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Background: Children born with major congenital anomalies (CAs) have lower academic achievement compared with their peers, but the existing evidence is restricted to a number of specific CAs. Objectives: To investigate academic outcomes at ages 11 and 16 in children with major isolated structural CAs and children with Down or Turner syndromes. Methods: This population‐based cohort study linked data on approximately 11,000 school‐aged children born with major CAs in 1994–2004 registered by four regional CA registries in England with education data from the National Pupil Database (NPD). The comparison group was a random sample of children without major CAs from the background population recorded in the NPD that were frequency matched (5:1) to children with CAs by birth year, sex and geographical area. Results: Overall, 71.9%, 73.0% and 80.9% of children with isolated structural CAs achieved the expected attainment level at age 11 compared to 78.3%, 80.6% and 86.7% of the comparison group in English language, Mathematics and Science, respectively. Children with nervous system CAs as a whole had the lowest proportion who achieved the expected attainment at age 11. At age 16, 46.9% of children with CAs achieved the expected level compared to 52.5% of their peers. Major CAs were associated with being up to 9% (95% confidence interval [CI] 8%, 11%) and 12% (95% CI 9%, 14%) less likely to achieve expected levels at ages 11 and 16, respectively, after adjustment for socioeconomic deprivation. Conclusions: Although many children with isolated CAs achieved the expected academic level at ages 11 and 16, they were at higher risk of underachievement compared to their peers. These stark yet cautiously encouraging results are important for counselling parents of children with specific CAs and also highlight the possible need for special education support to reduce potential academic difficulties. [ABSTRACT FROM AUTHOR]

Aim: The aim is to examine the risk of cerebral palsy, seizures/epilepsy, visual‐ and hearing impairments, cancer, injury/poisoning and child abuse in children with and without a congenital anomaly up to age 5 and 10 years. Methods: This is a population‐based data linkage cohort study linking information from the European Surveillance of Congenital Anomalies network (EUROCAT) and birth registries to hospital discharge databases. We included 91 504 live born children with major congenital anomalies born from 1995 to 2014 from nine EUROCAT registries in five countries and 1 960 727 live born children without congenital anomalies (reference children). Prevalence and relative risk (RR) were estimated for each of the co‐morbidities using Kaplan–Meier survival estimates. Results: Children with congenital anomalies had higher risks of the co‐morbidities than reference children. The prevalences in the reference children were generally very low. The RR was 13.8 (95% CI 12.5–15.1) for cerebral palsy, 2.5 (95% CI 2.4–2.6) for seizures/epilepsy, 40.8 (95% CI 33.2–50.2) for visual impairments, 10.0 (95% CI 9.2–10.9) for hearing loss, 3.6 (95% CI 3.2–4.2) for cancer, 1.5 (95% CI 1.4–1.5) for injuries/poisoning and 2.4 (95% CI 1.7–3.4) for child abuse. Conclusion: Children with congenital anomalies were more likely to be diagnosed with the specified co‐morbidities compared to reference children. [ABSTRACT FROM AUTHOR]

Background: Hirschsprung's disease is a rare congenital anomaly of the colon with absence of the ganglionic nerve cells. The treatment of the anomaly is surgical. Methods: This population‐based data‐linkage cohort study was part of the EUROlinkCAT project and investigated mortality and morbidity for the first 5 years of life for European children diagnosed with Hirschsprung's disease. Nine population‐based registries in five countries from the European surveillance of congenital anomalies network (EUROCAT) participated. Data on children born 1995–2014 and diagnosed with Hirschsprung's disease were linked to hospital databases. All analyses were adjusted for region and length of follow‐up, which differed by registry. Results: The study included 680 children with Hirschsprung's disease. One‐year survival was 97.7% (95% CI: 96.4–98.7). Overall, 85% (82–87) had a code for a specified intestinal surgery within the first year increasing to 92% (90–94) before age 5 years. The median age at the first intestinal surgery up to 5 years was 28 days (11–46) and the median number of intestinal surgical procedures was 3.5 (3.1–3.9). Thirty days mortality after neonatal surgery (within 28 days after birth) was 0.9% (0.2–2.5) for children with a code for intestinal surgery within the first 28 days after birth and there were no deaths for children with a code for stoma surgery in the neonatal period. Conclusion: Children with Hirschsprung's disease have a high morbidity in the first 5 years of life requiring more surgical procedures in addition to the initial surgery. Mortality after neonatal surgery is low. [ABSTRACT FROM AUTHOR]

