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STUDY QUESTION To what extent is preconception maternal or paternal coronavirus disease 2019 (COVID-19) vaccination associated with miscarriage incidence? SUMMARY ANSWER COVID-19 vaccination in either partner at any time before conception is not associated with an increased rate of miscarriage. WHAT IS KNOWN ALREADY Several observational studies have evaluated the safety of COVID-19 vaccination during pregnancy and found no association with miscarriage, though no study prospectively evaluated the risk of early miscarriage (gestational weeks [GW] <8) in relation to COVID-19 vaccination. Moreover, no study has evaluated the role of preconception vaccination in both male and female partners. STUDY DESIGN, SIZE, DURATION An Internet-based, prospective preconception cohort study of couples residing in the USA and Canada. We analyzed data from 1815 female participants who conceived during December 2020–November 2022, including 1570 couples with data on male partner vaccination. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible female participants were aged 21–45 years and were trying to conceive without use of fertility treatment at enrollment. Female participants completed questionnaires at baseline, every 8 weeks until pregnancy, and during early and late pregnancy; they could also invite their male partners to complete a baseline questionnaire. We collected data on COVID-19 vaccination (brand and date of doses), history of SARS-CoV-2 infection (yes/no and date of positive test), potential confounders (demographic, reproductive, and lifestyle characteristics), and pregnancy status on all questionnaires. Vaccination status was categorized as never (0 doses before conception), ever (≥1 dose before conception), having a full primary sequence before conception, and completing the full primary sequence ≤3 months before conception. These categories were not mutually exclusive. Participants were followed up from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss to follow-up, 20 weeks' gestation), whichever occurred first. We estimated incidence rate ratios (IRRs) for miscarriage and corresponding 95% CIs using Cox proportional hazards models with GW as the time scale. We used propensity score fine stratification weights to adjust for confounding. MAIN RESULTS AND THE ROLE OF CHANCE Among 1815 eligible female participants, 75% had received at least one dose of a COVID-19 vaccine by the time of conception. Almost one-quarter of pregnancies resulted in miscarriage, and 75% of miscarriages occurred <8 weeks' gestation. The propensity score-weighted IRR comparing female participants who received at least one dose any time before conception versus those who had not been vaccinated was 0.85 (95% CI: 0.63, 1.14). COVID-19 vaccination was not associated with increased risk of either early miscarriage (GW: <8) or late miscarriage (GW: 8–19). There was no indication of an increased risk of miscarriage associated with male partner vaccination (IRR = 0.90; 95% CI: 0.56, 1.44). LIMITATIONS, REASONS FOR CAUTION The present study relied on self-reported vaccination status and infection history. Thus, there may be some non-differential misclassification of exposure status. While misclassification of miscarriage is also possible, the preconception cohort design and high prevalence of home pregnancy testing in this cohort reduced the potential for under-ascertainment of miscarriage. As in all observational studies, residual or unmeasured confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to evaluate prospectively the relation between preconception COVID-19 vaccination in both partners and miscarriage, with more complete ascertainment of early miscarriages than earlier studies of vaccination. The findings are informative for individuals planning a pregnancy and their healthcare providers. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Health [R01-HD086742 (PI: L.A.W.); R01-HD105863S1 (PI: L.A.W. and M.L.E.)], the National Institute of Allergy and Infectious Diseases (R03-AI154544; PI: A.K.R.), and the National Science Foundation (NSF-1914792; PI: L.A.W.). The funders had no role in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. L.A.W. is a fibroid consultant for AbbVie, Inc. She also receives in-kind donations from Swiss Precision Diagnostics (Clearblue home pregnancy tests) and Kindara.com (fertility apps). M.L.E. received consulting fees from Ro, Hannah, Dadi, VSeat, and Underdog, holds stock in Ro, Hannah, Dadi, and Underdog, is a past president of SSMR, and is a board member of SMRU. K.F.H. reports being an investigator on grants to her institution from UCB and Takeda, unrelated to this study. S.H.-D. reports being an investigator on grants to her institution from Takeda, unrelated to this study, and a methods consultant for UCB and Roche for unrelated drugs. The authors report no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Measurement error is pervasive in epidemiologic research. Epidemiologists often assume that mismeasurement of study variables is nondifferential with respect to other analytical variables and then rely on the heuristic that "nondifferential misclassification will bias estimates towards the null." However, there are many exceptions to the heuristic for which bias towards the null cannot be assumed. In this paper, we compile and characterize 7 exceptions to this rule and encourage analysts to take a more critical and nuanced approach to evaluating and discussing bias from nondifferential mismeasurement. [ABSTRACT FROM AUTHOR]

