Importance: Animal experiments suggest that ingestion of pesticide mixtures at environmentally relevant concentrations decreases the number of live-born offspring. Whether the same is true in humans is unknown. Objective: To examine the association of preconception intake of pesticide residues in fruits and vegetables (FVs) with outcomes of infertility treatment with assisted reproductive technologies (ART). Design, Setting, and Participants: This analysis included 325 women who completed a diet assessment and subsequently underwent 541 ART cycles in the Environment and Reproductive Health (EARTH) prospective cohort study (2007-2016) at a fertility center at a teaching hospital. We categorized FVs as having high or low pesticide residues using a validated method based on surveillance data from the US Department of Agriculture. Cluster-weighted generalized estimating equations were used to analyze associations of high- and low-pesticide residue FV intake with ART outcomes. Main Outcomes and Measures: Adjusted probabilities of clinical pregnancy and live birth per treatment cycle. Results: In the 325 participants (mean [SD] age, 35.1 [4.0] y; body mass index, 24.1 [4.3]), mean (SD) intakes of high- and low-pesticide residue FVs were 1.7 (1.0) and 2.8 (1.6) servings/d, respectively. Greater intake of high-pesticide residue FVs was associated with a lower probability of clinical pregnancy and live birth. Compared with women in the lowest quartile of high-pesticide FV intake (<1.0 servings/d), women in the highest quartile (≥2.3 servings/d) had 18% (95% CI, 5%-30%) lower probability of clinical pregnancy and 26% (95% CI, 13%-37%) lower probability of live birth. Intake of low-pesticide residue FVs was not significantly related to ART outcomes. Conclusions and Relevance: Higher consumption of high-pesticide residue FVs was associated with lower probabilities of pregnancy and live birth following infertility treatment with ART. These data suggest that dietary pesticide exposure within the range of typical human exposure may be associated with adverse reproductive consequences.

During the past decade, as the use of assisted reproductive technologies (ART) has continued to increase worldwide, research investigating whether modifiable lifestyle factors, such as alcohol, caffeine, and smoking, may affect ART outcomes has grown. Despite the vast literature, there is still uncertainty regarding the effects of some of these exposures on ART outcomes. The objective of this review is to summarize the epidemiologic literature on intakes of caffeine and alcohol, smoking, and reproductive outcomes among women undergoing ART. Of the five epidemiologic studies on caffeine intake and ART outcomes, only one found a significant negative effect of caffeine intake on live birth following ART. There have been six epidemiologic studies exploring whether alcohol intake is associated with fertility outcomes among women undergoing ART. Three studies assessed current alcohol consumption and observed a negative effect on outcomes such as fertilization, embryo quality, and implantation. When alcohol intake in the year before treatment was assessed, no relationships were observed with clinical outcomes following ART. Finally, numerous epidemiologic studies and a handful of meta-analyses have confirmed that female current smokers have worse ART outcomes compared with nonsmokers. Although former smokers tend to have better ART outcomes than current smokers, very few individual studies have investigated the influence of smoking cessation on ART outcomes. Literature on male smoking, drinking, and caffeine habits in relation to ART outcomes is even sparser and inconsistent, making it difficult to draw strong conclusions on that topic. In summary, there is little evidence supporting a detrimental effect of moderate caffeine intake on ART outcomes. Current consumption of alcohol may have a negative effect on ART outcomes, but at present the evidence is limited. Women who currently smoke cigarettes have been consistently found to have poorer ART outcomes, including reduced live birth rates, but a quantification of the benefits of smoking cessation is lacking.

