Association of platinum-based chemotherapy with live birth and infertility in female survivors of adolescent and young adult cancer.

OBJECTIVE: To estimate the effect of platinum-based chemotherapy on live birth (LB) and infertility after cancer, in order to address a lack of treatment-specific fertility risks for female survivors of adolescent and young adult cancer, which limits counseling on fertility preservation decisions. DESIGN: Retrospective cohort study. SETTING: US administrative database. PATIENTS: We identified incident breast, colorectal, and ovarian cancer cases in females aged 15-39 years who received platinum-based chemotherapy or no chemotherapy and matched them to females without cancer. INTERVENTION: Platinum-based chemotherapy. MAIN OUTCOME MEASURES: We estimated the effect of chemotherapy on the incidence of LB and infertility after cancer, overall, and after accounting for competing events (recurrence, death, and sterilizing surgeries). RESULTS: There were 1,287 survivors in the chemotherapy group, 3,192 in the no chemotherapy group, and 34,147 women in the no cancer group, with a mean age of 33 years. Accounting for competing events, the overall 5-year LB incidence was lower in the chemotherapy group (3.9%) vs. the no chemotherapy group (6.4%). Adjusted relative risks vs. no chemotherapy and no cancer groups were 0.61 (95% confidence interval [CI] 0.42-0.82) and 0.70 (95% CI 0.51-0.93), respectively. The overall 5-year infertility incidence was similar in the chemotherapy group (21.8%) compared with the no chemotherapy group (20.7%). The adjusted relative risks vs. no chemotherapy and no cancer groups were 1.05 (95% CI 0.97-1.15) and 1.42 (95% CI 1.31-1.53), respectively. CONCLUSIONS: Cancer survivors treated with platinum-based chemotherapy experienced modestly increased adverse fertility outcomes. The estimated effects of platinum-based chemotherapy were affected by competing events, suggesting the importance of this analytic approach for interpretations that ultimately inform clinical fertility preservation decisions.

The impact of a lifestyle intervention on postpartum weight retention among US Hispanic women with overweight and obesity.

Introduction: To evaluate the effect of a culturally-modified, motivationally-targeted, individually-tailored lifestyle intervention on postpartum weight retention among Hispanic women with overweight/obesity. Materials and methods: Proyecto Mamá was a randomized controlled trial conducted in western Massachusetts (2014-2020). Hispanic women with overweight/obese pre-pregnancy BMI (n = 148) were randomized in early pregnancy to a Lifestyle Intervention (LI) or a Health & Wellness (HW) comparison arm. The LI was based upon theoretical concepts, used a low-cost, high-reach strategy, and focused on healthy exercise and diet with follow-up through 12-months postpartum. The primary outcome of change in weight was calculated as the difference between pre-pregnancy weight and 6-week, 6-month, and 12-month postpartum weight. The secondary outcome was achievement of 5 % weight reduction from pre-pregnancy weight. Retention was 68.2 % in the overall postpartum period and 31.0 % at 12-months. Results: In intent-to-treat analyses, compared to the HW arm, there was no difference in postpartum weight retention at 6-weeks (0.0 kg, 95 % CI: -3.4, 3.5), 6-months (-1.8 kg, 95 % CI: -5.6, 2.0), or 12-months (-2.0 kg, 95 % CI: -7.0, 3.1). In a secondary complete case analysis, compared to the HW arm, the LI arm had 5.5 times higher odds of meeting the postpartum weight reduction goal (aOR = 5.5, 95 % CI: 1.7, 17.9) adjusting for pre-pregnancy weight. Conclusions: A lifestyle intervention among at-risk Hispanic women with overweight/obesity had no overall impact on postpartum weight, but a beneficial impact among those who completed the trial. Future studies should focus on increasing the feasibility and acceptability of the intervention in this at-risk population.

The Impact of a Lifestyle Intervention on Postpartum Cardiometabolic Risk Factors Among Hispanic Women With Abnormal Glucose Tolerance During Pregnancy: Secondary Analysis of a Randomized Trial.

