Preconception use of antibiotics and fecundability: a Danish prospective cohort study.

OBJECTIVE: To assess the association between preconception antibiotic use and fecundability, the per menstrual cycle probability of conception. DESIGN: SnartForaeldre.dk, a Danish prospective cohort study of women trying to conceive (2007-2020). SETTING: Not applicable. SUBJECT(S): 9462 female participants, median age 29 years at enrollment. EXPOSURE: Antibiotic use was defined by filled prescriptions retrieved from the Danish National Prescription Registry, using Anatomical Therapeutic Chemical codes, and modeled as time-varying (menstrual cycle-varying) exposure. MAIN OUTCOME MEASURE(S): Pregnancy status was reported on female follow-up questionnaires every 8 weeks for up to 12 months or until conception. Fecundability ratios (FR) and 95% confidence intervals (CI) were computed using proportional probabilities regression models, with adjustment for age, partner age, education, smoking, folic acid supplementation, body mass index, parity, cycle regularity, timing of intercourse, and sexually transmitted infections. RESULT(S): During all cycles of observation, the percentage of participants filing at least 1 antibiotic prescription was 11.9%; 8.6% had a prescription for penicillins, 2.1% for sulfonamides, and 1.8% for macrolides. Based on life-table methods, 86.5% of participants conceived within 12 cycles of follow-up. Recent preconception antibiotic use was associated with reduced fecundability (≥1 prescription vs. none: adjusted FR = 0.86; 95% CI, 0.76-0.99). For participants using penicillins, sulfonamides, or macrolides, the adjusted FRs were 0.97 (95% CI, 0.83-1.12), 0.68 (95% CI, 0.47-0.98), and 0.59 (95% CI, 0.37-0.93), respectively. CONCLUSION(S): Preconception use of antibiotics, specifically sulfonamides and macrolides, was associated with decreased fecundability compared with no use. The observed associations may be explained plausibly by confounding by indication, as we lacked data on indications for the prescribed antibiotics. Consequently, we cannot separate the effect of the medication from the effect of the underlying infection.

Association of In Utero Antipsychotic Medication Exposure With Risk of Congenital Malformations in Nordic Countries and the US.

Importance: Psychiatric disorders are common among female individuals of reproductive age. While antipsychotic medication use is increasing, the safety of such medications in pregnancy is an area with large evidence gaps. Objective: To evaluate the risk of first-trimester antipsychotic exposure with respect to congenital malformations, focusing on individual drugs and specific malformation subtypes. Design, Setting, and Participants: This cohort study used data from nationwide health registers from the 5 Nordic countries and the US and spanned 1996 to 2018. The Nordic cohort included all pregnancies resulting in singleton live-born infants, and the US cohort consisted of publicly insured mothers linked to their live-born infants nested in the nationwide Medicaid Analytic eXtract. Data were analyzed from November 2020 to April 2022. Exposures: One or more first-trimester dispensing of any atypical, any typical, and individual antipsychotic drugs. Main Outcomes and Measures: Any major congenital malformation and specific malformation subtypes previously suggested to be associated with antipsychotic exposure in utero: cardiovascular malformations, oral clefts, neural tube defects, hip dysplasia, limb reduction defects, anorectal atresia/stenosis, gastroschisis, hydrocephalus, other specific brain anomalies, and esophageal disorders. Propensity score stratification was used to control for potential confounders. Pooled adjusted estimates were calculated using indirect standardization. Results: A total of 6 455 324 unexposed mothers (mean maternal age range across countries: 24-31 years), 21 751 mothers exposed to atypical antipsychotic drugs (mean age range, 26-31 years), and 6371 mothers exposed to typical antipsychotic drugs (mean age range, 27-32 years) were included in the study cohort. Prevalence of any major malformation was 2.7% (95% CI, 2.7%-2.8%) in unexposed infants, 4.3% (95% CI, 4.1%-4.6%) in infants with atypical antipsychotic drug exposure, and 3.1% (95% CI, 2.7%-3.5%) in infants with typical antipsychotic drug exposure in utero. Among the most prevalent exposure-outcome combinations, adjusted relative risks (aRR) were generally close to the null. One exception was olanzapine exposure and oral cleft (aRR, 2.1 [95% CI, 1.1-4.3]); however, estimates varied across sensitivity analyses. Among moderately prevalent combinations, increased risks were observed for gastroschisis and other specific brain anomalies after atypical antipsychotic exposure (aRR, 1.5 [95% CI, 0.8-2.6] and 1.9 [95% CI, 1.1-3.0]) and for cardiac malformations after chlorprothixene exposure (aRR, 1.6 [95% CI, 1.0-2.7]). While the association direction was consistent across sensitivity analyses, confidence intervals were wide, prohibiting firm conclusions. Conclusions and Relevance: In this study, considering the evidence from primary and sensitivity analyses and inevitable statistical noise for very rare exposure-outcome combinations, in utero antipsychotic exposure generally was not meaningfully associated with an increased risk of malformations. The observed increased risks of oral clefts associated with olanzapine, gastroschisis, and other specific brain anomalies with atypical antipsychotics and cardiac malformations with chlorprothixene requires confirmation as evidence continues to accumulate.

