Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data.

BACKGROUND: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. OBJECTIVE: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. DESIGN: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). SETTING: U.S. Medicaid health care administration database (2000 to 2018). PARTICIPANTS: 12 489 pregnant women who met the eligibility criteria. MEASUREMENTS: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. RESULTS: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). LIMITATION: Possible residual confounding by glycemic control and body mass index. CONCLUSION: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. PRIMARY FUNDING SOURCE: National Institutes of Health.

Hypothetical 22-Year Intervention With the Dietary Approaches to Stop Hypertension and Risk of Heart Failure in a General Population.

We used design principles of target trial methodology to emulate the effect of sustained adherence to the Dietary Approaches to Stop Hypertension (DASH) diet on the 22-year risk of heart failure. Women and men aged 45-83 years without previous heart failure, who answered questionnaires in 1997 from the Swedish Mammography Cohort and the Cohort of Swedish Men, were eligible. Follow-up questionnaires were sent in 2008-2009. Incidence of heart failure was ascertained using the Swedish Patient Register, updated until December 31, 2019. The parametric g-formula was used to estimate the 22-year risk of heart failure under sustained adherence to a population-adapted DASH diet compared with no intervention. Intakes before 1997 for before-baseline adjustment was available only for women. In total, 31,238 women and 34,939 men were eligible. The 22-year risk of heart failure was 14.5% with long-term adherence to the DASH diet compared with 15.2% with no intervention (risk difference = -0.7%, 95% confidence interval: 1.6, 0.0%) in women and correspondingly in men 15.3% vs. 16.2% (risk difference = -0.9%, 95% confidence interval: -1.6, -0.2%). Our hypothetical intervention suggests that sustained adherence to the population-adapted DASH diet may reduce risk of heart failure in middle-aged and elderly Swedish women and men.

Internal validation of gestational age estimation algorithms in healthcare databases using pregnancies conceived with fertility procedures.

Fertility procedures recorded in healthcare databases can be used to estimate the start of pregnancy, which can serve as a reference standard to validate gestational age estimates based on International Classification of Diseases (ICD) codes. In a cohort of 17,398 pregnancies conceived by fertility procedures in MarketScan (2011-2020), we estimated gestational age at the end of pregnancy using algorithms based on (1) days since fertility procedure (the reference); (2) ICD-9/ICD-10 (before/after October 2015) codes indicating gestational length recorded at the end of pregnancy (method A); and (3) ICD-10 enhanced with Z3A codes denoting specific gestation weeks recorded at prenatal visits (method B). We calculated the proportion of pregnancies with an estimated gestational age within 14 days of the reference. Method A accuracy was similar for ICD-9 and ICD-10 codes. After 2015, method B was more accurate than method A: For term births, within-14-day-agreements were 90.8% for method A and 98.7% for method B. Corresponding estimates were 70.1% and 95.6% for preterm births; 35.3% and 92.6% for stillbirths; 54.3% and 64.2% for spontaneous abortions; and 16.7% and 84.6% for elective terminations. ICD-10-based algorithms that incorporate Z3A codes improve the accuracy of gestational age estimation in healthcare databases, especially for preterm and non-live births.

Overweight or obesity in children born after assisted reproductive technologies in Denmark: A population-based cohort study.

BACKGROUND: The association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility. METHODS AND FINDINGS: This Danish cohort study included 327,301 children born between 2007 and 2012 (51% males, median age at follow-up 7 years). Of these, 13,675 were born after ART, 7,728 were born after ovulation induction with or without intrauterine insemination [OI/IUI], and 305,898 were born after no fertility treatments. Using the International Obesity Task Force (IOTF) standards, we defined overweight (BMI ≥ IOTF-25) and obesity (BMI ≥ IOTF-30). We compared children born after ART versus OI/IUI; intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilization (IVF); and frozen-thawed versus fresh embryo transfer and estimated crude and adjusted prevalences of children with overweight or obesity at age 5 to 8 years, prevalence odds ratios (PORs), and differences in mean BMI z-scores. Adjustment was performed using stabilized inverse probability of treatment weights, including parity, year of conception, parental causes of infertility, age, educational level, comorbidities, maternal country of origin, BMI, and smoking as covariates. The crude prevalence of obesity was 1.9% in children born after ART, 2.0% in those born after OI/IUI, and 2.7% in those born after no fertility treatment. After adjustment, children born after ART and OI/IUI had the same prevalence of being overweight (11%; POR 1.00, 95% confidence interval [CI] 0.91 to 1.11; p = 0.95) or obese (1.9%; POR 1.01, 95% CI 0.79 to 1.29; p = 0.94). Comparison of ICSI with conventional IVF yielded similar pattern (POR 0.95, 95% CI 0.83 to 1.07; p = 0.39 for overweight and POR 1.16, 95% CI 0.84 to 1.61; p = 0.36 for obesity). Obesity was more prevalent after frozen-thawed (2.7%) than fresh embryo transfer (1.8%) (POR 1.54, 95% CI 1.09 to 2.17; p = 0.01). The associations between fertility treatments and BMI were only modestly different in subgroups defined by the cause of infertility. Study limitations include potential residual confounding, restriction to live births, and lack of detailed technical information about the IVF procedures. CONCLUSIONS: We found no association with BMI at age 5 to 8 years when comparing ART versus OI/IUI or when comparing ICSI versus conventional IVF. However, use of frozen-thawed embryo transfer was associated with a 1.5-fold increased risk of obesity compared to fresh embryo transfer. Despite an elevated relative risk, the absolute risk difference was low.

