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Background: Congenital anomalies represent an important global health issue. Data on the prevalence and pattern of congenital anomalies in the Caribbean region are scarce and lacking altogether in Aruba, Bonaire and Curaçao (ABC islands). Methods: We performed a population-based surveillance study to determine the prevalence of structural congenital anomalies in the ABC islands, including all live births and stillbirths between January 1, 2008 and December 31, 2017 with major congenital anomalies according to EUROCAT guide 1.5. Terminations of pregnancy for fetal anomaly were included as well. Cases were identified by active case ascertainment, using multiple sources including pediatric patient files and discharge letters, delivery records, and clinical genetic patient files. Total and subgroup prevalence rates were compared between the three islands and to the French West Indies and Northern Netherlands. Results: Total prevalence of congenital anomalies on the ABC islands was 242.97 per 10,000 births. Total prevalence of congenital anomalies in Bonaire (325.15 per 10,000 births) was higher compared to Aruba (233.29 per 10,000 births) and Curaçao (238.58 per 10,000 births), which was mainly attributable to a higher prevalence of limb anomalies, in particular polydactyly, in Bonaire. Total prevalence of congenital anomalies on the ABC islands was comparable to the French West Indies (248.69 per 10,000 births) but significantly lower compared to the Northern Netherlands (298.98 per 10,000 births). In the subgroup prevalence analysis, the prevalence of polydactyly and atrial septal defect on the ABC islands was significantly higher compared with the French West Indies and the Northern Netherlands, while the prevalence of congenital anomalies of the kidney and urinary tract and genetic disorders was significantly lower. Conclusions: This is the first study to establish the prevalence and pattern of congenital anomalies on the ABC islands, which is important to inform healthcare managers and policymakers and to provide a basis for continuous surveillance of congenital anomalies.

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 2019and 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 see 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. info:eu-repo/semantics/publishedVersion

ObjectiveTo investigate the survival to 10 years of age of children with trisomy 13 (T13) and children with trisomy 18 (T18), born 1995–2014.DesignPopulation-based cohort study that linked mortality data to data on children born with T13 or T18, including translocations and mosaicisms, from 13 member registries of EUROCAT, a European network for the surveillance of congenital anomalies.Setting13 regions in nine Western European countries.Patients252 live births with T13 and 602 with T18.Main outcome measuresSurvival at 1 week, 4 weeks and 1, 5 and 10 years of age estimated by random-effects meta-analyses of registry-specific Kaplan-Meier survival estimates.ResultsSurvival estimates of children with T13 were 34% (95% CI 26% to 46%), 17% (95% CI 11% to 29%) and 11% (95% CI 6% to 18%) at 4 weeks, 1 and 10 years, respectively. The corresponding survival estimates were 38% (95% CI 31% to 45%), 13% (95% CI 10% to 17%) and 8% (95% CI 5% to 13%) for children with T18. The 10-year survival conditional on surviving to 4 weeks was 32% (95% CI 23% to 41%) and 21% (95% CI 15% to 28%) for children with T13 and T18, respectively.ConclusionsThis multi-registry European study found that despite extremely high neonatal mortality in children with T13 and T18, 32% and 21%, respectively, of those who survived to 4 weeks were likely to survive to age 10 years. These reliable survival estimates are useful to inform counselling of parents after prenatal diagnosis.

Background Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies. Objectives This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT). Methods Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. Results Five hundred cases were identified in the period 1998–2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams–Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. Conclusion To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies.

Background: Pierre Robin sequence (PRS) is a rare congenital anomaly. Respiratory disorders and feeding difficulties represent the main burden. Objective: The aim of this study was to investigate the epidemiology of PRS using a cohort of cases from EUROCAT, the European network of population-based registries of congenital anomalies. Methods: We analysed cases of PRS born in the period 1998-2017 collected by 29 population-based congenital anomaly registries in 17 different countries. We calculated prevalence estimates, prenatal detection rate, survival up to 1 week, and proportions of associated anomalies. The effect of maternal age was tested using a Poisson regression model. Results: Out of 11 669 155 surveyed births, a total of 1294 cases of PRS were identified. The estimate of the overall prevalence was 12.0 per 100 000 births (95% CI 9.9, 14.5). There was a total of 882 (68.2%) isolated cases, and the prevalence was 7.8 per 100 000 births (95% CI 6.7, 9.2). A total of 250 cases (19.3%) were associated with other structural congenital anomalies, 77 cases (6.0%) were associated with chromosomal anomalies and 77 (6.0%) with genetic syndromes. The prenatal detection rate in isolated cases was 12.0% (95% CI 9.8, 14.5) and increased to 16.0% (95% CI 12.7, 19.7) in the sub-period 2008-2017. The prevalence rate ratio of non-chromosomal cases with maternal age ≥35 was higher than in cases with maternal age

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.