Pretreatment Hemoglobin Adds Prognostic Information To The NCCN-IPI In Patients With Diffuse Large B-Cell Lymphoma Treated With Anthracycline-Containing Chemotherapy.

BACKGROUND: Hemoglobin (Hgb) concentration at diagnosis is associated with outcome in cancer. In a recently reported simplified 3-factor prognostic score in Hodgkin lymphoma, Hgb, along with age and clinical stage, outperformed the classical International Prognostic Score with seven parameters. METHODS: In the present study, we investigated if pretherapeutic Hgb concentration added prognostic information to the NCCN-IPI in diffuse large B-cell lymphoma. We included patients from the Danish Lymphoma Registry (LYFO; N = 3499) and from the Molecular Epidemiology Resource (MER; N = 1225), Mayo Clinic and University of Iowa. Four sex-specific Hgb groups were defined: below transfusion threshold, from transfusion threshold to below lower limit of normal, from lower limit of normal to the population mean, and above the mean. We used multivariable Cox regression to estimate the hazard rate ratios (HR) and 95% CIs for overall survival (OS) and event-free survival (EFS), adjusting for sex, NCCN-IPI, comorbidity, and rituximab treatment. RESULTS: Approximately half of the patients had Hgb levels below the lower limit of normal. Compared to patients with Hgb levels above the mean, an inferior OS was directly correlated with lower pretreatment Hgb within the predefined groups (HR=1.23, HR=1.51, and HR=2.05, respectively). These findings were validated in the MER. CONCLUSION: Based on multivariable analysis, lower pretreatment Hgb, even within the normal range but below the mean, added prognostic information to established indices such as the NCCN-IPI and the Charlson comorbidity index.

Post-authorisation Safety Study of Pioglitazone Use and Safety Endpoints of Interest in Denmark After Direct Healthcare Professional Communication.

INTRODUCTION: A Direct Healthcare Professional Communication (DHPC) sent in Denmark on 11 August 2011 provided information on new pioglitazone labelling and guidance on monitoring treatment effectiveness. We describe pioglitazone use in Denmark after the DHPC, estimate the incidence of heart failure (HF), quantify pioglitazone cessation following a diagnosis of bladder cancer (BC) or uninvestigated macroscopic haematuria, and describe glycated haemoglobin (HbA1c) values. METHODS: This was a cohort study. From Danish population-based registries, cohorts of type 2 diabetes mellitus incident or prevalent users of pioglitazone or insulin in 2011-2015 were created. Patient characteristics, treatment patterns, laboratory results (available for a regional subset of the population), and incidence rates of HF and BC were estimated. RESULTS: There were 80 pioglitazone and 17,699 insulin incident users, 140 pioglitazone and 13,183 insulin prevalent users. There were no new BC cases among incident pioglitazone users, and < 5 new BC cases among prevalent pioglitazone users. Pioglitazone was rarely the first-line treatment. History of haematuria was documented in < 5 incident and 11 prevalent pioglitazone users. During follow-up, there were < 5 HF cases among 77 incident pioglitazone users and < 5 among 133 prevalent pioglitazone users without a history of HF. Median HbA1c at index date was 7.8% and 8.8% in incident pioglitazone and insulin cohorts, and 7.5% and 7.6% in prevalent pioglitazone and insulin cohorts, respectively. During follow-up of up to 4.4 years, 28.8% incident and 20.7% prevalent pioglitazone users discontinued pioglitazone. CONCLUSIONS: Numbers of pioglitazone users in Denmark were low and decreased over time. Risks of BC or HF were low and risk estimates imprecise.

Phthalate Exposure and Breast Cancer Incidence: A Danish Nationwide Cohort Study.

