Early or late menarche is associated with reduced fecundability in the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is age at menarche associated with fecundability? SUMMARY ANSWER: Both early (<11 years) and late (>15 years) menarche is associated with decreased fecundability. WHAT IS KNOWN ALREADY: Previous studies on age at menarche and fecundability have been inconclusive. Women with early or late menarche are at increased risks of gynaecological and autoimmune diseases that may affect their ability to conceive. STUDY DESIGN, SIZE, DURATION: We conducted a retrospective cohort study including 67 613 pregnant women, participating in the Norwegian Mother, Father and Child Cohort Study between 1999 and 2008, with self-reported information on age at menarche and time to pregnancy. We included planned pregnancies that were conceived either naturally or with the help of assisted reproductive technologies. PARTICIPANTS/MATERIALS, SETTING, METHODS: We calculated fecundability ratios (FRs) with 95% CIs representing the cycle-specific probability of conception by categories of age at menarche. FRs were adjusted for participants' pre-pregnancy body mass index, highest completed or ongoing education level, and age at initiation of trying to conceive. MAIN RESULTS AND THE ROLE OF CHANCE: We observed a 7% lower probability of conceiving during any given menstrual cycle up to 12 cycles in women with early or late menarche. Among women with menarche >15 years, the adjusted FR was 0.93 (95% CI: 0.90-0.97), and among women with menarche <11 years, the adjusted FR was 0.93 (95% CI: 0.89-0.99), when compared to women with menarche between 12 and 14 years. LIMITATIONS, REASONS FOR CAUTION: The study-population consisted of women pregnant in their second trimester, excluding those with persistent infertility. Recall of age at menarche and time to pregnancy may be inaccurate. WIDER IMPLICATIONS OF THE FINDINGS: Both early (<11 years) and late (>15 years) menarche was associated with decreased fecundability. Women experiencing early menarche or late menarche may be counselled accordingly. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Norwegian Institute of Public Health, Oslo, Norway, and by Telemark Hospital Trust, Porsgrunn, Norway and was partly supported by the Research Council of Norway through its centres of excellence funding scheme (project number 262700) and the Research Council of Norway (project no. 320656). The project was co-funded by the European Union (ERC, BIOSFER, 101071773). Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 947684). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Time to pregnancy and life expectancy: a cohort study of 18 796 pregnant couples.

STUDY QUESTION: Is fecundity, measured as time to pregnancy (TTP), associated with mortality in parents? SUMMARY ANSWER: Prolonged TTP is associated with increased mortality in both mothers and fathers in a dose-response manner. WHAT IS KNOWN ALREADY: Several studies have linked both male and female fecundity to mortality. In women, infertility has been linked to several diseases, but studies suggest that the underlying conditions, rather than infertility, increase mortality. STUDY DESIGN, SIZE, DURATION: A prospective cohort study was carried out on 18 796 pregnant couples, in which the pregnant women attended prophylactic antenatal care between 1973 and 1987 at a primary and tertiary care unit. The couples were followed in Danish mortality registers from their child's birth date until death or until 2018. The follow-up period was up to 47 years, and there was complete follow-up until death, emigration or end of study. PARTICIPANTS/MATERIALS, SETTING, METHODS: At the first antenatal visit, the pregnant women were asked to report the time to the current pregnancy. Inclusion was restricted to the first pregnancy, and TTP was categorised into <12 months, ≥12 months, not planned, and not available. In sub-analyses, TTP ≥12 was further categorized into 12-35, 36-60, and >60 months. Information for parents was linked to several Danish nationwide health registries. Survival analysis was used to estimate the hazard ratios (HRs) with a 95% CI for survival and adjusted for age at the first attempt to become pregnant, year of birth, socioeconomic status, mother's smoking during pregnancy, and mother's BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Mothers and fathers with TTP >60 months survived, respectively, 3.5 (95% CI: 2.6-4.3) and 2.7 (95% CI: 1.8-3.7) years shorter than parents with a TTP <12 months. The mortality was higher for fathers (HR: 1.21, 95% CI: 1.09-1.34) and mothers (HR: 1.29, 95% CI: 1.12-1.49) with TTP ≥12 months compared to parents with TTP <12 months. The risk of all-cause mortality during the study period increased in a dose-response manner with the highest adjusted HR of 1.98 (95% CI: 1.62-2.41) for fathers and 2.03 (95% CI: 1.56-2.63) for mothers with TTP >60 months. Prolonged TTP was associated with several different causes of death in both fathers and mothers, indicating that the underlying causes of the relation between fecundity and survival may be multi-factorial. LIMITATIONS, REASONS FOR CAUTION: A limitation is that fecundity is measured using a pregnancy-based approach. Thus, the cohort is conditioned on fertility success and excludes sterile couples, unsuccessful attempts and spontaneous abortions. The question used to measure TTP when the pregnant woman was interviewed at her first attended prophylactic antenatal care: 'From the time you wanted a pregnancy until it occurred, how much time passed?' could potentially have led to serious misclassification if the woman did not answer on time starting unprotected intercourse but on the start of wishing to have a child. WIDER IMPLICATIONS OF THE FINDINGS: We found that TTP is a strong marker of survival, contributing to the still-emerging evidence that fecundity in men and women reflects their health and survival potential. STUDY FUNDING/COMPETING INTEREST(S): The authors acknowledge an unrestricted grant from Ferring. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. M.L.E. is an advisor to Ro, VSeat, Doveras, and Next. TRIAL REGISTRATION NUMBER: N/A.

