The association between the use of fertility indicators and fecundability in a Danish preconception cohort.

BACKGROUND: The use of fertility indicators to predict ovulation has largely been studied for contraceptive purposes, while less so as fertility-promoting tools. OBJECTIVE: To investigate the association between fertility indicators and fecundability in Danish women trying to conceive. METHODS: Web-based preconception cohort study. We analysed data from 11,328 females aged 18-49 years trying to conceive without fertility treatment for ≤6 menstrual cycles, from the Danish SnartGravid.dk and SnartForældre.dk cohorts (2007-2023). Participants reported the use of fertility indicators (counting days since the last menstrual period, cervical fluid monitoring, urinary ovulation testing, feeling ovulation, using a smartphone fertility app and measuring basal body temperature [BBT]). Time to pregnancy was measured in menstrual cycles ascertained by self-reported pregnancy status. We estimated fecundability ratios (FR) and 95% confidence intervals (CIs) using proportional probabilities regression models adjusted for age, socio-economic position, health indicators, reproductive history and gynaecological factors. RESULTS: Fertility indicators were used by 63.3% of participants at study entry. Counting days was the most common (46.9%), while measuring BBT was the least (3.0%). Other indicators ranged from 17.0% to 23.6%, with 69.7% using more than one indicator. Compared with non-use, use of any fertility indicator was associated with greater fecundability (adjusted FR 1.14, 95% CI 1.08, 1.19). Cervical fluid monitoring showed the strongest association (aFR 1.46, 95% CI 1.03, 2.07), followed by urinary ovulation testing (aFR 1.35, 95% CI 1.16, 1.58) and counting days (aFR 1.18, 95% CI 1.09, 1.29). Feeling ovulation and fertility apps were modestly associated with fecundability, while measuring BBT was not associated. Sensitivity analysis restricting to ≤2 cycles of attempt time and two cycles of follow-up showed an aFR for any indicator use of 1.21 (95% CI 1.13, 1.31). CONCLUSION: In this Danish preconception cohort, use of fertility indicators was associated with a higher fecundability, varying by type of indicator.

Benign and Malignant Outcomes in the Offspring of Females Exposed In Utero to Diethylstilbestrol (DES): An Update from the NCI Third Generation Study.

BACKGROUND: Females exposed prenatally to diethylstilbestrol (DES) have an elevated risk of cervical dysplasia, breast cancer, and clear cell adenocarcinoma (CCA) of the cervix/vagina. Testicular cancer risk is increased in prenatally exposed males. Epigenetic changes may mediate the transmission of DES effects to the next ("third") generation of offspring. METHODS: Using data self-reported by third-generation females, we assessed DES in relation to the risk of cancer and benign breast and reproductive tract conditions. Using data from prenatally DES-exposed and unexposed mothers, we assessed DES in relation to cancer risk in their female and male offspring. Cancer risk was assessed by standardized incidence ratios (SIR) and 95% confidence intervals (CI); the risks of benign and malignant diagnoses were assessed by hazard ratios (HR) and 95% CI. RESULTS: In self-reported data, DES exposure was not associated with an increased risk of overall cancer (HR 0.83; CI 0.36-1.90), breast cancer, or severe cervical dysplasia. No females reported CCA. The risk of borderline ovarian cancer appeared elevated, but the HR was imprecise (3.46; CI 0.37-32.42). Based on mothers' reports, DES exposure did not increase the risk of overall cancer (HR 0.80; CI 0.49-1.32) or of other cancers in third-generation females. Overall cancer risk in exposed males appeared elevated (HR 1.41; CI 0.70-2.86), but the CI was wide. The risk of testicular cancer was not elevated in exposed males; no cases of prostate cancer were reported. CONCLUSIONS: To date, there is little evidence that DES is associated with cancer risk in third-generation females or males, but these individuals are relatively young, and further follow-up is needed.

Residential Proximity to Oil and Gas Development and Mental Health in a North American Preconception Cohort Study: 2013-2023.