BACKGROUND: Women with abnormal glucose tolerance during pregnancy are at risk for cardiovascular disease (CVD), with higher rates among Hispanics. However, studies on the impact of lifestyle interventions on postpartum CVD profiles are sparse. METHODS: This is a secondary analysis of a controlled trial among a subsample of Hispanic women with abnormal glucose tolerance participating in Estudió PARTO (Project Aiming to Reduce Type twO diabetes; mean age = 28.2 y, SD: 5.8) who were randomized to a culturally modified Lifestyle intervention (n = 45) or a comparison Health and Wellness intervention (n = 55). Primary endpoints were biomarkers of cardiovascular risk (lipids, C-reactive protein, fetuin-A, and albumin-to-creatinine ratio) and insulin resistance (fasting insulin, glucose, HbA1c, homeostasis model assessment, leptin, tumor necrosis factor-alpha, and adiponectin) measured at baseline (6-wk postpartum) and 6 and 12 months. RESULTS: In intent-to-treat analyses, there were no significant differences in changes in biomarkers of CVD risk or insulin resistance over the postpartum year. In prespecified sensitivity analyses, women adherent with the Lifestyle Intervention had more favorable improvements in insulin (intervention effect = -4.87, SE: 1.93, P = .01) and HOMA-IR (intervention effect = -1.15, SE: 0.53, P = .03) compared with the Health and Wellness arm. In pooled analyses, regardless of intervention arm, women with higher postpartum sports/exercise had greater increase in HDL-cholesterol (intervention effect = 6.99, SE: 1.72, P = .0001). CONCLUSIONS: In this randomized controlled trial among Hispanic women with abnormal glucose tolerance, we did not observe a significant effect on postpartum biomarkers of CVD risk or insulin resistance. Women adherent to the intervention had more favorable changes in insulin and HOMA-IR.

Non-coding RNAs from seminal plasma extracellular vesicles and success of live birth among couples undergoing fertility treatment.

Background: Infertility remains a global health problem with male-factor infertility accounting for around 50% of cases. Understanding the molecular markers for the male contribution of live birth success has been limited. Here, we evaluated the expression levels of seminal plasma extracellular vesicle (spEV) non-coding RNAs (ncRNAs) in men of couples in relation with those with and without a successful live birth after infertility treatment. Method: Sperm-free spEV small RNA profiles were generated from 91 semen samples collected from male participants of couples undergoing assisted reproductive technology (ART) treatment. Couples were classified into two groups based on successful live birth (yes, n = 28) and (no, n = 63). Mapping of reads to human transcriptomes followed the order: miRNA > tRNA > piRNA > rRNA> "other" RNA > circRNA > lncRNA. Differential expression analysis of biotype-specific normalized read counts between groups were assessed using EdgeR (FDR<0.05). Result: We found a total of 12 differentially expressed spEV ncRNAs which included 10 circRNAs and two piRNAs between the live birth groups. Most (n = 8) of the identified circRNAs were downregulated in the no live birth group and targeted genes related to ontology terms such as negative reproductive system and head development, tissue morphogenesis, embryo development ending in birth or egg hatching, and vesicle-mediated transport. The differentially upregulated piRNAs overlapped with genomic regions including coding PID1 genes previously known to play a role in mitochondrion morphogenesis, signal transduction and cellular proliferation. Conclusion: This study identified novel ncRNAs profiles of spEVs differentiating men of couples with and without live birth and emphasizes the role of the male partner for ART success.

Urinary phthalate metabolites and small non-coding RNAs from seminal plasma extracellular vesicles among men undergoing infertility treatment.

Non-coding RNA (ncRNA) cargo of extracellular vesicles (EVs) in the male reproductive tract play critical roles in semen quality and emerging evidence suggests their susceptibility to environmental factors. Male phthalate exposures have been linked to poor semen quality, sperm DNA methylation profiles and embryo development; however, there is limited evidence on their potential impact on EV ncRNAs profiles. We evaluated the association between urinary phthalate metabolites and small ncRNAs (sncRNAs) of seminal plasma EVs (spEV) among men receiving clinical infertility care. We conducted sncRNA sequencing of EVs in 96 seminal plasma samples collected from the Sperm Environmental Epigenetics and Development Study (SEEDS). Sequencing reads were mapped to human transcriptome databases using STAR. Urinary metabolite concentrations of thirteen phthalates and two DiNCH, a phthalate alternative, were measured via tandem mass spectrometry. Associations with normalized counts were assessed using EdgeR (FDR<0.05) adjusting for urinary dilution via specific gravity, age, BMI, batch, and biotype-specific total counts. Select metabolites, MEOHP, MECPP, ∑DEHP, MCPP, MCNP, MCOP, were negatively (p < 0.05) correlated with miRNA relative abundance. Similarly, nine metabolites including MEOHP, MECPP, MEHP, MCPP, MHBP, MHiNCH, MiBP, MEHHP, MCOP and ∑DEHP were associated (q < 0.05) with normalized counts from 23 unique ncRNA transcripts (7 miRNAs (pre & mature); 6 tRFs; and 10 piRNAs), most (78%) of which displayed increased expression patterns. miRNA and tRFs gene targets were enriched in vesicle-mediated transport and developmental-related ontology terms, such as tyrosine kinase, head development, and cell morphogenesis. Six genes (MAPK1, BMPR1A/2, PTEN, TGFBR2, TP53 and APP) were present in all the ontology terms and predicted to form protein association networks. piRNAs were annotated to pseudogenes of genes important in EV cargo transfer and embryonic development. This is the first study to associate phthalate exposures to altered spEV sncRNA profiles. Future studies are needed to determine their impact on reproductive outcomes.

