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.

Reduction of Myocardial Infarction and All-Cause Mortality Associated to Statins in Patients Without Obstructive CAD.

OBJECTIVES: The aim of this work was to evaluate the prognostic impact of statin therapy in symptomatic patients without obstructive CAD. BACKGROUND: Information on the prognostic impact of post-coronary computed tomographic angiography (CTA) statin use in patients with no or nonobstructive coronary artery disease (CAD) is sparse. METHODS: Patients undergoing CTA with suspected CAD in western Denmark from 2008 to 2017 with <50% coronary stenoses were identified. Information on post-CTA use of statin therapy and cardiovascular events were obtained from national registries. RESULTS: The study included 33,552 patients, median aged 56 years, 58% female, with no (n = 19,669) or nonobstructive (n = 13,883) CAD and a median follow-up of 3.5 years. The absolute risk of the combined end point of myocardial infarction (MI) or all-cause mortality was directly associated with the CAD burden with an event rate/1,000 patient-years of 4.13 (95% CI: 3.69-4.61) in no, 7.74 (95% CI: 6.88-8.71) in mild (coronary artery calcium score [CACS] 0-99), 13.72 (95% CI: 11.61-16.23) in moderate (CACS 100-399), and 32.47 (95% CI: 26.25-40.16) in severe (CACS ≥400) nonobstructive CAD. Statin therapy was associated with a multivariable adjusted HR for MI and death of 0.52 (95% CI: 0.36-0.75) in no, 0.44 (95% CI: 0.32-0.62) in mild, 0.51 (95% CI: 0.34-0.75) in moderate, and 0.52 (95% CI: 0.32-0.86) in severe nonobstructive CAD. The estimated numbers needed to treat to prevent the primary end point were 92 (95% CI: 61-182) in no, 36 (95% CI: 26-58) in mild, 24 (95% CI: 15-61) in moderate, and 13 (95% CI: 7-86) in severe nonobstructive CAD. Residual confounding may persist, but not to an extent explaining all of the observed risk reduction associated with statin treatment. CONCLUSIONS: The risk of MI and all-cause mortality in patients without obstructive CAD is directly associated with the CAD burden. Statin therapy is associated with a reduction of MI and all-cause death across the spectrum of CAD, however, the absolute benefit of treatment is directionally proportional with the CAD burden.

The association of serum lipid levels with colorectal cancer recurrence.

BACKGROUND: Biologic and epidemiologic evidence suggests that tumor cells depend on reprogrammed lipid metabolic function for survival and growth. Lipids may promote tumor recurrence by providing energy needed for proliferation. Studies have found associations of serum lipids with cancer incidence, mortality, and disease-free mortality, though they have yet to evaluate the prognostic potential of serum lipids for colorectal cancer (CRC) recurrence. METHODS: 341 Danish CRC patients who underwent surgical resection were actively followed between 2003-2011 from date of surgery until December 31, 2012, or death. Serum lipids including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG), were collected at regular intervals. Lipids were assigned as time-varying exposures evaluated with a one-year lag. Cox proportional hazards models were used to assess recurrence rate, adjusting for clinically relevant covariates. A restricted analysis was performed in a group of non-statin users (n = 236). RESULTS: Among 341 CRC patients, increased HDL-C appeared to have a beneficial impact on recurrence-free survival (RFS) for CRC patients, especially among statin users (hazard ratio [HR] for 0.1 mmol/L increase = 0.58; 95 % confidence interval [CI]: 0.43, 0.78). Increased LDL-C and TG were not associated with RFS. Increased lipids showed a near-null effect on CRC recurrence [e.g. HR (95 % CI) for 0.1 mmol/L increase LDL = 1.01 (0.97, 1.19)] among non-statin users. CONCLUSION: Serum lipid levels of LDL-C and TG do not appear to be associated with CRC recurrence. Further investigation of the role of HDL-C in CRC recurrence may be of interest based on the suggestive inverse association observed here.