Objectives. To evaluate associations between oil and gas development (OGD) and mental health using cross-sectional data from a preconception cohort study, Pregnancy Study Online. Methods. We analyzed baseline data from a prospective cohort of US and Canadian women aged 21 to 45 years who were attempting conception without fertility treatment (2013-2023). We developed residential proximity measures for active OGD during preconception, including distance from nearest site. At baseline, participants completed validated scales for perceived stress (10-item Perceived Stress Scale, PSS) and depressive symptoms (Major Depression Inventory, MDI) and reported psychotropic medication use. We used log-binomial regression and restricted cubic splines to estimate prevalence ratios (PRs) and 95% confidence intervals (CIs). Results. Among 5725 participants across 37 states and provinces, residence at 2 km versus 20 to 50 km of active OGD was associated with moderate to high perceived stress (PSS ≥ 20 vs < 20: PR = 1.08; 95% CI = 0.98, 1.18), moderate to severe depressive symptoms (MDI ≥ 20 vs < 20: PR = 1.27; 95% CI = 1.11, 1.45), and psychotropic medication use (PR = 1.11; 95% CI = 0.97, 1.28). Conclusions. Among North American pregnancy planners, closer proximity to OGD was associated with adverse preconception mental health symptomatology. (Am J Public Health. 2024;114(9):923-934. https://doi.org/10.2105/AJPH.2024.307730).

Exposure to residential greenness, perceived stress, and depressive symptoms in a North American preconception cohort.

BACKGROUND: Studies suggest that greater exposure to natural vegetation (i.e., greenness) is associated with better mental health. However, there is limited research on greenness and mental health in the preconception period, a critical window of exposure in the life course. We investigated the associations of residential greenness with perceived stress and depressive symptoms using cross-sectional data from a cohort of pregnancy planners. METHODS: From 2013 to 2019, we enrolled female-identified participants aged 21-45 years who were trying to conceive without the use of fertility treatment into a North American preconception cohort study (Pregnancy Study Online [PRESTO]). On the baseline questionnaire, participants completed the 10-item Perceived Stress Scale (PSS) and the Major Depression Inventory (MDI). Using geocoded addresses, we estimated residential greenness exposure via satellite imagery (Normalized Difference Vegetation Index [NDVI]) in a 100m buffer. We estimated mean differences and 95% confidence intervals for the association of greenness with perceived stress and depression scores using linear regression models, adjusting for individual and neighborhood sociodemographic characteristics. We also evaluated the extent to which associations were modified by urbanicity and neighborhood socioeconomic status (SES). RESULTS: Among 9718 participants, mean age was 29.9 years, 81.5% identified as non-Hispanic White, 25% had household incomes <$50,000, and mean neighborhood income was $61,932. In adjusted models, higher greenness was associated with lower stress and depression scores (mean difference per interquartile range in greenness: -0.20, 95% CI: -0.39, -0.01; and -0.19, 95% CI: -0.48, 0.10, respectively). The association was stronger among residents of lower SES neighborhoods in urban areas (PSS: -0.57, 95% CI: -1.00, -0.15; MDI: -0.72, 95% CI: -1.40, -0.04). CONCLUSIONS: Higher greenness exposure was associated with lower stress and depressive symptoms among pregnancy planners, particularly in lower-SES neighborhoods.

Cervical intraepithelial neoplasia and fecundability: a prospective cohort study.

STUDY QUESTION: Is cervical intraepithelial neoplasia (CIN) associated with reduced fecundability, defined as the probability of conceiving per menstrual cycle? SUMMARY ANSWER: Overall, we observed no meaningful association between CIN and fecundability, regardless of surgical status, although a recent diagnosis of moderate or severe CIN might be associated with slightly reduced fecundability for 2 years after diagnosis. WHAT IS KNOWN ALREADY: About 15% of couples experience infertility. Few studies have examined the influence of CIN on fertility, and the results have been inconsistent. No study has investigated the association between fecundability and pathologist-reported CIN diagnoses, particularly with respect to the recency of the specific CIN diagnoses. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9586 women trying to conceive. The women were enrolled from 1 June 2007 to 3 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for up to 12 months or until pregnancy occurred. Data on cervical cytologies and biopsies were retrieved from The National Pathology Registry (DNPR), which holds records of all cervical specimens examined in Denmark. Women were categorized based on their most severe diagnosis of CIN: no lesion, other cervical changes, mild CIN (CIN1), or moderate/severe CIN (CIN2+) with or without surgery. To investigate the association between CIN and fecundability, we computed fecundability ratios (FR) and 95% confidence intervals (CI) using a proportional probabilities regression model. We adjusted for age at study entry, partner age, body mass index, smoking status, timing of intercourse, parity, education, number of sexual partners, and household income. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with no lesion, the adjusted FRs (95% CI) for the association between CIN and fecundability were: other cervical lesions, 0.97 (0.91-1.04); CIN1, 1.04 (0.96-1.13); CIN2+ no surgery, 1.00 (0.82-1.22); and CIN2+ with surgery 0.99 (0.89-1.10). The FRs (95% CI) for a recent diagnosis (<2 years) of CIN were 0.98 (0.86-1.11) for other cervical lesions; 1.13 (0.99-1.29) for CIN1; 0.89 (0.62-1.26) for CIN2+ no surgery and 0.91 (0.75-1.10) for CIN2+ with surgery compared with the no lesion group. LIMITATIONS, REASONS FOR CAUTION: In the analyses, we adjusted for several covariates related to the women. However, we had little information on the male partners which could lead to unmeasured confounding as fecundability is a couple-based measure of fertility. Furthermore, a CIN diagnosis may not be constant as it may regress or progress spontaneously; therefore, it is possible that we have misclassified some women, especially women categorized as having normal cells or CIN1. WIDER IMPLICATIONS OF THE FINDINGS: Our results contribute important knowledge to women who are concerned about their future fertility after receiving a CIN diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Danish Cancer Society (R167-A11036-17-S2). The overall cohorts were funded by the National Institute of Child Health and Human Development (R01-HD086742 and R03-HD094117). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Childhood adversity and time-to-pregnancy in a preconception cohort.

