Use of asthma medication during pregnancy and risk of specific congenital anomalies: A European case-malformed control study

Background. Pregnant women with asthma need to take medication during pregnancy. Objective. We sought to identify whether there is an increased risk of specific congenital anomalies after exposure to antiasthma medication in the first trimester of pregnancy. Methods. We performed a population-based case-malformed control study testing signals identified in a literature review. Odds ratios (ORs) of exposure to the main groups of asthma medication were calculated for each of the 10 signal anomalies compared with registrations with nonchromosomal, nonsignal anomalies as control registrations. In addition, exploratory analyses were done for each nonsignal anomaly. The data set included 76,249 registrations of congenital anomalies from 13 EUROmediCAT registries. Results. Cleft palate (OR, 1.63; 95% CI, 1.05-2.52) and gastroschisis (OR, 1.89; 95% CI, 1.12-3.20) had significantly increased odds of exposure to first-trimester use of inhaled β2-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled β2-agonists were found for spina bifida, cleft lip, anal atresia, severe congenital heart defects in general, or tetralogy of Fallot. None of the 4 literature signals of exposure to inhaled steroids were confirmed (cleft palate, cleft lip, anal atresia, and hypospadias). Exploratory analyses found an association between renal dysplasia and exposure to the combination of long-acting β2-agonists and inhaled corticosteroids (OR, 3.95; 95% CI, 1.99-7.85). Conclusions. The study confirmed increased odds of first-trimester exposure to inhaled β2-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting β2-agonists and inhaled corticosteroids. Use of inhaled corticosteroids during the first trimester of pregnancy seems to be safe in relation to the risk for a range of specific major congenital anomalies.publishedVersio

EUROlinkCAT: A linked European cohort of children with congenital anomalies

Objective To establish a linked European cohort of children with congenital anomalies (CAs) to evaluate mortality and morbidity outcomes of these children up to the age of 10 years. Method EUROlinkCAT supported 22 EUROCAT population-based congenital anomaly registries in 14 countries to link their data on children with CAs to mortality, vital statistics, hospital discharge and prescription databases. All live births with a CA born 1995-2014 recorded in the registries were followed up to age 10 years or to 31st December 2015. Each registry transformed their local mortality and morbidity data to a Common Data Model (CDM) and ran centrally created syntax scripts and produced tables/outputs in a standard form for meta-analysis. Analyses were performed on 100 different congenital anomaly subgroups for children <1 year,1-4 years, and 5-9 years. Results Sixteen registries linked their data on children with CAs to mortality databases, eleven to regional/national hospital databases, and six to prescription databases. Data on children without a CA born during the same time-period and from the same population area (reference population) were available for seven registries linking to hospital databases and for all six registries linking to prescription databases. For the mortality studies, linked information on survival was available for 96% of children recorded in the anomaly registries (180,00 live births). For the morbidity studies, 89% of children with a CA (n=99,000) and 95% of reference children (n=2 million) were linked. For the prescription studies, 95% of children with a CA (n=60,000) and 95% of reference children (n= 1,700,000) were linked. Conclusion The EUROlinkCAT project was successful in creating a linked cohort of children with and without CAs in Western Europe. More efforts are needed to support data linkage in Eastern European countries. We have developed a set of recommendations for data linkage studies based on our experiences in establishing this cohort

European Monitoring of Congenital Anomalies: JRC-EUROCAT Report on Statistical Monitoring of Congenital Anomalies (2006 – 2015)

