vitro fertilization cycles (P-interaction = 0.01). Men's α-carotene intake was inversely related to the probability of live birth. The adjusted probabilities of live birth for men in the lowest and highest quartiles of α-carotene intake were 43% (28-60%) and 22% (12-36%), respectively. CONCLUSIONS: Men's intake of vitamin C and ß-carotene is positively related to fertilization rate but this does not translate into higher pregnancy or live birth rates in couples undergoing infertility treatment.

Urinary triclosan concentrations and semen quality among men from a fertility clinic.

BACKGROUND: Triclosan, a widely-used antimicrobial in personal care products, has shown endocrine disrupting activity in experimental studies. However, there is limited evidence from epidemiologic studies on health effects. OBJECTIVE: To examine the association between urinary triclosan concentrations and semen quality. METHODS: A total of 262 men enrolled in the Environmental and Reproductive Health (EARTH) Study provided 581 paired urine and semen samples (2009-2017). Urinary triclosan concentrations were quantified and semen analysis was evaluated according to WHO guidelines. We used linear mixed regression models to estimate the associations between specific gravity-adjusted urinary triclosan concentrations with semen parameters, with a random intercept to account for multiple samples per man and adjusting for age, body mass index (BMI), smoking, physical activity, sexual abstinence time, and season and year of samples' collection. RESULTS: Men had a mean (standard deviation) age of 36.6 (5.24) years and BMI of 27.9 (5.94) kg/m2. Seventy four percent of the samples had detectable (>2.3 µg/L) concentrations. We did not observe significant dose response trends between SG-adjusted urinary triclosan concentrations and semen parameters. However, in the adjusted analysis, compared to men with non-detectable triclosan concentrations in the lowest quartile, those in the second, third, and fourth quartiles had -1.32% (95%CI: -2.04, -0.59), -0.91% (95%CI: -1.63, -0.18), and -0.46% (95%CI: -1.25, 0.33) lower percent morphologically normal sperm, respectively. Similarly, a lower percentage of morphologically normal sperm was found among men with detectable triclosan concentrations, compared to men with non-detectable triclosan [-0.96% (95% CI: -1.57, -0.35)]. In sensitivity analyses, there was stronger negative associations on the percent morphologically normal sperm in the earlier time period due to the significant negative trend in detectable triclosan concentrations over time. CONCLUSION: Despite the lack of observed dose response relationship, we found consistent patterns of lower percent morphologically normal sperm for men with urinary triclosan in the 2nd or 3rd quartile compared to undetectable concentrations.This association was stronger for samples obtained prior to 2013 when triclosan was more often detectable in urine.

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 paraben's 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.

Trimester-specific phthalate concentrations and glucose levels among women from a fertility clinic.

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.

Donor TSH level is associated with clinical pregnancy among oocyte donation cycles.

PURPOSE: The purpose of the study is to evaluate the association between donor TSH level (independent of recipient TSH level) and recipient pregnancy outcome among fresh donor oocyte IVF cycles. METHODS: This is a retrospective cohort study investigating 232 consecutive fresh donor-recipient cycles (200 total oocyte donors) at an academic medical center. Main outcome measures include clinical pregnancy and live birth. RESULTS: Cycles were categorized into two groups based on donor TSH level (< 2.5 and ≥ 2.5 mIU/L). After controlling for multiple donor and recipient characteristics, the probability of clinical pregnancy was significantly lower among donors with TSH levels ≥2.5 mIU/L compared to those with TSH values <2.5 mIU/L (43.1 %, 95 % CI 28.5-58.9, versus 66.7 %, 95 % CI 58.6-73.9, respectively, p = 0.01). The difference in live birth rates between the two groups did not achieve statistical significance (43.1 %, 95 % CI 28.8-58.6, versus 58.0 %, 95 % CI 50.0-65.6, respectively, p = 0.09). CONCLUSIONS: Donor TSH level, independent of recipient TSH level, is associated with recipient clinical pregnancy. These findings suggest that thyroid function may impact the likelihood of pregnancy at the level of the oocyte.

