Early pregnancy exposure to antihistamines and risk of congenital heart defects: results of two case-control studies.

UNLABELLED: We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring. DESIGN: Two case-control studies. SETTING: HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis. MAIN OUTCOME MEASURES: Odds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.

Antibiotics prescribed before, during and after pregnancy in the Netherlands: a drug utilization study.

PURPOSE: To describe the prescription of antibiotics before, during and after pregnancy, and the trends over a 16-year period in the Netherlands, and to determine whether they were prescribed according to national guidelines. METHODS: The IADB (http://iadb.nl) contains prescriptions dispensed by community pharmacies in the Netherlands. We extracted information on 18,873 pregnancies for 14,969 women between 1994 and 2009, focusing on antibiotics dispensed in the four trimesters before conception to two trimesters after birth (nine trimesters in total). We calculated trends in prescription rates during pregnancy and over time, and also compared the prescription of antibiotics in the Netherlands with safety category based on the Australian Drug Evaluation Committee. RESULTS: During pregnancy 20.8% of the women were prescribed at least one antibiotic. The 'beta-lactam antibacterials/penicillins' group and the specific antibiotic amoxicillin were most commonly prescribed in the nine trimesters covered. The prescription rate of the 'other antibacterials' group during pregnancy increased over the years, in contrast to that of the 'sulphonamides/trimethoprim' group, which decreased. In total, 2.0% of pregnancies were exposed to a 'potentially harmful' antibiotic and 0.8% to a 'harmful' antibiotic. Compared with the period before conception, 'safe' antibiotics were prescribed more often during pregnancy than the other groups. CONCLUSIONS: One in five women was prescribed at least one antibiotic during pregnancy in the Netherlands, which is comparable with rates in other European countries. Our results suggest that antibiotics appear to be prescribed to pregnant women generally in accordance with national recommendations.

Frailty as a Predictor of Mortality in Late-Life Depression: A Prospective Clinical Cohort Study.

OBJECTIVE: Frailty is a clinical phenotype that predicts negative health outcomes, including mortality, and is increasingly used for risk stratification in geriatric medicine. Similar to frailty, late-life depression is also associated with increased mortality rates. Therefore, we examined whether frailty and frailty-related biomarkers predict mortality among depressed older patients. METHODS: In our study of 378 older patients aged ≥ 60 years with a depressive disorder (DSM-IV criteria), we examined whether frailty predicts time-to-death during a 6-year follow-up using Cox proportional hazard regression analyses adjusted for confounders. Baseline data were collected from 2007 to September 2010. Frailty was defined according to the Fried Frailty Phenotype criteria (muscle weakness, slowness, exhaustion, low activity level, unintended weight loss). Similarly, we examined the predictive value of 3 inflammatory markers, vitamin D level, and leukocyte telomere length and whether these effects were independent of the frailty phenotype. RESULTS: During follow-up, 27 (26.2%) of 103 frail depressed patients died compared with 35 (12.7%) of 275 non-frail depressed patients (P < .001). Adjusted for confounders, the number of frailty components was associated with an increased mortality rate (hazard ratio = 1.38 [95% CI, 1.06-1.78], P = .015). All biomarkers except for interleukin 6 were prospectively associated with mortality, but only higher levels of high-sensitivity C-reactive protein and lower levels of vitamin D were independent of frailty associated with mortality. CONCLUSIONS: In late-life depression, frailty identifies older patients at increased risk of adverse negative health outcomes. Therefore, among frail depressed patients, treatment models that include frailty-specific interventions might reduce mortality rates.

Frailty and Somatic Comorbidity in Older Patients With Medically Unexplained Symptoms.

OBJECTIVES: To examine the level of frailty and somatic comorbidity in older patients with medically unexplained symptoms (MUS) and compare this to patients with medically explained symptoms (MES). DESIGN: Cross-sectional, comparative study. SETTING: Community, primary care, and secondary healthcare to recruit patients with MUS in various developmental and severity stages and primary care to recruit patients with MES. PARTICIPANTS: In total, 118 patients with MUS and 154 patients with MES, all aged ≥60 years. METHODS: Frailty was assessed according to the Fried criteria (gait speed, handgrip strength, unintentional weight loss, exhaustion, and low physical activity), somatic comorbidity according to the self-report Charlson comorbidity index, and the number of prescribed medications. RESULTS: Although patients with MUS had less physical comorbidity compared with patients with MES, they were prescribed the same number of medications. Moreover, patients with MUS were more often frail compared with patients with MES. Among patients with MUS, physical frailty was associated with the severity of unexplained symptoms, the level of hypochondriacal beliefs, and the level of somatisation. CONCLUSIONS AND IMPLICATIONS: Despite a lower prevalence of overt somatic diseases, patients with MUS are more frail compared with older patients with MES. These results suggest that at least in some patients age-related phenomena might be erroneously classified as MUS, which may affect treatment strategy.

Leucocyte telomere length is no molecular marker of physical frailty in late-life depression.