Worldwide, congenital anomalies are a leading cause of fetal death, infant mortality and morbidity in childhood. Of the 5.2 million births in the European Union (EU) each year, approximately 104,000 (2.5%) will be born with congenital anomalies. EUROCAT is a European network of population-based registries whose objectives are to provide essential epidemiologic information on congenital anomalies in Europe, to facilitate the early warning of new teratogenic exposures and to evaluate the effectiveness of primary prevention. Each year, EUROCAT performs statistical monitoring for both trends and clusters in time on 82 anomaly subgroups. Statistical monitoring relates to two of EUROCAT’s objectives: to provide essential epidemiologic information on congenital anomalies in Europe and to co-ordinate the detection of, and response to, clusters and early warning of teratogenic exposures. The results of the statistical monitoring are the basis for possible further investigations at the local registry level. In 2015 the Central Registry of EUROCAT was transferred from the University of Ulster to the JRC, and became part of the European Platform on Rare Diseases Registration. This is the first time the statistical monitoring has been performed by the JRC-EUROCAT Central registry. We report here the results of the monitoring performed on data for the birth years 2006-2015. Cases of congenital anomaly among livebirths, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly (TOPFA) at any gestation were included. We report both the statistical results and, where available, the outcome of preliminary investigations conducted by registries. For each anomaly, the trends in prevalence in each registry are shown and in addition the overall pan-European prevalence by single year of birth. Some congenital anomalies take a while to be reported; therefore the prevalence in the latest data is often underreported. Presenting the overall pan-European prevalence by single year allows for the influence of the most recent data (2015) to be evaluated.JRC.F.1-Health in Societ

Risk factors for admission and length of stay in hospital for children with and without congenital anomalies: A EUROlinkCAT study

Objective To explore risk factors for hospital admission, and length of stay (LOS) in hospital, among children with congenital anomalies (CAs) and reference children without CAs in Europe. Method A European population-based data-linkage cohort study was conducted including children with CAs (born 1995-2014) registered in seven EUROCAT CA registries and children without CAs (reference children) living in the same geographical areas. Data on hospitalisation and LOS (1995-2015) for all children aged <1 year and 1-4 years were obtained by linkage to hospital discharge databases. The effects of birth cohort, sex, gestational age, maternal age, multiple birth and socioeconomic status on risk of admission and LOS were estimated using Cox’s Proportional Hazards and negative binomial regression models. Random effects meta-analysis and quantile estimation methods were used to pool the estimates. Results A total of 79,036 children with CAs and 2,016,042 reference children were linked to hospital records. Children with CAs born pre-term (<32 weeks) were more than twice as likely to be admitted (adj. HR 2.35, 95% CI 1.45-3.80) and had almost 8 times longer stays (adj. IRR 7.95, 95% CI 6.12-10.33) compared to children with CAs born at term. Reference children were almost six times as likely to be admitted (adj. HR 5.87, 95% CI 3.10-11.09), and had almost 50 times longer stays (adj. IRR 49.49, 30.92-79.21) compared to reference children born at term. Children with CAs and reference children born preterm were also at increased risk of admission at 1-4 years of age, although the effect was less than for children aged <1 year. Conclusion The impact of risk factors for admission to hospital and LOS were similar between children with CAs and reference children but the impact was often greater in reference children. This study highlights the value of linking to hospital discharge records to obtain population-based information on morbidity for counselling parents

The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs:A Literature Review

BACKGROUND: More information is needed about possible associations between the newer anti-epileptic drugs (AEDs) in the first trimester of pregnancy and specific congenital anomalies of the fetus. OBJECTIVES: We performed a literature review to find signals for potential associations between newer AEDs (lamotrigine, topiramate, levetiracetam, gabapentin, oxcarbazepine, eslicarbazepine, felbamate, lacosamide, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, vigabatrin, and zonisamide) and specific congenital anomalies. METHODS: We searched PubMed and EMBASE to find observational studies with pregnancies exposed to newer AEDs and detailed information on congenital anomalies. The congenital anomalies in the studies were classified according to the congenital anomaly subgroups of European Surveillance of Congenital Anomalies (EUROCAT). We compared the prevalence of specific congenital anomalies in fetuses exposed to individual AEDs in the combined studies with that of the general population in a reference database. A significantly higher prevalence based on three or more fetuses with anomalies was considered a signal. RESULTS: Topiramate showed a higher rate of congenital anomalies than the other newer AEDs. Four signals were found. The signals for associations between topiramate and cleft lip with/without cleft palate and hypospadias were considered strong. Associations between lamotrigine and anencephaly and transposition of great vessels were found within one study and were not supported by other studies. No signals were found for the other newer AEDs, or the information was too limited to provide such a signal. CONCLUSION: In terms of associations between monotherapy with a newer AED in the first trimester of pregnancy and a specific congenital anomaly, the signals for topiramate and cleft lip with/without cleft palate and hypospadias should be investigated further