Background: Preterm birth and young maternal age are known risk factors for infant and childhood mortality. There is limited knowledge of the impact of these risk factors in children born with major congenital anomalies (CAs), who have inherently higher risks of death compared with other children. Objectives: To investigate the risk factors for mortality up to age 10 years in children born with specific major CAs. Methods: This population-based cohort study involved 150,198 livebirths from 1995 to 2014 in 13 European CA registries linked to mortality data. Cox proportional hazards models estimated the association of gestational age, maternal age and child's sex with death <1 year and 1-9 years for the whole cohort and by CA subgroup. Hazard ratios (HR) from each registry were pooled using multivariate meta-analysis. Results: Preterm birth had a dose-response association with mortality; compared with infants born at 37+ weeks gestation, those born at <28, 28-31 and 32-36 weeks had 14.88 (95% CI 12.57, 17.62), 8.39 (95% CI 7.16, 9.85) and 3.88 (95% CI 3.40, 4.43) times higher risk of death <1 year, respectively. The corresponding risks at 1-9 years were 4.99 (95% CI 2.94, 8.48), 3.09 (95% CI 2.28, 4.18) and 2.04 (95% CI 1.69, 2.46) times higher, respectively. Maternal age <20 years (versus 20-34 years) was a risk factor for death <1 year (HR 1.30, 95% CI 1.09, 1.54) and 1-9 years (HR 1.58, 95% CI 1.19, 2.10). Females had 1.22 (95% CI 1.07, 1.39) times higher risk of death between 1 and 9 years than males. Conclusion: Preterm birth was associated with considerably higher infant and childhood mortality in children with CAs, comparable to estimates reported elsewhere for the background population. Additional risk factors included young maternal age and female sex. Information on risk factors could benefit clinical care and guide counselling of parents following CA diagnoses. [ABSTRACT FROM AUTHOR]

Background: Turner syndrome is a rare congenital anomaly caused by complete or partial X chromosome monosomy that may affect mortality and morbidity in childhood. Methods: This population-based data-linkage cohort study, as part of the EUROlinkCAT project, investigated mortality and morbidity for the first 5 years of life for liveborn European children diagnosed with Turner syndrome. Thirteen population-based registries in 10 countries from the European surveillance of congenital anomalies (EUROCAT) network participated. Data on children born 1995-2014 and diagnosed with Turner syndrome were linked to mortality, hospital and prescription records. Children with any congenital anomaly and children without a congenital anomaly were included for comparison on morbidity. Results: Out of a population of 5.8 million livebirths 404 were diagnosed with Turner syndrome prenatally or in infancy and 95.5% survived to their fifth birthday. During the first year of life 72.3% (95% CI 59.5;81.6) of children with Turner syndrome were hospitalized, the median length of stay was 5.6 days (95% CI 3.5;7.7) and 18.7% (95% CI 13.9;23.9) underwent surgery. After the first year of life hospitalizations and length of stay decreased but more children underwent surgery (30.8% [95% CI 17.6;44.7]). In the first 5 years the percentage of children with Turner syndrome having a prescription for antibiotics was 12%-20% per year and increased with the age of child. Conclusions: In the first year of life, the burden of disease was relatively high for children with Turner syndrome. The outlook is more positive beyond the first year, though overall morbidity still exceeded that of children without congenital anomalies. [ABSTRACT FROM AUTHOR]