Application of the Adaptive Validation Substudy Design to Colorectal Cancer Recurrence.

BACKGROUND: Among men and women diagnosed with colorectal cancer (CRC), 20-50% will develop a cancer recurrence. Cancer recurrences are not routinely captured by most population-based registries; however, linkage across Danish registries allows for the development of predictive models to detect recurrence. Successful application of such models in population-based settings requires validation against a gold standard to ensure the accuracy of recurrence identification. OBJECTIVE: We apply a recently developed validation study design for prospectively collected validation data to validate predicted CRC recurrences against gold standard diagnoses from medical records in an actively followed cohort of CRC patients in Denmark. METHODS: We use a Bayesian monitoring framework, traditionally used in clinical trials, to iteratively update classification parameters (positive and negative predictive values, and sensitivity and specificity) in an adaptive validation substudy design. This design allows determination of the sample size necessary to estimate the corresponding parameters and to identify when validation efforts can cease based on predefined criteria for parameter values and levels of precision. RESULTS: Among 355 men and women diagnosed with CRC in Denmark and actively followed semi-annually, there were 63 recurrences diagnosed by active follow-up and 70 recurrences identified by a predictive algorithm. The adaptive validation design met stopping criteria for the classification parameters after 120 patients had their recurrence information validated. This stopping point yielded parameter estimates for the classification parameters similar to those obtained when the entire cohort was validated, with 66% less patients needed for the validation study. CONCLUSION: In this proof of concept application of the adaptive validation study design for outcome misclassification, we demonstrated the ability of the method to accurately determine when sufficient validation data have been collected. This method serves as a novel validation substudy design for prospectively collected data with simultaneous implementation of a validation study.

Seasonal patterns in fecundability in North America and Denmark: a preconception cohort study.

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.

Risk stratification by assessment of coronary artery disease using coronary computed tomography angiography in diabetes and non-diabetes patients: a study from the Western Denmark Cardiac Computed Tomography Registry.

AIMS: We examined whether severity of coronary artery disease (CAD) measured by coronary computed tomography angiography can be used to predict rates of myocardial infarction (MI) and death in patients with and without diabetes. METHODS AND RESULTS: A cohort study of consecutive patients (n = 48 731) registered in the Western Denmark Cardiac Computed Tomography Registry from 2008 to 2016. Patients were stratified by diabetes status and CAD severity (no, non-obstructive, or obstructive). Endpoints were MI and death. Event rates per 1000 person-years, unadjusted and adjusted incidence rate ratios were computed. Median follow-up was 3.6 years. Among non-diabetes patients, MI event rates per 1000 person-years were 1.4 for no CAD, 4.1 for non-obstructive CAD, and 9.1 for obstructive CAD. Among diabetes patients, the corresponding rates were 2.1 for no CAD, 4.8 for non-obstructive CAD, and 12.6 for obstructive CAD. Non-diabetes and diabetes patients without CAD had similar low rates of MI [adjusted incidence rate ratio 1.40, 95% confidence interval (CI): 0.71-2.78]. Among diabetes patients, the adjusted risk of MI increased with severity of CAD (no CAD: reference; non-obstructive CAD: adjusted incidence rate ratio 1.71, 95% CI: 0.79-3.68; obstructive CAD: adjusted incidence rate ratio 4.42, 95% CI: 2.14-9.17). Diabetes patients had higher death rates than non-diabetes patients, irrespective of CAD severity. CONCLUSION: In patients without CAD, diabetes patients have a low risk of MI similar to non-diabetes patients. Further, MI rates increase with CAD severity in both diabetes and non-diabetes patients; with diabetes patients with obstructive CAD having the highest risk of MI.

Validating registry data on statins prescriptions by blood measurements.