Evaluating Model Specification When Using the Parametric G-Formula in the Presence of Censoring.

The noniterative conditional expectation (NICE) parametric g-formula can be used to estimate the causal effect of sustained treatment strategies. In addition to identifiability conditions, the validity of the NICE parametric g-formula generally requires the correct specification of models for time-varying outcomes, treatments, and confounders at each follow-up time point. An informal approach for evaluating model specification is to compare the observed distributions of the outcome, treatments, and confounders with their parametric g-formula estimates under the "natural course." In the presence of loss to follow-up, however, the observed and natural-course risks can differ even if the identifiability conditions of the parametric g-formula hold and there is no model misspecification. Here, we describe 2 approaches for evaluating model specification when using the parametric g-formula in the presence of censoring: 1) comparing factual risks estimated by the g-formula with nonparametric Kaplan-Meier estimates and 2) comparing natural-course risks estimated by inverse probability weighting with those estimated by the g-formula. We also describe how to correctly compute natural-course estimates of time-varying covariate means when using a computationally efficient g-formula algorithm. We evaluate the proposed methods via simulation and implement them to estimate the effects of dietary interventions in 2 cohort studies.

Emulating a Target Trial of Interventions Initiated During Pregnancy with Healthcare Databases: The Example of COVID-19 Vaccination.

BACKGROUND: Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as an attempt to emulate a hypothetical pragmatic randomized trial: the target trial. OBJECTIVE: To provide a step-by-step description of how to use healthcare databases to estimate the effects of interventions initiated during pregnancy. As an example, we describe how to specify and emulate a target trial of COVID-19 vaccination during pregnancy, but the framework can be generally applied to point and sustained strategies involving both pharmacologic and non-pharmacologic interventions. METHODS: First, we specify the protocol of a target trial to evaluate the safety and effectiveness of vaccination during pregnancy. Second, we describe how to use observational data to emulate each component of the protocol of the target trial. We propose different target trials for different gestational periods because the outcomes of interest vary by gestational age at exposure. We identify challenges that affect (i) the target trial and thus its observational emulation (censoring and competing events), and (ii) mostly the observational emulation (confounding, immortal time, and measurement biases). CONCLUSION: Some biases may be unavoidable in observational emulations, but others are avoidable. For instance, immortal time bias can be avoided by aligning the start of follow-up with the gestational age at the time of the intervention, as we would do in the target trial. Explicitly emulating target trials at different gestational ages can help reduce bias and improve the interpretability of effect estimates for interventions during pregnancy.

Pesticide Residue Intake From Fruit and Vegetable Consumption and Risk of Glioma.

We aimed to determine whether intake of pesticide residues from fruits and vegetables was associated with glioma. Within 3 prospective cohorts from 1998-2016-the Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), and Health Professionals Follow-up Study-we computed multivariable-adjusted hazard ratios (MVHRs) and 95% confidence intervals (CI) for glioma by quintiles of intake of low- and high-pesticide-residue fruits and vegetables using Cox proportional hazards regression. Fruits and vegetables were categorized as high or low residue using a validated method based on pesticide surveillance data. We confirmed 275 glioma cases across 2,745,862 person-years. A significant association was observed between intake of high-residue fruits and vegetables and glioma in NHS (MVHR = 2.99, 95% CI: 1.38, 6.44 comparing highest with lowest quintile, P for trend = 0.02). This was not identified in NHSII (MVHR = 0.52, 95% CI: 0.19, 1.45, P for trend = 0.20) or Health Professionals Follow-up Study (MVHR = 1.01, 95% CI: 0.42, 2.45, P for trend = 0.39). No significant associations were observed by intake of low-residue fruits and vegetables; overall intake was not significantly associated with glioma in any cohort. We found no evidence for an inverse relationship of fruit and vegetable intake with glioma. Although limited in power, this study suggests a possible association between fruit-and-vegetable pesticide residue intake and risk of glioma that merits further study.

Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.

STUDY QUESTION: What are the comparative pregnancy outcomes in women who receive up to six consecutive cycles of ovulation induction with letrozole versus clomiphene citrate? SUMMARY ANSWER: The risks of pregnancy, livebirth, multiple gestation, preterm birth, neonatal intensive care unit (NICU) admission and congenital malformations were higher for letrozole compared with clomiphene in participants with polycystic ovarian syndrome (PCOS), though no treatment differences were observed in those with unexplained infertility. WHAT IS KNOWN ALREADY: Randomized trials have reported higher pregnancy and livebirth rates for letrozole versus clomiphene among individuals with PCOS, but no differences among those with unexplained infertility. None of these trials were designed to study maternal or neonatal complications. STUDY DESIGN, SIZE, DURATION: We emulated a hypothetical trial of the comparative effectiveness of letrozole versus clomiphene citrate for ovulation induction among all women, then stratified by PCOS and unexplained infertility status. We used real-world data from a large healthcare claims database in the USA (2011-2015). PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed data from 18 120 women who initiated letrozole and 49 647 women who initiated clomiphene during 2011-2014, and who were aged 18-45 years with no history of diabetes, thyroid disease, liver disease or breast cancer and had no fertility treatments for 3 months before trial initiation. The treatment strategies were clomiphene citrate or letrozole for six consecutive cycles. The outcomes were pregnancy, livebirth, multiple gestation, preterm birth, small for gestational age (SGA), NICU admission and major congenital malformations. We estimated the probability of each outcome under each strategy via pooled logistic regression and used standardization to adjust for confounding and selection bias due to loss to follow-up. MAIN RESULTS AND THE ROLE OF CHANCE: The estimated probabilities of pregnancy, livebirth and neonatal outcomes were similar under each strategy, both overall and among individuals with unexplained infertility. Among women with PCOS, the probability of pregnancy was 43% for letrozole vs 37% for clomiphene (risk difference [RD] = 6.0%; 95% CI: 4.4, 7.7) in the intention-to-treat analyses. The corresponding probability of livebirth was 32% vs 29% (RD = 3.1%; 95% CI: 1.5, 4.8). In per protocol analyses, the risk of multiple gestation was 19% vs 9%, the risk of preterm birth was 20% vs 15%, the risk of SGA was 5% vs 3%, the risk of NICU admission was 22% vs 16% and the risk of congenital malformation was 8% vs 2% among those with a livebirth. LIMITATIONS, REASONS FOR CAUTION: We cannot completely rule out the possibility of residual confounding by body mass index or duration of infertility. However, we adjusted for proxies identified in administrative data and results did not change. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that for women with unexplained infertility, the two treatments result in comparable probabilities of a livebirth. For women with PCOS, letrozole appears slightly more effective for attaining a livebirth. Neonatal outcomes were similar for the two treatments among women with unexplained infertility; we did not confirm the hypothesized higher risk of adverse neonatal outcomes for clomiphene versus letrozole. The risks of adverse neonatal outcomes were slightly greater among women with PCOS who were treated with letrozole versus clomiphene. It is likely that these effects are partially mediated through an increased risk of multiple gestation among women who received letrozole. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institute of Child Health and Human Development (R01HD088393). Y.-H.C. reports grants from the American Heart Association (834106) and NIH (R01HD097778). P.R. reports grants from the National Institutes of Health. J.H. reports grants from the National Institutes of Health, the Agency for Healthcare Research and Quality, and the California Health Care Foundation during the conduct of the study; and consulting for several health care delivery organizations including Cambridge Health Alliance, Columbia University, University of Southern California, Community Servings, and the Delta Health Alliance. S.H.-D. reports grants from the National Institutes of Health and the US Food and Drug Administration during the conduct of the study; grants to her institution from Takeda outside the submitted work; consulting for UCB (biopharmaceutical company) and Roche; and being an adviser for the Antipsychotics Pregnancy Registry and epidemiologist for the North American Antiepileptics Pregnancy Registry, both at Massachusetts General Hospital. M.A.H. reports grants from the National Institutes of Health and the U.S. Veterans Administration during the conduct of the study; being a consultant for Cytel; and being an adviser for ProPublica. TRIAL REGISTRATION NUMBER: N/A.

