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Alejandro Arana,1 Anton Pottegård,2 Josephina G Kuiper,3 Helen Booth,4 Johan Reutfors,5 Brian Calingaert,6 Lars Christian Lund,2 Elizabeth Crellin,4 Marcus Schmitt-Egenolf,5,7 James A Kaye,8 Karin Gembert,5 Kenneth J Rothman,8 Helle Kieler,5 Daniel Dedman,4 Eline Houben,3 Lia Gutiérrez,1 Jesper Hallas,2 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, 08028, Spain; 2Clinical Pharmacology, Pharmacy and Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense C, 5000, Denmark; 3The PHARMO Institute, Utrecht, 3528 AE, the Netherlands; 4Clinical Practice Research Datalink (CPRD), The Medicines and Healthcare Products Regulatory Agency, London, E14 4PU, UK; 5Centre for Pharmacoepidemiology, Karolinska Institutet, Solna, 171 76, Stockholm, Sweden; 6Department of Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 27709-2194, USA; 7Department of Public Health and Clinical Medicine, Umeå University, Umeå, 901 87, Sweden; 8Department of Epidemiology, RTI Health Solutions, Waltham, MA, 02451-1623, USACorrespondence: Alejandro AranaDepartment of Epidemiology, RTI Health Solutions, Av. Diagonal 605, 9-1, Barcelona, 08028, SpainTel +34 93 362 2805Fax +34 93 414 2610Email aarana@rti.orgPurpose: Evidence is insufficient to infer whether topical calcineurin inhibitors (TCIs; tacrolimus and pimecrolimus) cause malignancy. The study objective was to estimate the long-term risk of skin cancer and lymphoma associated with topical TCI use in adults and children, separately.Patients and Methods: A cohort study in Denmark, Sweden, UK, and the Netherlands was conducted. Adjusted incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated for nonmelanoma skin cancer (NMSC), melanoma, cutaneous T-cell lymphoma (CTCL), non-Hodgkin lymphoma (NHL) excluding CTCL, and Hodgkin lymphoma (HL) in new users of TCIs versus users of moderate/high-potency topical corticosteroids.Results: The study included 126,908/61,841 adults and 32,605/27,961 children initiating treatment with tacrolimus/pimecrolimus, respectively. Follow-up was ≥ 10 years for 19% of adults and 32% of children. Incidence rate ratios and (95% confidence intervals) for tacrolimus versus corticosteroid users in adults were < 1 for melanoma, non-Hodgkin lymphoma, and Hodgkin lymphoma; and 1.80 (1.25– 2.58) for cutaneous T-cell lymphoma. For pimecrolimus, IRRs in adults were < 1 for non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and Hodgkin’s lymphoma; and 1.21 (1.03– 1.41) for melanoma; and 1.28 (1.20– 1.35) for nonmelanoma skin cancer. In children, results were inconclusive due to few events. In adults, incidence rate ratios ≥ 5 years after first topical calcineurin inhibitor exposure were not higher than in overall analyses.Conclusion: Overall, we found little evidence associating use of topical calcineurin inhibitors with skin cancer and lymphoma; confounding by indication, surveillance bias, and reverse causation may have influenced these results. Even if causal, the public health impact of these excess risks would be low and confined to the first years of exposure.Keywords: tacrolimus, pimecrolimus, cutaneous T-cell lymphoma, malignant melanoma, non-melanoma skin cancer, database study