Gravidity modifies the associations of age and spousal age difference with couple's fecundability: a large cohort study from China.

STUDY QUESTION: Do couple's age ranges for optimal fecundability, and the associations with fecundability of couple's age combinations and age differences differ with gravidity? SUMMARY ANSWER: The couple's age range of optimal fecundability and age combinations differed with gravidity, and gravidity might modify the associations of age and spousal age difference with couple's fecundability. WHAT IS KNOWN ALREADY: Age is one of the strongest determinants of fecundability, but the existing studies have certain limitations in study population, couple's extreme age combinations and age differences, and have not explored whether the association between age and fecundability differs with gravidity. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study. 5 407 499 general reproductive-aged couples (not diagnosed with infertility) participated in the National Free Pre-conception Check-up Projects during 2015-2017. They were followed up for pregnancy outcomes through telephone interviews every 3 months until they became pregnant or were followed up for 1 year. PARTICIPANTS/MATERIALS, SETTING, METHODS: The main outcome was time to pregnancy, and the fecundability odds ratios and 95% CIs were estimated using the Cox models for discrete survival time. The associations of age and spousal age difference with fecundability were evaluated by restricted cubic splines. MAIN RESULTS AND THE ROLE OF CHANCE: In this large cohort of general reproductive-aged population, the age of optimal fecundability of multigravida couples was older than that of nulligravida couples, but their subsequent fecundability declined more sharply with age. The decline in female fecundability was more pronounced with age, with fecundability dropping by ∼30% in both nulligravida and multigravida couples whose female partners aged ≥35 years. In the nulligravida group, the fecundability of couples who were both ≤24 years with the same age was the highest, which decreased steadily with the increase of spousal age difference, and younger male partners did not seem to contribute to improving couple's fecundability. In the multigravida group, couples with female partners aged 25-34 years and a spousal age difference of -5 to 5 years showed higher fecundability, and the effect of spousal age difference on couple's fecundability became suddenly apparent when female partners aged around 40 years. Young male partners were unable to change the decisive effect of female partner's age over 40 years on couple's reduced fecundability, regardless of gravidity. LIMITATIONS, REASONS FOR CAUTION: Lacking the time for couples to attempt pregnancy before enrollment, and some couples might suspend pregnancy plans during follow-up because of certain emergencies, which would misestimate the fecundability. Due to the lack of information on sperm quality and sexual frequency of couples, we could not adjust for these factors. Moreover, due to population characteristics, the extrapolation of our results required caution. WIDER IMPLICATIONS OF THE FINDINGS: The couple's age range of optimal fecundability, age combinations, and spousal age difference on fecundability varied with gravidity. Female age-related decline in fecundability was more dominant in couple's fecundability. Targeted fertility guidance should be provided to couples with different age combinations and gravidities. STUDY FUNDING/COMPETING INTEREST(S): This research received funding from the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the National Human Genetic Resources Sharing Service Platform (Grant No. 2005DKA21300), People's Republic of China. The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Maternal exposure to metals and time-to-pregnancy: The MIREC cohort study.

OBJECTIVE: To study the association between maternal exposure to arsenic, cadmium, lead, manganese and mercury, time-to-pregnancy (TTP) and infertility. DESIGN: Pregnancy-based retrospective TTP cohort study. SETTING: Hospitals and clinics from ten cities across Canada. POPULATION: A total of 1784 pregnant women. METHODS: Concentrations of arsenic, cadmium, lead, manganese and mercury were measured in maternal whole blood during the first trimester of pregnancy as a proxy of preconception exposure. Discrete-time Cox proportional hazards models generated fecundability odds ratios (FOR) for the association between metals and TTP. Logistic regression generated odds ratios (OR) for the association between metals and infertility. Models were adjusted for maternal age, pre-pregnancy body mass index, education, income, recruitment site and plasma lipids. MAIN OUTCOME MEASURES: TTP was self-reported as the number of months of unprotected intercourse to become pregnant. Infertility was defined as TTP longer than 12 months. RESULTS: A total of 1784 women were eligible for the analysis. Mean ± SD maternal age and gestational age at interview were 32.2 ± 5.0 years, and 11.6 ± 1.6 weeks, respectively. Exposure to arsenic, cadmium, manganese or mercury was not associated with TTP or infertility. Increments of one standard deviation of lead concentrations resulted in a shorter TTP (adjusted FOR 1.09, 95% CI 1.02-1.16); however, the association was not linear when exposure was modelled in tertiles. CONCLUSION: Blood concentrations of metals at typical levels of exposure among Canadian pregnant women were not associated with TTP or infertility. Further studies are needed to assess the role of lead, if any, on TTP.

Delayed time to pregnancy and associated factors among pregnant women attending antenatal care in bale zone administrative towns health facilities: multi-center cross-sectional study.

