The Impact of a Lifestyle Intervention on Cardiometabolic Risk Factors among Postpartum Hispanic Women with Overweight and Obesity in a Randomized Controlled Trial (Proyecto Mamá).

INTRODUCTION: Maternal overweight or obesity has been associated with metabolic syndrome through 1 year postpartum, but it remains unknown whether a culturally-modified, motivationally-targeted, and individually-tailored Lifestyle Intervention could improve postpartum cardiometabolic health among Hispanic women with overweight or obesity. METHODS: Proyecto Mamá was a randomized controlled trial conducted in Western Massachusetts from 2014 to 2020 in which Hispanic women with overweight/obesity were randomized to a Lifestyle Intervention (LI) involving diet and exercise or to a comparison Health and Wellness Intervention (HW). Biomarkers of cardiovascular risk (i.e., lipids, C-reactive protein) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment [HOMA-IR], leptin, adiponectin) were measured at baseline (early pregnancy), mid-pregnancy, and 6 weeks, 6 months, and 12 months postpartum. Generalized linear mixed effect models were used to evaluate differences in the change in biomarkers over the course of postpartum follow-up time. RESULTS: In intent-to-treat analyses among eligible women (LI; n=51, HW; n=58) there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year; for example, the intervention effect for total cholesterol was 6.98 (SE: 6.36, p=0.27) and for HbA1c was -0.01 (SE: 0.4, p=0.85). In pooled analyses, regardless of intervention arm, women who participated in any vigorous activity had less of an increase in HbA1c (intervention effect = -0.17, SE: 0.05, p=0.002) compared to those with no vigorous activity, and similarly beneficial associations with other cardiovascular risk biomarkers (p<0.05). DISCUSSION: Women who participated in vigorous activity, regardless of their assigned intervention arm, had more favorable changes in biomarkers of insulin resistance.

Maternal comorbidity and adverse perinatal outcomes in survivors of adolescent and young adult cancer: A cohort study.

OBJECTIVE: To evaluate risks of preterm birth (PTB) and severe maternal morbidity (SMM) in female survivors of adolescent and young adult cancer and assess maternal comorbidity as a potential mechanism. To determine whether associations differ by use of assisted reproductive technology (ART). DESIGN: Retrospective cohort. SETTING: Commercially insured females in the USA. SAMPLE: Females with live births from 2000-2019 within a de-identified US administrative health claims data set. METHODS: Log-binomial regression models estimated relative risks of PTB and SMM by cancer status and tested for effect modification. Causal mediation analysis evaluated the proportions explained by maternal comorbidity. MAIN OUTCOME MEASURES: PTB and SMM. RESULTS: Among 46 064 cancer survivors, 2440 singleton births, 214 multiple births and 2590 linked newborns occurred after cancer diagnosis. In singleton births, the incidence of PTB was 14.8% in cancer survivors versus 12.4% in females without cancer (aRR 1.19, 95% CI 1.06-1.34); the incidence of SMM was 3.9% in cancer survivors versus 2.4% in females without cancer (aRR 1.44, 95% CI 1.13-1.83). Cancer survivors had more maternal comorbidities before and during pregnancy; 26% of the association between cancer and PTB and 30% of the association between cancer and SMM was mediated by maternal comorbidities. Tests for effect modification of cancer status on perinatal outcomes by ART were non-significant. CONCLUSIONS: Preterm birth and SMM risks were modestly increased after cancer. Significant proportions of elevated risks may result from increased comorbidities. ART did not significantly modify the association between adolescent and young adult cancer and adverse perinatal outcomes. The prevention and treatment of comorbidities provides an opportunity to improve perinatal outcomes among cancer survivors.

Race-specific associations between psychological distress and obesity: the role of social cohesion.