Some reproductive-aged individuals remain unvaccinated against coronavirus disease 2019 (COVID-19) because of concerns about potential adverse effects on fertility. Using data from an internet-based preconception cohort study, we examined the associations of COVID-19 vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with fertility among couples trying to conceive spontaneously. We enrolled 2,126 self-identified female participants aged 21–45 year residing in the United States or Canada during December 2020–September 2021 and followed them through November 2021. Participants completed questionnaires every 8 weeks on sociodemographics, lifestyle, medical factors, and partner information. We fit proportional probabilities regression models to estimate associations between self-reported COVID-19 vaccination and SARS-CoV-2 infection in both partners with fecundability (i.e. the per-cycle probability of conception), adjusting for potential confounders. COVID-19 vaccination was not appreciably associated with fecundability in either partner (female fecundability ratio (FR) = 1.08, 95% confidence interval (CI): 0.95, 1.23; male FR = 0.95, 95% CI: 0.83, 1.10). Female SARS-CoV-2 infection was not strongly associated with fecundability (FR = 1.07, 95% CI: 0.87, 1.31). Male infection was associated with a transient reduction in fecundability (for infection within 60 days, FR = 0.82, 95% CI: 0.47, 1.45; for infection after 60 days, FR = 1.16, 95% CI: 0.92, 1.47). These findings indicate that male SARS-CoV-2 infection may be associated with a short-term decline in fertility and that COVID-19 vaccination does not impair fertility in either partner. [ABSTRACT FROM AUTHOR]

Study Question: To what extent are ambient concentrations of particulate matter <2.5 microns (PM2.5), nitrogen dioxide (NO2) and ozone (O3) associated with risk of self-reported physician-diagnosed uterine leiomyomata (UL)?Summary Answer: In this large prospective cohort study of Black women, ambient concentrations of O3, but not PM2.5 or NO2, were associated with increased risk of UL.What Is Known Already: UL are benign tumors of the myometrium that are the leading cause of gynecologic inpatient care among reproductive-aged women. Black women are clinically diagnosed at two to three times the rate of white women and tend to exhibit earlier onset and more severe disease. Two epidemiologic studies have found positive associations between air pollution exposure and UL risk, but neither included large numbers of Black women.Study Design, Size, Duration: We conducted a prospective cohort study of 21 998 premenopausal Black women residing in 56 US metropolitan areas from 1997 to 2011.Participants/material, Setting, Methods: Women reported incident UL diagnosis and method of confirmation (i.e. ultrasound, surgery) on biennial follow-up questionnaires. We modeled annual residential concentrations of PM2.5, NO2 and O3 throughout the study period. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for a one-interquartile range (IQR) increase in air pollutant concentrations, adjusting for confounders and co-pollutants.Main Results and the Role Of Chance: During 196 685 person-years of follow-up, 6238 participants (28.4%) reported physician-diagnosed UL confirmed by ultrasound or surgery. Although concentrations of PM2.5 and NO2 were not appreciably associated with UL (HRs for a one-IQR increase: 1.01 (95% CI: 0.93, 1.10) and 1.05 (95% CI: 0.95, 1.16), respectively), O3 concentrations were associated with increased UL risk (HR for a one-IQR increase: 1.19, 95% CI: 1.07, 1.32). The association was stronger among women age <35 years (HR: 1.26, 95% CI: 0.98, 1.62) and parous women (HR: 1.28, 95% CI: 1.11, 1.48).Limitations, Reasons For Caution: Our measurement of air pollution is subject to misclassification, as monitoring data are not equally spatially distributed and we did not account for time-activity patterns. Our outcome measure was based on self-report of a physician diagnosis, likely resulting in under-ascertainment of UL. Although we controlled for several individual- and neighborhood-level confounding variables, residual confounding remains a possibility.Wider Implications Of the Findings: Inequitable burden of air pollution exposure has important implications for racial health disparities, and may be related to disparities in UL. Our results emphasize the need for additional research focused on environmental causes of UL.Study Funding/competing Interest(s): This research was funded by the National Cancer Institute (U01-CAA164974) and the National Institute of Environmental Health Sciences (R01-ES019573). L.A.W. is a fibroid consultant for AbbVie, Inc. and accepts in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, FertilityFriend.com and Kindara.com for primary data collection in Pregnancy Study Online (PRESTO). M.J. declares consultancy fees from the Health Effects Institute (as a member of the review committee). The remaining authors declare they have no actual or potential competing financial interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Administration of pain relievers has been associated with both lower and higher risks of adverse reproductive outcomes in animals. In the sole investigation of male pain-reliever use and human fertility carried out to date, Smarr et al. (Hum Reprod. 