Detection of growth-restricted fetuses during pregnancy is associated with fewer intrauterine deaths but increased adverse childhood outcomes: an observational study.

OBJECTIVE: Exploring associations between antenatal detection of fetal growth restriction (FGR) and adverse outcome. DESIGN: Retrospective, observational, register-based study. SETTING: Zealand, Denmark. POPULATION OR SAMPLE: Children born from 1 September 2012 to 31 August 2015. METHODS: Diagnoses from birth until 1 January 2018 were retrieved from The National Patient Registry. Detection was defined as estimated fetal weight less than the 2.3rd centile. Cox regression was used to associate detection status with the hazard rate of adverse outcome, adjusted for fetal weight deviation, maternal age, ethnicity, body mass index and smoking. MAIN OUTCOME MEASURES: Adverse neonatal outcome, adverse neuropsychiatric outcome, respiratory disorders, endocrine disorders, gastrointestinal/urogenital disorders. RESULTS: A total of 2425 FGR children were included. An association was found for gastrointestinal/urogenital disorders (hazard ratio [HR] 1.68, 95% CI 1.26-2.23, P < 0.001) and respiratory disorders (HR 1.22, 95% CI 1.02-1.46, P = 0.03) in detected versus undetected infants. For adverse neuropsychiatric outcome, HR was 1.32 (95% CI 1.00-1.75, P = 0.05). There was no evidence of an association between detection and adverse neonatal outcome (HR 1.00, 95% CI 0.62-1.61, P = 0.99) and endocrine disorders (HR 1.39, 95% CI 0.88-2.19, P = 0.16). Detected infants were smaller (median -28% versus -25%, P < 0.0001), more often born preterm (odds ratio [OR] 4.15, 3.12-5.52, P < 0.0001) and more often born after induction or caesarean section (OR 5.19, 95% CI 4.13-6.51, P < 0.0001). Stillbirth risk was increased in undetected FGR fetuses (OR 2.63, 95% CI 1.37-5.04, P = 0.004). CONCLUSIONS: We found an association between detection of FGR and risk of adverse childhood conditions, possibly caused by prematurity. Iatrogenic prematurity may be inevitable in stillbirth prevention, but is accompanied by a risk of long-term childhood conditions. TWEETABLE ABSTRACT: Antenatal detection of growth-restricted fetuses is associated with adverse childhood outcomes but fewer intrauterine deaths.

New drug candidates for depression - a nationwide population-based study.

OBJECTIVE: To investigate whether continued use of non-aspirin NSAID, low-dose aspirin, high-dose aspirin, statins, allopurinol and angiotensin agents decreases the rate of incident depression using Danish nationwide population-based registers. METHODS: All persons in Denmark who purchased the exposure medications of interest between 1995 and 2015 and a random sample of 30% of the Danish population was included in the study. Two different outcome measures were included, (i) a diagnosis of depressive disorder at a psychiatric hospital as in-patient or out-patient and (ii) a combined measure of a diagnosis of depression or use of antidepressants. RESULTS: A total of 1 576 253 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015. Continued use of low-dose aspirin, statins, allopurinol and angiotensin agents was associated with a decreased rate of incident depression according to both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident depression. CONCLUSION: The findings support the potential of agents acting on inflammation and the stress response system in depression as well as the potential of population-based registers to systematically identify drugs with repurposing potential.

Standard and reduced doses of dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation: a nationwide cohort study.

