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Introduction: Linking healthcare data sets can create valuable resources for research, particularly when investigating rare exposures or outcomes. However, across Europe, the permissions processes required to access data can be complex. This paper documents the processes required by the EUROlinkCAT study investigators to research the health and survival of children with congenital anomalies in Europe., Methods: Eighteen congenital anomaly registries in 14 countries provided information on all the permissions required to perform surveillance of congenital anomalies and to link their data on live births with available vital statistics and healthcare databases for research. Small number restrictions imposed by data providers were also documented., Results: The permissions requirements varied substantially, with certain registries able to conduct congenital anomaly surveillance as part of national or regional healthcare provision, while others were required to obtain ethics approvals or informed consent. Data linkage and analysis for research purposes added additional layers of complexity for registries, with some required to obtain several permissions, including ethics approvals to link the data. Restrictions relating to small numbers often resulted in a registry's data on specific congenital anomalies being unusable., Conclusion: The permissions required to obtain and link data on children with congenital anomalies varied greatly across Europe. The variation and complexity present a significant obstacle to the use of such data, especially in large data linkage projects. Furthermore, small number restrictions severely limited the research that could be performed for children with specific rare congenital anomalies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: The number of terminations of pregnancy for fetal anomalies in Europe (TOPFA) has increased over recent decades. Therefore, it is important that TOPFAs, in addition to all other birth outcomes, are included in the surveillance of congenital anomalies and in studies on possible teratogenic risks of pregnancy exposures. The aim of this study was to evaluate the quality and the accuracy of codes identifying TOPFA cases in hospital databases., Methods: TOPFA cases recorded in three EUROCAT congenital anomaly registries (Finland, 2010-2014; Funen in Denmark, 2005-2014; and northern Netherlands, 2013-2014) were linked to hospital databases using maternal IDs., Results: A total of 2,114 TOPFA cases over the study period were identified in the registries and 2,096 (99%) of these pregnancies were identified in the hospital databases. An end of pregnancy code was present for 91% of the cases and a code for a congenital anomaly was present for 82% (with some differences across registries). The proportion of TOPFA cases with a code for a specific congenital anomaly was <50% for cases with a structural anomaly (range 0%-50%) and 70% for cases with a chromosomal anomaly., Conclusion: Hospital databases have limited information or codes to identify TOPFAs for specific anomalies and the data are not detailed enough for surveillance of congenital anomalies or for studies analyzing pregnancy exposures and risk of congenital anomalies. However, hospital data may be used to identify the occurrence of a TOPFA to enable more detailed information to be obtained from the medical records., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Introduction: Congenital anomalies (CAs) are a major cause of infant mortality, childhood morbidity and long-term disability. Over 130 000 children born in Europe every year will have a CA. This paper describes the EUROlinkCAT study, which is investigating the health and educational outcomes of children with CAs for the first 10 years of their lives., Methods and Analysis: EUROCAT is a European network of population-based registries for the epidemiological surveillance of CAs. EUROlinkCAT is using the EUROCAT infrastructure to support 22 EUROCAT registries in 14 countries to link their data on births with CAs to mortality, hospital discharge, prescription and educational databases. Once linked, each registry transforms their case data into a common data model (CDM) format and they are then supplied with common STATA syntax scripts to analyse their data. The resulting aggregate tables and analysis results are submitted to a central results repository (CRR) and meta-analyses are performed to summarise the results across all registries. The CRR currently contains data on 155 594 children with a CA followed up to age 10 from a population of 6 million births from 1995 to 2014., Ethics: The CA registries have the required ethics permissions for routine surveillance and transmission of anonymised data to the EUROCAT central database. Each registry is responsible for applying for and obtaining additional ethics and other permissions required for their participation in EUROlinkCAT., Dissemination: The CDM and associated documentation, including linkage and standardisation procedures, will be available post-EUROlinkCAT thus facilitating future local, national and European-level analyses to improve healthcare. Recommendations to improve the accuracy of routinely collected data will be made.Findings will provide evidence to inform parents, health professionals, public health authorities and national treatment guidelines to optimise diagnosis, prevention and treatment for these children with a view to reducing health inequalities in Europe., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Public health organisations use public health indicators to guide health policy. Joint analysis of multiple public health indicators can provide a more comprehensive understanding of what they are intended to evaluate., Objective: To analyse variaitons in the prevalence of congenital anomaly-related perinatal mortality attributable to termination of pregnancy for foetal anomaly (TOPFA) and prenatal diagnosis of congenital anomaly prevalence., Methods: We included 55 363 cases of congenital anomalies notified to 18 EUROCAT registers in 10 countries during 2008-12. Incidence rate ratios (IRR) representing the risk of congenital anomaly-related perinatal mortality according to TOPFA and prenatal diagnosis prevalence were estimated using multilevel Poisson regression with country as a random effect. Between-country variation in congenital anomaly-related perinatal mortality was measured using random effects and compared between the null and adjusted models to estimate the percentage of variation in congenital anomaly-related perinatal mortality accounted for by TOPFA and prenatal diagnosis., Results: The risk of congenital anomaly-related perinatal mortality decreased as TOPFA and prenatal diagnosis prevalence increased (IRR 0.79, 95% confidence interval [CI] 0.72, 0.86; and IRR 0.88, 95% CI 0.79, 0.97). Modelling TOPFA and prenatal diagnosis together, the association between congenital anomaly-related perinatal mortality and TOPFA prevalence became stronger (RR 0.70, 95% CI 0.61, 0.81). The prevalence of TOPFA and prenatal diagnosis accounted for 75.5% and 37.7% of the between-country variation in perinatal mortality, respectively., Conclusion: We demonstrated an approach for analysing inter-linked public health indicators. In this example, as TOPFA and prenatal diagnosis of congenital anomaly prevalence decreased, the risk of congenital anomaly-related perinatal mortality increased. Much of the between-country variation in congenital anomaly-related perinatal mortality was accounted for by TOPFA, with a smaller proportion accounted for by prenatal diagnosis., (© 2020 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Objectives: To evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes., Design and Setting: A population-based cohort of women with pregestational diabetes (n=1661) who delivered between 1996 and 2012 was established retrospectively from seven European regions covered bythe European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries., Primary Outcome Measures: The risk of non-chromosomal major congenital anomaly in live births, fetal deaths and terminations for a fetal anomaly exposed to insulin analogues in the first trimester of pregnancy was compared with the risk in those exposed to human insulin only., Results: During the first trimester, 870 fetuses (52.4%) were exposed to human insulin only, 397 fetuses (23.9%) to insulin analogues only and 394 fetuses (23.7%) to both human insulin and insulin analogues. The risk of major congenital anomaly in fetuses exposed to insulin analogues only was lower than those exposed to human insulin only; the relative risk adjusted for glycaemic control and region was 0.56 (95% CI 0.29 to 1.06). The significantly lower risk related to exposure of insulin analogues only was observed in congenital heart defects: adjusted relative risk 0.14 (95% CI 0.03 to 0.62)., Conclusions: In this retrospective population-based cohort study across Europe, first-trimester exposure to insulin analogues did not increase the risk of major congenital anomaly compared with exposure to human insulin. A possible lower risk of congenital heart defects among fetuses exposed to insulin analogues only deserves further investigation., Competing Interests: Competing interests: EW-O is a member of Polish Novo Nordisk advisory board, she gives lectures and leads workshops organised by Eli Lilly and Novo Nordisk in Poland., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation., Methods: Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity., Results: Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists., Conclusion: Signals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible., (© 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Aims: Information about medication safety in pregnancy is inadequate. We aimed to develop a signal detection methodology to routinely identify unusual associations between medications and congenital anomalies using data collected by 15 European congenital anomaly registries., Methods: EUROmediCAT database data for 14 950 malformed foetuses/babies with first trimester medication exposures in 1995-2011 were analyzed. The odds of a specific medication exposure (coded according to chemical substance or subgroup) for a specific anomaly were compared with the odds of that exposure for all other anomalies for 40 385 medication anomaly combinations in the data. Simes multiple testing procedure with a 50% false discovery rate (FDR) identified associations least likely to be due to chance and those associations with more than two cases with the exposure and the anomaly were selected for further investigation. The methodology was evaluated by considering the detection of well-known teratogens., Results: The most common exposures were genitourinary system medications and sex hormones (35.2%), nervous system medications (28.0%) and anti-infectives for systemic use (25.7%). Fifty-two specific medication anomaly associations were identified. After discarding 10 overlapping and three protective associations, 39 associations were selected for further investigation. These associations included 16 which concerned well established teratogens, valproic acid (2) and maternal diabetes represented by use of insulin (14)., Conclusions: Medication exposure data in the EUROmediCAT central database can be analyzed systematically to determine a manageable set of associations for validation and then testing in independent datasets. Detection of teratogens depends on frequency of exposure, level of risk and teratogenic specificity., (© 2016 The British Pharmacological Society.)