2016;31(9):2119–2127) found a 35% reduction in fecundability among males with urinary acetaminophen concentrations in the highest quartile (>73.5 ng/mL) versus the lowest (<5.4 ng/mL). We analyzed data from 1,956 males participating in Pregnancy Study Online, a preconception cohort study of North American couples enrolled between 2013 and 2019. Males and females completed baseline questionnaires on sociodemographic characteristics, lifestyle, medication use, and medical history; females completed bimonthly follow-up questionnaires for up to 12 months. We categorized pain medications by active ingredient (ibuprofen, acetaminophen, naproxen, aspirin) and cumulative monthly dose. We used proportional probabilities models to calculate fecundability ratios and 95% confidence intervals, adjusting for potential confounders. In the 4 weeks before baseline, 51.7% of males used pain medications. Adjusted fecundability ratios were 1.02 for ibuprofen (95% confidence interval (CI): 0.91, 1.13), 0.89 for acetaminophen (95% CI: 0.77, 1.03), 1.07 for naproxen (95% CI: 0.85, 1.35), and 1.05 for aspirin (95% CI: 0.81, 1.35), as compared with nonuse of each medication. In this study, male use of pain medications at low doses was not notably associated with fecundability. [ABSTRACT FROM AUTHOR]

Study Question: To what extent does fecundability vary across seasons?Summary Answer: After accounting for seasonal patterns in pregnancy planning, we observed higher fecundability in the fall and lower fecundability in the spring, particularly at lower latitudes.What Is Known Already: In human populations, there are strong seasonal patterns of births that vary across geographic regions and time periods. However, previous studies of seasonality and fecundity are limited because they examine season of birth rather than season of conception and therefore neglect to account for seasonal variation in initiating attempts to conceive or pregnancy loss or differences in gestational length.Study Design, Size, Duration: We conducted a preconception cohort study of 14 331 women residing in North America (June 2013-May 2018: n = 5827) and Denmark (June 2007-May 2018: n = 8504). Participants were attempting to conceive without fertility treatment and had been attempting pregnancy for ≤6 menstrual cycles at enrolment.Participants/material, Setting, Methods: We collected information on season of each pregnancy attempt using last menstrual period dates over the study period. Pregnancy was reported on female bi-monthly follow-up questionnaires. We fit log-binomial models with trigonometric regression to examine periodic variation in fecundability. We accounted for seasonal variation in initiation of pregnancy attempts by including indicator variables for menstrual cycle of attempt in the regression models.Main Results and the Role Of Chance: Initiation of pregnancy attempts peaked in September, with stronger seasonality in North America than in Denmark (48 vs. 16% higher probability initiating attempts in September compared with March). After accounting for seasonal variation in initiation of pregnancy attempts, we observed modest seasonal variation in fecundability, with a peak in the late fall and early winter in both cohorts, but stronger peak/low ratios in North America (1.16; 95% confidence interval [CI]: 1.05, 1.28) than in Denmark (1.08; 95% CI: 1.00, 1.16). When we stratified the North American data by latitude, we observed the strongest seasonal variation in the southern USA (peak/low ratio of 1.45 [95% CI: 1.14, 1.84]), with peak fecundability in late November.Limitations, Reasons For Caution: We estimated menstrual cycle dates between follow-up questionnaires, which may have introduced exposure misclassification, particularly when women skipped follow-up questionnaires. We were unable to measure seasonally varying factors that may have influenced fecundability, including ambient temperature, vitamin D levels or infectious disease.Wider Implications Of the Findings: An understanding of how fecundability varies across seasons could help identify factors that can impair reproductive function. Neglecting to account for seasonal variation in initiation of pregnancy attempts could bias estimates of seasonal patterns in fecundability. This is the first preconception cohort study to examine seasonal variation in fecundability after accounting