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.

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.

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.

Mental disorders, participation, and trajectories in the Danish colorectal cancer programme: a population-based cohort study.

BACKGROUND: People with mental disorders exhibit increased mortality due to colorectal cancer, despite having a similar incidence to the general population. We aimed to evaluate the extent to which people with mental disorders participate in organised colorectal cancer screening. METHODS: We conducted a population-based cohort study of all Danish residents aged 50-74 years who were invited to undergo biennial faecal immunochemical testing between March 1, 2014, and Sept 30, 2018. We used national registry data from all first-time invitees. The primary endpoint was participation within 90 days of invitation. We calculated the proportion who participated and assessed their screening results and adherence to and completeness of follow-up colonoscopy according to their history of mental disorders, classified as none, mild or moderate, or severe. We computed crude and adjusted participation differences in percentage points and participation ratios using the pseudo-observations method. FINDINGS: Of 2 036 704 people who were invited, we included 2 036 352 in the final cohort, of whom 1 008 045 (49·5%) were men and 1 028 307 (50·5%) were women, with a mean age of 60·7 years (SD 8·3, range 49-78). Data on ethnicity were not collected. Compared with people with no mental disorders, the adjusted analysis showed lower participation among people with mild or moderate mental disorders (men: participation difference -4·4 percentage points [95% CI -4·7 to -4·1]; women: -3·8 percentage points [-4·1 to -3·6]) and severe mental disorders (men: participation difference -13·8 percentage points [-14·3 to -13·3]; women: -15·4 percentage points [-15·8 to -14·9]). People with mental disorders had a higher proportion of positive faecal immunochemical test results, lower adherence to colonoscopy, and more incomplete colonoscopies than people without mental disorders. INTERPRETATION: People with mental disorders were less likely to participate in colorectal cancer screening than those without these disorders. Patients with mental disorders could benefit from support or encouragement from their general practitioner or mental health-care facility to participate in cancer screening. Potential interventions should consider type of mental disorder, as needs might differ. FUNDING: Danish Cancer Society, Danish Health Foundation.

Effect of a FIT-Based Colorectal Cancer Screening Program on Mortality Estimated by the Regression Discontinuity Design.

The fecal immunochemical test (FIT) has been implemented in colorectal cancer (CRC) screening programs, but effect evaluations are lacking. We evaluated the effect of a positive FIT on all-cause and CRC mortality using the regression discontinuity design. The Danish CRC screening program invites all residents 50-74 years old, using a 20-µg hemoglobin/g feces cutoff for colonoscopy referral. In this cohort study, we followed all first-time screening participants from 2014-2019 until 2020. We estimated the local effect of screening results, of just above the cutoff vs. just below, as hazard ratios (HRs) between models fitted at each side of the cutoff. We conducted the analysis within a narrow hemoglobin range (≥17 and <23, n = 16,428) and a wider range (≥14 and <26, n = 35,353). Those screened just above the cutoff had lower all-cause mortality compared with below (HR = 0.87, 95% confidence interval: 0.69; 1.10), estimated from the narrow range. The CRC mortality analysis had few outcomes. In the wider range, those with a FIT just above the cutoff had a lower hazard of CRC mortality compared with just below the cutoff (HR = 0.49, 95% confidence interval: 0.17; 1.41). A FIT result just above the cutoff, leading to referral to colonoscopy, pointed towards reduced all-cause and CRC mortality compared with just below the cutoff.

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.

Glycemic Load, Dietary Fiber, Added Sugar, and Spontaneous Abortion in Two Preconception Cohorts.

BACKGROUND: Spontaneous abortion (SAB)-pregnancy loss before the 20th week of gestation-has adverse psychological and physical sequelae. Some medical conditions known to affect insulin sensitivity, including polycystic ovary syndrome and diabetes, can affect the risk of SAB. No prior studies have examined glycemic load and incidence of SAB in populations without conditions known to affect insulin sensitivity. OBJECTIVES: We prospectively evaluated the association between preconception glycemic load and intake of carbohydrates, dietary fiber, and added sugar and risk of SAB. METHODS: During 2013-2020, we recruited pregnancy planners from Denmark (SnartForaeldre.dk; SF) and the United States and Canada (Pregnancy Study Online; PRESTO). Participants completed a baseline questionnaire and a cohort-specific FFQ evaluated for validity. We estimated preconception glycemic load and intake of carbohydrates, dietary fiber, and added sugar from individual foods and mixed recipes. We included 2238 SF and 4246 PRESTO participants who reported a pregnancy during the course of the study. SAB data were derived from questionnaires and population registries. We used Cox proportional hazards regression to estimate HRs and 95% CIs. RESULTS: In the study population, 15% of SF participants and 22% of PRESTO participants experienced SAB. Across both cohorts, there was no appreciable association between glycemic load, carbohydrate quality, dietary fiber, or added sugar intake and SAB. Compared with daily mean glycemic load <110, the HR for women with daily mean glycemic load ≥130 was 0.76 (95% CI: 0.52, 1.10) in SF and 1.01 (95% CI: 0.86, 1.19) in PRESTO. CONCLUSIONS: Diets with high glycemic load, carbohydrates, and added sugars were not consistently associated with risk of SAB in parallel analyses of 2 preconception cohort studies of women in North America and Denmark.