OBJECTIVE: Nearly two-thirds of Black women in the US are obese. Studies have focused more on lifestyle and behavioral factors to explain racial disparities; less research has examined psychosocial factors such as psychological distress and social cohesion. While research suggests that social cohesion may confer benefits for health, no studies have assessed how social cohesion is related to both mental health and obesity, and potential racial differences. Our study examined associations between psychological distress, social cohesion, and obesity among Black and White adult women. DESIGN: Data are from the 2014-2018 National Health Interview Survey (n = 66,743). Participants self-reported psychological distress (Kessler K6 scale), obesity (body mass index≥30 kg/m2), and social cohesion. We fit logistic regression models of obesity with likelihood ratio tests for effect modification by social cohesion and by race. RESULTS: Psychological distress was associated with a 1.19 and 1.31 higher odds of obesity for Black (95% confidence interval: 1.05, 1.36) and White women (1.24, 1.39), respectively. Social cohesion was associated with a 0.75 lower odds of obesity among White (0.69, 0.81) but not Black women (odds ratio 0.94; 0.80, 1.10). Tests of interaction indicated no differences by social cohesion or race in the association between psychological distress and obesity. CONCLUSION: Findings highlight complex relationships between psychological distress, obesity, and social cohesion in Black and White women. Public health efforts should focus on understanding mechanisms relating social factors to health.

Association of In Utero Exposures With Risk of Early Natural Menopause.

Suboptimal pregnancy conditions may affect ovarian development in the fetus and be associated with early natural menopause (ENM) for offspring. A total of 106,633 premenopausal participants in Nurses' Health Study II who provided data on their own prenatal characteristics, including diethylstilbestrol (DES) exposure, maternal cigarette smoking exposure, multiplicity, prematurity, and birth weight, were followed from 1989 to 2017. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of in utero exposures with ENM. During 1.6 million person-years of follow-up, 2,579 participants experienced ENM. In multivariable models, women with prenatal DES exposure had higher risk of ENM compared with those without it (HR = 1.33, 95% CI: 1.06, 1.67). Increased risk of ENM was observed for those with low (<5.5 pounds (<2.5 kg)) versus normal (7.0-8.4 pounds (3.2-3.8 kg)) birth weight (HR = 1.21, 95% CI: 1.01, 1.45). Decreasing risk was observed per 1-pound (0.45-kg) increase in birth weight (HR = 0.93, 95% CI: 0.90, 0.97). Prenatal smoking exposure, being part of a multiple birth, and prematurity were not associated with ENM. In this large cohort study, lower birth weight and prenatal DES exposure were associated with higher risk of ENM. Our results support a need for future research to examine in utero exposures that may affect offspring reproductive health.

Anti-Müllerian hormone levels and breast cancer risk in the study of women's health across the nation.

PURPOSE: The relation of premenopausal anti-Müllerian hormone (AMH) levels with breast cancer risk has been evaluated in a few studies, but primarily in non-Hispanic White women. METHODS: We evaluated the association of AMH levels with breast cancer risk in Study of Women's Health Across the Nation (SWAN), a multi-ethnic cohort of women. At enrollment, participants had an intact uterus and ≥ 1 ovary, and ≥ 1 menstrual period in the last 3 months. AMH at first measurement was assessed in 1,529 pre- or perimenopausal women using a high-sensitivity ELISA assay; values were natural log transformed. Breast cancer diagnoses were assessed at enrollment and subsequent follow-up visits through 2018 (median 6.1 years). RESULTS: In total, 84 women reported an incident breast cancer diagnosis. In multivariable Cox regression models adjusting for age, race and ethnicity, body mass index, and other factors, higher AMH levels were associated with a non-significant increased breast cancer risk. Compared to women in the 1st quartile, the hazard ratio (95% confidence interval) for women in the 4th quartile was 1.77 (0.87-3.60). CONCLUSION: Our results did not suggest a significant association between AMH and breast cancer risk; however, estimates were consistent with prior studies that reported positive associations.

Sperm epigenetic clock associates with pregnancy outcomes in the general population.