Urinary bisphenol A concentrations and association with in vitro fertilization outcomes among women from a fertility clinic.

STUDY QUESTION: Are urinary BPA concentrations associated with in vitro fertilization (IVF) outcomes among women attending an academic fertility center? SUMMARY ANSWER: Urinary BPA concentrations were not associated with adverse reproductive and pregnancy outcomes among women from a fertility clinic. WHAT IS KNOWN ALREADY: Bisphenol A (BPA), an endocrine disruptor, is detected in the urine of most Americans. Although animal studies have demonstrated that BPA reduces female fertility through effects on the ovarian follicle and uterus, data from human populations are scarce and equivocal. STUDY DESIGN, SIZE AND DURATION: This prospective cohort study between 2004 and 2012 at the Massachusetts General Hospital Fertility Center included 256 women (n = 375 IVF cycles) who provided up to two urine samples prior to oocyte retrieval (total N = 673). PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Study participants were women enrolled in the Environment and Reproductive Health (EARTH) Study. Intermediate and clinical end-points of IVF treatments were abstracted from electronic medical records. We used generalized linear mixed models with random intercepts to evaluate the association between urinary BPA concentrations and IVF outcomes adjusted by age, race, body mass index, smoking status and infertility diagnosis. MAIN RESULTS AND THE ROLE OF CHANCE: The specific gravity-adjusted geometric mean of BPA was 1.87 µg/l, which is comparable to that for female participants in the National Health and Nutrition Examination Survey, 2011-2012. Urinary BPA concentrations were not associated with endometrial wall thickness, peak estradiol levels, proportion of high quality embryos or fertilization rates. Furthermore, there were no associations between urinary BPA concentrations and implantation, clinical pregnancy or live birth rates per initiated cycle or per embryo transfer. Although we did not find any associations between urinary BPA concentrations and IVF outcomes, the relation between BPA and endometrial wall thickness was modified by age. Younger women (<37 years old) had thicker endometrial thickness across increasing quartiles of urinary BPA concentrations, while older women (≥37 years old) had thinner endometrial thickness across increasing quartiles of urinary BPA concentrations. LIMITATIONS, REASONS FOR CAUTION: Limitations to this study include a possible misclassification of BPA exposure and difficulties in extrapolating the findings to the general population. WIDER IMPLICATIONS OF THE FINDINGS: Data on the relation between urinary BPA concentrations and reproductive outcomes remain scarce and additional research is needed to clarify its role in human reproduction. STUDY FUNDING/COMPETING INTERESTS: This work was supported by NIH grants R01ES022955, R01ES009718 and R01ES000002 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32DK00770316 from the National Institute of Child Health and Human Development (NICHD). None of the authors has any conflicts of interest to declare. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Investigation of central nervous system dysfunction in chronic pelvic pain using magnetic resonance spectroscopy and noninvasive brain stimulation.

BACKGROUND: Recent studies demonstrate that chronic pelvic pain is associated with altered afferent sensory input resulting in maladaptive changes in the neural circuitry of pain. To better understand the central changes associated with chronic pelvic pain, we investigated the contributions of critical pain-related neural circuits using single-voxel proton magnetic resonance spectroscopy (MRS) and transcranial direct current stimulation (tDCS). METHODS: We measured concentrations of neural metabolites in 4 regions of interest (thalamus, anterior cingulate cortex, primary motor, and occipital cortex [control]) at baseline and after 10 days of active or sham tDCS in patients with chronic pelvic pain. We then compared our results to those observed in healthy controls, matched by age and gender. RESULTS: We observed a significant increase in pain thresholds after active tDCS compared with sham conditions. There was a correlation between metabolite concentrations at baseline and quantitative sensory assessments. Chronic pelvic pain patients had significantly lower levels of NAA/Cr in the primary motor cortex compared with healthy patients. CONCLUSIONS: tDCS increases pain thresholds in patients with chronic pelvic pain. Biochemical changes in pain-related neural circuits are associated with pain levels as measured by objective pain testing. These findings support the further investigation of targeted cortical neuromodulatory interventions for chronic pelvic pain.