BACKGROUND: Comparative data of non-vitamin K antagonist oral anticoagulants (NOAC) are lacking in patients with atrial fibrillation (AF). OBJECTIVE: We compared effectiveness and safety of standard and reduced dose NOAC in AF patients. METHODS: Using Danish nationwide registries, we included all oral anticoagulant-naïve AF patients who initiated NOAC treatment (2012-2016). Outcome-specific and mortality-specific multiple Cox regressions were combined to compute average treatment effects as 1-year standardized differences in stroke and bleeding risks (g-formula). RESULTS: Amongst 31 522 AF patients, the distribution of NOAC/dose was as follows: dabigatran standard dose (22.4%), dabigatran-reduced dose (14.0%), rivaroxaban standard dose (21.8%), rivaroxaban reduced dose (6.7%), apixaban standard dose (22.9%), and apixaban reduced dose (12.2%). The 1-year standardized absolute risks of stroke/thromboembolism were 1.73-1.98% and 2.51-2.78% with standard and reduced NOAC dose, respectively, without statistically significant differences between NOACs for given dose level. Comparing standard doses, the 1-year standardized absolute risk (95% CI) for major bleeding was for rivaroxaban 2.78% (2.42-3.17%); corresponding absolute risk differences (95% CI) were for dabigatran -0.93% (-1.45% to -0.38%) and apixaban, -0.54% (-0.99% to -0.05%). The results for major bleeding were similar for reduced NOAC dose. The 1-year standardized absolute risk (95% CI) for intracranial bleeding was for standard dose dabigatran 0.19% (0.22-0.50%); corresponding absolute risk differences (95% CI) were for rivaroxaban 0.23% (0.06-0.41%) and apixaban, 0.18% (0.01-0.34%). CONCLUSIONS: Standard and reduced dose NOACs, respectively, showed no significant risk difference for associated stroke/thromboembolism. Rivaroxaban was associated with higher bleeding risk compared with dabigatran and apixaban and dabigatran was associated with lower intracranial bleeding risk compared with rivaroxaban and apixaban.

Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction.

BACKGROUND: Use of proton pump inhibitors (PPIs) has been associated with cardiovascular disease amongst patients not on antiplatelet therapy. The associations of PPI use, duration and dose, with risk of first-time ischemic stroke and myocardial infarction (MI) are poorly understood. METHODS: All Danish individuals with no prior history of MI or stroke, who had an elective upper gastrointestinal endoscopy performed between 1997 and 2012, were identified from nationwide registries. We used multiple Poisson regression to test associations with current PPI use and its dose and used multiple cause-specific Cox regression and g-formula methods to analyze long-term use. RESULTS: Amongst 214 998 individuals, during a median follow-up of 5.8 years, there were 7916 ischemic strokes and 5608 MIs. Current PPI exposure was associated with significantly higher rates of both ischemic stroke (Hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.08-1.19) and MI (HR 1.31, CI 1.23-1.39) after adjusting for age, sex, comorbidities and concomitant medication. High-dose PPI was associated with increased rates of ischemic stroke (HR 1.31, CI 1.21-1.42) and MI (HR 1.43, CI 1.30-1.57). Histamine H2 receptor antagonists (H2RAs) use was not significantly associated with ischemic stroke (HR 1.02, CI 0.84-1.24) or MI (HR 1.15, CI 0.92-1.43). Long-term users of PPIs, compared with nonusers, had a 29% (CI 5%-59%) greater absolute risk of ischemic stroke and a 36% (CI 7%-73%) greater risk of MI within a 6-month period. CONCLUSION: Use of PPIs was associated with increased risks of first-time ischemic stroke and MI, particularly amongst long-term users and at high doses.

Modifications of the National Early Warning Score for patients with chronic respiratory disease.