STUDY QUESTION: Is sperm epigenetic aging (SEA) associated with probability of pregnancy among couples in the general population? SUMMARY ANSWER: We observed a 17% lower cumulative probability at 12 months for couples with male partners in the older compared to the younger SEA categories. WHAT IS KNOWN ALREADY: The strong relation between chronological age and DNA methylation profiles has enabled the estimation of biological age as epigenetic 'clock' metrics in most somatic tissue. Such clocks in male germ cells are less developed and lack clinical relevance in terms of their utility to predict reproductive outcomes. STUDY DESIGN, SIZE, DURATION: This was a population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 and followed for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm DNA methylation from 379 semen samples was assessed via a beadchip array. A state-of-the-art ensemble machine learning algorithm was employed to predict age from the sperm DNA methylation data. SEA was estimated from clocks derived from individual CpGs (SEACpG) and differentially methylated regions (SEADMR). Probability of pregnancy within 1 year was compared by SEA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates. MAIN RESULTS AND THE ROLE OF CHANCE: Our SEACpG clock had the highest predictive performance with correlation between chronological and predicted age (r = 0.91). In adjusted discrete Cox models, SEACpG was negatively associated with TTP (fecundability odds ratios (FORs)=0.83; 95% CI: 0.76, 0.90; P = 1.2×10-5), indicating a longer TTP with advanced SEACpG. For subsequent birth outcomes, advanced SEACpG was associated with shorter gestational age (n = 192; -2.13 days; 95% CI: -3.67, -0.59; P = 0.007). Current smokers also displayed advanced SEACpG (P < 0.05). Finally, SEACpG showed a strong performance in an independent IVF cohort (n = 173; r = 0.83). SEADMR performance was comparable to SEACpG but with attenuated effect sizes. LIMITATIONS, REASONS FOR CAUTION: This prospective cohort study consisted primarily of Caucasian men and women, and thus analysis of large diverse cohorts is necessary to confirm the associations between SEA and couple pregnancy success in other races/ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: These data suggest that our sperm epigenetic clocks may have utility as a novel biomarker to predict TTP among couples in the general population and underscore the importance of the male partner for reproductive success. STUDY FUNDING/COMPETING INTEREST(S): This work was funded in part by grants the National Institute of Environmental Health Sciences, National Institutes of Health (R01 ES028298; PI: J.R.P. and P30 ES020957); Robert J. Sokol, MD Endowed Chair of Molecular Obstetrics and Gynecology (J.R.P.); and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). S.L.M. was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Urinary phthalate metabolites and their mixtures are associated with advanced sperm epigenetic aging in a general population.

INTRODUCTION: We have recently shown that sperm epigenetic age (SEA), a surrogate measure of biological aging in sperm, is associated with couples' time-to-pregnancy (TTP). Advanced SEA was also observed among smokers, suggesting its susceptibility to environmental exposures. Therefore, we assessed the association between urinary phthalate metabolites and SEA in male partners of couples planning to conceive among the general population. METHOD: The Longitudinal Investigation of Fertility and the Environment (LIFE) Study was a prospective multi-site and general population cohort study of couples who were interested in becoming pregnant. Among male partners (n = 333), eleven urinary phthalate metabolites were measured and SEA was previously developed using Super Learner ensemble algorithm. Multivariable linear regression was used to evaluate associations of SEA with individual metabolites. Bayesian kernel machine regression (BKMR), quantile g-computation (qgcomp) and weighted quantile sum (WQS) models were used for mixture analyses. Covariates included were BMI, cotinine, race and urinary creatinine. RESULT: In the single metabolite multivariate analyses, nine (82%) phthalate metabolites displayed positive trends with SEA (range: 0.05-0.47 years). Of these metabolites, advanced SEA was significantly associated with interquartile range increases in exposure of three phthalates [MEHHP (ß = 0.23, 95% CI: 0.03, 0.43, p = 0.03), MMP (ß = 0.24, 95% CI: 0.01, 0.47, p = 0.04), and MiBP (ß = 0.47, 95% CI: 0.14, 0.81, p = 0.01)]. Additionally, in BKMR and qgcomp (p = 0.06), but not WQS models, phthalate mixtures showed an overall positive trend with SEA, with MiBP, MMP and MBzP as major drivers of the mixture effects. CONCLUSION: This is the first study that combined single exposure and mixture models to associate male phthalate exposures with advanced epigenetic aging of sperm in men planning to conceive among the general population. Our findings suggest that phthalate exposure may contribute to the acceleration of biological aging of sperm.

The association between anthropometric factors and anti-Müllerian hormone levels in premenopausal women.