Perceived stress and semen quality.

BACKGROUND: Psychological stress is prevalent among reproductive-aged men. Assessment of semen quality for epidemiological studies is challenging as data collection is expensive and cumbersome, and studies evaluating the effect of perceived stress on semen quality are inconsistent. OBJECTIVE: To examine the association between perceived stress and semen quality. MATERIAL AND METHODS: We analyzed baseline data on 644 men (1,159 semen samples) from two prospective preconception cohort studies during 2015-2021: 592 in Pregnancy Study Online (PRESTO) and 52 in SnartForaeldre.dk (SF). At study entry, men aged ≥21 years (PRESTO) and ≥18 years (SF) trying to conceive without fertility treatment completed a questionnaire on reproductive and medical history, socio-demographics, lifestyle, and the 10-item version of the Perceived Stress Scale (PSS; interquartile range [IQR] of scores: 0-40). After enrollment (median weeks: 2.1, IQR: 1.3-3.7), men were invited to perform in-home semen testing, twice with 7-10 days between tests, using the Trak Male Fertility Testing System. Semen quality was characterized by semen volume, sperm concentration, and total sperm count. We fit generalized estimating equation linear regression models to estimate the percent difference in mean log-transformed semen parameters by four PSS groups (<10, 10-14, 15-19, ≥20), adjusting for potential confounders. RESULTS: The median PSS score and IQR was 15 (10-19), and 136 men (21.1%) had a PSS score ≥20. Comparing men with PSS scores ≥20 with <10, the adjusted percent difference was -2.7 (95% CI: -9.8; 5.0) for semen volume, 6.8 (95% CI: -10.9; 28.1) for sperm concentration, and 4.3 (95% CI: -13.8; 26.2) for total sperm count. CONCLUSION: Our findings indicate that perceived stress is not materially associated with semen volume, sperm concentration, or total sperm count.

Pre-pregnancy migraine diagnosis, medication use, and spontaneous abortion: a prospective cohort study.

BACKGROUND: Migraine is common among females of reproductive age (estimated prevalence:17-24%) and may be associated with reproductive health through underlying central nervous system excitability, autoimmune conditions, and autonomic dysfunction. We evaluated the extent to which pre-pregnancy migraine diagnosis and medication use are associated with risk of spontaneous abortion (SAB). METHODS: We analyzed data from a preconception study of pregnancy planners (2013-2021). Eligible participants self-identified as female, were aged 21-45 years, resided in the USA or Canada, and conceived during follow-up (n = 7890). Participants completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever occurred first. Pregnant participants then completed questionnaires during early (~ 8-9 weeks) and late (~ 32 weeks) gestation. We defined migraineurs as participants who reported a migraine diagnosis or use of a medication to treat migraine. Preconception questionnaires elicited migraine medication use during the past 4 weeks, and SAB on follow-up and pregnancy questionnaires. We used Cox regression models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations among preconception migraine, migraine medication use, and SAB, controlling for potential demographic, medical, and lifestyle confounders. RESULTS: Nineteen percent of study pregnancies ended in SAB. History of migraine before conception was not appreciably associated with SAB risk (HR = 1.03, 95% CI: 0.91-1.06). Use of any migraine medication was associated with a modest increase in SAB risk overall (HR = 1.14, 95% CI: 0.96-1.36). We observed the greatest increase in risk among those taking migraine medications daily (HR = 1.38, 95% CI: 0.81-2.35) and those taking prescription migraine prophylaxis (HR = 1.43, 95% CI: 0.72-2.84) or combination analgesic and caffeine medications (HR = 1.42, 95% CI: 0.99-2.04). CONCLUSIONS: Migraine medication use patterns suggesting greater underlying migraine severity were associated with increased risk of SAB. This research adds to the limited information available on the reproductive effects of migraine.

