AIM:Many women take medications during pregnancy. However, the risk to the fetus from most medications is uncertain. Congenital anomalies are one of the leading causes of infant death and contribute to long-term disability. Signal detection methods can be used to systematically identify possible medication-anomaly associations that require further investigation. METHODS:Data on first trimester medication exposures in pregnancies with a congenital anomaly reported to 14 EUROmediCAT registries with a birth year of 2005-2018 were analysed. Case-malformed disproportionality analysis identified medication-anomaly signals using a disproportionality signal detection method. Identified signals were then compared to previous EUROmediCAT signal detection studies and ranked based on a proxy for the severity of impact at a population level using the number of estimated excess congenital anomaly cases within the exposed population and the average additional time in hospital over the first year of life. Generalized linear mixed models were used to assess confounding by birth year and registry within the top 20 ranked signals. RESULTS:1611 medication-outcome pairs with at least three observations were analysed, and 153 signals for 63 different medications were identified. Of the top 20 ranked signals, 10 (involving nine medications) were prioritized for further independent investigation. CONCLUSION:The signals identified here are hypothesis forming only. Independent studies that adequately account for confounding are subsequently needed to evaluate if the identified signals are causal. Further investigation of signals with low population impact, but high potential individual risk is also recommended.

BACKGROUND:Biliary atresia is a rare but severe congenital anomaly associated with substantial morbidity and mortality in early childhood. Population-based estimates of survival, surgical management, and liver transplantation across Europe remain limited. This study aimed to describe mortality and morbidity among children born with biliary atresia using multinational population-based data. METHODS:We investigated children diagnosed with biliary atresia across nine registries from five countries within the European surveillance of congenital anomalies network (EUROCAT), covering births from 1995 to 2014. The data were linked to hospital databases and adjusted for regional differences and follow-up length. RESULTS:Our cohort included 171 children, with an infant mortality rate of 12.3% (95% CI: 7.8-17.6) and a mortality rate before age five of 18.5% (95% CI: 10.7-27.7). Among these children, 151 had undergone surgery, including 133 who received the Kasai procedure by the age of 1 year at a median age of 57 days (95% CI: 51-62 days). By age five, 37% (adjusted percentage, 95% CI: 30-44) had undergone liver transplantation, with the median age at transplantation being 318 days (95% CI: 244-391 days). Median age at death in the first year was over 6 months and was not immediately after surgery. CONCLUSION:The high mortality and the substantial need for liver transplantation within the first year of life underline the severity of biliary atresia. This highlights the urgent need for further research into pregnancy exposures that may contribute to this rare but severe congenital anomaly to develop primary prevention strategies.

PURPOSE:To describe mortality, surgical treatment, and hospitalization patterns in children with congenital diaphragmatic hernia (CDH) using population-based data, linked to congenital anomaly registries across Europe. METHODS:This cohort study used nine EUROCAT registries in five countries (Denmark, Finland, Italy, Spain, and the United Kingdom) linked to routinely collected hospital and mortality data. Children born alive with CDH between 2005 and 2014 were included and followed until age 5 in hospital data or age 10 in death data, with the final follow-up the end of 2015. Analyses were conducted for all CDH cases and separately for isolated CDH (CDH without additional major congenital anomalies). Standardized data processing and meta-analysis methods were used to generate pooled estimates of mortality, surgical interventions, and hospital stays. RESULTS:Among 567 children with CDH, most were isolated CDH. First year survival was 74.5% for isolated CDH, ranging from 63% to 83% between registries. Similar survival was noted for all children with CDH. Most deaths occurred within the first week. Mortality rates plateaued after infancy, with no deaths recorded after age 5. The median age at surgery was approximately 2 weeks, although this varied by region. Median hospital length of stay in infancy varied from 14 to 29 days between regions. CONCLUSION:In children with CDH, mortality is highest in the neonatal period, with long-term survival stabilizing after infancy. No deaths occurred after age 5 years. Regional differences in mortality and surgical timing highlight the value of population-based, harmonized data for benchmarking and international comparisons.

Introduction The diagnosis of congenital hip dislocation is historically included in the first clinical examination of the newborn baby[1].Later,the term developmental dysplasia of the hip was defined,with congenital hip dislocation being the most severe form of developmental dysplasia of the hip[2-4].