ObjectiveMethadone is a vital treatment for women with opioid use disorder in pregnancy. Previous reports suggested an association between methadone exposure and Pierre Robin sequence (PRS), a rare craniofacial anomaly. We assessed the association between gestational methadone exposure and PRS.Design/settingThis case-malformed control study used European Surveillance of Congenital Anomalies population-based registries in Ireland, the Netherlands, Italy, Switzerland, Croatia, Malta, Portugal, Germany, Wales, Norway and Spain, 1995–2011.PatientsCases included PRS based on International Classification of Disease (ICD), Ninth Edition-British Paediatric Association (BPA) code 75 603 or ICD, Tenth Edition-BPA code Q8708. Malformed controls were all non-PRS anomalies, excluding genetic conditions, among live births, fetal deaths from 20 weeks’ gestation and terminations of pregnancy for fetal anomalies. An exploratory analysis assessed the association between methadone exposure and other congenital anomalies (CAs) excluding PRS. Methadone exposure was ascertained from medical records and maternal interview.ResultsAmong 87 979 CA registrations, there were 127 methadone-exposed pregnancies and 336 PRS cases. There was an association between methadone exposure and PRS (OR adjusted for registry 12.3, 95% CI 5.7 to 26.8). In absolute terms, this association reflects a risk increase from approximately 1–12 cases per 10 000 births. A raised OR was found for cleft palate (adjusted OR 5.0, 95% CI 2.7 to 9.2).ConclusionsThese findings suggest that gestational methadone exposure is associated with PRS. The association may be explained by unmeasured confounding factors. The small increased risk of PRS in itself does not alter the risk–benefit balance for gestational methadone use. The association with cleft palate, a more common CA, should be assessed with independent data.

Background The VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association is the non-random occurrence of at least three of these congenital anomalies: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb anomalies. Diagnosing VACTERL patients is difficult, as many disorders have multiple features in common with VACTERL. The aims of this study were to clearly outline component features, describe the phenotypic spectrum among the largest group of VACTERL patients thus far reported, and to identify phenotypically similar subtypes. Methods A case-only study was performed assessing data on 501 cases recorded with VACTERL in the JRC-EUROCAT (Joint Research Centre-European Surveillance of Congenital Anomalies) central database (birth years: 1980-2015). We differentiated between major and minor VACTERL features and anomalies outside the VACTERL spectrum to create a clear definition of VACTERL. Results In total, 397 cases (79%) fulfilled our VACTERL diagnostic criteria. The most commonly observed major VACTERL features were anorectal malformations and esophageal atresia/tracheo-esophageal fistula (both occurring in 62% of VACTERL cases), followed by cardiac (57%), renal (51%), vertebral (33%), and limb anomalies (25%), in every possible combination. Three VACTERL subtypes were defined: STRICT-VACTERL, VACTERL-LIKE, and VACTERL-PLUS, based on severity and presence of additional congenital anomalies. Conclusion The clearly defined VACTERL component features and the VACTERL subtypes introduced will improve both clinical practice and etiologic research.

Background: The total prevalence of congenital heart defects (CHDs) varies by populations and over time. Studies that examine trends in the prevalence of CHD in different regions may shed light on our understanding of the occurrence of CHD and the impact of different risk factors. Objectives: To examine trends in total and live birth prevalence of nonsyndromic CHD in Europe between the years 2008 and 2015 and to investigate if the decreasing trend reported by previous studies is continuing. Methods: Cases of CHD delivered between January 1, 2008 and December 31, 2015 notified to 25 population-based EUROCAT (European Surveillance of Congenital Anomalies) registries in 14 countries, formed the population-based case-series. Prevalence (total/live) rates and 95% confidence intervals were calculated as the number of cases per 10,000 births (live and stillbirths). Time trends in prevalence of all nonsyndromic CHDs and for three CHD severity groups (very severe, severe, and less severe) were plotted using a Poisson regression multilevel approach. Results: The total prevalence of nonsyndromic CHD was 57.1 per 10,000 births (live births and stillbirths) for the 8-year period and remained stable across the three CHD severity groups while the live birth prevalence was 60.2 per 10,000 births. There was considerable variation in the reported total CHD prevalence and the direction of trends by registry. A decreasing prevalence ofCHD was observed for the Norway and England/Wales registries, whereas the CHD prevalence increased for registries in Italy and Croatia. Conclusions: The total prevalence of CHD in Europe between the years 2008 and 2015 remained stable for all CHD and across the three CHD severity groups. The decreasing trend reported by previous studies has not continued. However, we found significant differences in the total and live birth prevalence by registry. info:eu-repo/semantics/publishedVersion