Holly Michelle Crowe,1 Lauren Anne Wise,1 Amelia Kent Wesselink,1 Kenneth Jay Rothman,1,2 Ellen Margrethe Mikkelsen,3 Henrik Toft Sørensen,3 Allan Jay Walkey,4 Elizabeth Elliott Hatch1 1Department of Epidemiology, Boston University School of Public Health, Boston, MA 02118, USA; 2RTI International, Raleigh, NC 27709, USA; 3Department of Clinical Epidemiology, Aarhus University, Aarhus N 8200, Denmark; 4Boston University School of Medicine, Boston, MA 02118, USACorrespondence: Holly Michelle Crowe Email hcrowe@bu.eduPurpose: Asthma has been positively associated with irregular menses and infertility in some studies, but data are limited on the relation between asthma medication use and fecundability (i.e., average per-cycle probability of conception among non-contracepting couples). This study examines the extent to which a history of asthma, asthma medication use, and age at first asthma diagnosis are associated with fecundability among female pregnancy planners.Participants and Methods: Pregnancy Study Online (PRESTO) is an ongoing, web-based preconception cohort study of couples aged 21– 45 years from North America. Between July 2013 and July 2019, a total of 10,436 participants enrolled in PRESTO, and 8286 were included in the present analysis. At study enrollment, women reported whether they had ever been diagnosed with asthma and, if so, the year they were first diagnosed. Women who reported ever being diagnosed with asthma were asked about medication use, including medication type and frequency of use. Participants completed follow-up questionnaires every 8 weeks for up to 12 months or until pregnancy. Proportional probabilities regression models were used to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for potential confounders. Fecundability ratios below 1.00 indicate reduced probability of conception.Results: There was little association between a history of asthma diagnosis or asthma medication use and fecundability. Compared with no history of asthma, the FR for ever-diagnosis of asthma with medication use was 1.02 (95% CI: 0.91– 1.15) and for ever-diagnosis of asthma without medication use was 1.00 (95% CI: 0.91– 1.09). Highest intensity asthma medication use (daily plus extra dosing for symptoms), combination inhaled corticosteroid and long-acting beta-agonist inhaler use, and a first diagnosis of asthma after age 17 years were associated with small reductions in fecundability.Conclusion: The present study provides little evidence that asthma or asthma medication use is adversely associated with fecundability.Keywords: corticosteroid, beta agonist, time to pregnancy, fertility

Mary S Anthony,1 Mary Anne Armstrong,2 Darios Getahun,3 Delia Scholes,4 Jennifer Gatz,5 Renate Schulze-Rath,6 Debbie Postlethwaite,2 Maqdooda Merchant,2 Amy L Alabaster,2 Giulia Chillemi,2 Tina Raine-Bennett,2 Fagen Xie,3 Vicki Y Chiu,3 Theresa M Im,3 Harpreet S Takhar,3 Michael Fassett,3 Jane Grafton,4 David Cronkite,4 Laura Ichikawa,4 Susan D Reed,4,7 Siu Lui Hui,5 Mary E Ritchey,1 Catherine W Saltus,8 Elizabeth B Andrews,1 Kenneth J Rothman,8 Alex Asiimwe,6 Richard Lynen,9 Juliane Schoendorf101RTI Health Solutions, Research Triangle Park, NC, USA; 2Kaiser Permanente Northern California, Oakland, CA, USA; 3Kaiser Permanente Southern California, Pasadena, CA, USA; 4Kaiser Permanente Washington, Seattle, WA, USA; 5Regenstrief Institute, Indianapolis, IN, USA; 6Bayer AG, Berlin, Germany; 7University of Washington, Seattle, WA, USA; 8RTI Health Solutions, Waltham, MA, USA; 9Bayer HealthCare, Whippany, NJ, USA; 10Bayer OY, Espoo, FinlandObjective: To validate algorithms identifying uterine perforations and intrauterine device (IUD) expulsions and to ascertain availability of breastfeeding status at the time of IUD insertion.Study design and setting: Four health care systems with electronic health records (EHRs) participated: Kaiser Permanente Northern California (KPNC), Kaiser Permanente Southern California (KPSC), Kaiser Permanente Washington (KPWA), and Regenstrief Institute (RI). The study included women ≤50 years of age with an IUD insertion. Site-specific algorithms using structured and unstructured data were developed and a sample validated by EHR review. Positive predictive values (PPVs) of the algorithms were calculated. Breastfeeding status was assessed in a random sample of 125 women at each research site with IUD placement within 52 weeks postpartum.Results: The study population included 282,028 women with 325,582 IUD insertions. The PPVs for uterine perforation were KPNC 77%, KPSC 81%, KPWA 82%, and RI 47%; PPVs for IUD expulsion were KPNC 77%, KPSC 87%, KPWA 68%, and RI 37%. Across all research sites, breastfeeding status at the time of IUD insertion was determined for 94% of those sampled.Conclusions: Algorithms with a high PPV for uterine perforation and IUD expulsion were developed at 3 of the 4 research sites. Breastfeeding status at the time of IUD insertion could be determined at all research sites. Our findings suggest that a study to evaluate the associations of breastfeeding and postpartum IUD insertions with risk of uterine perforation and IUD expulsion can be successfully conducted retrospectively; however, automated application of algorithms must be supplemented with chart review for some outcomes at one research site due to low PPV.Keywords: electronic health records, intrauterine device, breastfeeding, validation study, algorithm, postpartum