The literature on the relationship between diet and human fertility has greatly expanded over the last decade, resulting in the identification of a few clear patterns. Intake of supplemental folic acid, particularly at doses higher than those recommended for the prevention of neural tube defects, has been consistently related to lower frequency of infertility, lower risk of pregnancy loss, and greater success in infertility treatment. On the other hand and despite promising evidence from animal models, vitamin D does not appear to exert an important role in human fertility in the absence of deficiency. Antioxidant supplementation does not appear to offer any benefits to women undergoing infertility treatment, but it appears to be beneficial when it is the male partner who is supplemented. However, the available evidence does not allow discerning which specific antioxidants, or at which doses, are responsible for this benefit. Long-chain omega-3 fatty acids appear to improve female fertility, although it remains unclear to what extent contamination of shared food sources, such as fish with high levels of environmental toxicants, can dampen this benefit. Lastly, adherence to healthy diets favoring seafood, poultry, whole grains, fruits, and vegetables are related to better fertility in women and better semen quality in men. The cumulative evidence has also piled against popular hypotheses. Dairy and soy, once proposed as reproductive toxicants, have not been consistently related to poor fertility. In fact, soy and soy supplements appear to exert a beneficial effect among women undergoing infertility treatment. Similarly, because data from large, high-quality studies continue to accumulate, the evidence of a potentially deleterious effect of moderate alcohol and caffeine intake on the ability to become pregnant seems less solid than it once did. While a complete picture of the role of nutrition on fertility is far from complete, much progress has been made. The most salient gaps in the current evidence include jointly considering female and male diets and testing the most consistent findings in randomized trials.

Background: The Environment and Reproductive Health (EARTH) Study is an ongoing prospective preconception cohort designed to investigate the impact of environmental, nutritional, and lifestyle factors among both women and men on fertility and pregnancy outcomes. Methods: The EARTH Study recruits women 18 to 45 years and men 18 to 55 years seeking fertility evaluation and treatment at the Massachusetts General Hospital (MGH) Fertility Center, Boston, USA. 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 collects biological samples, self-reported questionnaire data (including a food frequency questionnaire) and clinically abstracted information. Results: As of June 2017, the study cohort included 799 women and 487 men (447 couples; 40 men joined without female partners). Women were on average 34.7 years old at time of enrolment and predominantly Caucasian (81%), educated (49% have a graduate degree), and nulliparous (83%). Men were on average 36.6 years at baseline and mostly Caucasian (86%) and never-smokers (67%). Conclusions: The EARTH Study is one of the few cohorts designed to examine multiple potentially critical 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.

BACKGROUND: Dietary diversity scores (DDS) are considered as metrics for monitoring the implementation of the UN's Sustainable Development Goals, but they need to be rigorously evaluated. OBJECTIVE: To examine two DDS, the Food Groups Index (FGI), and the Minimum Dietary Diversity-Women (MDD-W), alongside two dietary quality scores, the Alternate Healthy Eating Index (AHEI-2010) and the Prime Diet Quality Score (PDQS), with risks of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDPs). DESIGN: The analysis included 21,312 (GDM) and 19,917 (HDPs) singleton births reported in the Nurses' Health Study II cohort (1991-2001), among women without major chronic disease or GDM/HDPs. Scores were derived using prepregnancy diet collected by a comprehensive food frequency questionnaire. Multivariable models were utilized to calculate relative risks (RR) and confidence intervals (95%CIs). RESULTS: Incident GDM (n = 916) and HDPs (n = 1,421) were reported. The MDD-W and FGI were not associated with risk of GDM or HDPs, but the AHEI-2010 and PDQS were associated with a lower risk of GDM and marginally lower risk of HDP. The RR's of GDM comparing the highest vs. lowest quintiles were 1.00 (95%CI: 0.79, 1.27; p-trend = 0.82) for MDD-W, 0.96 (95%CI: 0.76, 1.22; p-trend = 0.88) for FGI, 0.63 (95%CI: 0.50, 0.81; p-trend <0.0001) for the AHEI-2010 and 0.68 (95%CI: 0.54, 0.86; p-trend = 0.003) for the PDQS. Similarly, the RR's of HDPs were 0.92 (95%CI: 0.75, 1.12, p-trend = 0.94) for MDD-W, 0.97 (95%CI: 0.79, 1.17; p-trend = 0.83) for FGI, 0.84 (95%CI: 0.70, 1.02; p-trend = 0.07) for AHEI-2010 and 0.89 (95%CI: 0.74, 1.09; p-trend = 0.07) for PDQS. CONCLUSIONS: MDD-W and FGI did not predict the risk of GDM and HDPs. These DDS should not be widely used as metrics for achieving dietary goals in their present form. The Prime Diet Quality Score warrants further testing as a promising measure of a sustainable and healthy diet on a global scale.

