Jon Trærup Andersen

Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study

Objectives To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart. Design Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. Setting Denmark. Participants Pregnant women in Denmark between 1997 and 2009 and their offspring. Primary outcome measures For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy. Results The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage. Conclusions The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case.

Urinary Markers of Nucleic Acid Oxidation and Long-Term Mortality of Newly Diagnosed Type 2 Diabetic Patients

OBJECTIVE We analyzed data from a cohort of 1,381 newly diagnosed type 2 diabetic patients to test the hypothesis that urinary markers of nucleic acid oxidation are independent predictors of mortality. RESEARCH DESIGN AND METHODS We examined the relationship between urinary excretion of markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine [8-oxodG]) and RNA oxidation (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and long-term mortality using Cox proportional hazards regression. RESULTS After multivariate adjustment, the hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.44 (1.12–1.85) and 1.54 (1.13–2.10), respectively. Conversely, no significant associations between 8-oxodG and mortality were found in the adjusted analyses. CONCLUSIONS Urinary excretion of the RNA oxidation marker 8-oxoGuo measured shortly after diagnosis of type 2 diabetes predicts long-term mortality independently of conventional risk factors. This finding suggests that 8-oxoGuo could serve as a new clinical biomarker in diabetes.

Association between alcohol and substance use disorders and all-cause and cause-specific mortality in schizophrenia, bipolar disorder, and unipolar depression: a nationwide, prospective, register-based study

BACKGROUND People with severe mental illness have both increased mortality and are more likely to have a substance use disorder. We assessed the association between mortality and lifetime substance use disorder in patients with schizophrenia, bipolar disorder, or unipolar depression. METHODS In this prospective, register-based cohort study, we obtained data for all people with schizophrenia, bipolar disorder, or unipolar depression born in Denmark in 1955 or later from linked nationwide registers. We obtained information about treatment for substance use disorders (categorised into treatment for alcohol, cannabis, or hard drug misuse), date of death, primary cause of death, and education level. We calculated hazard ratios (HRs) for all-cause mortality and subhazard ratios (SHRs) for cause-specific mortality associated with substance use disorder of alcohol, cannabis, or hard drugs. We calculated standardised mortality ratios (SMRs) to compare the mortality in the study populations to that of the background population. FINDINGS Our population included 41 470 people with schizophrenia, 11 739 people with bipolar disorder, and 88 270 people with depression. In schizophrenia, the SMR in those with lifetime substance use disorder was 8·46 (95% CI 8·14-8·79), compared with 3·63 (3·42-3·83) in those without. The respective SMRs in bipolar disorder were 6·47 (5·87-7·06) and 2·93 (2·56-3·29), and in depression were 6·08 (5·82-6·34) and 1·93 (1·82-2·05). In schizophrenia, all substance use disorders were significantly associated with increased risk of all-cause mortality, both individually (alcohol, HR 1·52 [95% CI 1·40-1·65], p<0·0001; cannabis, 1·24 [1·04-1·48], p=0·0174; hard drugs, 1·78 [1·56-2·04], p<0·0001) and when combined. In bipolar disorder or depression, only substance use disorders of alcohol (bipolar disorder, HR 1·52 [95% CI 1·27-1·81], p<0·0001; depression, 2·01 [1·86-2·18], p<0·0001) or hard drugs (bipolar disorder, 1·89 [1·34-2·66], p=0·0003; depression, 2·27 [1·98-2·60], p<0·0001) increased risk of all-cause mortality individually. INTERPRETATION Mortality in people with mental illness is far higher in individuals with substance use disorders than in those without, particularly in people who misuse alcohol and hard drugs. Mortality-reducing interventions should focus on patients with a dual diagnosis and seek to prevent or treat substance use disorders. FUNDING The Lundbeck Foundation.