Dietary patterns and fecundability in 2 prospective preconception cohorts.

BACKGROUND: Diet is increasingly recognized as an important determinant of human fertility, with most research focused on specific nutrients or food groups. However, there has been limited assessment of the effect of dietary patterns on fertility. OBJECTIVES: We evaluated the association between 4 dietary patterns [the alternative Mediterranean Diet (aMed), the Healthy Eating Index-2010 (HEI-2010), the Danish Dietary Guidelines (DDGI), and the Dietary Inflammatory Index (DII)] and fecundability in 2 preconception cohorts of couples trying to conceive: SF (SnartForaeldre.dk) in Denmark and PRESTO (Pregnancy Study Online) in North America. METHODS: Participants completed a baseline questionnaire on sociodemographic, anthropometric, and lifestyle factors and, 10 d later, a validated cohort-specific FFQ. We used data from these respective FFQs to calculate adherence to each dietary pattern. Participants completed bimonthly follow-up questionnaires for ≤12 mo or until pregnancy, whichever came first. We restricted analyses to 3429 SF and 5803 PRESTO participants attempting pregnancy for ≤6 cycles at enrollment. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusting for potential confounders. RESULTS: Greater DII, indicative of a less anti-inflammatory diet (i.e., poorer diet quality), was associated with reduced fecundability in both SF and PRESTO (DII ≥ -1.5 compared with < -3.3: FR: 0.83; 95% CI: 0.71, 0.97 and FR: 0.82; 95% CI: 0.73, 0.93, respectively). In PRESTO, greater adherence to the aMed or to the HEI-2010 was associated with greater fecundability. In SF, there was no appreciable association between the aMed and fecundability, whereas greater adherence to the DDGI was associated with greater fecundability. CONCLUSIONS: In prospective preconception cohort studies from Denmark and North America, higher-quality diets, including diets lower in inflammatory effects, were associated with greater fecundability.

Male personal heat exposures and fecundability: A preconception cohort study.

BACKGROUND: Several studies indicate adverse effects of selected heat exposures on semen quality, but few studies have directly evaluated fertility as an endpoint. OBJECTIVE: We evaluated prospectively the association between male heat exposures and fecundability, the per-cycle probability of conception. MATERIALS AND METHODS: We analyzed data from 3041 couples residing in the United States or Canada who enrolled in a prospective preconception cohort study (2013-2021). At enrollment, males reported on several heat-related exposures, such as use of saunas, hot baths, seat heaters, and tight-fitting underwear. Pregnancy status was updated on female follow-up questionnaires every 8 weeks until conception or a censoring event (initiation of fertility treatment, cessation of pregnancy attempts, withdrawal, loss to follow-up, or 12 cycles), whichever came first. We used proportional probabilities regression models to estimate fecundability ratios (FR) and 95% confidence intervals (CIs) for the association between heat exposures and fecundability, mutually adjusting for heat exposures and other potential confounders. RESULTS: We observed small inverse associations for hot bath/tub use (≥3 vs. 0 times/month: FR = 0.87, 95% CI: 0.70-1.07) and fever in the 3 months before baseline (FR = 0.94, 95% CI: 0.79-1.12; one cycle of follow-up: FR = 0.84, 95% CI: 0.64-1.11). Little association was found for sauna use, hours of laptop use on one's lap, seat heater use, time spent sitting, and use of tight-fitting underwear. Based on a cumulative heat metric, FRs for 1, 2, 3, and ≥4 versus 0 heat exposures were 0.99 (95% CI: 0.87-1.12), 1.03 (95% CI: 0.89-1.19), 0.94 (95% CI: 0.74-1.19), and 0.77 (95% CI: 0.50-1.17), respectively. Associations were stronger among men aged ≥30 years (≥4 vs. 0 heat exposures: FR = 0.60, 95% CI: 0.34-1.04). CONCLUSION: Male use of hot tubs/baths and fever showed weak inverse associations with fecundability. Cumulative exposure to multiple heat sources was associated with a moderate reduction in fecundability, particularly among males aged ≥30 years.

Mental illness and participation in colorectal cancer screening: a scoping review.