Background Congenital anomalies are a leading cause of childhood morbidity, but little is known about the long-term outcomes. Objective To quantify the burden of disease in childhood for children with congenital anomalies by assessing the risk of hospitalisation, the number of days spent in hospital and proportion of children with extended stays (≥10 days). Methods European population-based record-linkage study in 11 regions in eight countries including children with congenital anomalies (EUROCAT children) and without congenital anomalies (reference children) living in the same regions. The children were born between 1995 and 2014 and were followed to their tenth birthday or 31/12/2015. European meta-analyses of the outcome measures were performed by two age groups, Results 99,416 EUROCAT children and 2,021,772 reference children were linked to hospital databases. Among EUROCAT children, 85% (95%-CI: 79–90%) were hospitalised in the first year and 56% (95%-CI: 51–61%) at ages 1–4 years, compared to 31% (95%-CI: 26–37%) and 25% (95%-CI: 19–31%) of the reference children. Median length of stay was 2–3 times longer for EUROCAT children in both age groups. The percentages of children with extended stays (≥10 days) in the first year were 24% (95%-CI: 20–29%) for EUROCAT children and 1% (95%-CI: 1–2%) for reference children. The median length of stay varied greatly between congenital anomaly subgroups, with children with gastrointestinal anomalies and congenital heart defects having the longest stays. Conclusions Children with congenital anomalies were more frequently hospitalised and median length of stay was longer. The outlook improves after the first year. Parents of children with congenital anomalies should be informed about the increased hospitalisations required for their child’s care and the impact on family life and siblings, and they should be adequately supported.

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA.Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation.Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 μg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements.Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year.

Background: Hypospadias is a common male birth defect that has shown widespread variation in reported prevalence estimates. Many countries have reported increasing trends over recent decades.Objective: To analyze the prevalence and trends of hypospadias for 27 international programs over a 31-yr period.Design, setting, and participants: The study population included live births, stillbirths, and elective terminations of pregnancy diagnosed with hypospadias during 1980-2010 from 27 surveillance programs around the world.Outcome measurements and statistical analysis: We used joinpoint regression to analyze changes over time in international total prevalence of hypospadias across programs, prevalence for each specific program, and prevalence across different degrees of severity of hypospadias.Results and limitations: The international total prevalence of hypospadias for all years was 20.9 (95% confidence interval: 19.2-22.6) per 10 000 births. The prevalence for each program ranged from 2.1 to 39.1 per 10 000 births. The international total prevalence increased 1.6 times during the study period, by 0.25 cases per 10 000 births per year (p Conclusions: Although there have been changes in clinical practice and registry ascertainment over time in some countries, the consistency in the observed increasing trends across many programs and by degrees of severity suggests that the total prevalence of hypospadias may be increasing in many countries. This observation is contrary to some previous reports that suggested that the total prevalence of hypospadias was no longer increasing in recent decades.Patient summary: We report on the prevalence and trends of hypospadias among 27 birth defect surveillance systems, which indicate that the prevalence of hypospadias continues to increase internationally. (C) 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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. acceptedVersion

Limb reduction defects (LRDs) that affect multiple limbs are considered to be more often heritable, but only few studies have substantiated this. We aimed to investigate if an etiological diagnosis (genetic disorder or clinically recognizable disorder) is more likely to be made when multiple limbs are affected compared to when only one limb is affected. We used data from EUROCAT Northern Netherlands and included 391 fetuses and children with LRDs born in 1981-2017. Cases were classified as having a transverse, longitudinal (preaxial/postaxial/central/mixed), intercalary, or complex LRD of one or more limbs and as having an isolated LRD or multiple congenital anomalies (MCA). We calculated the probability of obtaining an etiological diagnosis in cases with multiple affected limbs versus one affected limb using relative risk (RR) scores and Fisher's exact test. We showed that an etiological diagnosis was made three times more often when an LRD occurred in multiple limbs compared to when it occurred in one limb (RR 2.9, 95% CI 2.2-3.8, p