Yael I Nillni,1,2 Amelia K Wesselink,3 Elizabeth E Hatch,3 Ellen M Mikkelsen,4 Jaimie L Gradus,1–3 Kenneth J Rothman,3,5 Lauren A Wise3 1Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA; 2National Center for PTSD, Women’s Health Sciences Division at VA Boston Healthcare System, Boston, MA, USA; 3Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; 4Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark; 5RTI Health Solutions, Research Triangle, NC, USA Purpose: To examine the influence of depressive symptoms, perceived stress, and psychotropic medication use on prospectively assessed menstrual cycle regularity and length.Participants and methods: Data were obtained from Pregnancy Study Online, a prospective cohort study of pregnancy planners from North America. At baseline, women reported information on demographics, anthropometrics, lifestyle, and medical history, including their use of psychotropic medications. They also completed the Major Depression Inventory and the Perceived Stress Scale. Every 8 weeks for up to 12 months or until conception, women completed follow-up questionnaires to assess changes in psychotropic medication use, perceived stress, and menstrual cycle characteristics (ie, cycle regularity and length). Women who completed at least one follow-up questionnaire from 2013 to 2018 (n=3,346) were included in the primary analyses. A total of 5,439 women were included in secondary analyses utilizing baseline data only. Primary analyses estimated prevalence ratios (PR) and 95% CIs using log-binomial regression models.Results: Women with severe depressive symptoms at baseline, regardless of psychotropic medication use, had an 80% greater prevalence of irregular cycles during follow-up than women with no or low depressive symptoms (PR =1.80, 95% CI =1.48–2.19). Perceived stress was also associated with the prevalence of irregular cycles during follow-up (PR =1.33, 95% CI =1.14–1.55). Psychotropic medication use was not appreciably associated with menstrual characteristics after controlling for history of diagnosed depression and/or anxiety. Depressive symptoms, perceived stress, and psychotropic medication use showed little association with menstrual cycle length.Conclusion: Higher levels of depressive symptoms and perceived stress were associated with irregular menstrual cycles, but not appreciably associated with menstrual cycle length. Use of psychotropic medications was not meaningfully associated with cycle regularity or length. Keywords: depression, menstrual cycle irregularity, perceived stress, psychotropic medication

Jordi Castellsague,1 Josephina G Kuiper,2 Anton Pottegård,3 Ingegärd Anveden Berglind,4 Daniel Dedman,5 Lia Gutierrez,1 Brian Calingaert,6 Myrthe PP van Herk-Sukel,2 Jesper Hallas,3 Anders Sundström,4 Arlene M Gallagher,5 James A Kaye,7 Carolina Pardo,8 Kenneth J Rothman,7 Susana Perez-Gutthann1 1Department of Epidemiology, RTI Health Solutions, Barcelona, Spain; 2Department Research, PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands; 3Clinical Pharmacology and Pharmacy, Department of Public Health, University of Southern Denmark, Odense, Denmark; 4Centre for Pharmacoepidemiology, Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 5Clinical Practice Research Datalink, Medicines and Healthcare products Regulatory Agency, London, UK; 6Department Epidemiology, RTI Health Solutions, Research Triangle Park, NC, 7Department of Epidemiology, RTI Health Solutions, Waltham, MA, USA; 8Pharmacovigilance Department, Astellas Pharma Europe B.V., Leiden, the Netherlands Background: There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children.Objective: The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects.Methods: This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel–Haenszel methods for stratified analysis.Results: We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00–14.06) in children and 1.27 (0.94–1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58–17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81–3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33–5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60–43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer.Conclusion: Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results. Keywords: topical calcineurin inhibitors, cutaneous T-cell lymphoma, malignant melanoma skin cancer, database study