INTRODUCTION: Compared with the background population, persons with mental illness have increased colorectal cancer (CRC) mortality. Screening has the potential to alleviate the increased cancer mortality due to mental illness, but the extent to which persons with mental illness participate in CRC screening programs is uncertain. This scoping review aims to summarize the literature on CRC screening participation among persons with mental illness. MATERIALS AND METHODS: We searched four databases (PubMed, PsychInfo, Embase, and the Cochrane Library) to identify published literature on mental illness and participation in CRC screening programs. We included full-text papers available in English, published before February 2021, and excluded papers on dementia, intellectual disabilities, and developmental disabilities. RESULTS: In total, we included 17 studies and categorized the findings according to severity of mental illness. Across varying study designs, the studies found that persons with severe mental illness, e.g. schizophrenia, participate less in CRC screening compared with the background population. The results were ambiguous for common mental illness, such as depression and anxiety. In general, studies were small or lacked comparison groups and the estimates were imprecise. CONCLUSION: This is the first scoping review to evaluate participation in CRC screening programs among persons with mental illness. Overall, the existing literature lacks high quality evidence from large population-based studies and comparison groups based on organized screening programs.

Protein-rich food intake and risk of spontaneous abortion: a prospective cohort study.

PURPOSE: Diet quality is increasingly recognized as important for human reproductive capacity. We studied the association between intake of protein-rich foods and risk of spontaneous abortion (SAB). METHODS: During 2013-2020, we recruited pregnancy planners from the United States and Canada (Pregnancy Study Online; PRESTO) and Denmark (SnartForaeldre.dk; SF). Participants completed a baseline questionnaire and a validated cohort-specific food frequency questionnaire. We estimated preconception intake of red meat, poultry, processed meat, seafood, eggs, plant-based proteins, and dairy from individual foods and mixed recipes. We included 4,246 PRESTO and 2,953 SF participants who reported a pregnancy during the study. Data on SAB were derived from questionnaires and population registries. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI), representing the effect of substituting one type of protein-rich food for another. RESULTS: SAB risk was 23% in PRESTO and 16% in SF. In PRESTO, substitution of seafood with other protein-rich foods was associated with higher SAB risk [for example, the HR for replacing 100 g of seafood/week with 100 g of red meat was 1.10 (95% CI 1.00, 1.20)]. In contrast, in SF, substituting seafood with other protein-rich foods was associated with lower SAB risk [HR for replacing 100 g of seafood/week with 100 g of red meat was 0.89 (95% CI 0.82, 0.98)]. Other protein-rich food substitutions were not meaningfully associated with SAB risk. CONCLUSIONS: Preconception intake of protein-rich foods was largely unrelated to SAB risk, with the exception of seafood, which was associated with higher risk of SAB in Denmark, but a lower risk in North America.

A prospective study of preconception asthma and spontaneous abortion.

PURPOSE: To evaluate the relationships among history of asthma, asthma severity, and spontaneous abortion (SAB). METHODS: Pregnancy Study Online is a preconception cohort study of North American couples. During the preconception period, female participants reported their history of physician-diagnosed asthma, age at first diagnosis, and use of asthma medications in the previous 4 weeks. Asthma severity was classified by medication use proximal to conception, from level 0 to 3 in increasing severity. Pregnancy and SAB were identified using data from follow-up questionnaires. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 6325 participants who conceived, 19% experienced SAB and 17% reported a history of asthma. There was no appreciable association between asthma history and SAB incidence (HR = 0.98; 95% CI: 0.84, 1.14). HRs comparing severity levels 0, 1, and 2-3 with no asthma were 0.82 (95% CI: 0.67, 1.01), 1.20 (95% CI: 0.91, 1.60), and 1.31 (95% CI: 0.97, 1.78), respectively. Among women who conceived without the use of fertility treatment, level 2-3 severity was associated with SAB (HR = 1.39; 95% CI: 1.02, 1.89). CONCLUSIONS: While history of asthma diagnosis was not materially associated with SAB, having severe asthma (based on medication use) was associated with greater SAB risk.

A Prospective Cohort Study of Seasonal Variation in Spontaneous Abortion.