Background: Surveillance of congenital anomalies is important to identify potential teratogens. Despite known associations between different anomalies, current surveillance methods examine trends within each subgroup separately. We aimed to evaluate whether hierarchical statistical methods that combine information from several subgroups simultaneously would enhance current surveillance methods using data collected by EUROCAT, a European network of population-based congenital anomaly registries., Methods: Ten-year trends (2003 to 2012) in 18 EUROCAT registries over 11 countries were analyzed for the following groups of anomalies: neural tube defects, congenital heart defects, digestive system, and chromosomal anomalies. Hierarchical Poisson regression models that combined related subgroups together according to EUROCAT's hierarchy of subgroup coding were applied. Results from hierarchical models were compared with those from Poisson models that consider each congenital anomaly separately., Results: Hierarchical models gave similar results as those obtained when considering each anomaly subgroup in a separate analysis. Hierarchical models that included only around three subgroups showed poor convergence and were generally found to be over-parameterized. Larger sets of anomaly subgroups were found to be too heterogeneous to group together in this way., Conclusion: There were no substantial differences between independent analyses of each subgroup and hierarchical models when using the EUROCAT anomaly subgroups. Considering each anomaly separately, therefore, remains an appropriate method for the detection of potential changes in prevalence by surveillance systems. Hierarchical models do, however, remain an interesting alternative method of analysis when considering the risks of specific exposures in relation to the prevalence of congenital anomalies, which could be investigated in other studies. Birth Defects Research (Part A) 106:480-10, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