Background: Some dietary factors have been linked to outcomes of infertility treatment with assisted reproductive technology (ART), but the role of intake of meats and other protein-rich foods remains unclear. Objective: The aim of this manuscript was to study the relation between preconception intake of meat and other protein-rich foods and outcomes of infertility treatment with ART. Design: A total of 351 women enrolled in a prospective cohort at the Massachusetts General Hospital Fertility Center and underwent 598 ART cycles for infertility treatment. Meat intake was assessed with a validated food-frequency questionnaire, and ART outcomes were abstracted from electronic medical records. We estimated the associations between intake of protein-rich foods (meats, eggs, beans, nuts, and soy) and the outcome of live birth per initiated cycle using generalized linear mixed models. Results: The average total meat intake was 1.2 servings/d, with most coming from poultry (35%), fish (25%), processed meat (22%), and red meat (17%). Fish intake was positively related to the proportion of cycles resulting in live birth. The multivariable-adjusted probabilities of live birth for women in increasing quartiles of fish intake were 34.2% (95% CI: 26.5%, 42.9%), 38.4% (95% CI: 30.3%, 47.3%), 44.7% (95% CI: 36.3%, 53.4%), and 47.7% (95% CI: 38.3%, 57.3%), respectively (P-trend = 0.04). In the estimated substitution analyses, the ORs of live birth associated with increasing fish intake by 2 servings/wk were 1.54 (95% CI: 1.14, 2.07) when fish replaced any other meat, 1.50 (95% CI: 1.13, 1.98) when fish replaced any other protein-rich food, and 1.64 (95% CI: 1.14, 2.35) when fish replaced processed meat. Conclusions: Fish consumption is related to a higher probability of live birth following infertility treatment with ART. This trial was registered at clinicaltrials.gov as NCT00011713.

BACKGROUND: Little is known about the predictors of sexual intercourse frequency (SIF) among couples trying to conceive despite the well-established link between SIF and fecundity. AIM: To evaluate men's and women's demographic, occupational, and lifestyle predictors of SIF among couples. METHODS: 469 Couples without a history of infertility participating in the Longitudinal Investigation of Fertility and the Environment Study (2005-2009) were followed up for ≤1 year while trying to conceive. At enrollment, both partners were interviewed about demographic, occupational, lifestyle, and psychological characteristics using standardized questionnaires. Multivariable generalized linear mixed models with Poisson distribution were used to estimate the adjusted percent difference in SIF across exposure categories. OUTCOMES: SIF was recorded in daily journals and summarized as average SIF/mo. RESULTS: The median (interquartile range) SIF during follow-up was 6 (4-9) acts/mo. For every year increase in age for women and men, SIF decreased by -0.8% (95% CI -2.5 to 1.0%) and -1.7% (95% CI -3.1 to -0.3%). Women with high school education or less and those of non-white race had 34.4% and 16.0% higher SIF, respectively. A similar trend was seen for men's education and race. Only couples where both partners (but not just 1 partner) worked rotating shifts had -39.1% (95% CI -61.0 to -5.0%) lower SIF compared to couples where neither partner worked rotating shifts. Men's (but not women's) exercise was associated with 13.2% (95% CI 1.7-26.0%) higher SIF. Diagnosis of a mood or anxiety disorder in men (but not women) was associated with a 26.0% (95% CI -42.7 to -4.4%) lower SIF. Household income, smoking status, body mass index, night work, alcohol intake, and psychosocial stress were not associated with SIF. CLINICAL TRANSLATION: Even among couples trying to conceive, there was substantial variation in SIF. Both partners' age, education, race, and rotating shift work as well as men's exercise and mental health play an important role in determining SIF. CONCLUSIONS: As this was a secondary analysis of an existing study, we lacked information on many pertinent psychological and relationship quality variables and the hormonal status of participants, which could have affected SIF. The unique population-based couple design, however, captured both partners' demographics, occupational characteristics, and lifestyle behaviors in advance of their daily, prospective reporting of SIF, which was a major strength. Important predictors of SIF among couples attempting to conceive include men's exercise and mental health and both partners' age, education, race, and rotating shift work. Gaskins AJ, Sundaram R, Buck Louis GM, et al. Predictors of Sexual Intercourse Frequency Among Couples Trying to Conceive. J Sex Med 2018;15:519-528.