We examined the association between childhood adversity and fecundability (the per-cycle probability of conception), and the extent to which childhood social support modified this association. We used data from 6,318 female participants aged 21-45 years in Pregnancy Study Online (PRESTO), a North American prospective preconception cohort study (2013-2022). Participants completed a baseline questionnaire, bimonthly follow-up questionnaires (until pregnancy or a censoring event), and a supplemental questionnaire on experiences across the life course including adverse childhood experiences (ACE) and social support (using the modified Berkman-Syme Social Network Index [SNI]). We used proportional probabilities regression models to compute fecundability ratios (FR) and 95% confidence intervals (CI), adjusting for potential confounders and precision variables. Adjusted FRs for ACE scores 1-3 and ≥4 vs. 0 were 0.91 (95% CI: 0.85, 0.97) and 0.84 (95% CI: 0.77, 0.91), respectively. FRs for ACE scores ≥4 vs. 0 were 0.86 (95% CI: 0.78, 0.94) among participants reporting high childhood social support (SNI ≥4) and 0.78 (95% CI: 0.56, 1.07) among participants reporting low childhood social support (SNI <4). Our findings confirm results from two previous studies and indicate that high childhood social support slightly buffered the effects of childhood adversity on fecundability.

Predictive models of miscarriage on the basis of data from a preconception cohort study.

OBJECTIVE: To use self-reported preconception data to derive models that predict the risk of miscarriage. DESIGN: Prospective preconception cohort study. SETTING: Not applicable. PATIENTS: Study participants were female, aged 21-45 years, residents of the United States or Canada, and attempting spontaneous pregnancy at enrollment during 2013-2022. Participants were followed for up to 12 months of pregnancy attempts; those who conceived were followed through pregnancy and postpartum. We restricted analyses to participants who conceived during the study period. EXPOSURE: On baseline and follow-up questionnaires completed every 8 weeks until pregnancy, we collected self-reported data on sociodemographic factors, reproductive history, lifestyle, anthropometrics, diet, medical history, and male partner characteristics. We included 160 potential predictor variables in our models. MAIN OUTCOME MEASURES: The primary outcome was a miscarriage, defined as pregnancy loss before 20 weeks of gestation. We followed participants from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss of follow-up, or 20 weeks of gestation), whichever occurred first. We fit both survival and static models using Cox proportional hazards models, logistic regression, support vector machines, gradient-boosted trees, and random forest algorithms. We evaluated model performance using the concordance index (survival models) and the weighted F1 score (static models). RESULTS: Among the 8,720 participants who conceived, 20.4% reported miscarriage. In multivariable models, the strongest predictors of miscarriage were female age, history of miscarriage, and male partner age. The weighted F1 score ranged from 73%-89% for static models and the concordance index ranged from 53%-56% for survival models, indicating better discrimination for the static models compared with the survival models (i.e., the ability of the model to discriminate between individuals with and without miscarriage). No appreciable differences were observed across strata of miscarriage history or among models restricted to ≥8 weeks of gestation. CONCLUSION: Our findings suggest that miscarriage is not easily predicted on the basis of preconception lifestyle characteristics and that advancing age and a history of miscarriage are the most important predictors of incident miscarriage.

A preconception cohort study of sugar-sweetened beverage consumption and semen quality.