Given the increasing use of gabapentinoids and ongoing safety concerns, we assessed the association between first-trimester exposure to gabapentin and pregabalin and the risk of specific congenital anomalies (CAs) in the offspring. Using EUROmediCAT data, we conducted a case-malformed control study based on 170,126 registrants with major CAs from livebirths, fetal deaths (≥20 weeks), and terminations of pregnancy for fetal anomaly in nine European countries (2000–2020), covering 10.6 million births. We compared gabapentinoid use in registrants with a specific CA with those among other registrants with non-genetic CA (main control group) and among registrants with a genetic condition (secondary control group). We estimated odds ratios (OR) and 95

BACKGROUND:Children with congenital anomalies (CAs) are at an increased risk of developing epilepsy, but the relative risk (RR) for specific anomaly subtypes remains underexplored. This study aims to estimate the risk of epilepsy, as indicated by antiseizure medication (ASM) prescriptions, among children with various CAs compared to children without anomalies. METHODS:We utilized data from six European regions participating in the European network for surveillance of congenital anomalies registries, covering births from 2000 to 2015. Children with major CAs, classified by International Classification of Diseases codes, were compared to a reference population without anomalies. Epilepsy was identified based on >1 ASM prescription within a year. RRs were calculated using mixed-effects models to account for registry-specific variations. RESULTS:The study included 60,662 children with anomalies and 1,722,912 reference children, with a mean follow-up of 5.5 years. By age 5 years, ASM prevalence was 17.8 per 1000 in anomaly groups and 2.0 per 1000 in reference children. The highest RRs were observed in children with central nervous system anomalies, including anomalies of the corpus callosum, severe microcephaly, and hydrocephalus. Comparable RRs were found in children with severe congenital heart defects and gastrointestinal anomalies, primarily driven by diaphragmatic hernia. CONCLUSIONS:Children with CAs have a significantly higher risk of epilepsy, with central nervous system, chromosomal, severe congenital heart defect, and diaphragmatic hernia being key contributors. This study highlights the importance of tailored monitoring and early intervention for high-risk groups to improve neurological outcomes.

BACKGROUND:The evidence gap relating to the risk of congenital anomalies (CA) associated with first trimester medication exposure in pregnancy is well recognized. AIMS:We describe the EUROmediCAT network and databases, and the methodological approach to pregnancy pharmacovigilance. MATERIAL AND METHODS:Multidisciplinary expertise includes CA diagnosis and epidemiology, pharmacoepidemiology, pharmacology and teratology. The EUROmediCAT central database comprises standardized data from 19 EUROCAT CA registries in 14 countries, including more than 40 000 CA cases 1995-2021 with first trimester medication exposure data recorded, and a population coverage of 14.6 million births, growing by more than 650 000 births per year. The distributed database enables federated data analysis across eight countries which can link data from CA registries to electronic healthcare data, with population coverage of up to 900 000 births per year for linkage to maternal prescriptions, of which 300 000 births per year for linkage also to data on all births. RESULTS:The databases have enabled a variety of study designs: case-malformed control studies, cohort studies, disease cohort studies, signal detection studies, prevalence and ecological studies, and medication utilization studies. DISCUSSION:A key strength is that studies of CA risk can address accurately the specificity of risk by type of CA. CONCLUSION:EUROmediCAT presents a unique data and expert resource for tackling the enormous evidence gap regarding the safety of medication during pregnancy.

BACKGROUND:Although accessing administrative data in healthcare databases may be a more time-efficient and cost-effective method of conducting surveillance, there is evidence suggesting that administrative data alone are not sufficient for population-based surveillance of congenital anomalies. OBJECTIVE:To propose recommendations to maximise the potential use of healthcare databases for surveillance of congenital anomalies based on our data linkage experiences and results from the EUROlinkCAT study. METHODS:EUROlinkCAT is a population-based cohort study of 99,416 children with anomalies born between 1995 and 2014. The congenital anomaly case records of children in 11 European congenital anomaly (EUROCAT) registries (eight countries) were linked to standardised administrative healthcare data (birth records, death records and hospital discharge records) to evaluate mortality and morbidity outcomes in these children. Overall, 97% of children with anomalies were successfully matched to their records in their national or regional administrative databases. Recommendations to improve surveillance of anomalies when using healthcare data were developed through establishing and analysing data from this cohort. RESULTS:The primary recommendation is to develop systems to report anomalies diagnosed in foetuses who undergo a termination and link these data to their mothers. Each liveborn baby must be assigned a permanent unique identification number at birth to enable accurate linkage across healthcare databases. Implementing and improving existing algorithms to discriminate between major anomalies and suspected or minor anomalies will improve accuracy in coding. Heterogeneity in coding anomalies will improve by avoiding the use of 'unspecified' or 'other specified' codes in hospital databases. Relaxation of country-specific regulations concerning the suppression of small numbers are necessary to enable data to be combined across European countries. CONCLUSION:Implementation of these recommendations will enable the information in electronic healthcare databases, in conjunction with Congenital Anomaly registries, to be fully exploited and hence will improve the surveillance of anomalies in children.