PURPOSE: To investigate the relation between pre-pregnancy caffeine and caffeinated beverage intake and risk of spontaneous abortion (SAB). METHODS: Our prospective cohort study included 15,590 pregnancies from 11,072 women with no history of SAB in the Nurses' Health Study II (1991-2009). Beverage intake was assessed every 4 years using a validated questionnaire. Pregnancies were self-reported with case pregnancies lost spontaneously at <20 weeks gestation. Multivariable log-binomial regression models with generalized estimating equations were used to estimate the relative risks (RRs) and 95 % confidence intervals (CIs). RESULTS: There was a positive linear trend across categories of pre-pregnancy caffeine intake and risk of SAB such that women consuming >400 mg/day had 1.11 (95 % CI 0.98, 1.25) times the risk of SAB compared to women consuming <50 mg/day (p trend = 0.05). Total coffee intake had a positive, linear association with SAB. Compared to women with no pre-pregnancy coffee intake, women consuming ≥4 servings/day had a 20 % (6, 36 %) increased risk of SAB (p trend = 0.01). There was no difference in the association between caffeinated and decaffeinated coffee and risk of SAB. Pre-pregnancy intake of caffeinated tea, caffeinated soda, and decaffeinated soda had no association with SAB. CONCLUSIONS: Pre-pregnancy coffee consumption at levels ≥4 servings/day is associated with increased risk of SAB, particularly at weeks 8-19.

The impact of excess body weight on fertility is well recognized among both women attempting to conceive spontaneously and those attempting to conceive with medical assistance. Although many leading societies of reproductive medicine have proposed weight loss as a means to counteract the negative consequences of obesity on fertility, there is limited research on this topic. In this review, we provide a brief overview of the recent advances in the literature focused on how long- and short-term weight change affects fertility among women. Overall, despite initial hope that weight loss may be beneficial for fertility, two large well-conducted randomized controlled trials have consistently shown that short-term weight loss among overweight and obese women undergoing infertility treatment does not improve a woman's probability of live birth. The observational evidence among women attempting to conceive without medical assistance also suggests limited benefits of weight loss on fecundity or pregnancy loss. In contrast, substantial weight gain between consecutive pregnancies, in the year prior to pregnancy attempt, and throughout adulthood appears to be harmful for not only time to pregnancy but also pregnancy maintenance. Future research focused on efforts to prevent weight gain during adulthood is needed to better understand whether these types of interventions may have beneficial effects on fertility.

OBJECTIVE: We examined associations of residential distance to major roadways, as a proxy for traffic-related air pollution exposures, with sperm characteristics and male reproductive hormones. DESIGN: The cohort included 797 men recruited from Massachusetts General Hospital Fertility Center between 2000 and 2015 to participate in fertility research studies. MATERIALS AND METHODS: Men reported their residential addresses at enrollment and provided 1-6 semen samples and a blood sample during follow-up. We estimated the Euclidean distance to major roadways (e.g. interstates and highways: limited access highways, multi-lane highways (not limited access), other numbered routes, and major roads) using information from the Massachusetts Department of Geographic Information Systems. Semen parameters (1238 semen samples), sperm DNA integrity (389 semen samples), chromosomal disomy (101 semen samples), and serum reproductive hormones (405 serum samples) were assessed following standard procedures. RESULTS: Men in this cohort were primarily Caucasian (86%), not current smokers (92%), with a college or higher education (88%), and had an average age of 36 years and BMI of 27.7 kg/m. The median (interquartile range) residential distance to a major roadway was 111 (37, 248) meters. Residential proximity to major roadways was not associated with semen parameters, sperm DNA integrity, chromosomal disomy, or serum reproductive hormone concentrations. The adjusted percent change (95% CI) in semen quality parameters associated with a 500 m increase in residential distance to a major roadway was -1.0% (-6.3, 4.5) for semen volume, 4.3% (-5.8, 15.7) for sperm concentration, 3.1% (-7.2, 14.5) for sperm count, 1.1% (-1.2, 3.4) for % total motile sperm, and 0.1% (-0.3, 0.5) for % morphologically normal sperm. Results were consistent when we modeled the semen parameters dichotomized according to WHO 2010 reference values. CONCLUSION: Residential distance to major roadways, as a proxy for traffic-related air pollution exposure, was not related to sperm characteristics or serum reproductive hormones among men attending a fertility clinic in Massachusetts.