for seasonality in initiation of pregnancy attempts. Fecundability was highest in the fall and lowest in the spring, with stronger effects in southern latitudes of North America, suggesting that seasonal exposures may affect fecundity.Study Funding/competing Interest(s): This research was funded by the Eunice K. Shriver National Institute of Child Health and Human Development (R21-050264, R01-HD060680, R21-HD072326 and R01-HD086742) and the Danish Medical Research Council (271-07-0338). The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Study Question: To what extent is cigarette smoking associated with reduced fecundability?Summary Answer: Current female smokers, particularly those who had smoked ≥10 cigarettes/day for ≥10 years, had lower fecundability than never smokers, but current male smoking and passive smoking in either partner showed little association with reduced fecundability.What Is Known Already: Female smoking has been identified as a cause of infertility, yet there has been limited characterization of the dose and duration at which an effect is observed. Results for male active smoking and passive smoking in both partners are less consistent.Study Design, Size, Duration: We analyzed data from a North American internet-based preconception cohort study of 5473 female and 1411 male pregnancy planners, enrolled from 2013 to 2018. Participants had been attempting conception for ≤6 menstrual cycles at study entry.Participants/materials, Setting, Methods: We collected information on active and passive smoking history on baseline questionnaires. Pregnancy was reported on female bi-monthly follow-up questionnaires. We calculated fecundability ratios (FR) and 95% CI using proportional probabilities regression models, adjusted for demographic, behavioral, medical, reproductive and dietary variables.Main Results and the Role Of Chance: Female current regular smoking (FR = 0.90, 95% CI: 0.77, 1.07), current occasional smoking (FR = 0.88, 95% CI: 0.73, 1.06), and former smoking (FR = 0.89, 95% CI: 0.81, 0.98) were associated with small reductions in fecundability. Results were stronger among women who smoked ≥10 cigarettes/day for ≥10 years (FR = 0.77, 95% CI: 0.53, 1.10). Male current regular and former smoking, and current passive smoking in either partner were not meaningfully associated with reduced fecundability. In utero exposure to ≥10 cigarettes/day among females was associated with reduced fecundability (FR = 0.75, 95% CI: 0.52, 1.06).Limitations, Reasons For Caution: Numbers of cigarette smokers, particularly within categories of intensity and duration, were small. Under-reporting of smoking may have resulted in non-differential misclassification, and smokers were more likely to be lost to follow-up.Wider Implications Of the Findings: Given the consistency of our findings with results from previous studies and our observation of a dose-response relation in intensity of smoking, this study supports an association between female cigarette smoking and lower fecundability.Study Funding/competing Interest(s): This study was funded by the National Institute of Child Health and Human Development (R01-HD086742, R21-HD072326, R03-HD090315 and T32-HD052458). The authors declare no competing interests. [ABSTRACT FROM AUTHOR]

While some epidemiologic studies support the hypothesis that stress can adversely affect fertility, few prospective studies have assessed the association in couples from the general population. We used data from Pregnancy Study Online, a web-based preconception cohort study of pregnancy planners from the United States and Canada (2013–2018), to examine the association between women's and men's perceived stress levels prior to conception and fecundability. Women (aged 21–45 years) and their male partners (aged ≥21 years) who were attempting conception without fertility treatment were eligible. We measured perceived stress using the 10-item Perceived Stress Scale (PSS). We ascertained pregnancy information using bimonthly follow-up questionnaires of female participants. We followed 4,769 couples until self-reported pregnancy, initiation of fertility treatment, loss to follow-up, or 12 menstrual cycles of attempt time, whichever came first. We used proportional probabilities regression models to estimate fecundability ratios and 95% confidence intervals, adjusting for potential confounders. Higher PSS scores among the women were associated with slight reductions in fecundability (comparing PSS scores of ≥25 vs. <10, fecundability ratio = 0.87, 95% confidence interval: 0.74, 1.02). PSS scores among the men were not substantially associated with fecundability. [ABSTRACT FROM AUTHOR]

The article responds to comments made on the authors' article about the use of heuristics in epidemiology. Topics mentioned include the reasons for the occurrence of nondifferential misclassification bias, the use of quantitative bias analysis, the estimation of the effect of an exposure on an health outcome, and the role of bias due to nondifferential misclassification in changing the policy making on clinical care.