BACKGROUND: The National Early Warning Score (NEWS) uses physiological variables to detect deterioration in hospitalized patients. However, patients with chronic respiratory disease may have abnormal variables not requiring interventions. We studied how the Capital Region of Denmark NEWS Override System (CROS), the Chronic Respiratory Early Warning Score (CREWS) and the Salford NEWS (S-NEWS) affected NEWS total scores and NEWS performance. METHODS: In an observational study, we included patients with chronic respiratory disease. The frequency of use of CROS and the NEWS total score changes caused by CROS, CREWS and S-NEWS were described. NEWS, CROS, CREWS and S-NEWS were compared using 48-h mortality and intensive care unit (ICU) admission within 48 h as outcomes. RESULTS: We studied 11,266 patients during 25,978 admissions; the use of CROS lowered NEWS total scores in 40% of included patients. CROS, CREWS and S-NEWS had lower sensitivities than NEWS for 48-h mortality and ICU admission. Specificities and PPV were higher. CROS, CREWS and S-NEWS downgraded, respectively, 51.5%, 44.9% and 32.8% of the NEWS total scores from the 'mandatory doctor presence' and 'immediate doctor presence and specialist consultation' total score intervals to lower intervals. CONCLUSION: Capital Region of Denmark NEWS Override System was frequently used in patients with chronic respiratory disease. CROS, CREWS and S-NEWS reduced sensitivity for 48-h mortality and ICU admission. Using the methodology prevalent in the NEWS literature, we cannot conclude on the safety of these systems. Future prospective studies should investigate the balance between detection rate and alarm fatigue of different systems, or use controlled designs and patient-centred outcomes.

Continuation of lithium after a diagnosis of chronic kidney disease.

OBJECTIVE: To investigate whether continued lithium or anticonvulsant treatment after a first diagnosis of chronic kidney disease (CKD) was associated with progression to irreversible end-stage kidney disease. METHODS: Nationwide cohort study including all individuals in Denmark in a period from 1995 to 2012 with a diagnosis of CKD and (i) a history of lithium treatment (N = 754, among whom 238 patients had a diagnosis of bipolar disorder) or (ii) a history of anticonvulsant treatment (N = 5.004, among whom 199 patients had a diagnosis of bipolar disorder). End-stage CKD was defined as chronic dialysis or renal transplantation. RESULTS: Continuing lithium (HR = 0.58 (95% CI: 0.37-0.90) and continuing anticonvulsants (HR = 0.53 (95% CI: 0.44-0.64) were associated with decreased rates of end-stage CKD. In the subcohorts of patients with a diagnosis of bipolar disorder, continuing lithium was associated with decreased end-stage CKD (HR = 0.40 (95% CI: 0.17-0.98), whereas continuing anticonvulsants was not (HR = 0.70 (95% CI: 0.21-2.37). There were no interactions of continuing lithium and anticonvulsants. CONCLUSION: After an initial diagnosis of CKD, patients who are selected by their physicians to continue lithium treatment may not necessarily have an increased risk of developing end-stage CKD. Shifting to an anticonvulsant per se may not be associated with an advantage; however, this requires further investigation.

Association between PSA kinetics and cancer-specific mortality in patients with localised prostate cancer: analysis of the placebo arm of the SPCG-6 study.

BACKGROUND: The prognostic value of prostate-specific antigen (PSA) kinetics in untreated prostate cancer (PCa) patients is debatable. We investigated the association between PSA doubling time (PSAdt), PSA velocity (PSAvel) and PSAvel risk count (PSAvRC) and PCa mortality in a cohort of patients with localised PCa managed on watchful waiting. PATIENTS AND METHODS: Patients with clinically localised PCa managed observationally, who were randomised to and remained on placebo for minimum 18 months in the SPCG-6 study, were included. All patients survived at least 2 years and had a minimum of three PSA determinations available. The prognostic value of PSA kinetics was analysed and patients were stratified according to their PSA at consent: ≤10, 10.1-25, and >25 ng/ml. Cumulative incidences of PCa-specific mortality were estimated with the Aalen-Johansen method. RESULTS: Two hundred and sixty-three patients were included of which 116, 76 and 71 had a PSA at consent ≤10, 10.1-25, and >25 ng/ml, respectively. Median follow-up was 13.6 years. For patients with PSA at consent between 10.1 and 25 ng/ml, the 13-year risks of PCa mortality were associated with PSA kinetics: PSAdt ≤3 years: 62.0% versus PSAdt >3 years: 16.3% (Gray's test: P < 0.0001), PSAvel ≥2 ng/ml/year: 48.0% versus PSAvel <2 ng/ml/year: 11.0% (Gray's test: P = 0.0008), and PSAvRC 2: 45.0% versus 0-1: 3.8% (Gray's test: P = 0.001). In contrast, none of the PSA kinetics were significantly associated with changes of 13-year risks of PCa mortality in patients with PSA at consent ≤10 or >25 ng/ml. CONCLUSION: We found that magnitude changes in 13-year risks of PCa mortality that can be indicated by PSA kinetics depend on PSA level in patients with localised PCa who were managed observationally. Our results question PSA kinetics as surrogate marker for PCa mortality in patients with low and high PSA values. CLINICAL TRIAL NUMBER: NCT00672282.