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 <50 m (p-for-comparison, 0.04). Of the intermediate outcomes, there were suggestive associations between living closer to major roadways and slightly higher estradiol trigger concentrations (p-trend = 0.16) and lower endometrial thickness (p-trend = 0.06). Near-residence traffic density was not associated with outcomes of IVF. CONCLUSION: Closer residential proximity to major roadways was related to reduced likelihood of live birth following IVF.

Context: Marine long-chain omega-3 fatty acids have been positively related to markers of fecundity in both men and women. However, seafood, their primary food source, can also be a source of toxicants, which could counteract the reproductive benefits. Objective: To examine the relationship of male and female seafood intake with time to pregnancy (TTP). Design: Our prospective cohort study included 501 couples planning pregnancy, who participated in the Longitudinal Investigation of Fertility and the Environment study (2005 to 2009) and were followed up for ≤1 year or until pregnancy was detected. Seafood intake was collected daily during follow-up in journals. Setting: Couples residing in Michigan and Texas were recruited using population-based sampling frameworks. Main Outcome Measures: The primary outcome was the TTP, determined using an in-home pregnancy test. A secondary outcome was sexual intercourse frequency (SIF) as recorded in the daily journals. Results: Couples with male and female partners who consumed eight or more seafood servings per cycle had 47% (95% CI, 7% to 103%) and 60% (95% CI, 15% to 122%) greater fecundity (shorter TTP) than couples with male and female partners who consumed one or fewer seafood servings per cycle. Couples with both partners consuming eight or more seafood servings per cycle had 61% (95% CI, 17% to 122%) greater fecundity than couples consuming less. Male and female partners with the highest seafood intake (eight or more servings per cycle) also had 22% greater SIF. Conclusions: Greater male and female seafood intake was associated with a higher SIF and fecundity among a large prospective cohort of couples attempting pregnancy.

BACKGROUND: Multiple meta-analyses have shown sperm count declines in Western countries spanning eight decades. Secular trends in other parameters remain unclear, as are potential predictors of these trends. OBJECTIVE: To analyze secular trends in semen quality and to evaluate whether factors previously found to be related to semen quality were responsible for these patterns. METHODS: This is a prospective study including 936 men of couples seeking infertility treatment who provided 1618 semen samples at a single center (2000-2017). Self-reported demographic, nutritional and reproductive characteristics were collected using standardized questionnaires. Urinary concentrations of bisphenol A, parabens and phthalates were quantified by isotope-dilution tandem mass spectrometry. Semen samples were analyzed for volume, sperm concentration, count, motility and morphology following WHO guidelines. We estimated the differences in semen parameters over time by fitting generalized linear mixed models with random intercepts to account for repeated samples while adjusting for abstinence time. We also adjusted for demographic, nutritional and environmental factors to investigate these as potential predictors of time trends. RESULTS: Sperm concentration and count declined by 2.62% per year (95% CI -3.84, -1.38) and 3.12% per year (95% CI: -4.42, -1.80), corresponding to an overall decline of 37% and 42%, respectively, between 2000 and 2017. Decreasing trends were also observed for total motility (per year: -0.44 percentage units, 95% CI -0.71, -0.17) and morphologically normal sperm (per year: -0.069 percentage units, 95% CI -0.116, -0.023). These decreases reflected relative percentage declines of 15% and 16% over the 17 year study period, respectively. When reproductive factors were included in the model, the downward trends in sperm concentration and sperm count were attenuated by 29% and 26%, respectively, while the trends in motility and morphology were attenuated by 54% and 53%, respectively. Also, the downward trends in both sperm concentration and sperm morphology over time were attenuated by 19% when including the DEHP and non-DEHP metabolites, respectively. CONCLUSIONS: Sperm concentration, total count, motility and morphology significantly declined between 2000 and 2017 among subfertile men. These negative trends were attenuated when considering simultaneous changes in reproductive characteristics and urinary phthalates during the course of the study.