Kristen A Hahn,1 Lauren A Wise,1,2 Anders H Riis,3 Ellen M Mikkelsen,3 Kenneth J Rothman,1,4 Kristen Banholzer,1 Elizabeth E Hatch11Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; 2Slone Epidemiology Center, Boston University, Boston, MA, USA; 3Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 4RTI Health Solutions, Research Triangle Park, NC, USAObjective: We examined the association between lifestyle factors and menstrual cycle characteristics among nulliparous Danish women aged 18–40 years who were participating in an Internet-based prospective cohort study of pregnancy planners.Methods: We used cross-sectional data collected at baseline to assess the association of age, body mass index (BMI), physical activity, alcohol and caffeine consumption, and smoking with the prevalence of irregular cycles, short (≤25 days) and long (≥33 days) cycles, and duration and amount of menstrual flow. We used log-binomial and multinomial logistic regression to estimate prevalence ratios and 95% confidence intervals.Results: Low physical activity and heavy alcohol consumption were associated with an increased prevalence of irregular periods. High BMI, smoking, and caffeine and alcohol consumption were related to an increased prevalence of short menstrual cycles and heavy menstrual bleeding. Women in their mid-to-late thirties had shorter and lighter menstrual flow, but a lower prevalence of irregular cycles, compared with women 18–25 years of age.Discussion: In this study, increased age, high BMI, and sedentary behavior were associated with menstrual-pattern irregularities. These factors may influence the balance and level of endogenous hormones conducive to optimal menstrual function.Keywords: menstrual cycle, body mass index, alcohol drinking, smoking, caffeine, physical activity, menstruation

Heidi T Cueto,1 Anders H Riis,1 Elizabeth E Hatch,2 Lauren A Wise,2,4 Kenneth J Rothman,2,3 Ellen M Mikkelsen11Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA; 3RTI Health Solutions, Research Triangle Park, NC, USA; 4Slone Epidemiology Center, Boston University, Boston, MA, USAPurpose: Compliance with the Danish preconceptional folic acid (FA) recommendation – a daily supplement of 400 µg – is reported to be poor. Uncertainty remains, however, about the prevalence of compliers and health-related predictors of compliance in the preconceptional period.Methods: We used self-reported baseline data from 5383 women, aged 18–40 years, enrolled in an Internet-based prospective cohort study of Danish pregnancy planners during 2007–2011. We estimated the prevalence proportions of FA or multivitamin (MV) use in relation to selected sociodemographic, lifestyle, reproductive, and medical characteristics. Multivariate binomial regression was used to obtain prevalence proportion differences with 95% confidence intervals for each level of study predictors, adjusted for all other predictors.Results: Overall, 7.7% of women used FA supplements, 20.4% used MV supplements, 34.0% used both, 1.5% used other single vitamins or minerals, and 36.4% did not use any dietary supplements. The prevalence of FA or MV supplement use was higher among older women, women with higher education and income, and women with healthy lifestyle factors such as being a nonsmoker, nondrinker, physically active, maintaining a normal body mass index and having regular pap smears. Greater intercourse frequency and a history of spontaneous abortion were also positively associated with FA or MV supplement use. We found no clear association between use of FA or MV supplements and a diagnosis of hypertension, diabetes, thyroid disease, pelvic inflammatory disease, or chlamydia.Conclusion: A large proportion of pregnancy planners do not use FA or MV supplements. Pregnancy planners with generally risky lifestyle behaviors are less likely to comply with the FA recommendation.Keywords: pregnancy, preconceptional supplement use, vitamins, folic acid