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., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Question: What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist?, Methods: This was a population based, observational study using data on 11,353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends., Summary Answer and Limitations: Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10,000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD., What This Study Adds: In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification., Funding, Competing Interests, Data Sharing: The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available., (© Khoshnood et al 2015.)

Background: In the context of the European Surveillance of Congenital Anomalies (EUROCAT) surveillance response to the 2009 influenza pandemic, we sought to establish whether there was a detectable increase of congenital anomaly prevalence among pregnancies exposed to influenza seasons in general, and whether any increase was greater during the 2009 pandemic than during other seasons., Methods: We performed an ecologic time series analysis based on 26,967 pregnancies with nonchromosomal congenital anomaly conceived from January 2007 to March 2011, reported by 15 EUROCAT registries. Analysis was performed for EUROCAT-defined anomaly subgroups, divided by whether there was a prior hypothesis of association with influenza. Influenza season exposure was based on World Health Organization data. Prevalence rate ratios were calculated comparing pregnancies exposed to influenza season during the congenital anomaly-specific critical period for embryo-fetal development to nonexposed pregnancies., Results: There was no evidence for an increased overall prevalence of congenital anomalies among pregnancies exposed to influenza season. We detected an increased prevalence of ventricular septal defect and tricuspid atresia and stenosis during pandemic influenza season 2009, but not during 2007-2011 influenza seasons. For congenital anomalies, where there was no prior hypothesis, the prevalence of tetralogy of Fallot was strongly reduced during influenza seasons., Conclusions: Our data do not suggest an overall association of pandemic or seasonal influenza with congenital anomaly prevalence. One interpretation is that apparent influenza effects found in previous individual-based studies were confounded by or interacting with other risk factors. The associations of heart anomalies with pandemic influenza could be strain specific.