BACKGROUND: The desire to conceive and become parents is a fundamental aspect of human life that carries immense personal, emotional, and societal significance. For many couples, achieving pregnancy represents a long-cherished dream, but the journey to parenthood is not always straightforward. The duration it takes to achieve the desired pregnancy can vary significantly among individuals and is influenced by many factors. This study explores the factors that influence the delayed time of pregnancy among women with naturally planned conception. METHODS: An institutional-based cross-sectional study was conducted from May 1 to May 30, 2023, in public health facilities of Bale Zone administrative towns, Southeast Ethiopia. Using systematic random sampling, 388 women participated in the study and a pretested questionnaire was used to collect data. Bivariate logistic regression was done, and variables with p-values < 0.25 were exported to multivariable logistic regression, and a statistically significant association was declared at p-value < 0.05. RESULTS: The study revealed delayed time to pregnancy was 18.6% with 95% (CI = 14.67-22.44%). Women's age ≥ 35, (AOR = 2.61; 95%, CI: 1.17-5.82), menstrual irregularity (AOR = 3.79; 95% CI: 1.98-7.25), and frequency of sexual intercourse/week (AOR = 2.15; 95% CI: 1.05-4.41) and women's sexual dysfunction before conception (AOR = 3.12, 95% CI: 1.62-6.01) were significantly associated factors with delayed time to pregnancy at p-value < 0.05. CONCLUSION: The study revealed a substantial proportion of delayed time to pregnancy. This delayed time to pregnancy was associated with older maternal age, irregular menstrual cycles, coital activity per week, and the women's sexual dysfunction before pregnancy. Consequently, addressing delayed time to pregnancy requires a targeted approach, prioritizing initiatives such as raising awareness, fostering increased frequency of sexual activity per week, exploring interventions for women with irregular menstrual patterns, and challenges related to sexual dysfunction.

Phthalate exposure and subfecundity in preconception couples: A nested case-control study.

BACKGROUND: Phthalates (PAEs) are endocrine-disrupting chemicals ubiquitously found in the environment. This study aimed to examine the association between exposure of PAEs and subfecundity in preconception couples. METHODS: This is a nested case-control study based on preconception cohort. Preconception couples with intention to conceive were enrolled and followed up until a clinically confirmed pregnancy or 12 menstrual cycles of preparation for conception. A total of 107 couples with subfecundity- time to pregnancy (TTP) more than 12 menstrual cycles, and 144 couples ≤12 cycles were included in the analysis. The levels of PAE metabolites in one spot urine samples were detected and compared between the groups. The weighted quantile sum (WQS) regression model and Bayesian kernel machine regression (BKMR) model were used to examine the joint effects of couples' exposure to PAEs on subfecundity. RESULTS: Using the multivariate binary logistic regression model, compared to the lowest quartile of urinary ∑PAEs concentration group, both preconception females (aOR=2.42, 95% CI: 1.10-5.30, p=0.027) and males (aOR=2.99, 95% CI: 1.36-6.58, p=0.006) in the highest quartile group had an increased risk of subfecundity, and a dose-response relationship was observed between PAEs and the risk of subfecundity. The WQS analyses found that co-exposure to PAE mixture was a risk factor for subfecundity in preconception female (aOR=1.76, 95% CI: 1.38-2.26, p<0.001), male (aOR=1.58, 95% CI: 1.20-2.08, p=0.001), and couple (aOR=2.39, 95% CI: 1.61-3.52, p<0.001). The BKMR model found a positive combined effect of mixed exposure to PAEs on the risk of subfecundity. CONCLUSIONS: PAEs increase the risk of subfecundity in preconception couples. Our research reinforced the need of monitoring PAE exposure for the purpose of improving human reproductive health.

Testing on bacterial vaginosis in a subfertile population and time to pregnancy: a prospective cohort study.

PURPOSE: This study aimed to investigate the influence of bacterial vaginosis on time to pregnancy in subfertile couples. METHODS: Couples attending a teaching hospital in the Netherlands having an initial fertility assessment (IFA) between July 2019 and June 2022 were included in this prospective study, with follow-up of pregnancies until June 2023. Vaginal samples at IFA were analyzed on pH, qPCR BV, and 16S rRNA gene microbiome analysis of V1-V2 region. Main outcome measures were time from initial fertility assessment to ongoing pregnancy at 12 weeks and live birth, analyzed by Kaplan-Meier and Cox regression with adjustment for potential confounders. RESULTS: At IFA, 27% of 163 included participants tested positive for BV. BV status had no influence on time to ongoing pregnancy (HR 0.98, 0.60-1.61, aHR 0.97, 0.58-1.62). In persons with unexplained subfertility, positive BV status had a tendency of longer time to pregnancy. When persons had an indication for fertility treatment, positive BV status (HR 0.21, 0.05-0.88, aHR 0.19, 0.04-0.85) and microbiome community state type III and type IV had significant longer time to pregnancy. CONCLUSION: This study indicates that BV may have a potential negative impact on time to live birth pregnancy in subfertile persons with an indication for fertility treatment. This study did not find an association between BV and time to live birth pregnancy in a general group of subfertile couples or in unexplained subfertility. More research should be done in persons with unexplained subfertility and if treatment improves time to pregnancy.

Time to pregnancy recognition among users of an FDA-cleared fertility application.

Background: Previous investigations of time-to-pregnancy recognition have analysed data from national surveys and clinics, but this has not been investigated in the context of digital fertility applications. Timely pregnancy recognition can help individuals in health and pregnancy management, reducing maternal and foetal risk and costs, whilst increasing treatment options, availability, and cost. Methods: This dataset contained 23,728 pregnancies (conceived between June 2018 and December 2022) from 20,429 participants using a Food and Drug Administration (FDA) cleared fertility app in the United States. Most participants (with non-missing information) identified as Non-Hispanic White, and one-third reported obtaining a university degree. We used two-tailed Welch's t-test, Mann-Whitney U-test, and two-tailed Z-tests to compare time to pregnancy recognition between those using the app to conceive or contracept. Results: Participants using an app to conceive recognised pregnancy on average at 31.3 days from last menstrual period (LMP) compared to 35.9 days among those using the app to prevent pregnancy. Conclusion: Generalisability is limited, as all participants were using a fertility app and had relatively homogenous sociodemographic characteristics.