A growing literature indicates that changes in modifiable factors, including diet, can counteract the toxic developmental and reproductive health effects of chemical exposures. In this issue of the Journal , Gaskins et al. (Am J Epidemiol. 2019;000(000):000–000) present data supporting this hypothesis. Specifically, using data on a cohort of 304 women seeking fertility treatment in Boston, Massachusetts, they found that women with higher exposure to ambient air pollutants had lower fertility treatment success but only when they also consumed <800 μg/day of supplemental folate. No association was observed among women consuming ≥800 μg/day of supplemental folate. The public health importance of this interaction is high: Diet and dietary supplement intake are modifiable factors, whereas exposure to air pollution is less so. While this research question is grounded in a strong biological hypothesis related to epigenetic modifications, oxidative stress, and inflammation, this study raises several key questions. In this commentary, we discuss the inconsistency of the interaction across exposure metrics, the possibility of unmeasured confounding by folate intake, and the importance of examining this association in populations with lower folate intake and/or higher exposure to air pollution. [ABSTRACT FROM AUTHOR]

The association between dietary fat and fertility is not well studied. We evaluated intakes of total fat, saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, trans fatty acids (TFA), ω-3 fatty acids, and ω-6 fatty acids in relation to fecundability in Danish and North American preconception cohort studies. Women who were attempting to become pregnant completed a validated food frequency questionnaire at baseline. Pregnancy status was updated bimonthly for 12 months or until pregnancy. Fecundability ratios (FR) and 95% confidence intervals were estimated using multivariable proportional probabilities regression. Intakes of total fat and saturated, monounsaturated, polyunsaturated, and ω-6 fatty acids were not appreciably associated with fecundability. TFA intake was associated with reduced fecundability in North American women (for the fourth quartile vs. the first, FR = 0.86, 95% confidence interval (CI): 0.71, 1.04) but not Danish women (for the fourth quartile vs. the first, FR = 1.04, 95% CI: 0.86, 1.25), though intake among Danish women was low. In North America, ω-3 fatty acid intake was associated with higher fecundability, but there was no dose-response relationship (among persons who did not use fish oil supplements: for the fourth quartile vs. the first, FR = 1.40, 95% CI: 1.13, 1.73); no association was found in Danish women, among whom low intake was rare. In the present study, high TFA intake and low ω-3 fatty acid intake were associated with reduced fecundity. [ABSTRACT FROM AUTHOR]

Refusal to participate in studies related to sexual health can compromise the internal and external validity of findings. Research examining non-response to sexual health studies has primarily focused on predictors such as specific sexual attitudes and behaviors. Evaluate predictors of non-response to a supplemental sexual health survey added to a web-based cohort study, focusing on predictors that may be important in epidemiologic studies of sexual health. In March 2021, we added the "Sexual Health and Wellbeing Questionnaire" (SQ), an optional supplemental sexual health survey, to the protocol for Pregnancy Study Online , a web-based North American prospective cohort study. Eligible participants identified as female and were aged 21–45 years, actively trying to conceive, and in a relationship with a male partner. Participants completed a baseline questionnaire at enrollment and follow-up questionnaires every 8 weeks. Participants were invited to complete the SQ 30 days after baseline questionnaire completion. The analytic sample included all Pregnancy Study Online participants who enrolled between March 2021 and December 2021 and was divided into 3 mutually-exclusive groups: (i) those who completed the baseline questionnaire only (ie, did not complete a follow-up questionnaire or the SQ), (ii) those who completed at least 1 follow-up questionnaire but not the SQ, and (iii) participants who completed the SQ (with or without a follow-up questionnaire). We compared sociodemographic, medical, lifestyle, and reproductive factors across these groups. Of the 1,491 enrolled participants, 302 (20.3%) completed the baseline questionnaire only, 259 (17.4%) completed a follow-up questionnaire but not the SQ, and 930 (62.4%) completed the SQ. Strong predictors of non-response (absolute difference in response >10% comparing SQ responders to baseline-only responders) included longer pregnancy attempt time at study entry, a history of infertility, and lower income and education. Compared with response to the follow-up questionnaire only, SQ response was lower among Hispanic/Latina participants and participants aged <25 years. The addition of sexual health surveys to established cohort studies may be an effective way to expand epidemiologic sex research efforts. Study strengths include the prospective design, geographic heterogeneity of the cohort, and use of online methods. Our findings may not generalize to clinic-based sex research. We report that in an established North American cohort study, response to the SQ exceeded 60%. We observed few strong predictors for SQ non-response among engaged participants. Bond JC, Abrams J, Wesselink AK, et al. Predictors of Non-Response to a Sexual Health Survey in a North American Preconception Cohort Study. J Sex Med 2022;19:1707–1715. [ABSTRACT FROM AUTHOR]