Elevated day 3 follicle-stimulating hormone in younger women: is gonadotropin stimulation/intrauterine insemination a good option?

OBJECTIVE: The objective of the study was to determine the fecundity of young women (<35 years) with an elevated day 3 follicle stimulating hormone (FSH) undergoing gonadotropin-stimulation/intrauterine insemination. STUDY DESIGN: This was a retrospective study. The study was conducted at an academic fertility center. A total of 1396 gonadotropin stimulation/intrauterine insemination cycles from 563 women were stratified by day 3 FSH levels (<10 vs ≥10 U/L) and outcomes were compared. Gonadotropin dose, treatment duration, peak estradiol (E2), number of preovulatory follicles (total, large, and medium size), E2/follicle, endometrial thickness, spontaneous abortion, clinical and multiple pregnancy rates were measured. The statistics included a Student t test, a χ(2), regression, and a discrete survival analysis. RESULTS: An elevated day 3 FSH was found in 10.2% of the women, despite favorable age (31.9 ± 2.5 years). Women with a day 3 FSH of 10 U/L or greater when compared with women with a normal day 3 level required significantly more medication (1058.9 ± 1106.0 vs 632.7 ± 477.5 IU, P < .0001) were triggered a day earlier (10.6 ± 2.4 vs 11.5 ± 2.9 days, P = .0006) and had E2 levels (on the day of and the day prior to human chorionic gonadotropin administration) that were significantly higher (529.5 ± 244.3 vs 450.0 ± 244.2 and 359.6 ± 141.7 vs 306.8 ± 160.9 pg/mL, respectively, P < .05). Clinical pregnancy rates were comparable among the groups (14.6 vs 14%, respectively, P > .05). Spontaneous abortion and multiple pregnancy rates were higher among women with an FSH of 10U/L or greater but not significantly so (27.8% vs 12.0%, 22.2% vs 13.8% for FSH of ≥10 vs FSH < or >10 U/L, P > .05). CONCLUSION: Women younger than 35 years with an elevated day 3 FSH, when treated aggressively with gonadotropins have pregnancy rates comparable with those of women with a normal baseline FSH. To achieve this outcome, they need higher doses of medication to stimulate the production of a larger preovulatory follicular cohort.

Outcomes after intrauterine insemination are independent of provider type.

OBJECTIVE: We sought to determine whether the success of intrauterine insemination (IUI) varies based on the type of health care provider performing the procedure. STUDY DESIGN: This was a retrospective cohort study set at an infertility clinic at an academic institution. The patients who comprised this study were 1575 women who underwent 3475 IUI cycles from late 2003 through early 2012. Cycles were stratified into 3 groups according to the type of provider who performed the procedure: attending physician, fellow physician, or registered nurse (RN). The primary outcome was live birth. Additional outcomes of interest included positive pregnancy test and clinical pregnancy. Repeated measures log binomial regression was used to estimate the risk ratios (RR) and 95% confidence intervals (CI) for the outcomes and to evaluate the effect of potential confounders. All tests were 2-sided, and P values < .05 were considered statistically significant. RESULTS: Of the 3475 IUI cycles, 2030 (58.4%) were gonadotropin stimulated, 929 (26.7%) were clomiphene citrate stimulated, and 516 (14.9%) were natural. The incidences of clinical pregnancy and live birth among all cycles were 11.8% and 8.8%, respectively. After adjusting for female age, male partner age, and cycle type, the incidence of live birth was similar for RNs compared with attending physicians (RR, 0.80; 95% CI, 0.58-1.1) and fellow physicians compared with attending physicians (RR, 0.84; 95% CI, 0.58-1.2). Similar results were seen for positive pregnancy test and clinical pregnancy. CONCLUSION: There was no significant difference in live birth following IUI cycles in which the procedure was performed by a fellow physician or RN compared with an attending physician.