PURPOSE: To validate prescription registry data as a measurement of adherence to statins through a direct method using assays for selected statins in serial blood samples collected from two prospective cohorts of Danish colorectal cancer patients. METHODS: We linked information on statin prescriptions from the Aarhus University Prescription Database with the cancer cohorts from Aalborg University Hospital. For statin-prescribed patients, we calculated a prescription window covering the anticipated duration of the prescription. For each statin-prescribed patient with at least one blood sample in a prescription window, we selected without replacement a never-statin-prescribed patient matched on sex, age, and calendar year of surgery. Each of the selected blood samples were analyzed using assays to detect statins. We calculated the positive and negative predictive value of the prescription registry reporting using the assay result as the gold standard. RESULTS: We identified 73 ever-statin-prescribed patients with a total of 253 blood samples and 74 blood samples among never-statin-prescribed patients. The positive predictive value for prescribed patients, with presence of statins in at least one blood sample as the gold standard, was 93% (95% CI, 86%-97%) and the negative predictive value was 93% (95% CI, 86%-97%). Stratified results did not reveal substantial differences in predictive values. Fifty-two (71%) of the statin-prescribed patients had statins in every blood sample, suggesting continuous adherence. CONCLUSION: This study showed a high adherence with treatment with statins among colorectal cancer patients.

Fecundability among Danish women with a history of miscarriage: a prospective cohort study.

OBJECTIVE: To examine the association between history of miscarriage and fecundability (the cycle-specific probability of conception). DESIGN: Nationwide prospective cohort study using web-based questionnaires. SETTING: Denmark, 2007-2012. PARTICIPANTS: 977 women attempting to conceive, not using fertility treatment, and with a reproductive history of only miscarriage or only live birth. EXPOSURE AND OUTCOME MEASURES: Information on previous pregnancy outcomes, including miscarriage, came from self-report or from relevant registries. Participants were followed for up to 12 months or until they reported a pregnancy, stopped trying to conceive or started fertility treatment, whichever came first. We used Kaplan-Meier methods to estimate cumulative probabilities of conception for women whose reproductive history included only miscarriage or only live birth. Using proportional probabilities regression modelling, we computed fecundability ratios (FR) with 95% CI comparing women with a history of only miscarriage with women with a history of only live birth. RESULTS: After adjustment for potential confounders, the cumulative probabilities of conception within 12 cycles of follow-up were 85% (95% CI 81% to 89%) for women with a history of 1 miscarriage, 85% (95% CI 73% to 92%) for women with a history of ≥2 miscarriages and 88% (95% CI 87% to 89%) for women whose reproductive history included only live birth. Adjusted FRs were 0.87 (95% CI 0.71 to 1.07) and 0.65 (95% CI 0.36 to 1.17) for women with a history of 1 and ≥2 miscarriages, respectively. CONCLUSIONS: Our results indicate that women with a history of miscarriage may have slightly reduced fecundability compared with women with a history of only live birth. The reduction in fecundability was greater for women with repeated miscarriages, although the estimates were imprecise. Despite a potential delay in conception, women with previous miscarriage may have similar probability of pregnancy by 12 cycles of attempts to women with proven fertility.

Does low risk of infections as a marker of effective immunity predict increased risk of subsequent giant cell arteritis or polymyalgia rheumatica? A Danish population-based case-control study.