Contains fulltext : 229275.pdf (Publisher’s version ) (Open Access) BACKGROUND: The VACTERL association (VACTERL) includes at least three of these congenital anomalies: vertebral, anal, cardiac, trachea-esophageal, renal, and limb anomalies. Assisted reproductive techniques (ART), pregestational diabetes mellitus, and chronic lower obstructive pulmonary disorders (CLOPD) have been associated with VACTERL. We aimed to replicate these findings and were interested in additional maternal risk factors. METHODS: A case-control study using self-administered questionnaires was performed including 142 VACTERL cases and 2,135 population-based healthy controls. Multivariable logistic regression analyses were performed to estimate confounder adjusted odds ratios (aOR) and 95% confidence intervals (95%CI). RESULTS: Parents who used invasive ART had an increased risk of VACTERL in offspring (aOR 4.4 [95%CI 2.1-8.8]), whereas the increased risk for mothers with CLOPD could not be replicated. None of the case mothers had pregestational diabetes mellitus. Primiparity (1.5 [1.1-2.1]) and maternal pregestational overweight and obesity (1.8 [1.2-2.8] and 1.8 [1.0-3.4]) were associated with VACTERL. Consistent folic acid supplement use during the advised periconceptional period may reduce the risk of VACTERL (0.5 [0.3-1.0]). Maternal smoking resulted in an almost twofold increased risk of VACTERL. CONCLUSION: We identified invasive ART, primiparity, pregestational overweight and obesity, lack of folic acid supplement use, and smoking as risk factors for VACTERL.

The aim of the study is to determine the prevalence, outcomes, and survival (among live births [LB]), in pregnancies diagnosed with trisomy 13 (T13) and 18 (T18), by congenital anomaly register and region. Twenty-four population- and hospital-based birth defects surveillance registers from 18 countries, contributed data on T13 and T18 between 1974 and 2014 using a common data-reporting protocol. The mean total birth prevalence (i.e., LB, stillbirths, and elective termination of pregnancy for fetal anomalies [ETOPFA]) in the registers with ETOPFA (n = 15) for T13 was 1.68 (95% CI 1.3-2.06), and for T18 was 4.08 (95% CI 3.01-5.15), per 10,000 births. The prevalence varied among the various registers. The mean prevalence among LB in all registers for T13 was 0.55 (95%CI 0.38-0.72), and for T18 was 1.07 (95% CI 0.77-1.38), per 10,000 births. The median mortality in the first week of life was 48% for T13 and 42% for T18, across all registers, half of which occurred on the first day of life. Across 16 registers with complete 1-year follow-up, mortality in first year of life was 87% for T13 and 88% for T18. This study provides an international perspective on prevalence and mortality of T13 and T18. Overall outcomes and survival among LB were poor with about half of live born infants not surviving first week of life; nevertheless about 10% survived the first year of life. Prevalence and outcomes varied by country and termination policies. The study highlights the variation in screening, data collection, and reporting practices for these conditions.

ObjectivesTo assess international trends and patterns of prenatal diagnosis of critical congenital heart defects (CCHDs) and their relation to total and live birth CCHD prevalence and mortality.SettingFifteen birth defect surveillance programmes that participate in the International Clearinghouse for Birth Defects Surveillance and Research from 12 countries in Europe, North and South America and Asia.ParticipantsLive births, stillbirths and elective terminations of pregnancy for fetal anomaly diagnosed with 1 of 12 selected CCHD, ascertained by the 15 programmes for delivery years 2000 to 2014.Results18 243 CCHD cases were reported among 8 847 081 births. The median total prevalence was 19.1 per 10 000 births but varied threefold between programmes from 10.1 to 31.0 per 10 000. CCHD were prenatally detected for at least 50% of the cases in one-third of the programmes. However, prenatal detection varied from 13% in Slovak Republic to 87% in some areas in France. Prenatal detection was consistently high for hypoplastic left heart syndrome (64% overall) and was lowest for total anomalous pulmonary venous return (28% overall). Surveillance programmes in countries that do not legally permit terminations of pregnancy tended to have higher live birth prevalence of CCHD. Most programmes showed an increasing trend in prenatally diagnosed CCHD cases.Discussion and conclusionsPrenatal detection already accounts for 50% or more of CCHD detected in many programmes and is increasing. Local policies and access likely account for the wide variability of reported occurrence and prenatal diagnosis. Detection rates are high especially for CCHD that are more easily diagnosed on a standard obstetric four-chamber ultrasound or for fetuses that have extracardiac anomalies. These ongoing trends in prenatal diagnosis, potentially in combination with newborn pulse oximetry, are likely to modify the epidemiology and clinical outcomes of CCHD in the near future.