People who recognise pregnancy early may benefit, as earlier recognition can reduce costs and risks, and make more treatment options available. In the past, researchers have studied the time it takes for an individual to recognise that they are pregnant by asking them in national surveys or when they attend a clinic. However, with the advent of digital fertility tracking apps, we investigated the time it takes to recognise pregnancy when using such an app. We analysed data from 23,728 pregnancies from 20,429 users of the Natural Cycles app between June 2018 and December 2022. We found that participants using the app to try to get pregnant recognised pregnancy an average of 4.6 days earlier than those using the app to prevent pregnancy.

Approaches for Assessing Effects of Exposures on Human Fertility.

BACKGROUND: Fecundability (conception rate per menstrual cycle) varies among non-contracepting couples. Time-to-pregnancy studies can identify exposures contributing to that variability, using three designs: incident cohort, prevalent cohort, and retrospective. Typically, researchers then apply semi-parametric, generalized linear time-to-pregnancy models to data, with either a log or a logit "link," to estimate either a fecundability ratio (FR) or a fecundability odds ratio (FOR). The ongoing-attempt study design can also be informative. METHODS: We consider a different generalized linear model, based on an inverse link. It models the heterogeneity as beta distributed and enables estimation of both the FR and FOR, defined based on population mean fecundabilities, without requiring constancy across attempt time. Under an ongoing-attempt design, the parameter associated with a dichotomous exposure has no clear meaning with a log or a logit link, but under the proposed approach estimates the ratio of the two average times to pregnancy. Basing simulations on conception rates from a large study, we compare the three analytic approaches for confidence interval coverage and power. We also assess the performance of a commonly used method for verifying the constancy of FOR or FR across time. RESULTS: The inverse-link approach had slightly less power than the others, but its estimates maintained nominal confidence interval coverage under nonconstancy. A popular method for testing constancy across time for the FR and FOR had poor power. CONCLUSIONS: The inverse-link analysis offers a useful alternative to the usual methods, with estimation performance that generalizes to the ongoing-attempt design and does not require hard-to-verify constancy assumptions.

Association of male fatty acid intake with fecundability among couples planning pregnancy.

STUDY QUESTION: To what extent is male fatty acid intake associated with fecundability among couples planning pregnancy? SUMMARY ANSWER: We observed weak positive associations of male dietary intakes of total and saturated fatty acids with fecundability; no other fatty acid subtypes were appreciably associated with fecundability. WHAT IS KNOWN ALREADY: Male fatty acid intake has been associated with semen quality in previous studies. However, little is known about the extent to which male fatty acid intake is associated with fecundability among couples attempting spontaneous conception. STUDY DESIGN, SIZE, DURATION: We conducted an internet-based preconception prospective cohort study of 697 couples who enrolled during 2015-2022. During 12 cycles of observation, 53 couples (7.6%) were lost to follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were residents of the USA or Canada, aged 21-45 years, and not using fertility treatment at enrollment. At baseline, male participants completed a food frequency questionnaire from which we estimated intakes of total fat and fatty acid subtypes. We ascertained time to pregnancy using questionnaires completed every 8 weeks by female participants until conception or up to 12 months. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs for the associations of fat intakes with fecundability, adjusting for male and female partner characteristics. We used the multivariate nutrient density method to account for energy intake, allowing for interpretation of results as fat intake replacing carbohydrate intake. We conducted several sensitivity analyses to assess the potential for confounding, selection bias, and reverse causation. MAIN RESULTS AND THE ROLE OF CHANCE: Among 697 couples, we observed 465 pregnancies during 2970 menstrual cycles of follow-up. The cumulative incidence of pregnancy during 12 cycles of follow-up after accounting for censoring was 76%. Intakes of total and saturated fatty acids were weakly, positively associated with fecundability. Fully adjusted FRs for quartiles of total fat intake were 1.32 (95% CI 1.01-1.71), 1.16 (95% CI 0.88-1.51), and 1.43 (95% CI 1.09-1.88) for the second, third, and fourth vs the first quartile, respectively. Fully adjusted FRs for saturated fatty acid intake were 1.21 (95% CI 0.94-1.55), 1.16 (95% CI 0.89-1.51), and 1.23 (95% CI 0.94-1.62) for the second, third, and fourth vs the first quartile, respectively. Intakes of monounsaturated, polyunsaturated, trans-, omega-3, and omega-6 fatty acids were not strongly associated with fecundability. Results were similar after adjustment for the female partner's intakes of trans- and omega-3 fats. LIMITATIONS, REASONS FOR CAUTION: Dietary intakes estimated from the food frequency questionnaire may be subject to non-differential misclassification, which is expected to bias results toward the null in the extreme categories when exposures are modeled as quartiles. There may be residual confounding by unmeasured dietary, lifestyle, or environmental factors. Sample size was limited, especially in subgroup analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our results do not support a strong causal effect of male fatty acid intakes on fecundability among couples attempting to conceive spontaneously. The weak positive associations we observed between male dietary fat intakes and fecundability may reflect a combination of causal associations, measurement error, chance, and residual confounding. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the National Institutes of Health, grant numbers R01HD086742 and R01HD105863. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility app). L.A.W. is a consultant for AbbVie, Inc. M.L.E. is an advisor to Sandstone, Ro, Underdog, Dadi, Hannah, Doveras, and VSeat. The other authors have no competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Paraben exposure and couple fecundity: a preconception cohort study.