Abstract Background Noonan Syndrome (NS) is a rare multisystemic disorder with heterogeneous phenotypic manifestations. The aim of this study was to analyse rates of survival, hospitalisation, surgeries and prescriptions in children born with NS in the first 10 years of life. Methods This is a multi-centre population-based cohort study. Data on 175 liveborn children diagnosed with NS from 11 EUROCAT congenital anomaly registries were linked to healthcare databases. Each registry applied a common data model to standardise data and run common syntax scripts to produce aggregated results which were pooled using random effects meta-analyses. Results Mortality rates were high in the first year of life with 5.4% (95%CI 1.5%-10.1%) of children dying before the age of 1 year with a further 2% dying up to age 5. In the first year, 87.9% (95%CI 75.3%-94.3%) of children were hospitalized and the median Length Of hospital Stay (LOS) was 15.3 days (95%CI 9.3–21.2). After the first year, the proportion of children hospitalized remained higher than 70%, but the LOS decreased to 1.3 days per year. In the first 5 years, 65.2% of children underwent a median of two surgical procedures. The median age at first surgery was 29 weeks. The proportion of children with an antibiotic prescription increased from 53.6% at age 1 to 62.4% yearly until 4 years of age. Conclusions Children with NS have high mortality and morbidity not only in the first year of life but also up to five years of age. This study evaluated the health burden of NS and provided information for clinicians, health-care providers and families.

PurposeAntiretroviral drugs are recommended during pregnancy to achieve HIV viral suppression and reduce mother-to-child transmission. Congenital anomaly signals were reported after fetal exposure to antiretroviral drugs in several studies warranting further investigation. We aimed to evaluate the risk of congenital anomalies after fetal exposure to antiretroviral drugs using the European congenital anomaly registry data.MethodsA case/non-case study was performed, using the EUROmediCAT central database. All the congenital anomalies, exposed to any antiretroviral drugs, were included from 1995 to 2019. We explored each signal identified from the literature for associations between congenital anomalies and specific antiretroviral exposures. We compared antiretroviral exposure between the signal anomalies (cases) and all other malformed registrations (controls). Reporting odds ratio (ROR) and their 95% confidence intervals were estimated and adjusted for registry and maternal age.ResultsBetween 1995 and 2019, 173 cases of congenital anomalies were observed after any exposure to antiretroviral drugs. The signal previously identified in the literature between congenital heart defects and exposure to zidovudine was confirmed in the main analysis (aROR 3.66 [1.63-8.23]). Other signals identified in the literature were not confirmed, although two cases of hypospadias and two cases of limb defects were reported after zidovudine and atazanavir exposure, respectively. The signal detection analysis did not reveal any new signal after applying the Bonferroni correction.ConclusionsOur study does not reveal new signals but confirms the previously identified signal between congenital heart defects and fetal exposure to zidovudine. The physio-pathological hypothesis induced by zidovudine exposure should be explored in future studies.

ABSTRACT Background Globally, Down syndrome is the most common chromosomal anomaly, often co‐occurring with cardiac or gastrointestinal anomalies. There is a lack of robust data on specific healthcare needs of children with Down syndrome compared to children with other major congenital anomalies. Objectives To quantify the healthcare needs of children with Down syndrome in the first year of life compared to children with major congenital anomalies in a large population‐based cohort across Europe. Methods The EUROlinkCAT study was a multicentre data linkage study between congenital anomaly registries in Europe and hospital and mortality databases. Children born between 1st January 1997 and 31st December 2014 were included. Summary statistics were used to compare differences between children (those with Down syndrome compared to all major anomalies) and regions. Random‐effects meta‐analysis was used to pool results related to survival, need for intensive care and ventilation support. Results A total of 3554 children were born with Down syndrome out of 89,081 children with major congenital anomalies. The pooled 1‐year survival was 95.4%. In every region, > 80% of children with Down syndrome had a hospital admission excluding the birth admission. Hospital length of stay in the first year was higher for children with Down syndrome compared to those with all anomalies (median: 14 versus 7 days). Despite having similar need for ventilation support (9.7% vs. 8.4%), children with Down syndrome had higher rates of intensive care admission than all children with anomalies (24.8% vs. 13.0%). Conclusions There is a high need for hospital care for children born with Down syndrome in the first year of life. Future work should continue to explore the long‐term prognosis for children with Down syndrome to ensure their care needs are met.