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.

Preconception sleep duration, sleep timing, and shift work in association with fecundability and live birth among women with a history of pregnancy loss.

OBJECTIVE: To evaluate the associations between preconception sleep characteristics and shift work with fecundability and live birth. DESIGN: Secondary analysis of the Effects of Aspirin in Gestation and Reproduction study, a preconception cohort. SETTING: Four US academic medical centers. PATIENT(S): Women aged 18-40 with a history of 1-2 pregnancy losses who were attempting to conceive again. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURES(S): We evaluated baseline, self-reported sleep duration, sleep midpoint, social jetlag, and shift work among 1,228 women who were observed for ≤6 cycles of pregnancy attempts to ascertain fecundability. We ascertained live birth at the end of follow up via chart abstraction. We estimated fecundability odds ratios (FORs) using discrete, Cox proportional hazards models and risk ratios (RRs) for live birth using log-Poisson models. RESULT(S): Sleep duration ≥9 vs. 7 to <8 hours (FOR: 0.81, 95% confidence interval [CI], 0.61; 1.08), later sleep midpoints (3rd tertile vs. 2nd tertile: FOR: 0.85; 95% CI, 0.69, 1.04) and social jetlag (continuous per hour; FOR: 0.93, 95% CI: 0.86, 1.00) were not associated with reduced fecundability. In sensitivity analyses, excluding shift workers, sleep duration ≥9 vs. 7 to <8 hours (FOR: 0.62; 95% CI, 0.42; 0.93) was associated with low fecundability. Night shift work was not associated with fecundability (vs. non-night shift work FOR: 1.17, 95% CI, 0.96; 1.42). Preconception sleep was not associated with live birth. CONCLUSION(S): Overall, there does not appear to be a strong association between sleep characteristics, fecundability, and live birth. Although these findings may suggest weak and imprecise associations with some sleep characteristics, our findings should be evaluated in larger cohorts of women with extremes of sleep characteristics. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT00467363.

Altered non-coding RNA profiles of seminal plasma extracellular vesicles of men with poor semen quality undergoing in vitro fertilization treatment.

BACKGROUND: Currently, the precise mechanisms that underline male infertility are still unclear. Accumulating data implicate non-coding RNA cargo of seminal plasma extracellular vesicles due to their association with poor semen quality and higher expression levels relative to vesicle-free seminal plasma. METHOD: We assessed sperm-free seminal plasma extracellular vesicle non-coding RNA profiles from 91 semen samples collected from male participants of couples seeking infertility treatment. Men were classified into two groups (poor, n = 32; normal, n = 59) based on World Health Organization semen cutoffs. Small RNA sequencing reads were mapped to standard biotype-specific transcriptomes in the order micro RNA > transfer RNA > piwi-interacting RNA > ribosomal RNA  > ribosomal RNA > circular RNA > long non-coding RNA using STAR. Differential expression of normalized non-coding RNA read counts between the two groups was conducted by EdgeR (Fold change ≥1.5 and (false discovery rate [FDR] < 0.05). RESULT: Small RNA sequencing identified a wide variety of seminal plasma extracellular vesicle non-coding RNA biotypes including micro RNA, ribosomal RNAs, piwi-interacting RNAs, transfer RNA, long non-coding RNAs as well as circular RNAs, and fragments associated with pseudogenes, and nonsense-mediated decay. The expression levels of 57 seminal plasma extracellular vesicle non-coding RNAs (micro RNA: 6, piwi-interacting RNA: 4, ribosomal RNA: 6, circular RNA: 34, and long non-coding RNA: 7) were altered in men with poor semen quality relative to normal semen parameters, many (60%) of which were circular RNA species. Ontology analysis of differentially expressed micro RNAs and circular RNAs showed enrichment in functional terms related to cellular communication and early development. CONCLUSION: This is the first study to generate comprehensive seminal plasma extracellular vesicle non-coding RNA profiles in a clinical setting and to determine the differences between men with normal and abnormal semen parameters. Thus, our study suggests that seminal plasma extracellular vesicle non-coding RNAs may represent novel biomarkers of male reproductive phenotypes.

Association of adverse pregnancy outcomes and multiple gestation with natural menopause: A population-based cohort study.