Background: Many epidemiologic studies have evaluated the association between caffeine and fertility, with inconsistent results. Some studies suggest that various caffeine-containing beverages may affect fertility differently.Methods: We evaluated the relation of caffeine, coffee, tea, and sodas with time to pregnancy in a prospective cohort study of 3628 women planning a pregnancy, in Denmark (2007-2010). Women reported beverage intake at baseline and every 8 weeks during follow-up until they became pregnant or for up to 12 cycles. We used discrete-time Cox proportional hazards regression to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), controlling for potential confounders.Results: There was little relation between fecundability and caffeine intake of 300+ mg/day compared with < 100 mg/day (FR = 1.04 [95% CI = 0.90-1.21]) or coffee intake of 3+ servings/day compared with none (1.05 [0.85-1.33]). Soda consumption was associated with reduced fecundability: for all types of sodas combined, the adjusted FRs were 0.89 (0.80-0.98), 0.85 (0.71-1.02), 0.84 (0.57-1.25), and 0.48 (0.21-1.13) for < 1, 1, 2, and 3+ servings per day, respectively, compared with none. Tea drinking was associated with a slight increase in fecundability, with FR = 1.27 (0.98-1.64) for 2+ servings/day versus none.Conclusion: In this prospective study of time to pregnancy, the association between caffeine intake and fertility differed by beverage type. Although we controlled for many confounders, our findings of reduced fecundability among soda drinkers and increased fecundability among tea drinkers could have resulted from confounding by unmeasured lifestyle characteristics. [ABSTRACT FROM AUTHOR]

PURPOSE: Beryllium is classified as carcinogenic on the basis largely of limited human data showing a modest increase in lung cancer from occupational exposure. With occupational exposure now curtailed, earlier results merit more scrutiny. We simulated data to understand the design implications of a landmark case-control study. METHODS: We generated datasets from the original occupational cohort by randomly assigning lung cancer events to workers independently of their exposure. We analyzed the simulated data on the basis of different modes of risk-set sampling, with risk sets defined by calendar time, age, or both, to assess how much bias existed using several exposure metrics. We controlled for several time related variables to assess confounding. Finally, we re-analyzed the data from the original study, controlling for time-related covariates. RESULTS: No bias occurred using any type of risk-set sampling with unlagged exposures. When exposure was lagged 10 or 20 years, however, there was considerable confounding by year of birth and year of hire, which remained uncontrolled in the original study. CONCLUSIONS: Simulations and reanalysis show that much of the reported association with lagged exposure is attributable to confounding by year of birth and year of hire. Lagging changes the exposure variable and can thus lead to changes in the amount of confounding. [ABSTRACT FROM AUTHOR]

Using data from the San Diego Birth Center Study that enrolled underserved women between 1994 and 1996, we examined demographic, sociobehavioral, and medical predictors of hospital transfer in a group of women who intended to deliver at a freestanding birth center. Of the 1808 women, 34.6% transferred to the hospital antenatally and 19.6% transferred during labor, while 45.7% delivered at the birth center. Compared with multiparous women who had never had a cesarean and never had a previous hospital delivery, nulliparous women were 2.0 times more likely (95% confidence interval [CI], 1.4-2.7), multiparous women with a previous cesarean were 2.6 times more likely (95% CI, 1.7-3.8), and women without a previous cesarean but who had a previous hospital delivery were 2.1 times more likely (95% CI, 1.5-3.0) to transfer after adjusting for other predictors of transfer. Nulliparity, cesarean history and having a previous hospital delivery were among the strongest predictors of a hospital transfer even after adjusting for demographic, sociobehavioral, and other medical conditions. Understanding predictors of transfer may assist practitioners, patients, and policy makers in considering the appropriateness of individuals for birth center delivery or to target further education to reduce nonmedical transfers. [ABSTRACT FROM AUTHOR]