Aim: Children with congenital anomalies often require surgery but data on the burden of surgery for these children are limited. Methods: A population‐based record‐linkage study in Finland, Wales and regions of Denmark, England, Italy and Spain. A total of 91 504 children with congenital anomalies born in 1995–2014 were followed to their tenth birthday or the end of 2015. Electronic linkage to hospital databases provided data on inpatient surgical procedures and meta‐analyses of surgical procedures were performed by age groups. Results: The percentage of children having surgery in the first year was 38% with some differences across regions and 14% also underwent surgery at age 1–4 years. Regional differences in age at the time of their first surgical procedure were observed for children with cleft palate, hydronephrosis, hypospadias, clubfoot and craniosynostosis. The children had a median of 2.0 (95% CI 1.98, 2.02) surgical procedures before age 5 years with children with oesophageal atresia having the highest median number of procedures (4.5; 95% CI 3.3, 5.8). Conclusion: A third of children with congenital anomalies required surgery during infancy and often more than one procedure was needed before age 5 years. There was no European consensus on the preferred age for surgery for some anomalies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Congenital anomalies are a major cause of perinatal, neonatal and infant mortality. Objectives: The aim was to investigate temporal changes and geographical variation in survival of children with major congenital anomalies (CA) in different European areas. Methods: In this population‐based linkage cohort study, 17 CA registries members of EUROCAT, the European network for the surveillance of CAs, successfully linked data on 115,219 live births with CAs to mortality records. Registries estimated Kaplan–Meier survival at 28 days and 5 years of age and fitted Cox's proportional hazards models comparing mortality at 1 year and 1–9 years of age for children born during 2005–2014 with those born during 1995–2004. The hazard ratios (HR) from each registry were combined centrally using a random‐effects model. The 5‐year survival conditional on having survived to 28 days of age was calculated. Results: The overall risk of death by 1 year of age for children born with any major CA in 2005–2014 decreased compared to 1995–2004 (HR 0.68, 95% confidence interval [CI] 0.53, 0.89). Survival at 5 years of age ranged between registries from 97.6% to 87.0%. The lowest survival was observed for the registry of OMNI‐Net (Ukraine) (87.0%, 95% CI 86.1, 87.9). Conclusions: Survival of children with CAs improved for births in 2005–2014 compared with 1995–2004. The use of CA registry data linked to mortality data enables investigation of survival of children with CAs. Factors such as defining major CAs, proportion of terminations of pregnancy for foetal anomaly, source of mortality data and linkage methods are important to consider in the design of future studies and in the interpretation of the results on survival of children with CAs. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has accelerated pregnancy outcome research, but little attention has been given specifically to the risk of congenital anomalies (CA) and first trimester exposures. Objectives: We reviewed the main data sources and study designs used internationally, particularly in Europe, for CA research, and their strengths and limitations for investigating COVID‐19 disease, medications and vaccines. Population: We classify research designs based on four data sources: a) spontaneous adverse event reporting, where study subjects are positive for both exposure and outcome, b) pregnancy exposure registries, where study subjects are positive for exposure, c) congenital anomaly registries, where study subjects are positive for outcome and d) population healthcare data where the entire population of births is included, irrespective of exposure and outcome. Study Design: Each data source allows different study designs, including case series, exposed pregnancy cohorts (with external comparator), ecological studies, case‐control studies and population cohort studies (with internal comparator). Methods: The quality of data sources for CA studies is reviewed in relation to criteria including diagnostic accuracy of CA data, size of study population, inclusion of terminations of pregnancy for foetal anomaly, inclusion of first trimester COVID‐19‐related exposures and use of an internal comparator group. Multinational collaboration models are reviewed. Results: Pregnancy exposure registries have been the main design for COVID‐19 pregnancy studies, but lack detail regarding first trimester exposures relevant to CA, or a suitable comparator group. CA registries present opportunities for improving diagnostic accuracy in COVID‐19 research, especially when linked to other data sources. Availability of inpatient hospital medication use in population healthcare data is limited. More use of ongoing mother‐baby linkage systems would improve research efficiency. Multinational collaboration delivers statistical power. Conclusions: Challenges and opportunities exist to improve research on CA in relation to the COVID‐19 pandemic and future pandemics. [ABSTRACT FROM AUTHOR]

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project—Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation—with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother‐child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose To study patterns of antiepileptic drugs (AED) prescribing, particularly valproate, during pregnancy over a 10‐year period in the UK, Italy, and France. Methods: Data on pregnancies conceived after 1 January 2007 with outcomes before 31 December 2016 were extracted from four European electronic health care databases (380 499 in the United Kingdom (UK), 66 681 in France, and 649 918 in Italy [355 767 in Emilia Romagna and 294 151 in Tuscany]). Prevalence of AEDs with an ATC code starting N03A and clobazam (N05BA09) were stratified by country and calendar year. Results: AED prescribing during pregnancy varied from 3.0 (2.8‐3.1) per 1000 pregnancies in Emilia Romagna to 7.8 (7.5‐8.0) in the UK, 5.9 (5.6‐6.1) in Tuscany, and 6.3 (5.7‐6.9) in France. Lamotrigine was commonly prescribed in all regions with a third of women exposed to an AED during pregnancy taking lamotrigine in the UK and France. Valproate was prescribed to 28.6% of AED exposed pregnant women in Tuscany, 21.6% in France, 16.7% in Emilia Romagna, and 11.9% in the UK. Over the study period, the prevalence of AED prescribing increased in the UK mainly due to increases in pregabalin and gabapentin, declined in France mainly related to decreases in clonazepam, and remained constant in Italy. Valproate prescriptions declined to a prevalence <1 per 1000 pregnancies in 2015 to 2016 in the UK, France, and Emilia Romagna. Conclusions: Variations in AED prescribing during pregnancy indicate the potential for further reductions, particularly of valproate. Increases in pregabalin/gabapentin prescribing, for which risks are not well known, are a cause for concern. [ABSTRACT FROM AUTHOR]