The Effect of Prenatal Treatments on Offspring Events in the Presence of Competing Events: An Application to a Randomized Trial of Fertility Therapies.

When studying the effect of a prenatal treatment on events in the offspring, failure to produce a live birth is a competing event for events in the offspring. A common approach to handle this competing event is reporting both the treatment-specific probabilities of live births and of the event of interest among live births. However, when the treatment affects the competing event, the latter probability cannot be interpreted as the causal effect among live births. Here we provide guidance for researchers interested in the effects of prenatal treatments on events in the offspring in the presence of the competing event "no live birth." We review the total effect of treatment on a composite event and the total effect of treatment on the event of interest. These causal effects are helpful for decision making but are agnostic about the pathways through which treatment affects the event of interest. Therefore, based on recent work, we also review three causal effects that explicitly consider the pathways through which treatment may affect the event of interest in the presence of competing events: the direct effect of treatment on the event of interest under an intervention to eliminate the competing event, the separable direct and indirect effects of treatment on the event of interest, and the effect of treatment in the principal stratum of those who would have had a live birth irrespective of treatment choice. As an illustrative example, we use a randomized trial of fertility treatments and risk of neonatal complications.

Effects of intergenerational exposure interventions on adolescent outcomes: An application of inverse probability weighting to longitudinal pre-birth cohort data.

BACKGROUND: There is great interest in understanding whether interventions on sugar-sweetened beverage (SSB) consumption through pregnancy and early childhood affect adolescent body mass index (BMI). Without data from randomised trials, unbiased estimation of such effects might be achieved with observational data given sufficient and appropriate adjustment for both baseline and time-varying confounders. OBJECTIVES: To illustrate the use of inverse probability (IP) weighting of marginal structural models (MSM) for estimating the effects of SSB consumption through pregnancy and early childhood on the mean early adolescent BMI z-score. METHODS: Our baseline sample consisted of 1584 pregnant women from a pre-birth cohort. We defined 6 intervention intervals: early pregnancy, late pregnancy, 3, 4, 5, and 6 years. We fitted a MSM via a weighted linear regression with IP exposure and censoring weights to estimate the mean difference in BMI z-score under interventions: "maintain SSB consumption below (vs above) 0.5 servings/day in all intervals." RESULTS: The estimated difference in mean BMI z-score under interventions maintaining SSB consumption at or below (vs above) 0.5 servings/day from pregnancy to 6 years was -0.94 (95% confidence interval [CI] -1.52, -0.08). The effect estimate in pregnancy, while fixing the exposure range in childhood, was -0.05 (95% CI -0.34, 0.23), and in early childhood, while fixing the range in pregnancy was -0.89 (95% CI -1.46, -0.11). The effect estimates were largely unchanged under sensitivity analyses to different implementation choices except for the choice of time interval length. CONCLUSIONS: Under assumptions that include no unmeasured confounding and selection bias, and no model misspecification, results of this IP weighting application are in line with a lower mean BMI z-score in early adolescence under interventions ensuring lower, vs greater, SSB consumption in early life. This application provides a resource for researchers working with longitudinal birth cohort studies and interested in similar causal questions.

Intake of Antioxidants in Relation to Infertility Treatment Outcomes with Assisted Reproductive Technologies.

BACKGROUND: Randomized trials of supplementation with antioxidant mixtures during infertility treatment show no benefit on pregnancy or live birth rate. However, the roles of individual antioxidants are poorly understood. We examined the association of baseline intake of vitamins A, C, E, and carotenoids with outcomes of assisted reproductive technologies (ARTs). METHODS: We followed 349 women undergoing a total of 588 ART cycles for infertility treatment at the Massachusetts General Hospital. We assessed antioxidant intakes from food and supplements before treatment using a validated food frequency questionnaire. We used generalized linear mixed models to account for multiple ART cycles per woman while adjusting for confounding. RESULTS: Mean (SD) age and body mass index were 35.1 years (4.0 years) and 24.1 kg/m (4.3 kg/m), respectively. Total intake of vitamins A, C, and E was not associated with the probability of live birth. Women in the highest intake category of ß-carotene from foods had a lower probability of live birth than women in the lowest intake quartile (50% vs. 22%; P trend = 0.03); for lutein and zeaxanthin, the probability for the highest intake group was 44% vs. 28% for the lowest. Intake of ß-carotene from supplements and intakes of retinol and all other carotenoids were unrelated to live birth rates. CONCLUSIONS: We found unexpected inverse associations of ß-carotene intake from foods and of lutein and zeaxanthin intake with live birth rates. Within the observed intake ranges, total consumption of vitamins A, C, and E before starting infertility treatment with ART was not associated with live birth rates.