STUDY QUESTION: Is pre-conception exposure to parabens associated with fecundity in couples of childbearing age? SUMMARY ANSWER: Paraben exposure in female partners was associated with reduced couple fecundity and anti-Müllerian hormone (AMH) might be one of the possible mediators. WHAT IS KNOWN ALREADY: The reproductive toxicity of parabens, a class of widely used preservatives, has been suggested but evidence regarding their effects on couple fecundity is scarce. STUDY DESIGN, SIZE, DURATION: In this couple-based prospective cohort study, a total of 884 pre-conception couples who participated in the Shanghai Birth Cohort between 2013 and 2015 were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Concentrations of six parabens were measured in urine samples collected from couples. Malondialdehyde, C-reactive protein, and AMH were assessed in female partners. The outcomes included couple fecundability (time-to-pregnancy, TTP) and infertility (TTP > 12 menstrual cycles). Partner-specific and couple-based models were applied to estimate the associations. The joint effect of paraben mixture on couple fecundity was estimated by quantile-based g-computation (q-gcomp). Mediation analysis was used to assess the mediating roles of oxidative stress, inflammation and ovarian reserve. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 525 couples (59.4%) conceived spontaneously. In the partner-specific model, propyl paraben (PrP), butyl paraben (BuP), and heptyl paraben (HeP) in female partners were associated with reduced fecundability (fecundability odds ratio (95% CI): 0.96 (0.94-0.98) for PrP; 0.90 (0.87-0.94) for BuP; 0.42 (0.28-0.65) for HeP) and increased risk of infertility (rate ratio (95% CI): 1.06 (1.03-1.10) for PrP; 1.14 (1.08-1.21) for BuP; 1.89 (1.26-2.83) for HeP). Similar associations were observed in the couple-based model. AMH played a significant mediation role in the association (average causal mediation effect (95% CI): 0.001 (0.0001-0.003)). Paraben exposure in male partners was not associated with couple fecundity. The joint effect of paraben mixture on couple fecundity was non-significant. LIMITATIONS, REASONS FOR CAUTION: Self-reported pregnancy and single urine sample may lead to misclassification. The mediation analysis is limited in that levels of sex hormones were not measured. The inclusion of women with irregular menstrual cycles might affect the results. It is possible that the observed association was due to reverse causation. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to assess the effects of paraben exposure on couple fecundity in Asians. Given the widespread exposure to parabens in couples of childbearing age, the present findings may have important public health implications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported in part by the National Natural Science Foundation of China (41991314), the Shanghai Science and Technology Development Foundation (22YF1426700), the Science and Technology Commission of Shanghai Municipality (21410713500), and the Shanghai Municipal Health Commission (2020CXJQ01). All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Socioeconomic status and fecundability in a Danish preconception cohort.

STUDY QUESTION: To what extent is socioeconomic status (SES), as measured by educational attainment and household income, associated with fecundability in a cohort of Danish couples trying to conceive? SUMMARY ANSWER: In this preconception cohort, lower educational attainment and lower household income were associated with lower fecundability after adjusting for potential confounders. WHAT IS KNOWN ALREADY: Approximately 15% of couples are affected by infertility. Socioeconomic disparities in health are well established. However, little is known about socioeconomic disparity and its relation to fertility. STUDY DESIGN, SIZE, DURATION: This is a cohort study of Danish females aged 18-49 years who were trying to conceive between 2007 and 2021. Information was collected via baseline and bi-monthly follow-up questionnaires for 12 months or until reported pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 10 475 participants contributed 38 629 menstrual cycles and 6554 pregnancies during a maximum of 12 cycles of follow-up. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with upper tertiary education (highest level), fecundability was substantially lower for primary and secondary school (FR: 0.73, 95% CI: 0.62-0.85), upper secondary school (FR: 0.89, 95% CI: 0.79-1.00), vocational education (FR: 0.81, 95% CI: 0.75-0.89), and lower tertiary education (FR: 0.87, 95% CI: 0.80-0.95), but not for middle tertiary education (FR: 0.98, 95% CI: 0.93-1.03). Compared with a monthly household income of >65 000 DKK, fecundability was lower for household income <25 000 DKK (FR: 0.78, 95% CI: 0.72-0.85), 25 000-39 000 DKK (FR: 0.88, 95% CI: 0.82-0.94), and 40 000-65 000 DKK (FR: 0.94, 95% CI: 0.88-0.99). The results did not change appreciably after adjustment for potential confounders. LIMITATIONS, REASONS FOR CAUTION: We used educational attainment and household income as indicators of SES. However, SES is a complex concept, and these indicators may not reflect all aspects of SES. The study recruited couples planning to conceive, including the full spectrum of fertility from less fertile to highly fertile individuals. Our results may generalize to most couples who are trying to conceive. WIDER IMPLICATIONS OF THE FINDINGS: Our results are consistent with the literature indicating well-documented inequities in health across socioeconomic groups. The associations for income were surprisingly strong considering the Danish welfare state. These results indicate that the redistributive welfare system in Denmark does not suffice to eradicate inequities in reproductive health. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Department of Clinical Epidemiology, Aarhus University and Aarhus University Hospital, and the National Institute of Child Health and Human Development (RO1-HD086742, R21-HD050264, and R01-HD060680). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Variable selection for discrete survival model with frailty in presence of left truncation and right censoring: Studying association of environmental toxicants on time-to-pregnancy.