Objectives: In November 2014, the CMDh (a regulatory body representing EU Member States) advised doctors not to prescribe sodium valproate for epilepsy or bipolar disorder in preg nant women, in women who can become pregnant, or in girls unless other treatments are ineffective or not tolerated. This study aimed to determine if this warning led to changes in prescription patterns. Design and setting: Cohort of 5.4 million women aged between 10 and 50 years identified in electronic health care data from United Kingdom, France, and Italy (2007–2016). Main outcome measures: Anti‐epileptic drug (AED) prescriptions. Results: The prevalence of women receiving AED prescriptions in 2016 varied from 12.2 per 1000 to 29 per 1000 in the four regions. The incidence of prescribing any AED (excluding clonazepam, gabapentin, and pregabalin) fell each year on average by 7.5% (95% CI, 7.0%‐8.0%; Emilia Romagna), 9.6% (8.3%‐11.0%; France), 7.1% (6.7%‐7.6%; Tuscany), and 0.4% (0.2%‐1.0%; United Kingdom). The relative odds of prescribing sodium valproate rather than any other AED decreased more after 2014 compared with before the end of 2014 in France (OR = 0.77; 95% CI, 0.60‐0.98), Tuscany (0.81; 0.76‐0.86), Emilia Romagna (0.83; 0.76‐0.90), and the United Kingdom (0.92; 0.80‐1.06; not statistically significant). Conclusions: There is evidence that the CMDh warning did lead to changes in prescription patterns of sodium valproate in women of childbearing age. There were considerable differences in prescribing practice amongst regions of Europe. [ABSTRACT FROM AUTHOR]

We aimed to assess prevalence, birth outcome, associated anomalies and prenatal diagnosis of congenital clubfoot in Europe using data from the EUROCAT network, and to validate the recording of congenital clubfoot as a major congenital anomaly by EUROCAT registries. Cases of congenital clubfoot were included from 18 EUROCAT registries covering more than 4.8 million births in 1995–2011. Cases without chromosomal anomalies born during 2005–2009, were randomly selected for validation using a questionnaire on diagnostic details and treatment. There was 5,458 congenital clubfoot cases of which 5,056 (93%) were liveborn infants. Total prevalence of congenital clubfoot was 1.13 per 1,000 births (95% CI 1.10–1.16). Prevalence of congenital clubfoot without chromosomal anomaly was 1.08 per 1,000 births (95% CI 1.05–1.11) and prevalence of isolated congenital clubfoot was 0.92 per 1,000 births (95% CI 0.90–0.95), both with decreasing trends over time and large variations in prevalence by registry. The majority of cases were isolated congenital clubfoot (82%) and 11% had associated major congenital anomalies. Prenatal detection rate of isolated congenital clubfoot was 22% and increased over time. Among 301 validated congenital clubfoot cases, diagnosis was confirmed for 286 (95%). In conclusion, this large population‐based study found a decreasing trend of congenital clubfoot in Europe after 1999–2002, an increasing prenatal detection rate, and a high standard of coding of congenital clubfoot in EUROCAT. [ABSTRACT FROM AUTHOR]

Background: Gastroschisis, a congenital anomaly of the abdomen, is associated with young maternal age and has increased in prevalence in many countries. Maternal illness and medication exposure are among environmental risk factors implicated in its aetiology.Methods: A population-based case-malformed control study was conducted using data from 18 European congenital anomaly registries, with information on first trimester medication use, covering 8 million births 1995-2012. 1577 gastroschisis cases (of which 4% stillbirths, 11% terminations of pregnancy) were compared to 153 357 non-chromosomal/monogenic controls. Literature review identified previous associations concerning maternal illness and medication exposure to be tested as signals. Logistic regression adjusted for maternal age group, registry, and time period was used to evaluate associations.Results: Comparing gastroschisis to other congenital anomalies, the data supported signals concerning maternal depression (aOR 2.52, 95% CI 1.45, 4.39), antidepressant use (aOR 2.03, 95% CI 1.22, 3.38), postnatal depression/psychosis following a previous pregnancy (aOR 8.32, 95% CI 2.56, 27.01), sexually transmitted infections (aOR 2.85, 95% CI 1.13, 7.24), topical antivirals (aOR 5.31, 95% CI 1.63, 17.33), and continuation of oral contraceptives in early pregnancy (aOR 2.17, 95% CI 1.13, 4.18). Exploratory analyses suggested associations with a wider range of maternal infections and medications, including tonsillitis and the expectorant bromhexine.Conclusions: While it is difficult to disentangle the effects of the medication and underlying indication, our results add to the evidence base on preventable risk factors for gastroschisis. These risk factors may contribute to the higher risk among young mothers, and geographical and temporal variation in prevalence. [ABSTRACT FROM AUTHOR]