BACKGROUND: Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results. STUDY DESIGN: We used a retrospective cohort study design. SETTING & PARTICIPANTS: Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period. PREDICTOR: EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period. OUTCOME: All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics. RESULTS: 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio [HR], 1.31 per log unit increase; 95% confidence interval [CI], 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively. LIMITATIONS: This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable. CONCLUSIONS: The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies. Copyright © 2008 National Kidney Foundation, Inc. [ABSTRACT FROM AUTHOR]

Confounding can be a major source of bias in nonexperimental research. The authors recently introduced propensity score calibration (PSC), which combines propensity scores and regression calibration to address confounding by variables unobserved in the main study by using variables observed in a validation study. Here, the authors assess the performance of PSC using simulations in settings with and without violation of the key assumption of PSC: that the error-prone propensity score estimated in the main study is a surrogate for the gold-standard propensity score (i.e., it contains no additional information on the outcome). The assumption can be assessed if data on the outcome are available in the validation study. If data are simulated allowing for surrogacy to be violated, results depend largely on the extent of violation. If surrogacy holds, PSC leads to bias reduction between 32% and 106% (>100% representing overcorrection). If surrogacy is violated, PSC can lead to an increase in bias. Surrogacy is violated when the direction of confounding of the exposure-disease association caused by the unobserved variable(s) differs from that of the confounding due to observed variables. When surrogacy holds, PSC is a useful approach to adjust for unmeasured confounding using validation data. [ABSTRACT FROM AUTHOR]

Adult height has been found to be inversely associated with mortality. Recently, it has been suggested that growth in utero is linked with adult risk of several chronic diseases. The authors examined possible associations between birth weight, birth length, and adult height in young Danish men. They conducted the study in the fifth conscription district of Denmark including all the men born after January 1, 1973 who were residents in the study area during the period August 1, 1993 to July 31, 1994. The Danish Medical Birth Register contains information on all births in Denmark since January 1, 1973. Data on height from the Conscription Register were linked to the Danish Medical Birth Register in 4,300 conscripts examined. Nearly all Danish men have to register with the draft board around age 18 years of age where they undergo a physical examination. There was a strong positive association between birth weight and adult height; for subjects with birth weight < or = 2,500 g, mean height was 175.7 cm, while for those with birth weight > or = 4,501 g, mean height was 184.1 cm. A positive association was also found between birth length and adult height. For subjects with birth length < 47 cm, mean adult height was 175.2 cm, increasing to 184.3 cm at birth length > 56 cm. The associations between birth length and adult height persisted after adjustment for birth weight, gestational age, and other confounders, while the associations between birth weight and adult height almost disappeared when adjusting for birth length and the same confounders. Genetic and/or environmental factors operating both during the pre- and postnatal period may be responsible for the association between birth length and adult height. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between leisure-time physical activity (PA) and fecundability.Design: Prospective cohort study.Setting: Internet-based observational study of Danish women who were planning a pregnancy (2007-2009).Patient(s): A total of 3,628 women aged 18-40 years at baseline.Intervention(s): None.Main Outcome Measure(s): Time to pregnancy (TTP). Fecundability ratios (FRs) and 95% confidence intervals (CIs) were derived from discrete-time Cox models, with adjustment for potential confounders, such as body mass index (BMI).Result(s): We observed an inverse monotonic association between vigorous PA and fecundability (≥ 5 h/wk vs. none: FR 0.68, 95% CI 0.54-0.85) and a weak positive association between moderate PA and fecundability (≥ 5 vs. <1 h/wk: FR 1.18, 95% CI 0.98-1.43) after mutual adjustment for both PA types. Inverse associations between high vigorous PA and fecundability were observed within subgroups of age, parity status, and cycle regularity, but not among overweight or obese women (BMI ≥ 25 kg/m(2)).Conclusion(s): There was evidence for a dose-response relationship between increasing vigorous PA and delayed TTP in all subgroups of women with the exception of overweight and obese women. Moderate PA was associated with a small increase in fecundability regardless of BMI. These findings indicate that PA of any type might improve fertility among overweight and obese women, a subgroup at higher risk of infertility. Lean women who substitute vigorous PA with moderate PA may also improve their fertility. [ABSTRACT FROM AUTHOR]