OBJECTIVE: It has been suggested that a hyper-effective immune system ("hyper-immunity") is central to the pathogenesis of giant cell arteritis and polymyalgia rheumatica (GCA/PMR). We examined if a low risk of infections, as a marker of hyper-immunity, can predict increased subsequent risk of GCA/PMR. PATIENTS AND METHODS: We conducted a population-based case-control study including all patients aged ≥50 years with incident GCA/PMR diagnosed between 1997 and 2012 in Northern Denmark. For each case, we selected 10 population controls matched on gender, age, place of residence, and time spent in the region. Complete history of hospital-treated infections and community-based anti-infective prescriptions was assessed in population-based registries. We used conditional logistic regression to compute OR of GCA/PMR associated with infections while adjusting for comorbidities, immunosuppressive treatment, and other potential confounders. RESULTS: We included 7,225 GCA/PMR cases and 72,250 controls. When excluding all infections occurring within the last year before GCA/PMR diagnosis, there was no decreased risk for GCA/PMR in people with a history of hospital-treated infection (adjusted OR=1.04, 95% CI: 0.98-1.10) or community anti-infective treatment (adjusted OR=1.07, 95% CI: 0.99-1.16). Within the last year preceding the GCA/PMR index date, patients with hospital-treated infections (adjusted OR=1.59, 95% CI: 1.44-1.75) or community anti-infective treatment (adjusted OR=1.63, 95% CI: 1.48-1.79) had a greatly increased risk of a GCA/PMR diagnosis. CONCLUSION: These results do not support the hypothesis of "hyper-immunity" leading to GCA/PMR. Instead, incident GCA/PMR is preceded by a slightly increased risk of infection, which may be related to protopathic bias or support theories that infections may be directly involved in the pathogenesis of GCA/PMR.

Coronary CT Angiographic and Flow Reserve-Guided Management of Patients With Stable Ischemic Heart Disease.

BACKGROUND: Clinical outcomes following coronary computed tomography-derived fractional flow reserve (FFRCT) testing in clinical practice are unknown. OBJECTIVES: This study sought to assess real-world clinical outcomes following a diagnostic strategy including first-line coronary computed tomography angiography (CTA) with selective FFRCT testing. METHODS: The study reviewed the results of 3,674 consecutive patients with stable chest pain evaluated with CTA and FFRCT testing to guide downstream management in patients with intermediate stenosis (30% to 70%). The composite endpoint (all-cause death, myocardial infarction, hospitalization for unstable angina, and unplanned revascularization) was determined in 4 patient groups: 1) CTA stenosis <30%, optimal medical treatment (OMT), and no additional testing; 2) FFRCT >0.80, OMT, no additional testing; 3) FFRCT ≤0.80, OMT, no additional testing; and 4) FFRCT ≤0.80, OMT, and referral to invasive coronary angiography. Patients were followed for a median of 24 (range 8 to 41) months. RESULTS: FFRCT was available in 677 patients, and the test result was negative (>0.80) in 410 (61%) patients. In 75% of the patients with FFRCT >0.80, maximum coronary stenosis was ≥50%. The cumulative incidence proportion (95% confidence interval [CI]) of the composite endpoint at the end of follow-up was comparable in groups 1 (2.8%; 95% CI: 1.4% to 4.9%) and 2 (3.9%; 95% CI: 2.0% to 6.9%) (p = 0.58) but was higher (when compared with group 1) in groups 3 (9.4%; p = 0.04) and 4 (6.6%; p = 0.08). Risk of myocardial infarction was lower in group 4 (1.3%) than in group 3 (8%; p < 0.001). CONCLUSIONS: In patients with intermediate-range coronary stenosis, FFRCT is effective in differentiating patients who do not require further diagnostic testing or intervention (FFRCT >0.80) from higher-risk patients (FFRCT ≤0.80) in whom further testing with invasive coronary angiography and possibly intervention may be needed. Further studies assessing the risk and optimal management strategy in patients undergoing first-line CTA with selective FFRCT testing are needed.

Dietary Fat Intake and Fecundability in 2 Preconception Cohort Studies.

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.

Associations of Statin Use With Colorectal Cancer Recurrence and Mortality in a Danish Cohort.