European Monitoring of Congenital Anomalies: JRC-EUROCAT Report on Statistical Monitoring of Congenital Anomalies (2008 - 2017)

Worldwide, congenital anomalies are a leading cause of fetal death, infant mortality and morbidity in childhood. According to the EUROCAT estimates, of the 5.1 million births in the European Union (EU) each year approximately 127,000 (2.5%) have a congenital anomaly. EUROCAT is a European network of population-based registries whose objectives are to provide essential epidemiologic information on congenital anomalies in Europe, to facilitate the early warning of new teratogenic exposures and to evaluate the effectiveness of primary prevention. Each year, EUROCAT performs statistical monitoring for both trends and clusters in time on 84 anomaly subgroups. The results of the statistical monitoring are the basis for instigating possible further investigations at the local registry level. The present report shows the results of the monitoring performed on data for the birth years 2008-2017 by the JRC-EUROCAT Central Registry. Cases of congenital anomaly among livebirths, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly following prenatal diagnosis at any gestational age were included. We report both the statistical results and, where available, the outcome of the preliminary investigations conducted by registries.JRC.F.1-Health in Societ

Insulin analogues in pregnancy and specific congenital anomalies:a literature review

BACKGROUND: Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin.METHODS: We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analyzed to compare the congenital anomaly rate among fetuses of mothers using insulin analogues with fetuses of mothers using human insulin.RESULTS: Of 29 studies we included 1286 fetuses of mothers using short-acting insulin analogues with 1089 references of mothers using human insulin and 768 fetuses of mothers using long-acting insulin analogues with 685 references of mothers using long-acting human insulin (Neutral Protamine Hagedorn; NPH). The congenital anomaly rate was 4.84% and 4.29% among the fetuses of mothers using lispro and aspart. For glargine and detemir the congenital anomaly rate was 2.86% and 3.47% respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among fetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared to those exposed to human insulin or NPH insulin.CONCLUSION: The total prevalence of congenital anomalies was not increased for fetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies. This article is protected by copyright. All rights reserved.</p

Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival

Abstract Objective To describe the epidemiology of chromosomal and non-chromosomal cases of atrioventricular septal defects in Europe. Methods Data were obtained from EUROCAT, a European network of population-based registries collecting data on congenital anomalies. Data from 13 registries for the period 2000-2008 were included. Results There was a total of 993 cases of atrioventricular septal defects, with a total prevalence of 5.3 per 10,000 births (95% confidence interval 4.1 to 6.5). Of the total cases, 250 were isolated cardiac lesions, 583 were chromosomal cases, 79 had multiple anomalies, 58 had heterotaxia sequence, and 23 had a monogenic syndrome. The total prevalence of chromosomal cases was 3.1 per 10,000 (95% confidence interval 1.9 to 4.3), with a large variation between registers. Of the 993 cases, 639 cases were live births, 45 were stillbirths, and 309 were terminations of pregnancy owing to foetal anomaly. Among the groups, additional associated cardiac anomalies were most frequent in heterotaxia cases (38%) and least frequent in chromosomal cases (8%). Coarctation of the aorta was the most common associated cardiac defect. The 1-week survival rate for live births was 94%. Conclusion Of all cases, three-quarters were associated with other anomalies, both chromosomal and non-chromosomal. For infants with atrioventricular septal defects and no chromosomal anomalies, cardiac defects were often more complex compared with infants with atrioventricular septal defects and a chromosomal anomaly. Clinical outcomes for atrioventricular septal defects varied between regions. The proportion of termination of pregnancy for foetal anomaly was higher for cases with multiple anomalies, chromosomal anomalies, and heterotaxia sequenc

Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.