Adiposity has been associated with several health conditions as well as timing of menopause. Prior epidemiologic studies on the association of adiposity and anti-Müllerian hormone (AMH) have been inconsistent. We evaluated the relations of anthropometric measures with AMH at two time periods in a subset of premenopausal participants in the Nurses' Health Study II. This prospective study included 795 women who provided a premenopausal sample in 1996-1999 and in 2010-2012. Current weight and height, and weight at age 18 were assessed in 1989 and weight again in 1996-1999. Waist and hip circumference were measured and reported in 1993. In linear regression models adjusted for smoking, reproductive events, and other factors, AMH was inversely related to BMI at age 18 (P = .03) and in 1996-1999 (P < .0001). Higher waist circumference was related to lower AMH levels in 1996-1999 (p = .0009). BMI in 1996-1999 was inversely associated with AMH levels in 2010-2012 (P = .005). Weight gain between age 18 and 1996-1999 was strongly inversely associated with AMH levels in 1996-1999 (P < .0001) and in 2010-2012 (P < .0001). Our results indicate that adiposity and weight gain are associated with lower AMH levels, suggesting an adverse impact on ovarian function.

Invited Commentary: Theoretical Considerations and Real-World Challenges for Research on Proxy Exposures and Ovarian Reserve.

In this issue of the Journal, Upson et al. (Am J Epidemiol. 2021;190(1):116-124) assess urinary cadmium level as a potential environmental influence on ovarian reserve, as measured using serum follicle-stimulating hormone, in data from 1,681 US women (1988-1994). They compare 3 methods for modeling urinary proxy exposures-standardization, covariate adjustment, and covariate-adjusted standardization. Observing positive associations with all 3 approaches but higher-magnitude estimates using covariate adjustment as compared with standardization and covariate-adjusted standardization-proposed to be the result of collider-stratification bias-the authors conclude that cadmium may affect ovarian aging, and they recommend careful consideration of modeling approach. Comparisons of methodology in practice using real data are not straightforward, and additional complication arises from using a proxy outcome-serum follicle-stimulating hormone level to represent diminished ovarian reserve. In this commentary, I describe the theoretical basis for approaches for modeling urinary proxy exposures; consider potential explanations for why the approaches may yield different results in practice and describe why measurement error may play a larger role than collider-stratification bias; discuss challenges related to studies of ovarian reserve; and emphasize the importance of addressing both theoretical concerns and real-world challenges in methodological research and epidemiologic studies of ovarian reserve.

Teaching Epidemiology Online (Pandemic Edition).

In response to the threat posed by the coronavirus disease 2019 (COVID-19) pandemic, many universities are encouraging or requiring online instruction. Teaching an epidemiology course online is different in many respects from teaching in person. In this article, we review specific approaches and strategies related to teaching epidemiology online during the pandemic and beyond, including a discussion of options for course format, grading and assessment approaches, pandemic-related contingencies, and the use of technology. Throughout this article we present practical, epidemiology-specific teaching examples. Moreover, we also examine 1) how the lessons learned about the practice of epidemiology during the pandemic can be integrated into the didactic content of epidemiology training programs and 2) whether epidemiologic pedagogy and teaching strategies should change in the long term, beyond the COVID-19 pandemic. The pandemic has served to heighten our awareness of concerns related to student health and safety, as well as issues of accessibility, equity, and inclusion. Our goal is to present a practical overview connecting pandemic-era online teaching with thoughts about the future of epidemiologic instruction.

Is Alcohol Consumption Associated With Risk of Early Menopause?

Earlier age at menopause is associated with increased long-term health risks. Moderate alcohol intake has been suggested to delay menopause onset, but it is unknown whether alcohol subtypes are associated with early menopause onset at age 45 years. Therefore, we aimed to evaluate risk of early natural menopause among 107,817 members of the Nurses' Health Study II who were followed from 1989 to 2011. Alcohol consumption overall and by subtypes, including beer, red wine, white wine, and liquor, was assessed throughout follow-up. We estimated hazard ratios in multivariable models that were adjusted for age, body mass index, parity, smoking, and other potential confounders. Women who reported moderate current alcohol consumption had lower risks of early menopause than did nondrinkers. Those who reported consuming 10.0-14.9 g/day had a lower risk of early menopause than did nondrinkers (hazard ratio = 0.81, 95% confidence interval: 0.68, 0.97). Among specific beverages, evidence of lower early menopause risk was confined to consumption of white wine and potentially red wine and liquor, but not to beer. Data from this large prospective study suggest a weak association of moderate alcohol intake with lower risk of early menopause, which was most pronounced for consumption of white and red wine and liquor. High consumption was not related to lower risk of early menopause.