Prevalence of Antidepressant Use during Pregnancy in Denmark, a Nation-Wide Cohort Study

Aim The aim of this study was to assess the prevalence and patterns of exposure to antidepressants before, during and after pregnancy in a cohort including all pregnant women in Denmark between 1997 and 2010. Methods We performed a retrospective cohort study including 912 322 pregnancies. Information was retrieved from the Danish Birth Registry and The Register of Medicinal Product Statistics to identify women redeeming an antidepressant prescription during pregnancy. Exposure periods were based on standard treatment doses and dispensed pack sizes. Results We identified 19 740 pregnancies exposed to an antidepressant at some point during pregnancy. The rate of exposure increased from 0.2% in 1997 to 3.2% in 2010. We found that the rate of exposure was halved during the first 3 months of pregnancy. In contrast, we describe a clear increase in exposure after pregnancy among pre-delivery treatment-naïve women. Conclusions In spite of uncertainty concerning antidepressants’ safety during pregnancy we find a 16-fold increase in exposure rates between 1997 and 2010. The rates describe a sharp decrease in exposure during pregnancy that is probably caused by physicians’ hesitation to prescribe antidepressants and women’s fear of unwanted effects on the unborn child. More studies are needed to clarify the consequences of antidepressant discontinuation during pregnancy.

Combinations of Polymorphisms in Genes Involved in the 5-Fluorouracil Metabolism Pathway Are Associated with Gastrointestinal Toxicity in Chemotherapy-Treated Colorectal Cancer Patients

Purpose: The purpose of this study was to investigate whether specific combinations of polymorphisms in genes encoding proteins involved in 5-fluorouracil (5-FU) pharmacokinetics and pharmacodynamics are associated with increased risk of treatment-induced toxicity. Experimental Design: We analyzed two cohorts of 161 and 340 patients, the exploration and validation cohort, respectively. All patients were treated similarly with 5-FU–based adjuvant chemotherapy. We analyzed 13 functional polymorphisms and applied a four-fold analysis strategy using individual polymorphisms, haplotypes, and phenotypic enzyme activity or expression classifications based on combinations of functional polymorphisms in specific genes. Furthermore, multifactor dimensionality reduction analysis was used to identify a genetic interaction profile indicating an increased risk of toxicity. Results: Alleles associated with low activity of methylene tetrahydrofolate reductase (MTHFR) were associated with decreased risk of toxicity [ORExploration 0.39 (95% CI: 0.21–0.71, P = 0.003), ORValidation 0.63 (95% CI: 0.41–0.95, P = 0.03)]. A specific combination of the MTHFR 1298A>C and thymidylate synthase (TYMS) 3′-UTR (untranslated region) ins/del polymorphisms was significantly associated with increased toxicity in both cohorts [ORExploration 2.40 (95% CI: 1.33–4.29, P = 0.003), ORValidation 1.81 (95% CI: 1.18–2.79, P = 0.007)]. The specific combination was also associated with increased cumulative incidence and earlier occurrence of severe toxicity during treatment. Conclusions: Our results indicate that MTHFR activity and a specific combination of the MTHFR 1298A>C and TYMS 3′-UTR ins/del polymorphisms are possible predictors of 5-FU treatment–related toxicity. Clin Cancer Res; 17(11); 3822–9. ©2011 AACR.

Association between urinary markers of nucleic acid oxidation and mortality in type 2 diabetes: a population-based cohort study.