Objective: To provide prognostic information to help parents to reach an informed decision about termination or continuation of the pregnancy and to shape peripartum policy based on a large European cohort.Method: Thirteen registries from the European Surveillance of Congenital Anomalies (EUROCAT) network contributed data from January 1, 1998, to December 31, 2011. Terminations for fetal anomalies were excluded. Chromosomal anomalies, syndromes and isolated anomaly groups were distinguished according to EUROCAT guidelines. Perinatal mortality, stillbirths, and early and late neonatal mortality rates (NMRs) were analyzed by anomaly group and gestational age.Results: Among 73 337 cases, perinatal mortality associated with congenital anomaly was 1.27 per 1000 births (95% confidence interval, 1.23-1.31). Average stillbirth rate was 2.68% (range 0%-51.2%). Early and late NMR were 2.75% (range 0%-46.7%) and 0.97% (range 0%-17.9%), respectively. Chromosomal anomalies and syndromes, and most isolated anomalies, had significant differences regarding timing of fetal demise compared to the general population. Chromosomal and central nervous system anomalies had higher term stillbirth rates.Conclusions: We found relevant differences between anomalies regarding rates of stillbirth, NMR, and timing by gestational age. Our data can help parents to decide about their unborn child with a congenital anomaly and help inform maternal-fetal medicine specialists regarding peripartum management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the prevalence of trisomies 18 and 13 in Europe and the prevalence of associated anomalies. Twenty-five population-based registries in 16 European countries provided data from 2000-2011. Cases included live births, fetal deaths (20+ weeks' gestation), and terminations of pregnancy for fetal anomaly (TOPFAs). The prevalence of associated anomalies was reported in live births. The prevalence of trisomy 18 and trisomy 13 were 4.8 (95%CI: 4.7-5.0) and 1.9 (95%CI: 1.8-2.0) per 10,000 total births. Seventy three percent of cases with trisomy 18 or trisomy 13 resulted in a TOPFA. Amongst 468 live born babies with trisomy 18, 80% (76-83%) had a cardiac anomaly, 21% (17-25%) had a nervous system anomaly, 8% (6-11%) had esophageal atresia and 10% (8-13%) had an orofacial cleft. Amongst 240 Live born babies with trisomy 13, 57% (51-64%) had a cardiac anomaly, 39% (33-46%) had a nervous system anomaly, 30% (24-36%) had an eye anomaly, 44% (37-50%) had polydactyly and 45% (39-52%) had an orofacial cleft. For babies with trisomy 18 boys were less likely to have a cardiac anomaly compared with girls (OR=0.48 (0.30-0.77) and with trisomy 13 were less likely to have a nervous system anomaly [OR=0.46 (0.27-0.77)]. Babies with trisomy 18 or trisomy 13 do have a high proportion of associated anomalies with the distribution of anomalies being different in boys and girls. [ABSTRACT FROM AUTHOR]