In earlier studies of the influence of hydroxymethylglutaryl-coenzyme A reductase inhibitors (also known as statins) on colorectal cancer prognosis, investigators reported a reduced rate of cancer-specific mortality. Studies of recurrence are few and small. Using data from Danish registries, we followed 21,152 patients diagnosed with stage I-III colorectal cancer from 2001 to 2011. We estimated the association between statin use in the preceding year and cancer recurrence, cancer-specific mortality, and all-cause mortality rates. We identified 5,036 recurrences, 7,084 deaths from any cause, and 4,066 deaths from colorectal cancer. After adjustment for potential confounders, statin use was not associated with recurrence (adjusted hazard ratio (aHR) = 1.01, 95% confidence interval (CI): 0.93, 1.09), but it was associated with death from colorectal cancer (aHR = 0.72, 95% CI: 0.65, 0.79) and death from any cause (aHR = 0.72, 95% CI: 0.67, 0.76). Statin use in the year preceding recurrence was associated with a reduced risk of cancer-specific mortality (aHR = 0.83, 95% CI: 0.74, 0.92) but also a reduced risk of death from any other cause (aHR = 0.78, 95% CI: 0.61, 1.00). Statin use was not associated with a reduced rate of colorectal cancer recurrence, but it was associated with a reduced rate of cancer-specific mortality, which suggests that there is no cancer-directed benefit; therefore, there is no basis to prescribe statins to colorectal cancer patients who do not have cardiovascular indications.

Descriptive characteristics of colon and rectal cancer recurrence in a Danish population-based study.

BACKGROUND: Recurrence is a common outcome among patients that have undergone an intended curative resection for colorectal cancer. However, data on factors that influence colorectal cancer recurrence are sparse. We report descriptive characteristics of both colon and rectal cancer recurrence in an unselected population. MATERIAL AND METHODS: We identified 21,152 patients with colorectal cancer diagnosed between May 2001 and December 2011 and registered with the Danish Colorectal Cancer Group. Recurrences were identified in 3198 colon and 1838 rectal cancer patients during follow-up. We calculated the frequency, proportion, and incidence rates of colon and rectal cancer recurrence within descriptive categories, and the cumulative five- and ten-year incidences of recurrence, treating death as a competing risk. We used a Cox proportional hazard model to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Recurrence risk was highest in the first three years of follow-up. Patients <55 years old at initial diagnosis (incidence rate for colon: 7.2 per 100 person-years; 95% CI: 6.5-7.9; rectum: 8.1 per 100 person-years; 95% CI: 7.2-9.0) and patients diagnosed with stage III cancer (colon HR: 5.70; 95% CI: 4.61-7.06; rectal HR: 7.02; 95% CI: 5.58-8.82) had increased risk of recurrence. Patients diagnosed with stage III cancer from 2009 to 2011 had a lower incidence of recurrence than those diagnosed with stage III cancer in the years before. Cumulative incidences of colon and rectal cancer recurrence were similar for both cancer types among each descriptive category. CONCLUSIONS: In this population, increases in colorectal cancer recurrence risk were associated with younger age and increasing stage at diagnosis. Cumulative incidence of recurrence did not differ by cancer type. Descriptive characteristics of colon and rectal cancer recurrence may help to inform patient-physician decision-making, and could be used to determine adjuvant therapies or tailor surveillance strategies so that recurrence may be identified early, particularly within the first 3 years of follow-up.

Costs and Efficiency of Online and Offline Recruitment Methods: A Web-Based Cohort Study.