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.

Waist circumference in relation to outcomes of infertility treatment with assisted reproductive technologies.

BACKGROUND: Many studies have documented a lower likelihood of live birth with increasing body mass index among women undergoing assisted reproductive technology, but few have examined the association with waist circumference, an anthropometric measure that allows assessment of central adiposity. OBJECTIVE: To examine the relation between baseline waist circumference and infertility treatment outcomes among women undergoing treatment with assisted reproductive technology. MATERIALS AND METHODS: We followed up 264 women who underwent 445 assisted reproductive technology cycles for infertility treatment at the Massachusetts General Hospital between 2010 and 2017. Waist circumference was assessed at enrollment. We used cluster-weighted generalized estimating equation models to estimate the probability of live birth by tertiles of waist circumference (<77, 77-86, >86 cm), while accounting for multiple treatment cycles per woman and adjusting for age, race, smoking, infertility diagnosis, day 3 follicle-stimulating hormone, body mass index, and height. RESULTS: Mean (standard deviation) waist circumference and body mass index were 83.6 (12.6) cm and 24.1 (4.3) kg/m2, respectively. Waist circumference and body mass index were positively correlated (r = 0.69, P < .0001). Waist circumference was inversely related to the probability of live birth after adjusting for BMI and other confounders. The multivariable adjusted probability of live birth (95% confidence interval) for women in increasing tertiles of waist circumference were 53% (42-65%), 42% (32-53%), and 38% (28-50%) (P, trend = .04). When women were classified in joint categories of body mass index and waist circumference, women with a body mass index ≥25 kg/m2 and a waist circumference ≥77 cm had the lowest live birth rate (38% [27-50%]), whereas women with a body mass index between 18.5 and 25 kg/m2 and a waist circumference <77 cm had the highest (54% [42-66%]). The results were similar using different waist circumference cut-off values. CONCLUSION: Waist circumference was inversely related to the probability of live birth among women undergoing assisted reproductive technology independently of body mass index.

Dietary patterns and outcomes of assisted reproduction.

BACKGROUND: There is growing acceptance that nutrition may be related to fertility and specifically to assisted reproductive technologies success in women; however, there is still no specific dietary guidance. OBJECTIVE: The objective of the study was to evaluate the relationship between pretreatment adherence to various dietary patterns and outcomes of assisted reproductive technologies. STUDY DESIGN: We followed up 357 women enrolled in the prospective Environment and Reproductive Health (EARTH) study, who underwent 608 assisted reproductive technologies cycles (2007-2017). Using a validated food frequency questionnaire completed prior to treatment, we assessed adherence to the Mediterranean diet, the alternate Healthy Eating Index 2010, the Fertility Diet (developed based on risk factors for anovulatory infertility), and a profertility diet we developed based on factors previously related to assisted reproductive technologies outcomes (higher intake of supplemental folic acid, vitamin B12, vitamin D, low- rather than high-pesticide residue produce, whole grains, dairy, soy foods, and seafood rather than other meats). RESULTS: Higher adherence to the alternate Healthy Eating Index 2010 and Fertility Diet was not related to live birth following assisted reproductive technologies. Women in the second through the fourth quartiles of Mediterranean diet adherence had significantly higher probability of live birth (0.44, 95% confidence interval, 0.39-0.49) compared with women in the first quartile (0.31, 95% confidence interval, 0.25-0.39); however, there was no additional benefit of adherence to the Mediterranean diet above the second quartile. Increased adherence to the profertility diet was linearly associated with assisted reproductive technologies outcomes. The adjusted odds (95% confidence interval) of implantation, clinical pregnancy, and live birth were higher by 47% (21%, 77%), 43% (19%, 72%), and 53% (26%, 85%), respectively, per SD increase. The adjusted difference in the proportion of cycles resulting in live birth for women in the fourth vs first quartile of adherence to the profertility diet was 0.28 (95% confidence interval, 0.16-0.38). While the profertility diet was not related to estradiol levels, oocyte counts, or endometrial thickness, it was inversely associated with clinical pregnancy loss (odds ratio, 0.69, 95% confidence interval, 0.53-0.90 per SD increase). CONCLUSION: Higher pretreatment adherence to the profertility diet was associated with an increased probability of live birth among women undergoing assisted reproductive technologies. Commonly recommended dietary advice such as adhering to the Mediterranean diet may not provide the most appropriate guidance for women undergoing infertility treatment in the United States.