OBJECTIVE We recently showed that RNA oxidation, estimated by urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo), independently predicted mortality in a cohort of 1,381 treatment-naive patients with newly diagnosed type 2 diabetes. In the present investigation, we analyzed urine collected 6 years after the diagnosis to assess the association between urinary markers of nucleic acid oxidation and mortality in patients with established and treated diabetes. RESEARCH DESIGN AND METHODS We used data from the 970 patients who attended the screening for diabetes complications 6 years after the diagnosis. Cox proportional hazards regression was used to examine the relationship between urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2′-deoxyguanosine [8-oxodG] [n = 938]) and RNA oxidation (8-oxoGuo [n = 936]) and mortality. RESULTS During a median of 9.8 years of follow-up, 654 patients died. Urinary 8-oxoGuo assessed 6 years after the diagnosis was significantly associated with mortality. The multivariate-adjusted hazard ratios for all-cause and diabetes-related mortality of patients with 8-oxoGuo levels in the highest quartile compared with those in the lowest quartile were 1.86 (95% CI 1.34–2.58) and 1.72 (1.11–2.66), respectively. Conversely, 8-oxodG was not associated with mortality. In addition, we found an association between changes in 8-oxoGuo from diagnosis to 6-year follow-up and mortality, with increased risk in patients with an increase and decreased risk in patients with a decrease in 8-oxoGuo. CONCLUSIONS The RNA oxidation marker 8-oxoGuo is an independent predictor of mortality in patients with established and treated type 2 diabetes, and changes in 8-oxoGuo during the first 6 years after diagnosis are associated with mortality.

Exposure to Selective Serotonin Reuptake Inhibitors in Early Pregnancy and the Risk of Miscarriage

OBJECTIVE: To investigate whether exposure to selective serotonin reuptake inhibitors (SSRIs) in early pregnancy is associated with miscarriage. METHODS: This was a nationwide cohort study identifying all registered pregnancies in Denmark from 1997 to 2010. All births were identified using the Medical Birth Registry, and all records of induced abortion or miscarriage were gathered from the National Hospital Register. Data on SSRI use were gathered from the National Prescription Register. Cox proportional hazard regression models were used to calculate the hazard of miscarriage in women exposed to an SSRI in early pregnancy and the hazard of miscarriage in women discontinuing treatment before pregnancy. RESULTS: We identified 1,279,840 pregnancies (911,569 births, 142,093 miscarriages, 226,178 induced abortions). Of the 22,884 exposed to an SSRI during the first 35 days of pregnancy, 12.6% (2,883) ended in miscarriage compared with 11.1% among unexposed. The adjusted hazard ratio of having a miscarriage after exposure to an SSRI was 1.27 (95% confidence interval [CI] 1.22–1.33) compared with unexposed. Women discontinuing SSRI treatment 3–12 months before pregnancy also had an increased hazard ratio of having a miscarriage compared to unexposed (1.24, 95% CI 1.18–1.30). CONCLUSION: Women exposed to SSRIs during early pregnancy were at increased risk of miscarriage as were women discontinuing SSRI treatment before pregnancy, and these risks were similar. Therefore, treatment with SSRIs during pregnancy should not be discontinued as a result of fear of miscarriage. LEVEL OF EVIEDENCE: II

Association of beta‐adrenergic receptor polymorphisms and mortality in carvedilol‐treated chronic heart‐failure patients

AIM Pharmacogenetics can be used as a tool for stratified pharmacological therapy in cardiovascular medicine. We investigated whether a predefined combination of the Arg389Gly polymorphism in the adrenergic β(1) -receptor gene (ADRB1) and the Gln27Glu polymorphism in the adrenergic β(2) -receptor gene (ADRB2) could predict survival in carvedilol- and metoprolol-treated chronic heart failure (HF) patients. METHODS Five hundred and eighty-six HF patients (carvedilol n= 82, metoprolol n= 195) were genotyped for ADRB1 Arg389Gly (rs1801253) and ADRB2 Gln27Glu (rs1042714). The end-point was all-cause mortality, and median follow-up time was 6.7 years. Patients were classified into two functional genotype groups: group 1 combination of Arg389-homozygous and Gln27-carrier (46%) and group 2 any other genotype combination (54%). Results were fitted in two multivariate Cox models. RESULTS There was a significant interaction between functional genotype group and carvedilol treatment (adjusted(1) P= 0.033, adjusted(2) P= 0.040). Patients treated with carvedilol had shorter survival in functional genotype group 1 (P= 0.004; adjusted(1) hazard ratio (HR) 2.67, 95% CI 1.27, 5.59, P= 0.010; adjusted(2) HR 2.05, 95% CI 1.06, 3.95, P= 0.033). There was no interaction between genotype group and metoprolol treatment (P= 0.61), and there was no difference in overall survival between genotype groups (P= 0.69). CONCLUSIONS A combination of ADRB1 Arg389-homozygous and ADRB2 Gln27-carrier in HF patients treated with carvedilol was associated with a two-fold increase in mortality relative to all other genotype combinations. There was no difference in survival in metoprolol-treated HF patients between genotype groups. Patients in genotype group 1 may benefit more from metoprolol than carvedilol treatment.