Background: Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains. Objectives: To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries. Methods: We conducted an observational study, using data from 24 population- and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks' gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included. Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10 000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution. Results: Between years 2001 and 2012, the overall first-week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first-week mortality occurred on the first day of life. In programmes where information on long-term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%-96% in Europe, and 86%-96% in North America. Conclusions: Our multi-country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality. Fil: Bakker, Marian K.. University of Groningen; Países Bajos Fil: Kancherla, Vijaya. University of Emory; Estados Unidos Fil: Canfield, Mark A.. No especifíca; Fil: Bermejo-Sanchez, Eva. Instituto de Salud Carlos Iii (isciii); España Fil: Cragan, Janet D.. Centers for Disease Control and Prevention; Estados Unidos Fil: Dastgiri, Saeed. University Of Medical Sciences Tabriz; Irán Fil: De Walle, Hermien E. K.. Pontificia Universidad Javeriana; Colombia Fil: Feldkamp, Marcia L.. No especifíca; Fil: Groisman, Boris. Dirección Nacional de Instituto de Investigación.Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gatt, Miriam. Pontificia Universidad Javeriana; Colombia Fil: Hurtado Villa, Paula. Lund University; Suecia Fil: Kallen, Karin. No especifíca; Fil: Landau, Daniella. Sorbonne University; Francia Fil: Lelong, Nathalie. No especifíca; Fil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Martínez, Laura. Singleton Hospital; Reino Unido Fil: Morgan, Margery. No especifíca; Fil: Mutchinick, Osvaldo M.. No especifíca; Fil: Nembhard, Wendy N.. No especifíca; Fil: Pierini, Anna. No especifíca; Fil: Rissmann, Anke. Otto-von-Guericke-Universität Magdeburg; Alemania Fil: Sipek, Antonin. No especifíca; Fil: Szabova, Elena. No especifíca; Fil: Tagliabue, Giovanna. No especifíca; Fil: Wertelecki, Wladimir. No especifíca; Fil: Zarante, Ignacio. Pontificia Universidad Javeriana; Colombia Fil: Mastroiacovo, Pierpaolo. No especifíca

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.

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.

ObjectivesTo 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 settingA 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 measuresThe 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.ResultsDuring 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).ConclusionsIn 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.

OBJECTIVE: To describe prevalence, time of diagnosis and type of birth in children and fetuses with urinary tract (UT) anomalies after the introduction of the anomaly scan in the Netherlands in 2007.METHODS: We selected, from a population-based congenital anomaly registry, children and fetuses with UT anomalies born between 2008-2014. Cases were defined according to type of UT anomaly and whether isolated or with associated anomalies. Information was collected on time of diagnosis and type of birth.RESULTS: We included 487 cases. Total prevalence increased from 34.0 in 2008 to 42.3 per 10,000 births in 2014, mainly by an increase in anomalies of the collecting system. Almost 70% presented as isolated. Anomalies of the renal parenchyma were more often associated with genetic or other anomalies (47.3%) than anomalies of the collecting system (19.0%). The proportion of prenatally diagnosed cases increased from 59.3 % in 2008 to 80.9% in 2014. Termination of pregnancy occurred in 14.8%, of which the majority were UT anomalies associated with a genetic disorder or other anomalies.CONCLUSION: In the period after the introduction of the anomaly scan we observed an increasing prevalence of anomalies of the collecting system, but no increase in termination of pregnancies.

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.

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

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 73337 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.

Background Pharmacogenetics is an emerging field currently being implemented to improve safety when prescribing drugs. While many women who take drugs during pregnancy would likely benefit from such personalized drug therapy, data is lacking on the awareness towards pharmacogenetics among women. We aim to determine the level of knowledge and acceptance of formerly pregnant women in the Netherlands regarding pharmacogenetics and its implementation, and their interest in pharmacogenetic research. Methods A population-based survey using postal questionnaires was conducted among formerly pregnant women in the Northern parts of the Netherlands. A total of 986 women were invited to participate. Results Of the 219 women who returned completed questionnaires (22.2% response rate), only 22.8% had heard of pharmacogenetics, although the majority understood the concept (64.8%). Women who had experience with drug side-effects were more likely to know about pharmacogenetics [OR = 2.06, 95% CI 1.16, 3.65]. Of the respondents, 53.9% were positive towards implementing pharmacogenetics in their future drug therapy, while 46.6% would be willing to participate in pharmacogenetic research. Among those who were either not willing or undecided in this regard, their concerns were about the consequences of the pharmacogenetic test, including the privacy and anonymity of their genetic information. Conclusion The knowledge and attitude regarding the concept of pharmacogenetics among our population of interest is good. Also, their interest in pharmacogenetic research provides opportunities for future research related to drug use during pregnancy and fetal outcome. Electronic supplementary material The online version of this article (doi:10.1186/s12884-017-1290-z) contains supplementary material, which is available to authorized users.