Serum beta-carotene modifies the association between phthalate mixtures and insulin resistance: The National Health and Nutrition Examination Survey 2003-2006.

Animal models suggest a protective role of antioxidants against the adverse effect of di-2-ethylhexyl phthalate (DEHP) on insulin resistance. However, no epidemiologic study has examined the effects observed in the animal model. We conduct a study to examine associations of urinary concentrations of phthalate metabolites (individually and as a mixture) with insulin resistance, along with potential effect modification by serum antioxidant concentrations. This cross-sectional study included 1605 participants (51% males) aged 12-85 from the National Health and Nutrition Examination Surveys (2003-2006). Urinary concentrations of 9 phthalate metabolites were measured from spot urine samples. Antioxidant (vitamin A, C, E, and carotenoids) concentrations were measured from a fasting serum sample. We used Bayesian Kernel Machine Regression (BKMR) to evaluate associations between phthalate metabolite mixtures and insulin resistance, and examined whether serum antioxidant levels modified these associations, while accounting for the correlations of multiple concurrent exposures. A change in urinary ΣDEHP concentrations from the 25th to the 75th percentile was associated with a higher log HOMA-IR of 0.07 (95% CI = 0.01, 0.14) (4.85% increase in HOMA-IR). In contrast, the same change in urinary monoethyl phthalate (MEP) was associated with a lower HOMA-IR of -0.07 (95% CI = -0.14, -0.02) (6.68% decrease in HOMA-IR). The positive association between ΣDEHP and HOMA-IR became weaker at higher concentrations of serum ß-carotene. The relationship between MEP and HOMA-IR, however, was not modified by the serum antioxidants examined. The remaining phthalate metabolites were unrelated to HOMA-IR. In this cross-sectional study, the positive association between DEHP exposure and insulin resistance weakened among participants with higher concentrations of serum ß-carotene. As this is the first human report on the protective role of serum ß-carotene on DEHP induced insulin resistance, future studies are needed.

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.

A prospective analysis of circulating saturated and monounsaturated fatty acids and risk of non-Hodgkin lymphoma.

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non-Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre-diagnosis red blood cell (RBC) specimens in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T-NHL), B cell NHL (B-NHL) and three individual B-NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B-NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0 and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T-NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B-NHLs other than CLL/SLL and for VLCSFA and MUFA with T-NHL suggest an influence of fatty acid metabolism on lymphomagenesis.

Type of underwear worn and markers of testicular function among men attending a fertility center.

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.

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.

What Does a Single Semen Sample Tell You? Implications for Male Factor Infertility Research.

Semen parameters are variable within individuals, but it is unclear whether 1 semen sample could represent a man's long-term average values in epidemiologic studies. Between 2005 and 2014, a total of 329 men from a fertility clinic in Boston, Massachusetts, provided 768 semen samples as part of the Environment and Reproductive Health (EARTH) Study. Total sperm count, sperm concentration, morphology, motility, and ejaculate volume were assessed. We used linear mixed models to compare values from men's first semen samples with their long-term averages and to calculate intraclass correlation coefficients for each parameter. We calculated positive predictive values (PPVs) and negative predictive values (NPVs) by comparing agreement in classification according to World Health Organization reference limits. There were no differences in mean semen parameters between men's first samples and the remaining replicates. Intraclass correlation coefficients ranged from 0.61 for morphology to 0.75 for concentration, indicating consistently greater between-man variability than within-man variability. Nevertheless, using 1 sample alone resulted in high NPVs but low PPVs (range, 43%-91%). The average of 2 samples was needed to achieve high PPVs (range, 86%-100%) and NPVs (range, 91%-100%). We conclude that 1 semen sample may suffice for studies aimed at identifying average differences in semen quality between individuals. Studies aimed at classifying men based on World Health Organization reference limits may benefit from collection of 2 or more samples.