Although electronic cigarette (e-cigarette) aerosol contains similar toxicants to combustible cigarettes, few studies have examined their influence on fecundability. We assessed the association between e-cigarette use and fecundability, overall and according to combustible cigarette smoking history, in a cohort of 4,586 North American women (aged 21–45 years) enrolled during 2017–2020 in Pregnancy Study Online, a Web-based prospective preconception study. Women reported current and former e-cigarette use on baseline and follow-up questionnaires, and they completed bimonthly follow-up questionnaires until self-reported pregnancy or censoring. Fecundability ratios and 95% confidence intervals were calculated using proportional probabilities models, controlling for potential confounders. Overall, 17% of women had ever used e-cigarettes and 4% were current users. Compared with never use of e-cigarettes, current e-cigarette use was associated with slightly lower fecundability (fecundability ratio = 0.84, 95% confidence interval (CI): 0.67, 1.06). Compared with current nonusers of e-cigarettes and combustible cigarettes, fecundability ratios were 0.83 (95% CI: 0.54, 1.29) for current dual users of e-cigarettes and combustible cigarettes, 0.91 (95% CI: 0.70, 1.18) for current e-cigarette users who were nonsmokers of combustible cigarettes, and 1.01 (95% CI: 0.85, 1.20) for nonusers of e-cigarettes who were current smokers of combustible cigarettes. Current e-cigarette use was associated with slightly reduced fecundability, but estimates of its independent and joint associations with combustible cigarette smoking were inconsistent and imprecise. [ABSTRACT FROM AUTHOR]

Uterine leiomyomata (UL) are associated with severe reproductive morbidity and are the primary indication for hysterectomy in the United States. A recent prospective cohort study of Black women reported positive associations between intakes of marine-sourced ω-3 fatty acids and UL risk. We examined whether intakes of dietary fat were associated with UL incidence in a 5-year prospective study of premenopausal Black women living in Detroit who underwent serial ultrasound. At baseline (2010–2012) and 20, 40, and 60 months of follow-up, participants underwent transvaginal ultrasound. Among 1,171 UL-free women at baseline, incident UL were detected in 277 women. Cox regression was used to estimate hazard ratios and 95% confidence intervals for the association of dietary fat and UL incidence. Intakes of total fat and saturated, monounsaturated, polyunsaturated, and trans -fat were not appreciably associated with UL incidence. Intake of the marine ω-3 polyunsaturated fatty acid, docosahexaenoic acid, was associated with 49% higher UL incidence (quartile 4 vs. 1: hazard ratio = 1.49, 95% confidence interval: 1.04, 2.14; P for trend = 0.01). Intakes of total marine ω-3 polyunsaturated fatty acids were similarly associated with elevated UL incidence (hazard ratio = 1.35, 95% confidence interval: 0.94, 1.93; P for trend = 0.03). It remains unclear whether the fatty acids or persistent environmental pollutants drive the association. [ABSTRACT FROM AUTHOR]

Chemical hair straighteners ("relaxers") are used by millions of North Americans, particularly women of color. Hair relaxers may contain endocrine-disrupting compounds, which can harm fertility. We evaluated the association between hair relaxer use and fecundability among 11,274 participants from Pregnancy Study Online (PRESTO), a North American preconception cohort study. During 2014–2022, participants completed a baseline questionnaire in which they reported their history of relaxer use and completed follow-up questionnaires every 8 weeks for 12 months or until pregnancy, whichever came first. We used multivariable-adjusted proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs). Relative to never use, fecundability was lower among current (FR = 0.81, 95% CI: 0.64, 1.03) and former (FR = 0.89, 95% CI: 0.81, 0.98) users of hair relaxers. FRs for first use of hair relaxers at ages <10, 10–19, and ≥20 years were 0.73 (95% CI: 0.55, 0.96), 0.93 (95% CI: 0.83, 1.04), and 0.85 (95% CI: 0.74, 0.98), respectively. Fecundability was lowest among those with longer durations of use (≥10 years vs. never: FR = 0.71, 95% CI: 0.54, 0.91) and more frequent use (≥5 times/year vs. never: FR = 0.82, 95% CI: 0.60, 1.11), but associations were nonmonotonic. In this preconception cohort study, use of chemical hair straighteners was associated with slightly reduced fecundability. [ABSTRACT FROM AUTHOR]