Introduction: Published prevalence rates of congenital diaphragmatic hernia (CDH) vary. This study aims to describe the epidemiology of CDH using data from high-quality, population-based registers belonging to the European Surveillance of Congenital Anomalies (EUROCAT)., Methods: Cases of CDH delivered between 1980 and 2009 notified to 31 EUROCAT registers formed the population-based case series. Prevalence over time was estimated using multilevel Poisson regression, and heterogeneity between registers was evaluated from the random component of the intercept., Results: There were 3373 CDH cases reported among 12 155 491 registered births. Of 3131 singleton cases, 353 (10.4%) were associated with a chromosomal anomaly, genetic syndrome or microdeletion, 784 (28.2%) were associated with other major structural anomalies. The male to female ratio of CDH cases overall was 1:0.69. Total prevalence was 2.3 (95% CI 2.2 to 2.4) per 10 000 births and 1.6 (95% CI 1.6 to 1.7) for isolated CDH cases. There was a small but significant increase (relative risk (per year)=1.01, 95% credible interval 1.00-1.01; p=0.030) in the prevalence of total CDH over time but there was no significant increase for isolated cases (ie, CDH cases that did not occur with any other congenital anomaly). There was significant variation in total and isolated CDH prevalence between registers. The proportion of cases that survived to 1 week was 69.3% (1392 cases) for total CDH cases and 72.7% (1107) for isolated cases., Conclusions: This large population-based study found an increase in total CDH prevalence over time. CDH prevalence also varied significantly according to geographical location. No significant association was found with maternal age., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Previous studies have shown that over 40% of babies with Down syndrome have a major cardiac anomaly and are more likely to have other major congenital anomalies. Since 2000, many countries in Europe have introduced national antenatal screening programs for Down syndrome. This study aimed to determine if the introduction of these screening programs and the subsequent termination of prenatally detected pregnancies were associated with any decline in the prevalence of additional anomalies in babies born with Down syndrome. The study sample consisted of 7,044 live births and fetal deaths with Down syndrome registered in 28 European population-based congenital anomaly registries covering seven million births during 2000-2010. Overall, 43.6% (95% CI: 42.4-44.7%) of births with Down syndrome had a cardiac anomaly and 15.0% (14.2-15.8%) had a non-cardiac anomaly. Female babies with Down syndrome were significantly more likely to have a cardiac anomaly compared to male babies (47.6% compared with 40.4%, P < 0.001) and significantly less likely to have a non-cardiac anomaly (12.9% compared with 16.7%, P < 0.001). The prevalence of cardiac and non-cardiac congenital anomalies in babies with Down syndrome has remained constant, suggesting that population screening for Down syndrome and subsequent terminations has not influenced the prevalence of specific congenital anomalies in these babies., (© 2014 Wiley Periodicals, Inc.)

Background: This study describes seasonality of congenital anomalies in Europe to provide a baseline against which to assess the impact of specific time varying exposures such as the H1N1 pandemic influenza, and to provide a comprehensive and recent picture of seasonality and its possible relation to etiologic factors., Methods: Data on births conceived in 2000 to 2008 were extracted from 20 European Surveillance for Congenital Anomalies population-based congenital anomaly registries in 14 European countries. We performed Poisson regression analysis encompassing sine and cosine terms to investigate seasonality of 65,764 nonchromosomal and 12,682 chromosomal congenital anomalies covering 3.3 million births. Analysis was performed by estimated month of conception. Analyses were performed for 86 congenital anomaly subgroups, including a combined subgroup of congenital anomalies previously associated with influenza., Results: We detected statistically significant seasonality in prevalence of anomalies previously associated with influenza, but the conception peak was in June (2.4% excess). We also detected seasonality in congenital cataract (April conceptions, 27%), hip dislocation and/or dysplasia (April, 12%), congenital hydronephrosis (July, 12%), urinary defects (July, 5%), and situs inversus (December, 36%), but not for nonchromosomal anomalies combined, chromosomal anomalies combined, or other anomalies analyzed., Conclusion: We have confirmed previously described seasonality for congenital cataract and hip dislocation and/or dysplasia, and found seasonality for congenital hydronephrosis and situs inversus which have not previously been studied. We did not find evidence of seasonality for several anomalies which had previously been found to be seasonal. Influenza does not appear to be an important factor in the seasonality of congenital anomalies., (Copyright © 2014 Wiley Periodicals, Inc.)