Psychosocial stress and ovarian function in adolescent and young adult cancer survivors.

STUDY QUESTION: Is psychosocial stress associated with ovarian function in reproductive-aged survivors of cancer diagnosed as adolescents and young adults (AYA survivors)? SUMMARY ANSWER: We observed no association between self-reported and biomarkers of psychosocial stress and ovarian function in AYA survivors. WHAT IS KNOWN ALREADY: Psychosocial stress suppresses hypothalamic-pituitary-ovarian axis, resulting in ovulatory dysfunction, decreased sex steroidogenesis and lower fertility in reproductive-aged women. Many cancer survivors experience high psychosocial stress and hypothalamic-pituitary-adrenal axis dysregulation. The menstrual pattern disturbances and infertility they experience have been attributed to ovarian follicle destruction, but the contribution of psychosocial stress to these phenotypes is unknown. STUDY DESIGN, SIZE, DURATION: A cross-sectional study was conducted estimating the association between perceived stress, measured by self-report and saliva cortisol, and ovarian function, measured by bleeding pattern, dried blood spot (DBS) FSH and LH, and saliva estradiol. We included 377 AYA survivor participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: AYA survivor participants were ages 15-35 at cancer diagnosis and ages 18-40 at study enrollment, had completed primary cancer treatment, had a uterus and at least one ovary, did not have uncontrolled endocrinopathy and were not on hormone therapy. Recruited from cancer registries, physician referrals and cancer advocacy groups, participants provided self-reported information on psychosocial stress (Perceived Stress Scale-10 (PSS-10)) and on cancer and reproductive (fertility, contraception, menstrual pattern) characteristics. DBS samples were collected timed to the early follicular phase (cycle Days 3-7) for menstruating individuals and on a random day for amenorrheic individuals; saliva samples were collected three time points within 1 day. FSH and LH were measured by DBS ELISAs, cortisol was measured by ELISA and estradiol was measured by liquid chromatography tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: The median age of participants was 34.0 years (range 19-41) at a median of 6.0 years since cancer diagnosis. The most common cancer was breast (32.1%). Median PSS-10 score was 15 (range 0-36), with 5.3% scoring ≥26, the cut point suggestive of severe stress. Cortisol levels followed a diurnal pattern and cortisol AUC was negatively correlated with PSS-10 scores (P = 0.03). Neither PSS-10 scores nor cortisol AUC were associated with FSH, LH, estradiol levels or menstrual pattern. Waking and evening cortisol and the cortisol awakening response also were not related to ovarian function measures. LIMITATIONS, REASONS FOR CAUTION: Our analysis is limited by its cross-sectional nature, heterogeneity of cancer diagnosis and treatments and low prevalence of severe stress. WIDER IMPLICATIONS OF THE FINDINGS: The lack of association between psychosocial stress and a variety of ovarian function measures in female AYA cancer survivors suggests that psychosocial stress does not have a significant impact on the reproductive axis of AYA survivors. This finding is important in counseling this population on their menstrual pattern and family building plans. STUDY FUNDING/COMPETING INTEREST(S): NIH HD080952, South Korea Health Industry Development Institute HI18C1837 (JK). Dr A.D. works for Bluebird Bio, Inc., Dr D.Z. works for ZRT Labs and Dr P.M.S. works for Ansh Labs, which did not sponsor, support or have oversight of this research. Other authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Higher reproductive concerns associated with fertility consultation: a cross-sectional study of young adult male cancer survivors.