OBJECTIVE: Adverse pregnancy outcomes (APOs) and early menopause are each associated with increased risk of cardiovascular disease (CVD); whether APOs are associated with age at menopause is unclear. We examined the association of gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preterm birth, and multiple gestation with age at natural menopause. STUDY DESIGN: Observational, prospective study within the Nurses' Health Study II cohort (1989-2019). MAIN OUTCOMES MEASURES: Risk of early natural menopause, defined as occurring before the age of 45 years, and age at onset of natural menopause (hazard ratio (HR) >1 indicates younger age at menopause). RESULTS: The mean [SD] baseline age of 69,880 parous participants was 34.5 [4.7] years. Compared with participants who had a term singleton first birth, those with a term multiple-gestation first birth had higher risk of early menopause (HR: 1.65, 95% CI: 1.05, 2.60) and younger age at natural menopause (HR: 1.46, 95% CI: 1.31, 1.63). Estimates for preterm multiple gestation were of similar magnitude. Menopause occurred at a younger age for those with a preterm birth with spontaneous labor (HR: 1.08, 95% CI: 1.03, 1.14) compared to those with a term birth with spontaneous labor. Conversely, estimates for GDM (HR: 0.95, 95% CI: 0.89, 1.02) and HDP (preeclampsia, HR: 0.93, 95% CI: 0.89, 0.97) suggested an association with older age at menopause. CONCLUSIONS: In this large cohort study, several statistically significant associations between APOs and age at natural menopause were observed. A deeper understanding of the relationships among APOs, menopause, and CVD is needed to help identify people at higher risk for early menopause and later CVD.

Racism-Related Experiences and Adiposity: Findings From the Black Women's Experiences Living With Lupus (BeWELL) Study.

INTRODUCTION: Studies suggest that higher rates of excess adiposity in Black women may in part be driven by experiences of racism. Racial microaggressions, which include unintentional and subtle slights and insults, and responses to racism such as racism-related vigilance, may contribute to adiposity in this population. This study examined these understudied racism-related facets as well as interpersonal racial discrimination in relation to adiposity in a cohort of Black women with systemic lupus erythematosus. METHODS: Data are from the Black Women's Experiences Living with Lupus (BeWELL) Study (2015-2017; n = 432). Linear regression was used to examine adiposity measures (body mass index [BMI], percent body fat, and waist-to-hip ratio), measured during a physical examination, in relation to self-reported measures of racial microaggressions, racism-related vigilance, and interpersonal racial discrimination. RESULTS: Compared with infrequent microaggressions, very frequent experiences of microaggressions were associated with 2.9 kg/m2 higher BMI (95% confidence [CI], 0.63-5.21) and 2.6% higher body fat (95% CI, 0.32-4.80) after adjusting for covariates. Racism-related vigilance, measured continuously, was positively associated with BMI (b = 0.84; 95% CI-0.08, 1.61) and percent body fat (b = 0.89; 95% CI, 0.14-1.64). Very frequent experiences of everyday discrimination were associated with a higher BMI (b = 2.70; 95% CI, 0.58-4.83) and waist-to-hip ratio (b = 0.32; 95% CI, 0.09-0.55) compared with less frequent everyday discrimination. CONCLUSIONS: Our results suggest that various dimensions of racism are associated with excess adiposity. Efforts to address obesity among Black women with systemic lupus erythematosus should consider these multiple aspects to decrease racial inequities in adiposity.

Limited evidence of a threshold effect for increasing adiposity on risk of symptoms at midlife.

OBJECTIVE: To assess the nature of relationships between increasing body mass index (BMI) and the prevalence of midlife symptoms in a population with high adiposity. METHODS: In the cross-sectional Study of Women's Health in Qatar, 841 participants aged 40 to 60 years were recruited from nine primary health centers in Doha. Face-to-face interviews collected demographic, menopause, and symptom information. BMI (kg/m 2 ) was categorized as healthy, overweight, or class I, II, or III obesity. Multivariate logistic regression models were used to examine aches/stiffness in joints, trouble sleeping, shortness of breath, urinary incontinence, and hot flashes with BMI categories. Restricted cubic splines (RCSs) were used to estimate relationships between continuous BMI and each symptom and to conduct formal tests of nonlinearity. RESULTS: Mean BMI was 34.3 kg/m 2 (SD, 6.0 kg/m 2 ). Women with class II and III obesity had higher odds of reporting aches/stiffness than women with a healthy BMI, and the odds of reporting urinary incontinence were three times higher among women with class III obesity (odds ratio, 3.08; 95% confidence interval, 1.17-8.14). Using restricted cubic spline models, a significant nonlinear association ( P = 0.002) was observed between aches/stiffness and BMI with an apparent threshold of 38 kg/m 2 . Linear relationships were observed with BMI for urinary incontinence ( P < 0.001 for linear trend) and shortness of breath ( P = 0.005 for linear trend). Trouble sleeping and hot flashes were not associated with BMI. CONCLUSIONS: Even at very high levels of BMI, likelihood of urinary incontinence and shortness of breath increases with BMI. In contrast, likelihood of aches/stiffness has a nonlinear relationship with BMI, increasing to a threshold level.

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.

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.