BACKGROUND: Up to 30% of pregnancies end in spontaneous abortion, yet few risk factors have been identified. Examining seasonal patterns in risk of spontaneous abortion can generate new hypotheses regarding environmental and lifestyle determinants. METHODS: We used data from Pregnancy Study Online-a preconception cohort study of pregnancy planners from the United States and Canada-to examine seasonal variation in spontaneous abortion risk. We enrolled 12,197 women during 2013 to 2020, 6104 of whom reported a conception within 12 months of enrollment. On follow-up questionnaires, participants reported date of spontaneous abortion and weeks gestation at time of loss. We used periodic regression to estimate two aspects of seasonal occurrence: peak/low ratio-a measure of intensity of seasonal variation-and peak timing. We examined season at risk (from the date of each gestational week) in relation to spontaneous abortion; in a secondary analysis, we examined season of conception in relation to spontaneous abortion. We controlled for seasonal patterns in attempt initiation via month the pregnancy attempt began. RESULTS: Almost 20% of women experienced spontaneous abortion. Risk was highest in late August, with a peak/low ratio of 1.3 (95% confidence interval [CI] = 1.1, 1.6). This seasonal pattern was evident almost exclusively for spontaneous abortion at <8 weeks since the last menstrual period date (peak/low ratio = 1.4; 95% CI = 1.2, 1.8), and associations were stronger among women living in the Southern and Midwestern United States. CONCLUSIONS: Environmental or lifestyle factors more prevalent in late summer may be associated with increased risk of early spontaneous abortion.

Risk-stratified selection to colonoscopy in FIT colorectal cancer screening: development and temporal validation of a prediction model.

BACKGROUND: Faecal immunochemical tests (FITs) yield many false positives and challenge colonoscopy capacity in colorectal cancer (CRC) screening programmes. We aimed to develop a risk-based selection of participants to undergo diagnostic colonoscopy. METHODS: The study was observational and used registry data from the Danish CRC screening programme. We included all participants invited 2014-2016 with a positive FIT (≥ 20 µg fHb/g) who underwent colonoscopy (n = 56,459). We predicted the risk of CRC or advanced neoplasia (AN) from age, gender and FIT value using logistic regression. We evaluated calibration and discrimination and conducted temporal validation. We compared the number of CRCs and adenomas identified by risk cut-offs and by a corresponding FIT cut-off. RESULTS: AUCs were 74.9% (95% CI: 73.6; 76.3) and 67.4% (95% CI: 66.8%; 68.0%) for the models predicting CRC and AN in the validation dataset. The cut-off of CRC risk calculated from age, gender and FIT value identified 1.03 times (95% CI: 1.02; 1.05) more CRCs and 1.01 times (95% CI: 1.01; 1.01) more medium/high-risk adenomas compared with the corresponding FIT cut-off. CONCLUSIONS: With existing data, risk-stratified FIT screening using a risk cut-off instead of a FIT cut-off can slightly improve the selection to colonoscopy of those at highest risk of cancer and adenomas.

A Prospective Cohort Study of COVID-19 Vaccination, SARS-CoV-2 Infection, and Fertility.

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.

Dietary folate intake and fecundability in two preconception cohorts.

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.

Air pollution and fecundability: Results from a Danish preconception cohort study.

BACKGROUND: Animal and epidemiologic studies indicate that air pollution may adversely affect fertility. Epidemiologic studies have been restricted largely to couples undergoing fertility treatment or have retrospectively ascertained time-to-pregnancy among pregnant women. OBJECTIVES: We examined the association between residential ambient air pollution and fecundability, the per-cycle probability of conception, in a large preconception cohort of Danish pregnancy planners. METHODS: During 2007-2018, we used the Internet to recruit and follow women who were trying to conceive without the use of fertility treatment. Participants completed an online baseline questionnaire eliciting socio-demographic characteristics, lifestyle factors, and medical and reproductive histories and follow-up questionnaires every 8 weeks to ascertain pregnancy status. We determined concentrations of ambient nitrogen oxides (NOx ), nitrogen dioxide (NO2 ), carbon monoxide (CO), ozone (O3 ), particulate matter <2.5 µm (PM2.5 ) and <10 µm (PM10 ), and sulphur dioxide (SO2 ) at each participant's residential address. We calculated average exposure during the year before baseline, during each menstrual cycle over follow-up and during the entire pregnancy attempt time. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders and co-pollutants. The analysis was restricted to the 10,183 participants who were trying to conceive for <12 cycles at study entry whose addresses could be geocoded. RESULTS: During 12 months of follow-up, 73% of participants conceived. Higher concentrations of PM2.5 and PM10 were associated with small reductions in fecundability. For example, the FRs for a one interquartile range (IQR) increase in PM2.5 (IQR = 3.2 µg/m3 ) and PM10 (IQR = 5.3 µg/m3 ) during each menstrual cycle were 0.93 (95% CI: 0.87, 0.99) and 0.91 (95% CI: 0.84, 0.99), respectively. Other air pollutants were not appreciably associated with fecundability. CONCLUSIONS: In this preconception cohort study of Danish women, residential exposures to PM2.5 and PM10 were associated with reduced fecundability.