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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]

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]

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]

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]

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]