BACKGROUND: Although average life-expectancy is still increasing worldwide, ageing processes markedly differ between individuals, which has stimulated the search for biomarkers of biological ageing. OBJECTIVES: Firstly, to explore the cross-sectional and longitudinal association between leucocyte telomere length (LTL) as molecular marker of ageing and the physical frailty phenotype (PFP) as a clinical marker of ageing and secondly, to examine whether these associations are moderated by the presence of a depressive disorder, as depression can be considered a condition of accelerated ageing. METHODS: Among 378 depressed older patients (according to DSM-IV criteria) and 132 non-depressed older persons participating in the Netherlands Study of Depression in Older persons, we have assessed the physical frailty phenotype and LTL. The PFP was defined according to Fried's criteria and its components were reassessed at two-year follow-up. RESULTS: LTL was neither associated with the PFP at baseline by Spearman rank correlation tests, nor did it predict change in frailty parameters over a two-year follow-up using regression analyses adjusted for potential confounders. CONCLUSION: LTL is not associated with frailty; neither in non-depressed nor in depressed older persons. As LTL and physical frailty appear to represent different aspects of ageing, they may complement each other in future studies.

Actual Use of Medications Prescribed During Pregnancy: A Cross-Sectional Study Using Data from a Population-Based Congenital Anomaly Registry.

INTRODUCTION AND AIM: Data from prescription databases are increasingly being used to study associations between maternal medications used in pregnancy and congenital anomalies. We therefore investigated the extent to which prescriptions reflect the actual use of medication during pregnancy, and whether medicines used during pregnancy are taken according to the prescribed dosage and duration. METHODS: We performed a cross-sectional study in a population-based congenital anomaly register (EUROCAT Northern Netherlands). We included 202 women who had at least one prescription during their pregnancy and who gave birth between 2009 and 2011. Compliance with the prescribed medication was verified by telephone interview. We calculated the compliance rates for several medication groups by dividing the number of mothers who confirmed they had taken the medication by the total number to whom it had been prescribed. Compliance was positive if the mother confirmed she took the medication, even if she only took one of several prescriptions from the same medication group. For each prescription taken, we also determined whether her use conformed to the prescribed dosage and duration. RESULTS: During the first trimester, the compliance rates ranged from 0.84 (for chronic diseases) to 0.92 (for pregnancy-related symptoms). Most of the medications actually taken were used at the prescribed dosage or lower. More than half of the medications actually taken were used for the duration prescribed or shorter. CONCLUSION: Prescription records are generally a relatively reliable source of data for research into associations between medication use in pregnancy and congenital anomalies compared with other data sources. Pharmacy records of medication use in pregnancy might represent an overestimation, which should be taken into account. However, our results show that, except for 'corticosteroids, dermatological preparations'; 'ear, eye, nose and throat preparations'; and 'anxiolytics, hypnotics and sedatives', this overestimation generally seems minimal.

Improving Information on Maternal Medication Use by Linking Prescription Data to Congenital Anomaly Registers: A EUROmediCAT Study.

INTRODUCTION: Research on associations between medication use during pregnancy and congenital anomalies is significative for assessing the safe use of a medicine in pregnancy. Congenital anomaly (CA) registries do not have optimal information on medicine exposure, in contrast to prescription databases. Linkage of prescription databases to the CA registries is a potentially effective method of obtaining accurate information on medicine use in pregnancies and the risk of congenital anomalies. METHODS: We linked data from primary care and prescription databases to five European Surveillance of Congenital Anomalies (EUROCAT) CA registries. The linkage was evaluated by looking at linkage rate, characteristics of linked and non-linked cases, first trimester exposure rates for six groups of medicines according to the prescription data and information on medication use registered in the CA databases, and agreement of exposure. RESULTS: Of the 52,619 cases registered in the CA databases, 26,552 could be linked. The linkage rate varied between registries over time and by type of birth. The first trimester exposure rates and the agreements between the databases varied for the different medicine groups. Information on anti-epileptic drugs and insulins and analogue medicine use recorded by CA registries was of good quality. For selective serotonin reuptake inhibitors, anti-asthmatics, antibacterials for systemic use, and gonadotropins and other ovulation stimulants, the recorded information was less complete. CONCLUSION: Linkage of primary care or prescription databases to CA registries improved the quality of information on maternal use of medicines in pregnancy, especially for medicine groups that are less fully registered in CA registries.

Identifying associations between maternal medication use and birth defects using a case-population approach: an exploratory study on signal detection.

BACKGROUND: The effects of many drugs on the unborn child are unknown. In a case-population design, drug exposure of cases is compared with that of a source population; this kind of study can be useful for generating signals. OBJECTIVE: To see whether a comparison of drug use rates from the birth defect registry EUROCAT NNL (cases) with prescription rates from a population-based prescription database, the IADB (population), could be used to detect signals of teratogenic risk of drugs. METHODS: We defined 3,212 cases from the EUROCAT NNL database, a population-based birth defect registry in the Northern Netherlands and 29,223 population controls from the IADB, a prescription database with data from community pharmacies in the same geographical area, born between 1998 and 2008. We classified the malformations of the 3,212 cases into several malformation groups according to organ system (based on the International Classification of Diseases codes and the EUROCAT guidelines). If a child had multiple malformations in several organ systems (n = 253, 7.9 %), he/she was counted in all the categories represented. For several groups of malformations we calculated rate ratios (RR) and 95 % confidence intervals for drugs acting on the central nervous system and for drugs considered to be safe for use in pregnancy. The RRs were based on first-trimester drug use rates from the cases in the EUROCAT NNL database and prescription rates from the population controls in the IADB. RESULTS: For drugs acting on the central nervous system we found significantly increased RRs for the anti-epileptic drug valproic acid and for some selective serotonin reuptake inhibitors. For drugs considered to be safe only the anti-hypertensive methyldopa showed significantly increased RRs. CONCLUSION: We show that a case-population study is a suitable method for detecting signals of possible teratogenicity, provided that the teratogenic effects and the drugs under study are as specific as possible and the drugs are widely used.