PURPOSE: This study examined associations between fertility consultation (FC) and multiple dimensions of reproductive concerns among young adult (YA) male cancer survivors. METHODS: One hundred and seventy YA male cancer survivors (age 18 to 35) across the USA completed an online survey between 2016 and 2018. Participants reported demographics, receipt of FC, and reproductive concerns. Reproductive concerns were measured multidimensionally using the Reproductive Concerns after Cancer-Male scale. We used log binomial regression to examine associations between FC and high reproductive concerns across multiple domains. RESULTS: In multivariate analyses adjusting for desire for children, FC was associated with higher likelihood of having at least one high reproductive concern (relative risk [RR] 1.4, 95% CI 1.2-1.7). Across subscales, FC was associated with greater likelihood of having high concerns about fertility potential (RR 1.7, 95% CI 1.0-3.0), achieving pregnancy (RR 3.5, 95% CI 1.3-9.5), their (potential) child's health (RR 1.5, 95% CI 1.1-2.2), and disclosing infertility to a partner (RR 2.7, 95% CI 1.8-4.1). In contrast, associations were not observed between FC and likelihood of high concerns about personal health (RR 1.4, 95% CI 0.5-3.8) or acceptance of infertility (RR 1.8, 95% CI 0.8-3.9). CONCLUSIONS: YA male cancer survivors who received FC were more likely to have high reproductive concerns than those who did not receive FC. Men who seek out FC after cancer diagnosis may need additional support for their reproductive concerns. Research is needed to identify strategies to alleviate these concerns among this population.

Sperm mitochondrial DNA biomarkers and couple fecundity.

STUDY QUESTION: Do sperm mitochondrial DNA measures predict probability of pregnancy among couples in the general population? SUMMARY ANSWER: Those with high sperm mitochondrial DNA copy number (mtDNAcn) had as much as 50% lower odds of cycle-specific pregnancy, and 18% lower probability of pregnancy within 12 months. WHAT IS KNOWN ALREADY: Semen parameters have been found to poorly predict reproductive success yet are the most prevalent diagnostic tool for male infertility. Increased sperm mtDNAcn and mitochondrial DNA deletions (mtDNAdel) have been associated with decreased semen quality and lower odds of fertilization in men seeking fertility treatment. STUDY DESIGN, SIZE, DURATION: A population-based prospective cohort study of couples discontinuing contraception to become pregnant recruited from 16 US counties from 2005 to 2009 followed for up to 16 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sperm mtDNAcn and mtDNAdel from 384 semen samples were assessed via triplex probe-based quantitative PCR. Probability of pregnancy within 1 year was compared by mitochondrial DNA, and discrete-time proportional hazards models were used to evaluate the relations with time-to-pregnancy (TTP) with adjustment for covariates. MAIN RESULTS AND THE ROLE OF CHANCE: Higher sperm mtDNAcn was associated with lower pregnancy probability within 12 months and longer TTP. In unadjusted comparisons by quartile (Q), those in Q4 had a pregnancy probability of 63.5% (95% CI: 53.1% to 73.1%) compared to 82.3% (95% CI: 73.2% to 89.9%) for Q1 (P = 0.002). Similar results were observed in survival analyses adjusting for covariates to estimate fecundability odds ratios (FORs) comparing mtDNAcn in quartiles. Relative to those in Q1 of mtDNAcn, FORs (95% CI) were for Q2 of 0.78 (0.52 to 1.16), Q3 of 0.65 (0.44 to 0.96) and Q4 of 0.55 (0.37 to 0.81), and this trend of decreasing fecundability with increasing mtDNAcn quartile was statistically significant (FOR per log mtDNAcn = 0.37; P < 0.001). Sperm mtDNAdel was not associated with TTP. LIMITATIONS, REASONS FOR CAUTION: This prospective cohort study consisted primarily of Caucasian men and women and thus large diverse cohorts are necessary to confirm the associations between sperm mtDNAcn and couple pregnancy success in other races/ethnicities. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate that sperm mtDNAcn has utility as a biomarker of male reproductive health and probability of pregnancy success in the general population. STUDY FUNDING/COMPETING INTEREST(S): This work was funded in part by the National Institute of Environmental Health Sciences, National Institutes of Health (R01-ES028298; PI: J.R.P.) and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contracts N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Confounding and effect measure modification in reproductive medicine research.

The majority of research within reproductive and gynecologic health, or investigating ART, is observational in design. One of the most critical challenges for observational studies is confounding, while one of the most important for discovery and inference is effect modification. In this commentary, we explain what confounding and effect modification are and why they matter. We present examples illustrating how failing to adjust for a confounder leads to invalid conclusions, as well as examples where adjusting for a factor that is not a confounder also leads to invalid or imprecise conclusions. Careful consideration of which factors may act as confounders or modifiers of the association of interest is critical to conducting sound research, particularly with complex observational studies in reproductive medicine.