BACKGROUND:Parents and carers of children with congenital anomalies can experience stress when managing their child's healthcare needs. It is important that they are well supported. This study explored the support needs of parents/carers of children with a congenital anomaly across Europe. METHODS:We developed a cross-sectional online survey to measure parents' experiences of support at diagnosis and in subsequent years. We recruited parents/carers of children (0-10 years) with cleft lip, congenital heart defect requiring surgery, Down syndrome and/or spina bifida, online via relevant organisations in 10 European countries (March-July 2021). RESULTS:A total of 1109 parents/carers were recruited in Poland (n = 476), the United Kingdom (n = 120), Germany (n = 97), Belgium/Netherlands (n = 74), Croatia (n = 68), Italy (n = 59), other European countries (n = 92) and unspecified/non-European countries (n = 84). At diagnosis, only 27% (262/984) of parents/carers reported feeling well supported by HCPs, and 49% (468/959) reported that they would have liked professional psychological support but did not receive it. After diagnosis, satisfaction with support from HCPs differed significantly across countries, whereas satisfaction with support from participants' personal networks was more consistent. CONCLUSION:Our findings suggest that parents require greater support from HCPs at diagnosis, particularly psychological support. Further research in a European context is needed to understand what the barriers to support might be and how it may be integrated more effectively into existing healthcare systems.

OBJECTIVE:To evaluate risk factors for hospital admission and length of stay (LOS) among children with and without congenital anomalies (CAs). DESIGN:A population-based linkage cohort study including 50 353 children with major CAs and 1 259 925 children without CAs from four EUROCAT registry areas in three countries. Data on children born 1995-2014 were linked to hospital discharge databases 1995-2015. HRs and incidence rate ratios estimated risk of admission and LOS for children aged <1 and 1-4 years by birth cohort, gestational age, sex, maternal age, multiple births and maternal education. Estimates were pooled using random effects meta-analysis. RESULTS:In children <1 year, twins/triplets with CAs were 34% more likely to be admitted and had over two times the LOS compared with singletons, while twins/triplets without CAs were over two and a half times as likely to be admitted and had six times longer stays. Despite this, a higher proportion of twins/triplets with CAs were admitted compared to those without CAs (91% vs 65%) and had longer LOS (20 days vs 10). Smaller increases in risk of admission or LOS were found in boys, young mothers and low maternal education. Preterm birth was a major risk factor for admission and LOS. CONCLUSIONS:While the impact of risk factors on hospital admission and LOS was generally greater in children without CAs, a higher proportion of children with CAs were admitted and had longer stays. These findings have implications for health care planning and for counselling parents regarding their child's future healthcare needs.

ABSTRACT Background In Europe, the prevalence of congenital ocular anomaly (COA) is estimated at 3.7 per 10,000 births. While certain COAs have a genetic origin, the cause for most patients remains unknown. The role of medications administered during pregnancy in COA genesis in humans is unclear. Objective To investigate any association between fetal exposure in the first trimester of pregnancy to medications and the occurrence of COA. Methods We conducted a case‐malformed‐control study using data on 298,351 cases registered as having congenital anomalies (CA) from 19 registries and one healthcare database in 13 European countries. Two analyses were performed: (i) A signal confirmation analysis of signals from the literature, examining associations between COA and specific medications (nitrofurantoin, NSAIDs, opioids, alprazolam, antihypertensives, asthma medications, pyridoxine, and hydroxyethylrutoside). (ii) A signal detection analysis of all medications reported in the database. Results We identified 4185 COA cases and 232,718 nongenetic and 38,409 genetic controls. We confirmed the association between prenatal opioid exposure and COA (aROR: 2.66, 95% CI: 1.18, 6.02, and 3.22, 95% CI: 1.35, 7.69, for nongenetic and genetic controls, respectively). Signal detection analysis revealed consistent associations for antiglaucoma preparations and miotics ( p < 0.01) related to COA. Other associations included congenital cataracts and lens anomalies with desloratadine, congenital glaucoma with antiepileptics, and eyelid malformations with dermatological hydrocortisone. Conclusions This pharmacoepidemiological study in Europe analyzing COA following fetal medication exposure confirmed reported signals regarding opioids and COA and identified new associations. Validation in independent datasets is necessary to consolidate these findings.