Study Question: To what extent is preconception use of pain-relieving medication associated with female fecundability?Summary Answer: Women who used naproxen or opioids had slightly lower fecundability than women who did not use any pain-relieving medications; use of acetaminophen, aspirin and ibuprofen was not appreciably associated with fecundability.What Is Known Already: Over-the-counter pain-relieving medications are commonly used by women of reproductive age in the USA. Studies investigating the effects of pain-relieving medication use on ovulation, implantation and fecundability have shown conflicting results.Study Design, Size, Duration: We analyzed data from an internet-based prospective cohort study of 2573 female pregnancy planners aged 21-45 years from the USA and Canada. Participants were enrolled and followed from June 2013 through September 2015. Participants completed a baseline questionnaire and bimonthly follow-up questionnaires until a reported pregnancy or for 12 months, whichever occurred first. Over 80% of participants completed at least one follow-up questionnaire.Participants/materials, Setting, Methods: Use of pain-relieving medication during the past month was assessed at baseline and on each follow-up questionnaire. Medications were categorized according to type (acetaminophen, aspirin, ibuprofen, naproxen and opioids) and total monthly dose. Self-reported pregnancy was assessed at each follow-up. Multivariable-adjusted fecundability ratios (FRs) and 95% CI were calculated using proportional probabilities regression. Models were adjusted for demographic, lifestyle and anthropometric factors; reproductive history; gynecologic morbidity; and indications for use of pain medications. Models were also run with and without adjustment for parity. After restricting to women with 6 or fewer months of attempt time at study entry, 1763 were included in the analyses.Main Results and the Role Of Chance: At baseline, 1279 (73%) women reported using ≥1 pain-relieving medications in the previous month. When compared with non-use of pain-relieving medications, FRs for use of naproxen and opioids at baseline were 0.78 (95% CI: 0.64-0.97) and 0.81 (95% CI: 0.60-1.10), respectively. A dose-response relation was observed between naproxen use and fecundability; FRs for use of <1500 and ≥1500 mg of naproxen were 0.85 (95% CI: 0.68-1.07) and 0.58 (95% CI: 0.36-0.94), respectively. Small numbers (n = 74) precluded the examination of opioid use by dose. Overall, there was little evidence of an association between fecundability and acetaminophen (FR 1.04, 95% CI: 0.92-1.18), aspirin (FR 1.00, 95% CI: 0.80-1.25), or ibuprofen (FR 1.00, 95% CI: 0.89-1.11). Similar results were observed when exposure information was updated over time.Limitations, Reasons For Caution: Numbers of opioid users were small. Information collected on reason for use of pain medications was not specific to each type of pain medication. Therefore, we cannot rule out confounding by indication as an explanation of these results.Wider Implications Of the Findings: Use of naproxen and opioids was associated with a small reduction in fecundability, but there was little association between other pain-relieving medications and fecundability.Study Funding/competing Interests: This study was supported through funds provided by National Institute of Child Health and Human Development, National Institute of Health (R21 HD072326, T32 HD052458). The authors have no conflicts of interest to disclose.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Study Question: To what extent is dietary folate intake and total folate intake (dietary and supplemental intakes) associated with fecundability, the per cycle probability of conception?Summary Answer: Preconception dietary folate intake was positively associated with fecundability in a monotonic pattern.What Is Known Already: Supplemental folic acid has been associated with improved fertility, but little is known about the relation between dietary folate and fecundability.Study Design, Size, Duration: A prospective cohort study including 9559 women trying to conceive without fertility treatment and enrolled in the period 2013-2020.Participants/materials, Setting, Methods: We used data from two internet-based prospective cohort studies of pregnancy planners from Denmark, where folic acid fortification is not performed (SnartForældre.dk (SF); n = 3755) and North America, where the food supply is fortified with folic acid (Pregnancy Study Online (PRESTO); n = 5804). Women contributed menstrual cycles at risk until they reported conception or experienced a censoring event. We used proportional probabilities regression models to compute fecundability ratios (FRs) and 95% CI, adjusting for potential confounders.Main Results and the Role Of Chance: Compared with a dietary folate intake ≥400 µg/day, the adjusted FRs for women in SF were 0.92 (95% CI: 0.85-0.99) for intake 250-399 µg/day, and 0.80 (95% CI: 0.68-0.94) for intake of <250 µg/day. The corresponding FRs in PRESTO were 0.95 (95% CI: 0.89-1.01) and 0.81 (95% CI: 0.65-1.00). Compared with the highest level of total folate intake (diet folate ≥400 µg/day plus folic acid supplementation), in both cohorts fecundability was lowest among women with the lowest dietary intake <250 µg/day dietary folate and no supplementation (FR: 0.76, 95% CI: 0.59-0.98 [SF] and 0.49, 95% CI: 0.31-0.77 [PRESTO]). Further, total intake dietary folate <250 µg/day plus supplementation was associated with reduced fecundability for SF participants (FR; 0.79, 95% CI: 0.65-0.98) and for PRESTO participants (FR; 0.92, 95% CI: 0.72-1.16).Limitations, Reasons For Caution: It is unknown whether dietary folate and folic acid intake affect fecundability on its own or if there is an interaction with other micronutrients provided in healthy diet. Thus, the observed associations may not reflect dietary folate intake alone, but overall healthy diet.Wider Implications Of the Findings: Recommendations for preconception dietary folate intake and folic acid supplementation are of importance not only to prevent neural tube defects but also to enhance fecundability.Study Funding/competing Interest(s): The study was supported