PURPOSE: Phthalate exposure is ubiquitous and especially high among users of drug products formulated with phthalates. Some phthalates mimic estradiol and may promote breast cancer. Existing epidemiologic studies on this topic are small, mostly not prospective, and have given inconsistent results. We estimated associations between longitudinal phthalate exposures and breast cancer risk in a Danish nationwide cohort, using redeemed prescriptions for phthalate-containing drug products to measure exposure. METHODS: We ascertained the phthalate content of drugs marketed in Denmark using an internal Danish Medicines Agency ingredient database. We enrolled a Danish nationwide cohort of 1.12 million women at risk for a first cancer diagnosis on January 1, 2005. By combining drug ingredient data with the Danish National Prescription registry, we characterized annual, cumulative phthalate exposure through redeemed prescriptions. We then fit multivariable Cox regression models to estimate associations between phthalate exposures and incident invasive breast carcinoma according to tumor estrogen receptor status. RESULTS: Over 9.99 million woman-years of follow-up, most phthalate exposures were not associated with breast cancer incidence. High-level dibutyl phthalate exposure (≥ 10,000 cumulative mg) was associated with an approximately two-fold increase in the rate of estrogen receptor-positive breast cancer (hazard ratio, 1.9; 95% CI, 1.1 to 3.5), consistent with in vitro evidence for an estrogenic effect of this compound. Lower levels of dibutyl phthalate exposure were not associated with breast cancer incidence. CONCLUSION: Our results suggest that women should avoid high-level exposure to dibutyl phthalate, such as through long-term treatment with pharmaceuticals formulated with dibutyl phthalate.

Depth of neutrophil nadir after first cycle of R-CHOP predicts outcome in diffuse large B-cell lymphoma - a nationwide population-based cohort study.

We investigated if survival was predicted by nadir neutrophil counts after the first cycle of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Neutrophil counts (109/L) were categorized in four grades in the nadir time frame. Prognostic indices and comorbidity levels were calculated and used to adjust the Cox regression model. Kaplan-Meier and Cox regression methods were used to estimate and compare survival. We identified 965 patients. Grade 4 neutropenia was present in 432 (45%). Grade 0 patients had a 5-year overall survival of 67%, grade 1-2: 78%, grade 3: 64%, and grade 4: 57%. Compared with grade 0 adjusted hazard ratios (HR) for death were: 0.77 (95% CI 0.49-1.21) for grade 1-2, 1.18 (95% CI 0.82-1.71) for grade 3, and 1.33 (95% CI 1.02-1.73) for grade 4. Grade 4 neutropenia after the 1st cycle of chemotherapy predicted inferior outcome compared with grade 0 and 1-2. Grade 1-2 neutropenia seemed to have superior outcome.

Increased mortality among patients with rheumatoid arthritis and COPD: A population-based study.

OBJECTIVES: Only few studies have addressed the prognostic impact of chronic obstructive pulmonary disease (COPD) among patients with rheumatoid arthritis (RA), although both diseases are frequent and smoking is a shared risk factor. The objectives of the present study were to investigate the burden of COPD among RA patients and the subsequent mortality. METHODS: We included patients who had a first-time diagnosis of RA in the Danish National Patient Registry between 2004 and 2016. RA patients with COPD were identified and matched with RA patients without COPD for year of birth, gender, and age at RA diagnosis. Mortality risks were assessed using Kaplan-Meier mortality curves. Adjusted hazard rate ratios (aHRRs) for death were estimated using Cox regression models. RESULTS: The study population included 31,333 individuals with RA. 3254 of those (10.4%) had a diagnosis of COPD and were matched to 9706 RA patients without COPD. The mortality risks in RA patients with COPD and RA patients without COPD were 4.5% and 1.5% within 2-6 months (aHRR = 3.0, CI 2.3-3.9), and 59.3% and 39.8% within 0.5-10 years (aHRR = 2.1, CI 1.9-2.1). CONCLUSION: Mortality was significantly increased among RA patients with COPD. The relative mortality risk remained significantly increased throughout the course of follow up.

Use of risk-adjusted CUSUM charts to monitor 30-day mortality in Danish hospitals.