BACKGROUND: The Internet is widely used to conduct research studies on health issues. Many different methods are used to recruit participants for such studies, but little is known about how various recruitment methods compare in terms of efficiency and costs. OBJECTIVE: The aim of our study was to compare online and offline recruitment methods for Internet-based studies in terms of efficiency (number of recruited participants) and costs per participant. METHODS: We employed several online and offline recruitment methods to enroll 18- to 45-year-old women in an Internet-based Danish prospective cohort study on fertility. Offline methods included press releases, posters, and flyers. Online methods comprised advertisements placed on five different websites, including Facebook and Netdoktor.dk. We defined seven categories of mutually exclusive recruitment methods and used electronic tracking via unique Uniform Resource Locator (URL) and self-reported data to identify the recruitment method for each participant. For each method, we calculated the average cost per participant and efficiency, that is, the total number of recruited participants. RESULTS: We recruited 8252 study participants. Of these, 534 were excluded as they could not be assigned to a specific recruitment method. The final study population included 7724 participants, of whom 803 (10.4%) were recruited by offline methods, 3985 (51.6%) by online methods, 2382 (30.8%) by online methods not initiated by us, and 554 (7.2%) by other methods. Overall, the average cost per participant was €6.22 for online methods initiated by us versus €9.06 for offline methods. Costs per participant ranged from €2.74 to €105.53 for online methods and from €0 to €67.50 for offline methods. Lowest average costs per participant were for those recruited from Netdoktor.dk (€2.99) and from Facebook (€3.44). CONCLUSIONS: In our Internet-based cohort study, online recruitment methods were superior to offline methods in terms of efficiency (total number of participants enrolled). The average cost per recruited participant was also lower for online than for offline methods, although costs varied greatly among both online and offline recruitment methods. We observed a decrease in the efficiency of some online recruitment methods over time, suggesting that it may be optimal to adopt multiple online methods.

Female exposure to phthalates and time to pregnancy: a first pregnancy planner study.

STUDY QUESTION: Is female exposure to phthalate metabolites associated with reduced fecundity, as estimated by prolonged time to pregnancy (TTP)? SUMMARY ANSWER: Female exposure to monoethyl phthalate (MEP) but not monobutyl phthalate (MBP), monobenzyl phthalate (MBzP) and monoethylhexyl phthalate (MEHP) was associated with a longer TTP. WHAT IS KNOWN ALREADY: Male exposure to phthalates is potentially associated with adverse effects on human fecundity in epidemiological studies, but little is known about the potential effects on female reproduction. STUDY DESIGN SIZE AND DURATION: A cohort study with prospective data based on 229 women from a Danish cohort of 430 first pregnancy planning couples enrolled in 1992-1994. In 2009, urinary analyses of phthalate metabolites were performed on stored urine samples from this cohort. PARTICIPANTS/MATERIALS, SETTING AND METHODS: We analyzed MEP, MBP, MBzP and MEHP in female morning spot urine samples collected daily during the first 10 days of menstrual cycles after discontinuation of contraception. The exposure assessment was based on the mean of two measurements from each woman collected in a period of 6 menstrual cycles. We used Cox regression with discrete time to estimate fecundability ratios (FRs) and 95% CI in relation to the average urine metabolite concentration exposure level, controlled for age and BMI, and the time-varying variables smoking and alcohol. MAIN RESULT AND ROLE OF CHANCE: Urinary concentration of MEP was associated with a decreased fecundity (adjusted FR 0.79; 95% CI: 0.63; 0.99) corresponding to a 21% decreased probability of conception for each natural log (ln) unit increase in MEP. No significant association with TTP was found for MBP, MBzP and MEHP. LIMITATIONS REASONS FOR CAUTION: Subfertile women were overrepresented in the study population due to exclusion of 77 high fertile women who became pregnant in the first cycle when urine collection began. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that female exposure to MEP may have an adverse effect on female fecundity, but these findings need to be replicated in a larger and newer cohort study with sufficient exposure contrast if the use of diethyl phthalate (DEP) and thereby MEP in the future potentially should be regulated in cosmetics and industrial consumer products. STUDY FUNDING/COMPETING INTERESTS: The original data collected were founded by Aarhus University Research Foundation, the Danish Medical Research Council and the Danish Medical Health Insurance Foundation. There are no conflicts of interest to be declared. TRIAL REGISTRATION NUMBER: N/A.

Alcohol consumption and fecundability: prospective Danish cohort study.