OBJECTIVE: To identify specific major congenital malformations associated with use of carbamazepine in the first trimester of pregnancy. DESIGN: A review of all published cohort studies to identify key indications and a population based case-control study to test these indications. SETTING: Review of PubMed, Web of Science, and Embase for papers about carbamazepine exposure in the first trimester of pregnancy and specific malformations, and the EUROCAT Antiepileptic Study Database, including data from 19 European population based congenital anomaly registries, 1995-2005. PARTICIPANTS: The literature review covered eight cohort studies of 2680 pregnancies with carbamazepine monotherapy exposure, and the EUROCAT dataset included 98 075 registrations of malformations covering over 3.8 million births. MAIN OUTCOME MEASURES: Overall prevalence for a major congenital malformation after exposure to carbamazepine monotherapy in the first trimester. Odds ratios for malformations with exposure to carbamazepine among cases (five types of malformation identified in the literature review) compared with two groups of controls: other non-chromosomal registrations of malformations and chromosomal syndromes. RESULTS: The literature review yielded an overall prevalence for a major congenital malformation of 3.3% (95% confidence interval 2.7 to 4.2) after exposure to carbamazepine monotherapy in the first trimester. In 131 registrations of malformations, the fetus had been exposed to carbamazepine monotherapy. Spina bifida was the only specific major congenital malformation significantly associated with exposure to carbamazepine monotherapy (odds ratio 2.6 (95% confidence interval 1.2 to 5.3) compared with no antiepileptic drug), but the risk was smaller for carbamazepine than for valproic acid (0.2, 0.1 to 0.6). There was no evidence for an association with total anomalous pulmonary venous return (no cases with carbamazepine exposure), cleft lip (with or without palate) (0.2, 0.0 to 1.3), diaphragmatic hernia (0.9, 0.1 to 6.6), or hypospadias (0.7, 0.3 to 1.6) compared with no exposure to antiepileptic drugs. Further exploratory analysis suggested a higher risk of single ventricle and atrioventricular septal defect. CONCLUSION: Carbamazepine teratogenicity is relatively specific to spina bifida, though the risk is less than with valproic acid. Despite the large dataset, there was not enough power to detect moderate risks for some rare major congenital malformations

Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy - a cohort linkage study

OBJECTIVE: To examine the effect of maternal exposure to asthma medications on the risk of congenital anomalies. DESIGN: Meta‐analysis of aggregated data from three cohort studies. SETTING: Linkage between healthcare databases and EUROCAT congenital anomaly registries. POPULATION: 519 242 pregnancies in Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010). METHODS: Exposure defined as having at least one prescription for asthma medications issued (Wales) or dispensed (Norway, Denmark) from 91 days before to 91 days after the pregnancy start date. Odds ratios (ORs) were estimated separately for each register and combined in meta‐analyses. MAIN OUTCOME MEASURES: ORs for all congenital anomalies and specific congenital anomalies. RESULTS: Overall exposure prevalence was 3.76%. For exposure to asthma medication in general, the adjusted OR (adjOR) for a major congenital anomaly was 1.21 (99% CI 1.09–1.34) after adjustment for maternal age and socioeconomic position. The OR of anal atresia was significantly increased in pregnancies exposed to inhaled corticosteroids (3.40; 99% CI 1.15–10.04). For severe congenital heart defects, an increased OR (1.97; 1.12–3.49) was associated with exposure to combination treatment with inhaled corticosteroids and long‐acting beta‐2‐agonists. Associations with renal dysplasia were driven by exposure to short‐acting beta‐2‐agonists (2.37; 1.20–4.67). CONCLUSION: The increased risk of congenital anomalies for women taking asthma medication is small with little confounding by maternal age or socioeconomic status. The study confirmed the association of inhaled corticosteroids with anal atresia found in earlier research and found potential new associations with combination treatment. The potential new associations should be interpreted with caution due to the large number of comparisons undertaken. TWEETABLE ABSTRACT: This cohort study found a small increased risk of congenital anomalies for women taking asthma medication