BACKGROUND/AIM:Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are rare imprinting disorders caused by the aberrant expression of 15q11.2-q13 imprinted genes. Due to their rarity, data on health outcomes during infancy are limited. This EUROlinkCAT study aimed to investigate major health outcomes of children with these chromosomal disorders. METHODS:Data of children born in 1995-2014 and diagnosed with PWS (n=150) or AS (n=46), collected by 11 population-based congenital anomaly registries, were linked to local electronic healthcare and mortality databases and analysed. RESULTS:Children with PWS had a survival rate of 94% (95% CI 89.5% to 98.7%) by 10 years of age. Nearly all children (99.5%, 95% CI 97.6% to 99.9%) with PWS required hospitalisation during the first year of life with a median length of stay of 25 days; a high proportion continued to need hospital care later in life (93.2% at 1-4 years and 79.6% at 5-9 years) with shorter stays (1.2 and 0.5 days per year, respectively). In comparison, no deaths occurred among children with AS by 10 years of age. Fewer children with AS required hospitalisation in the first year of life (59.0%, 95% CI 39.6% to 74.0%); as they grew older, the proportion admitted was 68% (95% CI 40.0% to 85.0%) at 5-9 years. Children with PWS and AS underwent first surgery at approximately 1.8 years and 2.5 years, respectively. CONCLUSIONS:This study provides valuable evidence for improving family counselling and promoting an adequate healthcare support system.

BACKGROUND:Surveillance of congenital anomaly prevalence over time can identify new teratogens. Anomalies with a genetic cause are excluded from the monitoring. OBJECTIVES:We examined temporal changes in the proportion of genetic diagnoses among cases with a congenital anomaly. METHODS:Data was used from twenty EUROCAT congenital anomaly registries over the birth years 2013 and 2022. All pregnancy outcomes were included. Multilevel binomial regression models were fitted to estimate the annual change in the proportion of genetic diagnoses of all anomalies by registry. Results were additionally reported, excluding cases with trisomy 13, 18, or 21. RESULTS:Overall, 20% of the 100,099 cases in the study had a genetic diagnosis, and this proportion increased annually by 1.4% (95% CI, 0.8%-1.9%); an absolute increase of approximately 3% from 2013 to 2022. After excluding the trisomies, the overall proportion was 10% with an annual increase of 1.2% (95% CI 0.4%-2.0%). There was considerable variation in the proportion of genetic cases per registry. An increasing proportion of genetic diagnoses was found for five congenital anomaly groups, after excluding the trisomies. We hypothesise that the increase in genetic diagnoses is due to increased access to clinical genetic services, more extensive genetic testing, and the identification of new genes as causes of congenital anomalies. CONCLUSIONS:The modest increase in genetic diagnoses among cases with a congenital anomaly is not expected to have a large impact on the surveillance of the non-genetic anomalies in the EUROCAT network. EUROCAT will continue to monitor the proportion of genetic diagnoses every five years.

Background: Management and outcomes amongst children with congenital heart defects (CHD) are relatively heterogeneous. Traditionally, the highest-risk conditions and procedures have received the most attention, with less focus on outcome for less severe CHDs. Objectives: Evaluate the management of children born with certain less severe CHDs across Europe. Methods: This population-based linkage cohort study included children diagnosed with ventricular septal defect (VSD), atrial septal defect (ASD), pulmonary valve stenosis (PS), and patent arterial duct (PDA) from nine European regions. Data on surgery/intervention and survival from 1995 to the age of 10 years or until the end of 2014 were collected through electronic linkage to mortality and hospital databases. Kaplan-Meier survival estimates and meta-analyses were used to analyze the proportion of children undergoing surgery/intervention and survival rates. Results: The study included 20,608 children with the less severe CHDs. Surgical correction rates for the anomaly within the first year of life varied significantly, particularly for VSD. The median age for initial surgery/intervention was consistent for VSD but varied for other conditions. Most conditions were corrected in a single procedure, except for PS, which required a median of 1.7 (95 % CI; 1.4-2.0) interventions. Postoperative mortality was highest for neonates undergoing VSD surgery/intervention, 8.7 (95 % CI; 4.0-15.8) deaths per 100 surgeries. The overall 5-year survival rate for all conditions was approximately 98 %. Conclusion: There was considerable variation in the management of less severe CHDs across Europe, particularly in the timing of surgical interventions. Despite these differences, the overall 5-year survival rate is comparable and high.