OBJECTIVE:  To investigate to what extent alcohol consumption affects female fecundability. DESIGN:  Prospective cohort study. SETTING:  Denmark, 1 June 2007 to 5 January 2016. PARTICIPANTS:  6120 female Danish residents, aged 21-45 years, in a stable relationship with a male partner, who were trying to conceive and not receiving fertility treatment. MAIN OUTCOME MEASURES:  Alcohol consumption was self reported as beer (330 mL bottles), red or white wine (120 mL glasses), dessert wine (50 mL glasses), and spirits (20 mL) and categorized in standard servings per week (none, 1-3, 4-7, 8-13, and ≥14). Participants contributed menstrual cycles at risk until the report of pregnancy, start of fertility treatment, loss to follow-up, or end of observation (maximum 12 menstrual cycles). A proportional probability regression model was used to estimate fecundability ratios (cycle specific probability of conception among exposed women divided by that among unexposed women). RESULTS:  4210 (69%) participants achieved a pregnancy during follow-up. Median alcohol intake was 2.0 (interquartile range 0-3.5) servings per week. Compared with no alcohol consumption, the adjusted fecundability ratios for alcohol consumption of 1-3, 4-7, 8-13, and 14 or more servings per week were 0.97 (95% confidence interval 0.91 to 1.03), 1.01 (0.93 to 1.10), 1.01 (0.87 to 1.16) and 0.82 (0.60 to 1.12), respectively. Compared with no alcohol intake, the adjusted fecundability ratios for women who consumed only wine (≥3 servings), beer (≥3 servings), or spirits (≥2 servings) were 1.05 (0.91 to1.21), 0.92 (0.65 to 1.29), and 0.85 (0.61 to 1.17), respectively. The data did not distinguish between regular and binge drinking, which may be important if large amounts of alcohol are consumed during the fertile window. CONCLUSION:  Consumption of less than 14 servings of alcohol per week seemed to have no discernible effect on fertility. No appreciable difference in fecundability was observed by level of consumption of beer and wine.

Brief Report: Cesarean Delivery and Subsequent Fecundability.

BACKGROUND: Studies have shown that cesarean delivery is associated with fewer subsequent births relative to vaginal delivery, but it is unclear whether confounding by pregnancy intention or indication for surgery explained these results. We evaluated the association between cesarean delivery and subsequent fecundability among 910 primiparous women after singleton live birth. METHODS: In a cohort of Danish women planning pregnancy (2007-2012), obstetrical history was obtained via registry linkage; time-to-pregnancy and covariate data were collected via questionnaire. Fecundability ratios (FRs) and 95% confidence intervals (CIs) were adjusted for potential confounders. RESULTS: Relative to spontaneous vaginal delivery, emergency cesarean delivery with cephalic presentation showed little association with fecundability (FR = 1.0, 95% CI = 0.83, 1.3), but cesarean delivery with breech presentation (FR = 0.72, 95% CI = 0.53, 0.97) and planned cesarean delivery with cephalic presentation (FR = 0.51, 95% CI = 0.25, 1.0) were associated with reduced fecundability. CONCLUSIONS: The cesarean-fecundability association varied by previous fetal presentation and emergency status.

Evaluation of Selection Bias in an Internet-based Study of Pregnancy Planners.