BACKGROUND: Monitoring hospital outcomes and clinical processes as a measure of clinical performance is an integral part of modern health care. The risk-adjusted cumulative sum (CUSUM) chart is a frequently used sequential analysis technique that can be implemented to monitor a wide range of different types of outcomes. OBJECTIVE: The aim of this study was to describe how risk-adjusted CUSUM charts based on population-based nationwide medical registers were used to monitor 30-day mortality in Danish hospitals and to give an example on how alarms of increased hospital mortality from the charts can guide further in-depth analyses. MATERIALS AND METHODS: We used routinely collected administrative data from the Danish National Patient Registry and the Danish Civil Registration System to create risk-adjusted CUSUM charts. We monitored 30-day mortality after hospital admission with one of 77 selected diagnoses in 24 hospital units in Denmark in 2015. The charts were set to detect a 50% increase in 30-day mortality, and control limits were determined by simulations. RESULTS: Among 1,085,576 hospital admissions, 441,352 admissions had one of the 77 selected diagnoses as their primary diagnosis and were included in the risk-adjusted CUSUM charts. The charts yielded a total of eight alarms of increased mortality. The median of the hospitals' estimated average time to detect a 50% increase in 30-day mortality was 50 days (interquartile interval, 43;54). In the selected example of an alarm, descriptive analyses indicated performance problems with 30-day mortality following hip fracture surgery and diagnosis of chronic obstructive pulmonary disease. CONCLUSION: The presented implementation of risk-adjusted CUSUM charts can detect significant increases in 30-day mortality within 2 months, on average, in most Danish hospitals. Together with descriptive analyses, it was possible to use an alarm from a risk-adjusted CUSUM chart to identify potential performance problems.

Thirty-year trends in heart failure hospitalization and mortality rates and the prognostic impact of co-morbidity: a Danish nationwide cohort study.

AIMS: We examined 30-year nationwide trends in heart failure hospitalization and mortality rates, and the prognostic impact of co-morbidity. METHODS AND RESULTS: We conducted a population-based cohort study of 317 161 patients with first-time inpatient hospitalizations for heart failure during 1983-2012. We computed the standardized hospitalization rate and 5-year mortality risk. Co-morbidity levels and calendar periods of diagnosis were compared by means of mortality rate ratios (MRRs) based on Cox regression. The standardized hospitalization rate (per 100 000 persons) decreased between 1983 and 2012 by 25% for women (from 192 to 144) and by 14% for men (from 217 to 186). The decrease reflected an average annual 1% increase until 2000 and a 3.5% decline thereafter. Between 1983-1987 and 2008-2012, 1-year mortality declined from 45% to 33% and 1- to 5-year mortality from 59% to 43%. The decline occurred independently of patients' co-morbidity levels. Comparing 2008-2012 with 1983-1987, the 5-year age-, sex-, and co-morbidity-adjusted MRR was 0.57 [95% confidence interval (CI) 0.56-0.58]. Using low co-morbidity as reference, the adjusted 5-year MRR in 2003-2007 was increased by 43% for moderate, 66% for severe, and 2.2-fold for very severe co-morbidity. The magnitude of co-morbidity-associated mortality increased over time and was highest in the youngest patients. CONCLUSIONS: Hospitalization rates for heart failure have declined markedly since 2000 in Denmark. One- and five-year mortality declined >40% over the last three decades. The decline in mortality occurred for patients with all levels of co-morbidity, but co-morbidity burden was a strong prognostic factor.

Liver disease and 30-day mortality after colorectal cancer surgery: a Danish population-based cohort study.

BACKGROUND: Colorectal cancer (CRC) is common, with surgery as the main curative treatment. The prevalence of chronic liver disease has increased, but knowledge is limited on postoperative mortality in patients with liver disease who undergo CRC surgery. Hence, we examined 30-day mortality after CRC surgery in patients with liver disease compared to those without liver disease. METHODS: We used medical databases to conduct a nationwide cohort study of all patients undergoing CRC surgery in Denmark from 1996 through 2009. We further identified patients diagnosed with any liver disease before CRC surgery and categorized them into two cohorts: patients with non-cirrhotic liver disease and patients with liver cirrhosis. Patients without liver disease were defined as the comparison cohort. Using the Kaplan-Meier method, we computed 30-day mortality after CRC surgery in each cohort. We used a Cox regression model to compute hazard ratios as measures of the relative risk (RR) of death, controlling for potential confounders including comorbidities. In order to examine the impact of liver disease in different subgroups, we stratified patients by gender, age, cancer stage, cancer site, timing of admission, type of surgery, comorbidity level, and non-hepatic alcohol-related disease. RESULTS: Overall, 39,840 patients underwent CRC surgery: 369 (0.9%) had non-cirrhotic liver disease and 158 (0.4%) had liver cirrhosis. Thirty-day mortality after CRC surgery was 8.7% in patients without liver disease and 13.3% in patients with non-cirrhotic liver disease (adjusted RR of 1.49 95% confidence interval (CI): 1.12-1.98). Among patients with liver cirrhosis, mortality was 24.1%, corresponding to an adjusted RR of 2.59 (95% CI: 1.86-3.61). The negative impact of liver disease on postoperative mortality was found in all subgroups. CONCLUSIONS: Pre-existing liver disease was associated with a markedly increased 30-day mortality following CRC surgery.