by the National Institute of Child Health and Human Development (R01-HD086742). The authors report no competing interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Can we derive adequate models to predict the probability of conception among couples actively trying to conceive?Summary Answer: Leveraging data collected from female participants in a North American preconception cohort study, we developed models to predict pregnancy with performance of ∼70% in the area under the receiver operating characteristic curve (AUC).What Is Known Already: Earlier work has focused primarily on identifying individual risk factors for infertility. Several predictive models have been developed in subfertile populations, with relatively low discrimination (AUC: 59-64%).Study Design, Size, Duration: Study participants were female, aged 21-45 years, residents of the USA or Canada, not using fertility treatment, and actively trying to conceive at enrollment (2013-2019). Participants completed a baseline questionnaire at enrollment and follow-up questionnaires every 2 months for up to 12 months or until conception. We used data from 4133 participants with no more than one menstrual cycle of pregnancy attempt at study entry.Participants/materials, Setting, Methods: On the baseline questionnaire, participants reported data on sociodemographic factors, lifestyle and behavioral factors, diet quality, medical history and selected male partner characteristics. A total of 163 predictors were considered in this study. We implemented regularized logistic regression, support vector machines, neural networks and gradient boosted decision trees to derive models predicting the probability of pregnancy: (i) within fewer than 12 menstrual cycles of pregnancy attempt time (Model I), and (ii) within 6 menstrual cycles of pregnancy attempt time (Model II). Cox models were used to predict the probability of pregnancy within each menstrual cycle for up to 12 cycles of follow-up (Model III). We assessed model performance using the AUC and the weighted-F1 score for Models I and II, and the concordance index for Model III.Main Results and the Role Of Chance: Model I and II AUCs were 70% and 66%, respectively, in parsimonious models, and the concordance index for Model III was 63%. The predictors that were positively associated with pregnancy in all models were: having previously breastfed an infant and using multivitamins or folic acid supplements. The predictors that were inversely associated with pregnancy in all models were: female age, female BMI and history of infertility. Among nulligravid women with no history of infertility, the most important predictors were: female age, female BMI, male BMI, use of a fertility app, attempt time at study entry and perceived stress.Limitations, Reasons For Caution: Reliance on self-reported predictor data could have introduced misclassification, which would likely be non-differential with respect to the pregnancy outcome given the prospective design. In addition, we cannot be certain that all relevant predictor variables were considered. Finally, though we validated the models using split-sample replication techniques, we did not conduct an external validation study.Wider Implications Of the Findings: Given a wide range of predictor data, machine learning algorithms can be leveraged to analyze epidemiologic data and predict the probability of conception with discrimination that exceeds earlier work.Study Funding/competing Interest(s): The research was partially supported by the U.S. National Science Foundation (under grants DMS-1664644, CNS-1645681 and IIS-1914792) and the National Institutes for Health (under grants R01 GM135930 and UL54 TR004130). In the last 3 years, L.A.W. has received in-kind donations for primary data collection in PRESTO from FertilityFriend.com, Kindara.com, Sandstone Diagnostics and Swiss Precision Diagnostics. L.A.W. also serves as a fibroid consultant to AbbVie, Inc. The other authors declare no competing interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

We conducted a parallel, nonblinded randomized trial to assess whether offering home pregnancy tests (HPTs) to preconception cohort study participants influenced cohort retention or pregnancy detection. Pregnancy Study Online participants were female, aged 21–45 years, attempting pregnancy, and not using fertility treatment. At enrollment (2017–2018), 1,493 participants with 6 or fewer cycles of attempt time were randomly assigned with 50% probability to receive 12 Clearblue visual HPTs plus the standard protocol (n  = 720) or the standard protocol alone (n  = 773). Women completed bimonthly questionnaires for 12 months or until conception, whichever came first. In intent-to-treat analyses, retention (≥1 follow-up) was higher in the HPT arm (n  = 598; 83%) than the standard protocol arm (n  = 535 (69%); mean difference = 15%, 95% CI: 10, 19). Mean time at first pregnancy testing was identical in both arms (2 days before expected menses), as was mean gestational weeks at first positive pregnancy test (4 weeks). Conception was reported by 78% of women in the HPT arm and 75% in the standard protocol arm. Spontaneous abortion was reported by 21% in the HPT arm (mean gestational weeks = 7) and 21% in the standard protocol arm (mean gestational weeks = 6). Randomization of HPTs was associated with greater cohort retention but had little impact on incidence or timing of pregnancy detection. [ABSTRACT FROM AUTHOR]