ABSTRACT Objectives The aim of this study is to describe the prenatal diagnosis and epidemiology of multicystic kidney dysplasia (MCKD). Methods The study is based on routinely collected data from a European database of major congenital anomalies including 13 registries with cases born in 1997-2006 and covering 1 458 552 births. Results There were 601 MCKD cases giving an overall prevalence of 4.12 per 10 000 births with regional variation. In live births, 87% of cases had an isolated renal anomaly and 13% had associated major nonrenal anomalies (chromosomal, syndrome or other major anomalies). For the cases with isolated renal anomalies, 51/386 (11%) and 7/386 (2%) choose to terminate the pregnancy or resulted in an intrauterine fetal death, respectively. The prenatal detection rate was 88% in both unilateral and bilateral cases. Birth outcome differed with 92% of unilateral MCKD cases being liveborn compared with 33% of bilateral MCKD cases. For unilateral MCKD cases, 84% had an isolated renal anomaly compared with 51% of bilateral MCKD cases ( p < 0.001). Conclusions Cases with unilateral MCKD are mainly liveborn, and only 16% have associated major malformations or a syndrome. Cases with bilateral MCKD are often associated with nonrenal major congenital anomalies or part of a syndrome, and only one third of bilateral MCKD cases in this study were liveborn. Prenatal detection rate of MCKD was high for both unilateral and bilateral cases. © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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. Birth Defects Research (Part A) 100:270-276, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Fraser syndrome is a rare autosomal recessive disorder characterized by cryptophthalmos, cutaneous syndactyly, laryngeal, and urogenital malformations. We present a population-based epidemiological study using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network of birth defect registries. Between January 1990 and December 2008, we identified 26 cases of Fraser syndrome in the monitored population of 12,886,464 births (minimal estimated prevalence of 0.20 per 100,000 or 1:495,633 births). Most cases (18/26; 69%) were registered in the western part of Europe, where the mean prevalence is 1 in 230,695 births, compared to the prevalence 1 in 1,091,175 for the rest of Europe ( P = 0.0003). Consanguinity was present in 7/26 (27%) families. Ten (38%) cases were liveborn, 14 (54%) pregnancies were terminated following prenatal detection of a serious anomaly, and 2 (8%) were stillborn. Eye anomalies were found in 20/24 (83%), syndactyly in 14/24 (58%), and laryngeal anomalies in 5/24 (21%) patients. Ambiguous genitalia were observed in 3/24 (13%) cases. Bilateral renal agenesis was present in 12/24 (50%) and unilateral in 4/24 (17%) cases. The frequency of anorectal anomalies was particularly high (42%). Most cases of Fraser syndrome (85%) are suspected prenatally, often due to the presence of the association of renal agenesis and cryptophthalmos. In the European population, a high proportion (82%) of pregnancies is terminated, thus reducing the live birth prevalence to a third of the total prevalence rate. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND Maternal pregestational diabetes is a well-known risk factor for congenital anomalies. This study analyses the spectrum of congenital anomalies associated with maternal diabetes using data from a large European database for the population-based surveillance of congenital anomalies. METHODS Data from 18 population-based EUROCAT registries of congenital anomalies in 1990-2005. All malformed cases occurring to mothers with pregestational diabetes (diabetes cases) were compared to all malformed cases in the same registry areas to mothers without diabetes (non-diabetes cases). RESULTS There were 669 diabetes cases and 92,976 non diabetes cases. Odds ratios in diabetes pregnancies relative to non-diabetes pregnancies comparing each EUROCAT subgroup to all other non-chromosomal anomalies combined showed significantly increased odds ratios for neural tube defects (anencephaly and encephalocele, but not spina bifida) and several subgroups of congenital heart defects. Other subgroups with significantly increased odds ratios were anotia, omphalocele and bilateral renal agenesis. Frequency of hip dislocation was significantly lower among diabetes (odds ratio 0.15, 95% CI 0.05-0.39) than non-diabetes cases. Multiple congenital anomalies were present in 13.6 % of diabetes cases and 6.1 % of non-diabetes cases. The odds ratio for caudal regression sequence was very high (26.40,95% CI 8.98-77.64), but only 17% of all caudal regression cases resulted from a pregnancy with pregestational diabetes. CONCLUSIONS The increased risk of congenital anomalies in pregnancies with pregestational diabetes is related to specific non-chromosomal congenital anomalies and multiple congenital anomalies and not a general increased risk. Birth Defects Research (Part A), 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The European Surveillance of Congenital Anomalies (EUROCAT) is a network of population-based congenital anomaly registries in Europe, funded by the European Union, which has been in operation for more than 30 years. It currently surveys more than 1.7 million births per year, including 31% of births in the European Union, and includes almost all population-based European congenital anomaly registries as its members. EUROCAT member registries collect data, ascertained from multiple sources, on all major structural congenital and chromosomal anomalies. EUROCAT surveillance relates to three areas: prevalence, primary prevention, and prenatal screening. This article describes the history of EUROCAT and gives an overview of the current methodology and work of EUROCAT covering the database content and management, coding and classification of anomalies, core surveillance, prevalence tables, statistical monitoring. The monitoring of new developments in prenatal diagnosis, medication during pregnancy, use of folic acid, and investigation of clusters and exposures are overseen by working groups responsible for organizing research and producing regular reports. The EUROCAT Web site includes current data on prevalence rates and prenatal detection rates-an example of information useful to clinicians, public health service managers, and patients. Birth Defects Research (Part A), 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The European Surveillance of Congenital Anomalies (EUROCAT) network of population-based congenital anomaly registries is an important source of epidemiologic information on congenital anomalies in Europe covering live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly. EUROCAT's policy is to strive for high-quality data, while ensuring consistency and transparency across all member registries. A set of 30 data quality indicators (DQIs) was developed to assess five key elements of data quality: completeness of case ascertainment, accuracy of diagnosis, completeness of information on EUROCAT variables, timeliness of data transmission, and availability of population denominator information. This article describes each of the individual DQIs and presents the output for each registry as well as the EUROCAT (unweighted) average, for 29 full member registries for 2004-2008. This information is also available on the EUROCAT website for previous years. The EUROCAT DQIs allow registries to evaluate their performance in relation to other registries and allows appropriate interpretations to be made of the data collected. The DQIs provide direction for improving data collection and ascertainment, and they allow annual assessment for monitoring continuous improvement. The DQI are constantly reviewed and refined to best document registry procedures and processes regarding data collection, to ensure appropriateness of DQI, and to ensure transparency so that the data collected can make a substantial and useful contribution to epidemiologic research on congenital anomalies. Birth Defects Research (Part A), 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE The purpose of this article is to present the specific public health indicators recently developed by EUROCAT that aim to summarize important aspects of the public health impact of congenital anomalies in a few quantitative measures. METHODS The six indicators are: (1) congenital anomaly perinatal mortality, (2) congenital anomaly prenatal diagnosis prevalence, (3) congenital anomaly termination of pregnancy, (4) Down syndrome livebirth prevalence, (5) congenital anomaly pediatric surgery, and (6) neural tube defects (NTD) total prevalence. Data presented for this report pertained to all cases (livebirths, fetal deaths, or stillbirths after 20 weeks of gestation and terminations of pregnancy for fetal anomaly [TOPFA]) of congenital anomaly from 27 full member registries of EUROCAT that could provide data for at least 3 years during the period 2004 to 2008. Prevalence of anomalies, prenatal diagnosis, TOPFA, pediatric surgery, and perinatal mortality were calculated per 1000 births. RESULTS The overall perinatal mortality was approximately 1.0 per 1000 births for EUROCAT registries with almost half due to fetal and the other half due to first week deaths. There were wide variations in perinatal mortality across the registries with the highest rates observed in Dublin and Malta, registries in countries where TOPFA are illegal, and in Ukraine. The overall perinatal mortality across EUROCAT registries slightly decreased between 2004 and 2008 due to a decrease in first week deaths. The prevalence of TOPFA was fairly stable at about 4 per 1000 births. There were variations in livebirth prevalence of cases typically requiring surgery across the registries; however, for most registries this prevalence was between 3 and 5 per 1000 births. Prevalence of NTD decreased by about 10% from 1.05 in 2004 to 0.94 per 1000 in 2008. CONCLUSION It is hoped that by publishing the data on EUROCAT indicators, the public health importance of congenital anomalies can be clearly summarized to policy makers, the need for accurate data from registries emphasized, the need for primary prevention and treatment services highlighted, and the impact of current services measured. Birth Defects Research (Part A), 2011.© 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as 'multiple congenital anomaly' cases. RESULTS A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as 'potentially multiple congenital anomalies'. After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research. Birth Defects Research (Part A), 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