Background: Despite safety-related concerns, psychotropic medications are frequently prescribed to manage behavioural symptoms in older adults, particularly those with dementia. We assessed the comparative safety of different classes of psychotropic medications used in nursing home residents.Methods: We identified a cohort of patients who were aged 65 years or older and had initiated treatment with psychotropics after admission to a nursing home in British Columbia between 1996 and 2006. We used proportional hazards models to compare rates of death and rates of hospital admissions for medical events within 180 days after treatment initiation. We used propensity-score adjustments to control for confounders.Results: Of 10,900 patients admitted to nursing homes, atypical antipsychotics were initiated by 1942, conventional antipsychotics by 1902, antidepressants by 2169 and benzodiazepines by 4887. Compared with users of atypical antipsychotics, users of conventional antipsychotics and antidepressants had an increased risk of death (rate ratio [RR] 1.47, 95% confidence interval [CI] 1.14-1.91 for conventional antipsychotics and RR 1.20, 95% CI 0.96-1.50 for antidepressants), and an increased risk of femur fracture (RR 1.61, 95% CI 1.03-2.51 for conventional antipsychotics and RR 1.29, 95% CI 0.86-1.94 for antidepressants). Users of benzodiazepines had a higher risk of death (RR 1.28, 95% CI 1.04-1.58) compared with users of atypical antipsychotics. The RR for heart failure was 1.54 (95% CI 0.89-2.67), and for pneumonia it was 0.85 (95% CI 0.56-1.31).Interpretation: Among older patients admitted to nursing homes, the risks of death and femur fracture associated with conventional antipsychotics, antidepressants and benzodiazepines are comparable to or greater than the risks associated with atypical antipsychotics. Clinicians should weigh these risks against the potential benefits when making prescribing decisions. [ABSTRACT FROM AUTHOR]

Concepts of cause and causal inference are largely self-taught from early learning experiences. A model of causation that describes causes in terms of sufficient causes and their component causes illuminates important principles such as multicausality, the dependence of the strength of component causes on the prevalence of complementary component causes, and interaction between component causes.Philosophers agree that causal propositions cannot be proved, and find flaws or practical limitations in all philosophies of causal inference. Hence, the role of logic, belief, and observation in evaluating causal propositions is not settled. Causal inference in epidemiology is better viewed as an exercise in measurement of an effect rather than as a criterion-guided process for deciding whether an effect is present or not. [ABSTRACT FROM AUTHOR]

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/m 2 ., Conclusion: Greater SSB consumption was associated with reduced semen quality in a North American preconception cohort., (© 2024 American Society of Andrology and European Academy of Andrology.)

Background: The target trial framework was developed as a strategy to design and analyze observational epidemiologic studies with the aim of reducing bias due to analytic decisions. It involves designing a hypothetical randomized trial to answer a question of interest and systematically considering how to use observational data to emulate each trial component., Aims: The primary aim of this paper is to provide a detailed example of the application of the target trial framework to a research question in oral epidemiology., Materials and Methods: We describe the development of a hypothetical target trial and emulation protocol to evaluate the effect of preconception periodontitis treatment on time-to-pregnancy. We leverage data from Pregnancy Study Online (PRESTO), a preconception cohort, to ground our example in existing observational data. We discuss the decision-making process for each trial component, as well as limitations encountered., Results: Our target trial application revealed data limitations that precluded us from carrying out the proposed emulation. Implications for data quality are discussed and we provide recommendations for researchers interested in conducting trial emulations in the field of oral epidemiology., Discussion: The target trial framework has the potential to improve the validity of observational research in oral health, when properly applied., Conclusion: We encourage the broad adoption of the target trial framework to the field of observational oral health research and demonstrate its value as a tool to identify directions for future research., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2024 The Author(s). Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)