BACKGROUND: Dietary factors, including high sugar intake, may have adverse effects on male reproduction. Studies of the association between sugar-sweetened beverage (SSB) intake and semen quality have reported inconsistent results. OBJECTIVE: We estimated the effects of SSB consumption on semen quality in a North American preconception cohort study. METHODS: We analyzed baseline data from 690 males (n = 1,247 samples) participating in Pregnancy Study Online (PRESTO) during 2015-2022. Participants aged ≥21 years completed a baseline questionnaire on which they reported information about intake of SSBs, including sodas, energy drinks, sports drinks, and fruit juices. After enrollment, we invited U.S. participants to a semen testing substudy, in which they collected and analyzed two samples using an at-home semen testing kit. We used linear regression models to estimate adjusted percent differences (%D) and 95% confidence intervals (CI) for associations of SSB intake with semen volume, sperm concentration, total sperm count (TSC), motility, and total motile sperm count (TMSC). We used modified Poisson regression models to estimate adjusted risk ratios (RRs) and 95% CIs for the association of SSB intake with World Health Organization semen parameter cut points. RESULTS: Relative to non-consumers of SSBs, those who consumed ≥7 SSBs/week had lower semen volume (%D = -6, 95% CI: -13, 0), sperm concentration (%D = -22, 95% CI: -38, 0), TSC (%D = -22, 95% CI: -38, -2), motility (%D = -4, 95% CI: -10, 2), and TMSC (%D = -25, 95% CI: -43, -2). High SSB consumers also had greater risks of low sperm concentration (≤16 million/mL; RR = 1.89, 95% CI: 1.11, 3.21), low TSC (≤39 million; RR = 1.75, 95% CI: 0.92, 3.33), low motility (≤42%; RR = 1.23, 95% CI: 0.87, 1.75) and low TMSC (≤21 million; RR = 1.95, 95% CI: 1.12, 3.38). Associations were stronger among participants with body mass index ≥ 25 kg/m2 . CONCLUSION: Greater SSB consumption was associated with reduced semen quality in a North American preconception cohort.

An Update on Prenatal Diethylstilbestrol Exposure and High-Grade Squamous Intraepithelial Lesions of the Lower Genital Tract.

Women with prenatal diethylstilbestrol exposure are excluded from less frequent cervical cancer screening because of their increased neoplasia risk. We report the results of a prospective follow-up study of prenatal diethylstilbestrol exposure and lower genital tract high-grade (grade 2 or higher) squamous intraepithelial lesions (HSIL). The age-adjusted risk of HSIL among diethylstilbestrol-exposed women (n=4,062) was higher than among the diethylstilbestrol unexposed (n=1,837) through age 44 years (hazard ratio 2.03, 95% CI, 1.31-3.14) but not age 45 years or older. Elevated HSIL risk remained higher in diethylstilbestrol-exposed women, after accounting for frequency of cervical cancer screening. Compared with unexposed women, HSIL risk was higher among women with earlier gestational and high-dose diethylstilbestrol exposure. These data confirm the appropriateness of more frequent screening among diethylstilbestrol-exposed women through age 44 years. Whether those aged 45 years or older should continue to have increased screening will require careful weighing of possible risks and benefits.

Ambient air pollution and rate of spontaneous abortion.

Spontaneous abortion (SAB), defined as a pregnancy loss before 20 weeks of gestation, affects up to 30% of conceptions, yet few modifiable risk factors have been identified. We estimated the effect of ambient air pollution exposure on SAB incidence in Pregnancy Study Online (PRESTO), a preconception cohort study of North American couples who were trying to conceive. Participants completed questionnaires at baseline, every 8 weeks during preconception follow-up, and in early and late pregnancy. We analyzed data on 4643 United States (U.S.) participants and 851 Canadian participants who enrolled during 2013-2019 and conceived during 12 months of follow-up. We used country-specific national spatiotemporal models to estimate concentrations of particulate matter <2.5 µm (PM2.5), nitrogen dioxide (NO2), and ozone (O3) during the preconception and prenatal periods at each participant's residential address. On follow-up and pregnancy questionnaires, participants reported information on pregnancy status, including SAB incidence and timing. We fit Cox proportional hazards regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of time-varying prenatal concentrations of PM2.5, NO2, and O3 with rate of SAB, adjusting for individual- and neighborhood-level factors. Nineteen percent of pregnancies ended in SAB. Greater PM2.5 concentrations were associated with a higher incidence of SAB in Canada, but not in the U.S. (HRs for a 5 µg/m3 increase = 1.29, 95% CI: 0.99, 1.68 and 0.94, 95% CI: 0.83, 1.08, respectively). NO2 and O3 concentrations were not appreciably associated with SAB incidence. Results did not vary substantially by gestational weeks or season at risk. In summary, we found little evidence for an effect of residential ambient PM2.5, NO2, and O3 concentrations on SAB incidence in the U.S., but a moderate positive association of PM2.5 with SAB incidence in Canada.