The Danish Centre for Strategic Research in Type 2 Diabetes (DD2) study: Collection of baseline data from the first 580 patients.

This paper provides an overview of the baseline data collected in the nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project. The paper presents descriptive data from the first 580 patients enrolled in the DD2. The DD2 database will contain detailed interview data, clinical examination data, and urine and blood samples from up to 10,000 patients newly diagnosed with type 2 diabetes each year, collected from general practitioners and hospital outpatient clinics in all of Denmark. Of the first DD2 patients enrolled, blood and urine samples have been obtained from 97%. The median age of the first 580 patients was 59 years and 322 (56%) were men. Median weight gain from age 20 to maximum lifetime weight was 29 kg for men and 31 kg for women, and 364 patients (63%) did not currently participate in regular sports activities. Two hundred and ninety two patients (50%) had a known family history of diabetes. Two hundred fifty (43%) of the 580 DD2 patients have also been enrolled in the Danish Diabetes Database for Adults from which additional clinical data can be obtained. Among these 250 patients (154 of whom were men, 96 women), 75 (49%) men were currently obese, and 63 (41%) were overweight, whereas 62 (65%) women were obese, and another 21 (22%) were overweight. Twenty-nine patients (12%) received insulin, 164 patients (66%) received oral antidiabetics only, and 57 (23%) received no antidiabetic treatment. Glycemic regulation was modest (the glycosylated hemoglobin A of 46% was ≥7.5%). Two thirds of the patients received antihypertensive and hypolipidemic treatment. Self-reported daily tobacco smoking (23%) and alcohol overuse (6%) seemed comparable to occurrence in the general Danish population. One quarter of the patients with newly diagnosed diabetes had a history of hospital-diagnosed comorbidity at baseline as included in the Charlson comorbidity index, in particular prior myocardial infarction (5%), cerebrovascular disease (5%), peripheral vascular disease (4%), chronic pulmonary disease (6%), and previous solid cancer (6%). In the future, the DD2 database represents a valuable source for outcome studies in type 2 diabetes.

Use of glucocorticoids and risk of breast cancer: a Danish population-based case-control study.

INTRODUCTION: Glucocorticoids are widely prescribed drugs. In the human body, glucocorticoid is the main stress hormone and controls a variety of physiological and cellular processes, including metabolism and immune response. It belongs to the same steroid superfamily as estrogens, which are known to play a role in breast cancer. However, the effect of glucocorticoid use on the risk of breast cancer is not clear. METHODS: We conducted a case-control study using population-based medical databases from Northern Denmark (1.8 million inhabitants) to investigate the association between glucocorticoid prescriptions and breast cancer risk. The study included 9,488 incident breast cancer cases diagnosed between 1994 and 2008 and 94,876 population controls. We estimated the odds ratios (ORs) and 95% confidence intervals (CIs) associating glucocorticoid use with breast cancer occurrence, controlling for prescriptions of postmenopausal hormone replacement therapy, anti-diabetics, immunosuppressive drugs, and hospital diagnosis of obesity, diabetes, chronic pulmonary diseases and autoimmune diseases. RESULTS: We found no effect on breast cancer risk in ever users (> 2 prescriptions) of any glucocorticoids (adjusted odds ratio (aOR) = 1.0; 95% CI: 0.96, 1.1), systemic glucocorticoids (aOR = 1.0; 95% CI: 0.96, 1.1), or inhaled glucocorticoids (aOR = 1.0; 95% CI: 0.95, 1.1), each compared to never users of any glucocorticoids. Associations for recent use (preceding two years) and former use (more than two years earlier) were near null in all dose categories (low, medium and high number of prescriptions). Intensity of systemic glucocorticoid use (cumulative prednisolone equivalent doses), regardless of duration (< 1, 1 to 5, 5+ years), was also not associated with breast cancer risk. CONCLUSIONS: Overall, our study provides no evidence that glucocorticoid use affects the risk of breast cancer.