Background: This study describes the prevalence, associated anomalies, and demographic characteristics of cases of multiple congenital anomalies (MCA) in 19 population-based European registries (EUROCAT) covering 959,446 births in 2004 and 2010., Methods: EUROCAT implemented a computer algorithm for classification of congenital anomaly cases followed by manual review of potential MCA cases by geneticists. MCA cases are defined as cases with two or more major anomalies of different organ systems, excluding sequences, chromosomal and monogenic syndromes., Results: The combination of an epidemiological and clinical approach for classification of cases has improved the quality and accuracy of the MCA data. Total prevalence of MCA cases was 15.8 per 10,000 births. Fetal deaths and termination of pregnancy were significantly more frequent in MCA cases compared with isolated cases (p < 0.001) and MCA cases were more frequently prenatally diagnosed (p < 0.001). Live born infants with MCA were more often born preterm (p < 0.01) and with birth weight < 2500 grams (p < 0.01). Respiratory and ear, face, and neck anomalies were the most likely to occur with other anomalies (34% and 32%) and congenital heart defects and limb anomalies were the least likely to occur with other anomalies (13%) (p < 0.01). However, due to their high prevalence, congenital heart defects were present in half of all MCA cases. Among males with MCA, the frequency of genital anomalies was significantly greater than the frequency of genital anomalies among females with MCA (p < 0.001)., Conclusion: Although rare, MCA cases are an important public health issue, because of their severity. The EUROCAT database of MCA cases will allow future investigation on the epidemiology of these conditions and related clinical and diagnostic problems., (Copyright © 2014 Wiley Periodicals, Inc.)

Objectives: To identify preferential associations between oral clefts (CL = cleft lip only, CLP = cleft lip with cleft palate, CP = cleft palate) and nonoral cleft anomalies, to interpret them on clinical grounds, and, based on the patterns of associated defects, to establish whether CL and CLP are different conditions., Design and Settings: Included were 1416 cleft cases (CL = 131, CLP = 565, CP = 720), among 8304 live- and stillborn infants with multiple congenital anomalies, from 6,559,028 births reported to the International Clearinghouse for Birth Defects Surveillance and Research by 15 registries between 1994 and 2004. Rates of associated anomalies were established, and multinomial logistic regressions applied to identify significant associations., Results: Positive associations with clefts were observed for only a few defects, among which anencephaly, encephaloceles, club feet, and ear anomalies were the most outstanding. Anomalies negatively associated with clefts included congenital heart defects, VATER complex (vertebral defects, imperforate anus, tracheoesophageal fistula, and radial and renal dysplasia), and spina bifida., Conclusion: The strong association between all types of clefts and anencephaly seems to be attributable to cases with disruptions; the association between CP and club feet seems to be attributable to conditions with fetal akinesia. Some negative associations may depend on methodologic factors, while others, such as clefts with VATER components or clefts with spina bifida, may depend on biological factors. The different patterns of defects associated with CL and CLP, indicating different underlying mechanisms, suggest that CL and CLP reflect more than just variable degrees of severity, and that distinct pathways might be involved.

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.

Background: Two crucial issues relative to the benefits and impact of folic acid in the prevention of birth defects are whether supplementation recommendations alone, without fortification, are effective in reducing the population-wide rates of neural tube defects (NTDs), and whether such policies can reduce the occurrence of other birth defects. Using data from 15 registries, we assessed rates and trends of 14 major defects, including NTDs, in areas with official recommendations or fortification to assess the effectiveness of recommendations and fortification on a wide range of major birth defects., Methods: We evaluated surveillance data through 2003 on major birth defects from population-based registries from Europe, North America, and Australia. All included ascertainment of pregnancy terminations (where legal). Trends before and after policies or fortification were assessed via Poisson regression and were compared via rate ratios., Results: Significant changes in trends were seen for NTDs in areas with fortification but not in areas with supplementation recommendations alone. For other major birth defects, there was an overall lack of major trend changes after recommendations or fortification. However, some significant declines were observed for select birth defects in individual areas., Conclusions: Recommendations alone remain an ineffective approach in translating the known protective effect of folic acid in population-wide decline in NTD rates. Fortification appears to be effective in reducing NTDs. The effect on other birth defects remains unclear., ((c) 2006 Wiley-Liss, Inc.)