STUDY QUESTION: Are serum polyunsaturated fatty acids (PUFA) concentrations, including omega-3 (ω3-PUFA) and omega-6 (ω6-PUFA), related to ART outcomes? SUMMARY ANSWER: Serum levels of long-chain ω3-PUFA were positively associated with probability of live birth among women undergoing ART. WHAT IS KNOWN ALREADY: Intake of ω3-PUFA improves oocyte and embryo quality in animal and human studies. However, a recent cohort study found no relation between circulating ω3-PUFA levels and pregnancy rates after ART. STUDY DESIGN SIZE, AND DURATION: This analysis included a random sample of 100 women from a prospective cohort study (EARTH) at the Massachusetts General Hospital Fertility Center who underwent 136 ART cycles within one year of blood collection. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum fatty acids (expressed as percentage of total fatty acids) were measured by gas chromatography in samples taken between Days 3 and 9 of a stimulated cycle. Primary outcomes included the probability of implantation, clinical pregnancy and live birth per initiated cycle. Cluster-weighted generalized estimating equation (GEE) models were used to analyze the association of total and specific PUFAs with ART outcomes adjusting for age, body mass index, smoking status, physical activity, use of multivitamins and history of live birth. MAIN RESULTS AND ROLE OF CHANCE: The median [25th, 75th percentile] serum level of ω3-PUFA was 4.7% [3.8%, 5.8%] of total fatty acids. Higher levels of serum long-chain ω3-PUFA were associated with higher probability of clinical pregnancy and live birth. Specifically, after multivariable adjustment, the probability of clinical pregnancy and live birth increased by 8% (4%, 11%) and 8% (95% CI: 1%, 16%), respectively, for every 1% increase in serum long-chain ω3-PUFA levels. Intake of long-chain ω3-PUFA was also associated with a higher probability of life birth in these women, with RR of 2.37 (95% CI: 1.02, 5.51) when replacing 1% energy of long-chain ω3-PUFA for 1% energy of saturated fatty acids. Serum ω6-PUFA, ratios of ω6 and ω3-PUFA, and total PUFA were not associated with ART outcomes. LIMITATIONS REASONS FOR CAUTION: The generalizability of the findings to populations not undergoing infertility treatment may be limited. The use of a single measurement of serum fatty acids to characterize exposure may lead to potential misclassification during follow up. WIDER IMPLICATIONS OF THE FINDINGS: Serum ω3-PUFA are considered biomarkers of dietary intake. The association of higher serum long chain ω3-PUFA levels with improved ART outcomes suggests that increased intake of these fats be may be beneficial for women undergoing infertility treatment with ART. STUDY FUNDING/COMPETING INTERESTS: NIH grants R01-ES009718 from the National Institute of Environmental Health Sciences, P30-DK046200 and T32-DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases, and L50-HD085359 from the National Institute of Child Health and Human Development, and the Early Life Nutrition Fund from Danone Nutricia US. Dr Rueda is involved in a patent 9,295,662, methods for enhancing, improving, or increasing fertility or reproductive function (http://patents.com/us-9295662.html). This patent, however, does not lead to financial gain for Dr Rueda, or for Massachusetts General Hospital. Dr Rueda does not own any part of the company nor does he have any equity in any fertility related company. As Dr Rueda is not a physician, he does not evaluate patients or prescribe medications. All other coauthors have no conflicts of interest to declare.