Risk of fetal loss associated with invasive testing following combined first-trimester screening for Down syndrome: a national cohort of 147,987 singleton pregnancies.

OBJECTIVE: To assess prospectively the risk of fetal loss associated with chorionic villus sampling (CVS) and amniocentesis (AC) following combined first-trimester screening (cFTS) for Down syndrome. METHODS: This was a nationwide population-based study (Danish Fetal Medicine Database, 2008-2010) including 147,987 women with singleton pregnancy who underwent cFTS. Propensity score stratification was used to assess the risk of fetal loss with and without invasive testing. Analyses were performed between 3 and 21 days after cFTS for CVS and between 28 and 42 days after cFTS for AC. Results are reported as average risk differences with 95% CIs. RESULTS: The risks of miscarriage and stillbirth were not higher in women exposed to CVS or AC compared with unexposed women, independent of the analysis time-point. The average effect of CVS on risk of miscarriage was -0.08% (95% CI, -0.64; 0.47) at 3 days and -0.21% (95% CI, -0.58; 0.15) at 21 days after cFTS, while the effect on risk of stillbirth was -0.18% (95% CI, -0.50; 0.13) at 3 days and -0.27% (95% CI, -0.58; 0.04) at 21 days after cFTS. Regarding the effect of AC on risk of miscarriage, the analysis at 28 days after cFTS showed an average effect of 0.56% (95% CI, -0.21; 1.33), while the effect on risk of stillbirth was 0.09% (95% CI, -0.39; 0.58) at 42 days after cFTS. CONCLUSION: Neither CVS nor AC was associated with increased risk of miscarriage or stillbirth. These findings indicate that the procedure-related risk of CVS and AC is very low.

Risk charts to identify low and excessive responders among first-cycle IVF/ICSI standard patients.

Ovarian stimulation carries a risk of either low or excessive ovarian response. The aim was to develop prognostic models for identification of standard (ovulatory and normal basal FSH) patients' risks of low and excessive response to conventional stimulation for IVF/intracytoplasmic sperm injection. Prospectively collected data on 276 first-cycle patients treated with 150 IU recombinant FSH (rFSH)/day in a long agonist protocol were analysed. Logistic regression analysis was applied to the outcome variables:low (seven or less follicles) and excessive (20 or more follicles) response. Variables were woman's age, menstrual cycle length, weight or body mass index, ovarian volume, antral follicle count (AFC) and basal FSH. The predictive performance of the models was evaluated from the prediction error (Brier score, %) where zero corresponds to a perfect prediction. Model stability was assessed using 1000 bootstrap cross-validation steps. The best prognostic model to predict low response included AFC and age (Brier score 7.94) and the best model to predict excessive response included AFC and cycle length (Brier score 15.82). Charts were developed to identify risks of low and excessive ovarian response. They can be used for evidence-based risk assessment before ovarian stimulation and may assist clinicians in individual dosage of their patients.

Bystander cardiopulmonary resuscitation and survival in patients with out-of-hospital cardiac arrest of non-cardiac origin.