Understanding the association between mixtures of environmental toxicants and time-to-pregnancy (TTP) is an important scientific question as sufficient evidence has emerged about the impact of individual toxicants on reproductive health and that individuals are exposed to a whole host of toxicants rather than an individual toxicant. Assessing mixtures of chemical effects on TTP poses significant statistical challenges, namely (i) TTP being a discrete survival outcome, typically subject to left truncation and right censoring, (ii) chemical exposures being strongly correlated, (iii) appropriate transformation to account for some lipid-binding chemicals, (iv) non-linear effects of some chemicals, and (v) high percentage of concentration below the limit of detection (LOD) for some chemicals. We propose a discrete frailty modeling framework (named Discnet) that allows selection of correlated covariates while appropriately addressing the methodological issues mentioned above. Discnet is shown to have better and stable false negative and false positive rates compared to alternative methods in various simulation settings. We did a detailed analysis of the pre-conception endocrine disrupting chemicals and TTP from the LIFE study and found that older females, female exposure to cotinine (smoking), DDT conferred a delay in getting pregnant, which was consistent across various approaches to account for LOD as well as non-linear associations.

The association between the pre-pregnancy vaginal microbiome and time-to-pregnancy: a Chinese pregnancy-planning cohort study.

BACKGROUND: Although sexually transmitted infections are regarded as the main cause of tubal infertility, the association between the common vaginal microbiome and female fecundability has yet to be determined. The objective of this study was to find convincing evidence relating to the impact of the vaginal bacterial structure on the fecundability of women planning pregnancy. METHODS: We recruited women who took part in the Free Pre-pregnancy Health Examination Project from 13 June 2018 to 31 October 2018 (n = 89, phase I) and from 1 November 2018 to 30 May 2020 (n = 389, phase II). We collected pre-pregnancy vaginal swabs from each subject; then, we followed up each subject to acquire the pregnancy-planning outcome in 1 year. In phase I, 16S rRNA gene sequencing was performed to investigate the vaginal bacterial content between the pregnancy and non-pregnancy groups. These findings were verified in phase II by applying a quantitative real-time polymerase chain reaction for the measurement of the absolute abundance of specific species. Cox models were used to estimate fecundability ratios (FR) for each vaginal microbiome type. RESULTS: In phase I, 59.6% (53/89) of women became pregnant within 1 year. The principal coordinate analysis showed that the pre-pregnancy vaginal microbial community structures of the pregnant and non-pregnant groups were significantly different (PERMANOVA test, R2 = 0.025, P = 0.049). The abundance of the genus Lactobacillus in the pregnancy group was higher than that of the non-pregnant group (linear discriminant analysis effect size (LDA) > 4.0). The abundance of the genus Gardnerella in the non-pregnant group was higher than those in the pregnant group (LDA > 4.0). In phase II, female fecundability increased with higher absolute loads of Lactobacillus gasseri (quartile Q4 vs Q1, FR = 1.71, 95%CI 1.02-2.87) but decreased with higher absolute loads of Fannyhessea vaginae (Q4 vs Q1, FR = 0.62, 95%CI 0.38-1.00). Clustering analysis showed that the vaginal microbiome of type D (characterized by a higher abundance of Lactobacillus iners, a lower abundance of Lactobacillus crispatus and Lactobacillus gassri) was associated with a 55% reduction of fecundability (FR = 0.45, 95%CI 0.26-0.76) compared with type A (featuring three Lactobacillus species, low Gardnerella vaginalis and Fannyhessea vaginae abundance). CONCLUSIONS: This cohort study demonstrated an association between the pre-pregnancy vaginal microbiome and female fecundability. A vaginal microbiome characterized by a higher abundance of L. iners and lower abundances of L. crispatus and L. gasseri appeared to be associated with a lower fecundability. Further research now needs to confirm whether manipulation of the vaginal microenvironment might improve human fecundability.

Inflammation and Conception in a Prospective Time-to-Pregnancy Cohort.

BACKGROUND: Inflammation may contribute to subfertility but this has not been well-explored in large prospective cohort studies. METHODS: We conducted a prospective 12-month cohort study of time to pregnancy in North Carolina, the Time to Conceive study (2010-2016). Participants were 30-44 years old, without a history of infertility (N = 727). We analyzed blood samples with a high sensitivity assay for C-reactive protein (CRP). Women reported their weight, height, and other covariates. We natural log-transformed CRP and examined it (1) linearly, after exploration using restricted cubic splines and (2) in categories based on American Heart Association criteria. We estimated fecundability ratios (FRs) with log-binomial discrete-time-to-pregnancy models. Separate models included an interaction term with body mass index (BMI). RESULTS: The adjusted estimated FR per natural log-unit increase in CRP level was 0.97 (confidence interval [CI] = 0.91, 1.0). The FR (CI) for high CRP (>10 mg/L) compared with low CRP (<1 mg/L) was 0.78 (0.52, 1.2). Compared with normal-weight women with low CRP, women with obesity and high CRP had lower estimated fecundability, but the confidence interval was wide (FR = 0.63; CI = 0.35, 1.1). There was no pattern in the estimated fecundability across levels of CRP within categories of BMI. CONCLUSIONS: There was no evidence of an association between CRP and fecundability either alone or within levels of BMI. Further studies of CRP and fecundability should include higher levels of CRP and additional markers of inflammation.

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.