Background: EUROCAT is a network of population-based registries for the epidemiologic surveillance of congenital anomalies covering approximately one quarter of births in the European Union. Down syndrome constitutes approximately 8% of cases of registered congenital anomaly in Europe, with over 7000 affected pregnancies in the 15 current member states of the European Union each year. In this paper, we aim to examine trends in the live birth prevalence of Down syndrome in Europe in the light of trends in maternal age and in prenatal diagnosis., Methods: Descriptive analysis of data from 24 EUROCAT registries, covering 8.3 million births 1980-99. Cases include live births, stillbirths and terminations of pregnancy following prenatal diagnosis., Results: Since 1980, the proportion of births to mothers of 35 years of age and over has risen quite dramatically from 8 to 14% for the European Union as a whole, with steeper rises in some regions. By 1995-1999, the proportion of "older" mothers varied between regions from 10% to 25%, and the total prevalence (including terminations of pregnancy) of Down syndrome varied from 1 to 3 per 1000 births. Some European regions have shown a more than twofold increase in total prevalence of Down syndrome since 1980. The proportion of cases of Down syndrome which were prenatally diagnosed followed by termination of pregnancy in 1995-1999 varied from 0% in the three regions of Ireland and Malta where termination of pregnancy is illegal, to less than 50% in 14 further regions, to 77% in Paris. The extent to which terminations of pregnancy were concen trated among older mothers varied between regions. The live birth prevalence has since 1980 increasingly diverged from the rising total prevalence, in some areas remaining approximately stable, in others decreasing over time., Conclusion: The rise in average maternal age in Europe has brought with it an increase in the number of pregnancies affected by Down syndrome. The widespread practice of prenatal screening and termination of pregnancy has in most of the regions covered by EUROCAT counteracted the effect of maternal age in its effect on live birth prevalence. Under the joint influences of maternal age and prenatal screening the pattern of geographic inequalities in Down syndrome live birth prevalence in Europe has also been changed.

Each year, more than 4500 pregnancies in the European Union are affected by neural tube defects (NTD). Unambiguous evidence of the effectiveness of periconceptional folic acid in preventing the majority of neural tube defects has been available since 1991. We report on trends in the total prevalence of neural tube defects up to 2002, in the context of a survey in 18 European countries of periconceptional folic acid supplementation (PFAS) policies and their implementation. EUROCAT is a network of population-based registries in Europe collaborating in the epidemiological surveillance of congenital anomalies. Representatives from 18 participating countries provided information about policy, health education campaigns and surveys of PFAS uptake. The yearly total prevalence of neural tube defects including livebirths, stillbirths and terminations of pregnancy was calculated from 1980 to 2002 for 34 registries, with UK and Ireland estimated separately from the rest of Europe. A meta-analysis of changes in NTD total prevalence between 1989-1991 and 2000-2002 according to PFAS policy was undertaken for 24 registries. By 2005, 13 countries had a government recommendation that women planning a pregnancy should take 0.4mg folic acid supplement daily, accompanied in 7 countries by government-led health education initiatives. In the UK and Ireland, countries with PFAS policy, there was a 30% decline in NTD total prevalence (95% CI 16-42%) but it was difficult to distinguish this from the pre-existing strong decline. In other European countries with PFAS policy, there was virtually no decline in NTD total prevalence whether a policy was in place by 1999 (2%, 95% CI 28% reduction to 32% increase) or not (8%, 95% CI 26% reduction to 16% increase). The potential for preventing NTDs by periconceptional folic acid supplementation is still far from being fulfilled in Europe. Only a public health policy including folic acid fortification of staple foods is likely to result in large-scale prevention of NTDs.

The study evaluated the sex distribution of major isolated malformations and common trisomies among a large and geographically varied sample. Eighteen registries from 24 countries contributed cases, which were centrally reviewed and classified in three clinical types as isolated, associated, or syndromic. We selected cases of 26 major defects (n = 108,534); trisomy 21, 18, and 13 (n = 30,114); other syndromes (n = 2,898); and multiple congenital anomalies (n = 24,197), for a total of 165,743 cases. We observed a significant deviation of sex distribution (compared to a sex ratio of 1.06 or male proportion of 51.4%) for 24 of the 29 groups (a male excess in 16, a female excess in 8), and in 8 of such groups these estimates varied significantly across registries. A male excess was noted for two left obstructive cardiac defects (hypoplastic left heart and coarctation of the aorta) and a female excess for all the main types of neural tube defects. A male excess was seen for omphalocele but not gastroschisis. For neural tube defects the female excess tended to be stronger in areas with historically high prevalence for these defects. For 15 of the 26 birth defects the sex distribution differed among isolated, associated, and syndromic cases. Some of these epidemiologic commonalities are consistent with known or putative developmental processes. Further, the geographic variation for some defects may reflect local prevalence rates and risk factors. Finally, the findings underscore the need for clinical classification (e.g., into isolated, multiple, syndromes) in studies of birth defects.