Selection bias is a potential concern in all epidemiologic studies, but it is usually difficult to assess. Recently, concerns have been raised that internet-based prospective cohort studies may be particularly prone to selection bias. Although use of the internet is efficient and facilitates recruitment of subjects that are otherwise difficult to enroll, any compromise in internal validity would be of great concern. Few studies have evaluated selection bias in internet-based prospective cohort studies. Using data from the Danish Medical Birth Registry from 2008 to 2012, we compared six well-known perinatal associations (e.g., smoking and birth weight) in an internet-based preconception cohort (Snart Gravid n = 4,801) with the total population of singleton live births in the registry (n = 239,791). We used log-binomial models to estimate risk ratios (RRs) and 95% confidence intervals (CIs) for each association. We found that most results in both populations were very similar. For example, maternal obesity was associated with an increased risk of delivering a macrosomic infant in Snart Gravid (RR = 1.5; 95% CI: 1.2, 1.7) and the total population (RR = 1.5; 95% CI: 1.45, 1.53), and maternal smoking of >10 cigarettes per day was associated with a higher risk of low birth weight (RR = 2.7; 95% CI: 1.2, 5.9 vs. RR = 2.9; 95% CI: 2.6, 3.1) in Snart Gravid and the total population, respectively. We cannot be certain that our results would apply to other associations or different populations. Nevertheless, our results suggest that recruitment of reproductive aged women via the internet may be no more prone to selection bias than traditional methods of recruitment.

Maternal Recall Error in Retrospectively Reported Time-to-Pregnancy: an Assessment and Bias Analysis.

BACKGROUND: Epidemiologic studies of fecundability often use retrospectively measured time-to-pregnancy (TTP), thereby introducing potential for recall error. Little is known about how recall error affects the bias and precision of the fecundability odds ratio (FOR) in such studies. METHODS: Using data from the Danish Snart-Gravid Study (2007-12), we quantified error for TTP recalled in the first trimester of pregnancy relative to prospectively measured TTP among 421 women who enrolled at the start of their pregnancy attempt and became pregnant within 12 months. We defined recall error as retrospectively measured TTP minus prospectively measured TTP. Using linear regression, we assessed mean differences in recall error by maternal characteristics. We evaluated the resulting bias in the FOR and 95% confidence interval (CI) using simulation analyses that compared corrected and uncorrected retrospectively measured TTP values. RESULTS: Recall error (mean = -0.11 months, 95% CI -0.25, 0.04) was not appreciably associated with maternal age, gravidity, or recent oral contraceptive use. Women with TTP > 2 months were more likely to underestimate their TTP than women with TTP ≤ 2 months (unadjusted mean difference in error: -0.40 months, 95% CI -0.71, -0.09). FORs of recent oral contraceptive use calculated from prospectively measured, retrospectively measured, and corrected TTPs were 0.82 (95% CI 0.67, 0.99), 0.74 (95% CI 0.61, 0.90), and 0.77 (95% CI 0.62, 0.96), respectively. CONCLUSIONS: Recall error was small on average among pregnancy planners who became pregnant within 12 months. Recall error biased the FOR of recent oral contraceptive use away from the null by 10%. Quantitative bias analysis of the FOR can help researchers quantify the bias from recall error.

History of oral contraceptive use and risk of spontaneous abortion.

PURPOSE: To examine the association between pregravid oral contraceptive (OC) use and spontaneous abortion (SAB). METHODS: In an Internet-based preconception cohort study of 4862 Danish pregnancy planners, we used Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals (CIs) for the association between OC use and SAB. We controlled for maternal age, physical activity, parity, education, alcohol and caffeine consumption, body mass index, and smoking. RESULTS: Compared with women who discontinued OCs >1 year before conception, HRs were 0.95 (95% confidence interval (CI) = 0.77-1.17), 0.99 (95% CI = 0.82-1.19), and 0.80 (95% CI = 0.60-1.06) for women who discontinued OCs 7-12, 2-6, and 0-1 months before conception, respectively. Compared with less than 4 years of OC use, HRs for 4-7, 8-11, and 12 years or more of OC use were 1.05 (95% CI = 0.80-1.37), 0.92 (95% CI = 0.71-1.19), and 0.88 (95% CI = 0.65-1.19), respectively. Dose of estrogen and generation of progestin were not materially associated with SAB risk. CONCLUSIONS: We found no evidence that pregravid OC use is associated with an increase in SAB. Use within 1 month of conception was associated with a slightly lower risk of SAB, but this may be due to increased reproductive fitness in women who conceive quickly after discontinuation of OCs.