BACKGROUND As part of EUROCAT's surveillance of congenital anomalies in Europe, a statistical monitoring system has been developed to detect recent clusters or long-term (10 year) time trends. The purpose of this article is to describe the system for the identification and investigation of 10-year time trends, conceived as a 'screening' tool ultimately leading to the identification of trends which may be due to changing teratogenic factors. METHODS The EUROCAT database consists of all cases of congenital anomalies including livebirths, fetal deaths from 20 weeks gestational age, and terminations of pregnancy for fetal anomaly. Monitoring of 10-year trends is performed for each registry for each of 96 non-independent EUROCAT congenital anomaly subgroups, while Pan-Europe analysis combines data from all registries. The monitoring results are reviewed, prioritized according to a prioritization strategy, and communicated to registries for investigation. Twenty-one registries covering over 4 million births, from 1999 to 2008, were included in monitoring in 2010. CONCLUSIONS Significant increasing trends were detected for abdominal wall anomalies, gastroschisis, hypospadias, Trisomy 18 and renal dysplasia in the Pan-Europe analysis while 68 increasing trends were identified in individual registries. A decreasing trend was detected in over one-third of anomaly subgroups in the Pan-Europe analysis, and 16.9% of individual registry tests. Registry preliminary investigations indicated that many trends are due to changes in data quality, ascertainment, screening, or diagnostic methods. Some trends are inevitably chance phenomena related to multiple testing, while others seem to represent real and continuing change needing further investigation and response by regional/national public health authorities. Birth Defects Research (Part A), 2011.© 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Gastroschisis is an abdominal wall defect more prevalent in offspring of young mothers. It is known to be increasing in prevalence despite the general decrease in the proportion of births to young European women. We investigated whether the increase in prevalence was restricted to the high-risk younger mothers. We analysed 936 cases of gastroschisis from 25 population-based registries in 15 European countries, 1980–2002. We fitted a Bayesian Hierarchical Model which allowed us to estimate trend, to estimate which registries were significantly different from the common distribution, and to adjust simultaneously for maternal age, time (in grouped years) and the random variation between registries. The maternal age-standardised prevalence (standardised to the year 2000 European maternal age structure) increased almost fourfold from 0.54 [95% Credible Interval (CrI) 0.37, 0.75] per 10 000 births in 1980–84 to 2.12 [95% CrI 1.85, 2.40] per 10 000 births in 2000–02. The relative risk of gastroschisis for mothers <20 years of age in 1995–2002 was 7.0 [95% CrI 5.6, 8.7]. There were geographical differences within Europe, with higher rates of gastroschisis in the UK, and lower rates in Italy after adjusting for maternal age. After standardising for regional variation, our results showed that the increase in risk over time was the same for mothers of all ages – the increase for mothers <20 years was 3.96-fold compared with an increase of 3.95-fold for mothers in the other age groups. These findings indicate that the phenomenon of increasing gastroschisis prevalence is not restricted to younger mothers only. [ABSTRACT FROM AUTHOR]