Parents' age at birth and daughters' time to pregnancy: a study within the Norwegian Mother, Father and Child Cohort.

STUDY QUESTION: Is parents' age at birth associated with daughters' fecundability? SUMMARY ANSWER: Daughters born to mothers <25 years or fathers ≥35 years had slightly lower fecundability. WHAT IS KNOWN ALREADY: Two recent studies reported lower fecundability in women born to mothers <20 years, which may be partly due to daughters of young mothers being less likely to plan their pregnancies. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 58 496 pregnancy planners (4290 of whom conceived with treatment) and 14 194 non-planners enrolled in the Norwegian Mother, Father and Child Cohort Study (MoBa) between 2000 and 2008, linked with the Medical Birth Registry of Norway. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were born in Norway between 1967 and 1990. We estimated fecundability ratios (FRs) and 95% CI as a function of both parents' (F1) age at the daughter's (F2) birth among non-treated planners and the relative risk of time to pregnancy (TTP) ≥12 months or treatment among all planners. We explored whether daughters of young mothers were under-represented among planners, compared with the underlying population. Finally, we estimated FRs after adding non-planners, randomly assigned to conceiving in the first cycle with probabilities of 0.60 and 0.70. MAIN RESULTS AND THE ROLE OF CHANCE: For both mother and father, the reference category was 25-29 years. Fecundability was slightly lower among daughters of older fathers (FRs (95% CI): 0.95 (0.92, 0.98) for F1 father's age 35-39 years and 0.93 (0.89, 0.97) for ≥40 years) and daughters of young mothers (0.92 (0.89, 0.96) for F1 mother's age <20 years and 0.97 (0.95, 0.99) for 20-24 years). Results were similar for the composite outcome TTP ≥ 12 months or treatment, although driven by TTP ≥ 12. Compared with Norwegian-born women with ≥1 pregnancy, planners born to mothers <20 years were underrepresented. Including non-planners with very high fecundability weakened the association with mother's age <20 years. LIMITATIONS, REASONS FOR CAUTION: This was a pregnancy cohort with retrospectively reported information on planning and TTP. Selection bias appears unlikely to fully explain the association with mother's age <20 years. WIDER IMPLICATIONS OF THE FINDINGS: Daughters of young mothers or older fathers may have slightly lower fecundability. If corroborated, the finding about older paternal age is relevant, given the widespread tendency to delay childbearing. STUDY FUNDING/COMPETING INTEREST(S): This work was partly funded by the Research Council of Norway (project no. 320656), and through its Centres of Excellence funding scheme (project no. 262700). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 947684). No competing interests. TRIAL REGISTRATION NUMBER: N/A.

Omega-3 fatty acid supplementation and fecundability.

STUDY QUESTION: Is self-reported use of omega-3 fatty acid supplements associated with fecundability, the probability of natural conception, in a given menstrual cycle? SUMMARY ANSWER: Prospectively recorded omega-3 supplement use was associated with an increased probability of conceiving. WHAT IS KNOWN ALREADY: In infertile women, omega-3 fatty acid intake has been associated with increased probability of pregnancy following IVF. In natural fertility, studies are conflicting, and no study of natural fertility has evaluated omega-3 fatty acid supplementation and fecundity. STUDY DESIGN, SIZE, DURATION: Secondary data analysis of 900 women contributing 2510 cycles in Time to Conceive (TTC), a prospective, time to pregnancy cohort study from 2008 to December 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 30-44 years, trying to conceive <3 months, without history of infertility were followed using standardized pregnancy testing. While attempting to conceive, women daily recorded menstrual cycle events and supplement and medication intake using the Cerner Multum Drug Database. Supplements and vitamins containing omega-3 were identified. Omega-3 use, defined as use in at least 20% of days in a given menstrual cycle, in each pregnancy attempt cycle was determined. A discrete-time Cox proportional hazards model was used to calculate the fecundability ratio. MAIN RESULTS AND THE ROLE OF CHANCE: Women taking omega-3 supplementation were more likely to be younger, thinner, nulligravid, white and to take vitamin D, prenatal and multivitamins compared to women not taking omega-3s. After adjusting for age, obesity, race, previous pregnancy, vitamin D and prenatal and multivitamin use, women taking omega-3 supplements had 1.51 (95% CI 1.12, 2.04) times the probability of conceiving compared to women not taking omega-3s. LIMITATIONS, REASONS FOR CAUTION: Our study was not a randomized controlled trial. The women who used omega-3 supplements may represent a more health-conscious population. We sought to address this by adjusting for multiple factors in our model. Additionally, the omega-3 fatty acid supplements that TTC participants used included multiple types and brands with varying dosages of omega-3 fatty acids. Women reported the type of supplement they were taking but not the concentration of omega-3s in that supplement. It is therefore not possible to compare dosing or a dose-response relationship in our study. WIDER IMPLICATIONS OF THE FINDINGS: Omega-3 supplementation may present a feasible and inexpensive modifiable factor to improve fertility. Randomized controlled trials are needed to further investigate the benefits of omega-3 supplementation for women trying to conceive naturally. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Division of Reproductive Endocrinology and Infertility at the University of North Carolina at Chapel Hill, the NIH/NICHD (R21 HD060229-01 and R01 HD067683-01), and in part by the Intramural Research Program of the National Institute of Environmental Health Sciences (Z01ES103333). The authors declare that there is no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The association between miscarriage and fecundability: the Norwegian Mother, Father and Child Cohort Study.