Objectives: To evaluate the effectiveness of policies and recommendations on folic acid aimed at reducing the occurrence of neural tube defects., Design: Retrospective cohort study of births monitored by birth defect registries., Setting: 13 birth defects registries monitoring rates of neural tube defects from 1988 to 1998 in Norway, Finland, Northern Netherlands, England and Wales, Ireland, France (Paris, Strasbourg, and Central East), Hungary, Italy (Emilia Romagna and Campania), Portugal, and Israel. Cases of neural tube defects were ascertained among liveborn infants, stillbirths, and pregnancy terminations (where legal). Policies and recommendations were ascertained by interview and literature review., Main Outcome Measures: Incidences and trends in rates of neural tube defects before and after 1992 (the year of the first recommendations) and before and after the year of local recommendations (when applicable)., Results: The issuing of recommendations on folic acid was followed by no detectable improvement in the trends of incidence of neural tube defects., Conclusions: Recommendations alone did not seem to influence trends in neural tube defects up to six years after the confirmation of the effectiveness of folic acid in clinical trials. New cases of neural tube defects preventable by folic acid continue to accumulate. A reasonable strategy would be to quickly integrate food fortification with fuller implementation of recommendations on supplements.

Objective: To investigate outcomes of ultrasound investigations (US) and invasive diagnostic procedures in cases of congenital malformations (CM), and to compare the use of invasive prenatal test techniques (amniocentesis (AC) versus chorionic villus sampling (CVS)) among European populations., Design: Analysis of data from population-based registries of CM., Subjects: 25 400 cases of CM recorded by 14 EUROCAT registries covering a total population of 1,013,352 births 1995-99., Results: US were performed in 91% of cases, and positively detected CM in 35% of cases. AC was performed in 24% of the cases and CVS in 3% of cases. Thirty-eight percent of invasive tests gave positive results. Fifty-two percent of cases with maternal age > or = 35 years had an invasive test performed compared to 20% of cases with younger mothers. Considerable variation was found between registries in the uptake rate of invasive tests in cases with older maternal age and on the use of invasive tests with only four regions employing CVS techniques in at least a third of the cases having invasive tests. For chromosomal anomalies US gave positive results in 46% of cases with maternal age < 35 years with US performed and in 36% of cases with maternal age > or = 35 years with US performed., Conclusion: Prenatal US was performed in 91% of all pregnancies with CM but the test was only positive in a third of the cases. There was large regional variation in the uptake rate of invasive tests with maternal age of 35 years or more. For every CVS carried out there were nine AC tests. US is an important tool in the prenatal diagnosis of chromosomal anomalies in Europe., (Copyright 2004 John Wiley & Sons, Ltd.)

Concern about apparent increases in the prevalence of hypospadias--a congenital male reproductive-tract abnormality--in the 1960s to 1980s and the possible connection to increasing exposures to endocrine-disrupting chemicals have underlined the importance of effective surveillance of hypospadias prevalence in the population. We report here the prevalence of hypospadias from 1980 to 1999 in 20 regions of Europe with EUROCAT (European Surveillance of Congenital Anomalies) population-based congenital anomaly registers, 14 of which implemented a guideline to exclude glanular hypospadias. We also report data from the England and Wales National Congenital Anomaly System (NCAS). Our results do not suggest a continuation of rising trends of hypospadias prevalence in Europe. However, a survey of the registers and a special validation study conducted for the years 1994-1996 in nine EUROCAT registers as well as NCAS identified a clear need for a change in the guidelines for registration of hypospadias. We recommend that all hypospadias be included in surveillance, but that information from surgeons be obtained to verify location of the meatus, and whether surgery was performed, in order to interpret trends. Investing resources in repeated special surveys may be more cost-effective than continuous population surveillance. We conclude that it is doubtful whether we have had the systems in place worldwide for the effective surveillance of hypospadias in relation to exposure to potential endocrine-disrupting chemicals.