The aim of the study was to analyse the degree to which gestational age (GA) has been shortened due to prenatal diagnosis of gastrointestinal malformations (GIM). The data source for the study was 14 population-based registries of congenital malformations (EUROCAT). All liveborn infants with GIMs and without chromosomal anomalies, born 1997–2002, were included. The 14 registries identified 1047 liveborn infants with one or more GIMs (oesophageal atresia, duodenal atresia, omphalocele, gastroschisis and diaphragmatic hernia). Median GA at birth was lower in prenatally diagnosed cases for all five malformations, although not statistically significant for gastroschisis. There was little difference in median birthweight by GA for the pre- and postnatally diagnosed infants. The difference in GA at birth between prenatally and postnatally diagnosed infants with GIMs is enough to increase the risk of mortality for the prenatally diagnosed infants. Clinicians need to balance the risk of early delivery against the benefits of clinical convenience when making case management decisions after prenatal diagnosis. Very few studies have been able to show benefits of prenatal diagnosis of congenital malformations for liveborn infants. This may be because the benefits of prenatal diagnosis are outweighed by the problems arising from a lower GA at birth. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Amniotic band syndrome (ABS) and limb body wall complex (LBWC) have an overlapping phenotype of multiple congenital anomalies and their etiology is unknown. We aimed to determine the prevalence of ABS and LBWC in Europe from 1980 to 2019 and to describe the spectrum of congenital anomalies. In addition, we investigated maternal age and multiple birth as possible risk factors for the occurrence of ABS and LBWC. We used data from the European surveillance of congenital anomalies (EUROCAT) network including data from 30 registries over 1980-2019. We included all pregnancy outcomes, including live births, stillbirths, and terminations of pregnancy for fetal anomalies. ABS and LBWC cases were extracted from the central EUROCAT database using coding information responses from the registries. In total, 866 ABS cases and 451 LBWC cases were included in this study. The mean prevalence was 0.53/10,000 births for ABS and 0.34/10,000 births for LBWC during the 40 years. Prevalence of both ABS and LBWC was lower in the 1980s and higher in the United Kingdom. Limb anomalies and neural tube defects were commonly seen in ABS, whereas in LBWC abdominal and thoracic wall defects and limb anomalies were most prevalent. Twinning was confirmed as a risk factor for both ABS and LBWC. This study includes the largest cohort of ABS and LBWC cases ever reported over a large time period using standardized EUROCAT data. Prevalence, clinical characteristics, and the phenotypic spectrum are described, and twinning is confirmed as a risk factor., (© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

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.)

Cornelia de Lange syndrome (CdLS) is a multiple congenital anomaly/mental retardation syndrome consisting of characteristic dysmorphic features, microcephaly, hypertrichosis, upper limb defects, growth retardation, developmental delay, and a variety of associated malformations. We present a population-based epidemiological study of the classical form of CdLS. The data were extracted from the database of European Surveillance of Congenital Anomalies (EUROCAT) database, a European network of birth defect registries which follow a standard methodology. Based on 23 years of epidemiologic monitoring (8,558,346 births in the 1980-2002 period), we found the prevalence of the classical form of CdLS to be 1.24/100,000 births or 1:81,000 births and estimated the overall CdLS prevalence at 1.6-2.2/100,000. Live born children accounted for 91.5% (97/106) of cases, fetal deaths 2.8% (3/106), and terminations of pregnancy following prenatal diagnosis 5.7% (6/106). The most frequent associated congenital malformations were limb defects (73.1%), congenital heart defects (45.6%), central nervous system malformations (40.2%), and cleft palate (21.7%). In the last 11 years, as much as 68% of cases with major malformations were not detected by routine prenatal US. Live born infants with CdLS have a high first week survival (91.4%). All patients were sporadic. Maternal and paternal age did not seem to be risk factors for CdLS. Almost 70% of patients, born after the 37th week of gestation, weighed