STUDY QUESTION: Is fecundability associated with miscarriage history and future miscarriage risk? SUMMARY ANSWER: Prior miscarriage was associated with lower fecundability, and participants with a history of subfertility (time-to-pregnancy (TTP) ≥12 months) were at a higher risk of subsequent miscarriage. WHAT IS KNOWN ALREADY: Although miscarriage and low fecundability share common risk factors, prior studies have reported both lower and higher fecundability after miscarriage. STUDY DESIGN, SIZE, DURATION: In this study, we examined two related associations: one, between miscarriage history and subsequent fecundability and, two, between fecundability and miscarriage risk in the subsequent pregnancy. The study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa). In addition, the outcome of the pregnancy after the MoBa index pregnancy was obtained by linking information from three national health registries: the Medical Birth Registry of Norway, the Norwegian Patient Registry and the general practice database. PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the association between number of prior miscarriages and fecundability in 48 537 naturally conceived, planned pregnancies in participants with at least one prior pregnancy. We estimated fecundability ratios (FRs) and 95% CIs using proportional probability regression. We further estimated the relative risk (RR) of miscarriage in the subsequent pregnancy as a function of TTP in the MoBa index pregnancy for 7889 pregnancies using log-binomial regression. Multivariable analyses adjusted for maternal age, pre-pregnancy maternal BMI, smoking status, cycle regularity, income level and highest completed or ongoing education. MAIN RESULTS AND THE ROLE OF CHANCE: Fecundability decreased as the number of prior miscarriages increased. The adjusted FRs among women with one, two and three or more prior miscarriages were 0.83 (95% CI: 0.80-0.85), 0.79 (95% CI: 0.74-0.83) and 0.74 (95% CI: 0.67-0.82), respectively, compared with women with no prior miscarriages. Compared to women with a TTP of <3 months, the adjusted RR of miscarriage in the subsequent pregnancy was 1.16 (0.99-1.35) with TTP of 3-6 months, 1.18 (0.93-1.49) with TTP of 7-11 months and 1.43 (1.13-1.81) with TTP of 12 or more months. LIMITATIONS, REASONS FOR CAUTION: Information on TTP and prior miscarriages was obtained retrospectively, and TTP was self-reported. MoBa is a pregnancy cohort, and findings may not be generalizable to all women. We were unable to examine the effect of changing partners between pregnancies, as well as other paternal factors such as seminal parameters. We also did not know what proportion of our participants had changed partners between their prior pregnancies and the index pregnancy. Furthermore, it is likely that many early miscarriages are not recognized. WIDER IMPLICATIONS OF THE FINDINGS: The association between miscarriage and fecundability may reflect a contribution of occult pregnancy losses to TTP, as well as shared underlying causes for reduced fecundability and miscarriage. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Research Council of Norway through its Medical Student Research Program funding scheme (project number 271555/F20), its Centres of Excellence funding scheme (project number 262700) and through the project 'Women's fertility - an essential component of health and well-being' (project number 320656). M.C.M. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement number 947684). A.J.W. is supported by the Intramural Program of the National Institute of Environmental Health Sciences at the National Institutes of Health, USA. The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Preconception vitamin D and miscarriage in a prospective cohort study.

STUDY QUESTION: Is preconception vitamin D level associated with the risk of miscarriage? SUMMARY ANSWER: Preconception vitamin D levels are not associated with the risk of miscarriage in a population of women conceiving naturally. WHAT IS KNOWN ALREADY: In humans, low vitamin D has been associated with prolonged menstrual cycles, delayed ovulation and a lower probability of conception. Animal and in vitro data indicate that vitamin D may affect implantation. STUDY DESIGN, SIZE, DURATION: This prospective time-to-pregnancy study included 362 women who were trying to conceive naturally between 2008 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study included participants who had been trying to conceive naturally for 3 months or less at enrollment and aged 30-44 years. A preconception blood sample was collected and 25-hydroxyvitamin D [25(OH)D] was measured. Women who conceived (N = 362) were at risk of a miscarriage from the day of a reported positive pregnancy test until either a participant-reported pregnancy loss or 20 weeks post day of last menstrual period, whichever came first. Gestational age was defined by ovulation. Time to miscarriage (days) or censoring was modeled using a multivariate Cox proportional hazards model. Multiple imputation was performed for missing covariates and missing day of ovulation. MAIN RESULTS AND THE ROLE OF CHANCE: The mean age was 33 years (SD: 3.0 years). Mean 25(OH)D was lower among those who reported their race as African-American and those with a higher BMI. After adjustment for age, race, BMI, education, exercise, alcohol and caffeine intake, compared to the referent group (30-<40 ng/ml), the hazard ratio (HR) and 95% CI for those with a low 25(OH)D level (<30 ng/ml) was 1.10 (CI: 0.62, 1.91). Among participants with a higher 25(OH)D level (≥40 ng/ml), the HR was 1.07 (CI: 0.62, 1.84). LIMITATIONS, REASONS FOR CAUTION: This study was limited by a 25(OH)D measurement at only a single time point. A large percentage of women in this study had sufficient vitamin D levels, which may have limited our power to detect an effect of deficiency. Women in this study were older (30-44 years), and predominantly reported their race as White which may limit generalizability. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study do not suggest an association between preconception vitamin D and miscarriage. Future research should focus on women at greater risk for miscarriage or in populations at risk for vitamin D deficiency or on supplementation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01ES103333). This research was also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award numbers R00HD079659 and R01HD067683. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.