BACKGROUND: Knowledge about the effect of bystander cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OHCA) of non-cardiac origin is lacking. We aimed to investigate the association between bystander CPR and survival in OHCA of presumed non-cardiac origin. METHODS: From the Danish Cardiac Arrest Registry and through linkage with national Danish healthcare registries we identified all patients with OHCA of presumed non-cardiac origin in Denmark (2001-2014). These were categorized further into OHCA of medical and non-medical cause. We analyzed temporal trends in bystander CPR and 30-day survival during the study period. Multiple logistic regression was used to examine the association between bystander CPR and 30-day survival and reported as standardized 30-day survival chances with versus without bystander CPR standardized to the prehospital OHCA-factors and patient characteristics of all patients in the study population. RESULTS: We identified 10,761 OHCAs of presumed non-cardiac origin. Bystander CPR was associated with a significantly higher 30-day survival chance of 3.4% (95% confidence interval [CI]: 2.9-3.9) versus 1.8% (95% CI: 1.4-2.2) without bystander CPR. A similar association was found in subgroups of both medical and non-medical OHCA. During the study period, the overall bystander CPR rates increased from 13.6% (95% CI: 11.2-16.5) to 62.7% (95% CI: 60.2-65.2). 30-day survival increased overall from 1.3% (95% CI: 0.7-2.6) to 4.0% (95% CI: 3.1-5.2). CONCLUSION: Bystander CPR was associated with a higher chance of 30-day survival among OHCA of presumed non-cardiac origin regardless of the underlying cause (medical/non-medical). Rates of bystander CPR and 30-day survival improved during the study period.

Prediction of survival after surgery due to skeletal metastases in the extremities.

AIMS: The purpose of this study was to develop a prognostic model for predicting survival of patients undergoing surgery owing to metastatic bone disease (MBD) in the appendicular skeleton. METHODS: We included a historical cohort of 130 consecutive patients (mean age 64 years, 30 to 85; 76 females/54 males) who underwent joint arthroplasty surgery (140 procedures) owing to MBD in the appendicular skeleton during the period between January 2003 and December 2008. Primary cancer, pre-operative haemoglobin, fracture versus impending fracture, Karnofsky score, visceral metastases, multiple bony metastases and American Society of Anaesthesiologist's score were included into a series of logistic regression models. The outcome was the survival status at three, six and 12 months respectively. Results were internally validated based on 1000 cross-validations and reported as time-dependent area under the receiver-operating characteristic curves (AUC) for predictions of outcome. RESULTS: The predictive scores obtained showed AUC values of 79.1% (95% confidence intervals (CI) 65.6 to 89.6), 80.9% (95% CI 70.3 to 90.84) and 85.1% (95% CI 73.5 to 93.9) at three, six and 12 months. DISCUSSION: In conclusion, we have presented and internally validated a model for predicting survival after surgery owing to MBD in the appendicular skeleton. The model is the first, to our knowledge, built solely on material from patients who only had surgery in the appendicular skeleton. TAKE HOME MESSAGE: Applying this prognostic model will help determine whether the patients' anticipated survival makes it reasonable to subject them to extensive reconstructive surgery for which there may be an extended period of rehabilitation. Cite this article: Bone Joint J 2016;98-B:271-7.

Long-term survival after allogeneic haematopoietic cell transplantation for AML in remission: single-centre results after TBI-based myeloablative and non-myeloablative conditioning.

We report the results of non-myeloablative (NM) and myeloablative (MA) conditioning for haematopoietic cell transplantation in 207 consecutive AML patients at a single institution. A total of 122 patients were transplanted in first CR (CR1) and 67 in second CR (CR2). MA conditioning was given to 60 patients in CR1 and 50 in CR2. NM conditioning was given to 62 patients in CR1 and 17 patients in CR2. MA patients in CR1 experienced more acute GVHD than NM patients, 60.5% versus 22.9%, but the 5-year post transplant cumulative TRM was not different. Relapse incidence at 5 years in CR1 patients was 23.7% which is not statistically different from 28.5% in NM patients. Leukaemia-free survival at 5 years in CR1 patients was 57.7% after MA conditioning and 58.3% after NM conditioning. No statistical difference in overall 5-year survival after MA or NM conditioning was observed in CR1 patients (63.9 versus 64%) and CR2 patients (51.2 versus 64.7%). Durable remission can be obtained in older patients with AML in remission after NM conditioning, which may also be applicable to younger patients.