STUDY QUESTION: Is self-reported type of underwear worn associated with markers of testicular function among men at a fertility center? SUMMARY ANSWER: Men who reported most frequently wearing boxers had higher sperm concentration and total count, and lower FSH levels, compared to men who did not. WHAT IS KNOWN ALREADY: Elevated scrotal temperatures are known to adversely affect testicular function. However, the epidemiologic literature on type of underwear, as a proxy of scrotal temperature, and male testicular function is inconsistent. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional study including 656 male partners of couples seeking infertility treatment at a fertility center (2000-2017). PARTICIPANTS/MATERIALS, SETTING, METHODS: Self-reported information on type of underwear worn was collected from a take-home questionnaire. Semen samples were analyzed following World Health Organization guidelines. Enzyme immunoassays were used to assess reproductive hormone levels and neutral comet assays for sperm DNA damage. We fit linear regression models to evaluate the association between underwear type and testicular function, adjusting for covariates and accounting for multiple semen samples. MAIN RESULTS AND THE ROLE OF CHANCE: Men had a median (interquartile range) age of 35.5 (32.0, 39.3) years and BMI of 26.3 (24.4, 29.9) kg/m2. About half of the men (53%; n = 345) reported usually wearing boxers. Men who reported primarily wearing boxers had a 25% higher sperm concentration (95% CI = 7, 31%), 17% higher total count (95% CI = 0, 28%) and 14% lower serum FSH levels (95% CI = -27, -1%) than men who reported not primarily wearing boxers. Sperm concentration and total count were inversely related to serum FSH. Furthermore, the differences in sperm concentration and total count according to type of underwear were attenuated after adjustment for serum FSH. No associations with other measured reproductive outcomes were observed. LIMITATIONS, REASONS FOR CAUTION: Our results may not be generalizable to men from the general population. Underwear use was self-reported in a questionnaire and there may be misclassification of the exposure. The cross-sectional design limits causal inference, and residual confounding is still possible owing to lack of information on other modifiable life styles that can also modify scrotal heat (e.g. type of trousers worn, textile fabric of the underwear). Blood sampling was not limited to the morning and, as a result, we may have missed associations with testosterone or other hormones with significant circadian variation despite statistical adjustment for time of blood draw. WIDER IMPLICATIONS OF THE FINDINGS: Certain styles of male underwear may impair spermatogenesis and this may result in a compensatory increase in gonadotrophin secretion, as reflected by higher serum FSH levels among men who reported most frequently wearing tight underwear. Confirmation of these findings, and in particular the findings on FSH levels suggesting a compensatory mechanism, is warranted. STUDY FUNDING/COMPETING INTEREST(S): The project was financed by Grants (R01ES022955, R01ES009718, P30ES000002, and K99ES026648) from the National Institutes of Health. None of the authors has any conflicts of interest to declare.

Phthalates are a class of chemicals found in a large variety of consumer products. Available experimental and limited human data show adverse effects of some phthalates on ovarian function, which has raised concerns regarding potential effects on fertility. The aim of the current study was to determine whether urinary concentrations of metabolites of phthalates and phthalate alternatives are associated with intermediate and clinical in vitro fertilization (IVF) outcomes. We enrolled 136 women undergoing IVF in a Tertiary University Affiliated Hospital. Participants provided one to two urine samples per cycle during ovarian stimulation and before oocyte retrieval. IVF outcomes were abstracted from medical records. Concentrations of 17 phthalate metabolites and two metabolites of the phthalate alternative di(isononyl) cyclohexane-1,2-dicarboxylate (DINCH) were measured. Multivariable Poisson regression models with log link were used to analyze associations between tertiles of specific gravity adjusted phthalate or DINCH metabolites and number of total oocytes, mature oocytes, fertilized oocytes, and top quality embryos. Multivariable logistic regression models were applied to evaluate the association between tertiles of specific gravity adjusted phthalate or DINCH metabolites and probability of live birth. Urinary concentrations of the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) and the individual metabolites mono-2-ethyl-5-hydroxyhexyl phthalate, mono-2-ethyl-5-oxohexyl phthalate, and mono-2-ethyl-5-carboxypentyl phthalate were negatively associated with the number of total oocytes, mature oocytes, fertilized oocytes, and top quality embryos. Of the low molecular weight phthalates, higher monoethyl phthalate and mono-n-butyl phthalate concentrations were associated with significantly fewer total, mature, and fertilized oocytes. None of the urinary phthalate metabolite concentrations were associated with a reduced probability implantation, clinical pregnancy or live birth. Metabolites of DINCH were not associated with intermediate or clinical IVF outcomes. Our results suggest that DEHP may impair early IVF outcomes, specifically oocyte parameters. Additional research is needed to elucidate the potential effect of DEHP on female fertility in the general population.