SSRI use during pregnancy and risk of stillbirth and neonatal mortality.

OBJECTIVE The authors investigated whether in utero exposure to selective serotonin reuptake inhibitors (SSRIs) increases the risk of stillbirth or neonatal mortality. METHOD The authors conducted a population-based cohort study using the Danish Fertility Database to identify every birth in Denmark between 1995 and 2008. Time of exposure to SSRIs was calculated on the basis of standard treatment dosages and dispensed pack sizes according to the prescription register. Exposure was divided into first-, second-, and third-trimester exposure. Multivariate logistic regression models were used. RESULTS The authors identified 920,620 births; the incidence of stillbirths was 0.45%, and the incidence of neonatal mortality was 0.34%. A total of 12,425 offspring were exposed to an SSRI during pregnancy. Stillbirth was not associated with first-trimester SSRI use (adjusted odds ratio=0.77, 95% CI=0.43-1.36), first- and second-trimester use (odds ratio=0.84, 95% CI=0.40-1.77), or first-, second-, and third-trimester use (odds ratio=1.06, 95% CI=0.71-1.58). Neonatal mortality was not associated with SSRI first-trimester use (odds ratio=0.56, 95% CI=0.25-1.24), first- and second-trimester use (odds ratio=0.90, 95% CI=0.37-2.17), or first-, second-, and third-trimester use (odds ratio=1.27, 95% CI=0.82-1.99). CONCLUSIONS This study found no association between exposure to SSRIs during pregnancy and stillbirth or neonatal mortality.

Clarithromycin in Early Pregnancy and the Risk of Miscarriage and Malformation: A Register Based Nationwide Cohort Study

Background The antibiotic clarithromycin has been associated with fetal loss in animals and a study has found a doubling in the frequency of miscarriages among women using clarithromycin in pregnancy. The aim of the study was to investigate whether clarithromycin use in early pregnancy was associated with an increased risk for miscarriages and major malformations. Methods We conducted a nationwide cohort study including all women in Denmark with a known conception between 1997 and 2007. The Fertility Database was used to identify all women giving birth and the National Hospital Register was used to identify all women with a record of miscarriage or induced abortion. Prescription data was obtained from the National Prescription Register. The primary outcome was the number of miscarriages and offspring with major congenital malformations among users of clarithromycin compared to non-users. Results We identified 931 504 pregnancies (705 837 live births, 77 553 miscarriages, and 148 114 induced abortions). 401 women redeemed a prescription of clarithromycin in the first trimester of which 40 (10.0%) experienced a miscarriage and among the live born nine (3.6%) had offspring with malformations. The hazard ratio (HR) of having a miscarriage after exposure to clarithromycin was 1.56 (CI95% 1.14–2.13). There was no increased hazard of having a miscarriage when being exposed to penicillin or erythromycin. There was no increased prevalence (OR = 1.03 (CI95% 0.52–2.00)) of having offspring with malformations after exposure to clarithromycin. Conclusions We found an increased hazard of miscarriage but no increased prevalance of having offspring with malformations among women redeeming a prescription of clarithromycin in early pregnancy. This is supported by previous studies in animals and humans. However, further research is required to explore the possible effect of treatment indication on the associations found.