ObjectiveTo validate the estimates of Global Burden of Disease (GBD) due to congenital anomaly for Europe by comparing infant mortality data collected by EUROCAT registries with the WHO Mortality Database, and by assessing the significance of stillbirths and terminations of pregnancy for fetal anomaly (TOPFA) in the interpretation of infant mortality statistics.Design, setting and outcome measuresEUROCAT is a network of congenital anomaly registries collecting data on live births, fetal deaths from 20 weeks’ gestation and TOPFA. Data from 29 registries in 19 countries were analysed for 2005–2009, and infant mortality (deaths of live births at age ResultsAccording to WHO, 17%–42% of infant mortality was attributed to congenital anomaly. In 11 EUROCAT countries, average infant mortality with congenital anomaly was 1.1 per 1000 births, with higher rates where TOPFA is illegal (Malta 3.0, Ireland 2.1). The rate of stillbirths with congenital anomaly was 0.6 per 1000. The average TOPFA prevalence was 4.6 per 1000, nearly three times more prevalent than stillbirths and infant deaths combined. TOPFA also impacted on the prevalence of postneonatal survivors with non-lethal congenital anomaly.ConclusionsBy excluding TOPFA and stillbirths from GBD years of life lost (YLL) estimates, GBD underestimates the burden of disease due to congenital anomaly, and thus declining YLL over time may obscure lack of progress in primary, secondary and tertiary prevention.

Objective: To study whether specific congenital anomalies occur more often with a history of subfertility and/or the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI).Design: Case-only analyses.Setting: Not applicable.Patient(s): We included live births, stillbirths, and terminated pregnancies with congenital anomalies without a known cause that had a birth year between 1997 and 2010 (n = 4,525). A total of 4,185 malformed cases were born to fertile couples and 340 to subfertile couples, of whom 139 had conceived after IVF/ICSI and 201 had conceived naturally after >12 months.Intervention(s): None.Main Outcome Measure(s): The contribution, expressed in odds ratios (ORs), of a history of subfertility and IVF/ICSI to each specific type of congenital anomaly, imprinting disorder, and syndromal disorder.Result(s): We found subfertility to be associated with an increase in abdominal wall defects (adjusted OR [aOR] 2.43, 95% CI 1.05-5.62), penoscrotal hypospadia (aOR 9.83, 95% CI 3.58-27.04), right ventricular outflow tract obstruction (aOR 1.77, 95% CI 1.06-2.97), and methylation defects causing imprinting disorders (aOR 13.49, 95% CI 2.93-62.06). In vitro fertilization/ICSI was associated with an increased risk of polydactyly (OR 4.83, 95% CI 1.39-16.77) and more specifically polydactyly of the hands (OR 5.02, 95% CI 1.43-17.65).Conclusion(s): In our registry-based study, parental subfertility was associated with an increase in abdominal wall defects, penoscrotal hypospadia, right ventricular outflow tract obstruction, and methylation defects causing imprinting disorders. In vitro fertilization/ICSI was associated with an increase in polydactyly, mainly of the hands. (C) 2015 by American Society for Reproductive Medicine.

Objectives: Microcephaly is a congenital anomaly where the baby’s head is smaller than expected when compared with babies of the same sex, age and ethnicity. Many of these babies will have underdeveloped brains. This study aimed to provide contemporary estimates of the prevalence of microcephaly in Europe, determine if the diagnosis of microcephaly is consistent across Europe and to evaluate whether changes in prevalence would be detected using the current European surveillance performed by EUROCAT (the European Surveillance of Congenital Anomalies). Design: A questionnaire and a population-based, observational study Setting: 24 EUROCAT registries covering 570,000 births annually in 15 countries. Participants: 2443 cases of microcephaly not associated with a genetic condition, among live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly at any gestation. Main Outcome Measures: Prevalence of microcephaly (1st Jan 2003- 31st Dec 2012) analysed using random effects Poisson regression models to account for heterogeneity across registries. Results: Sixteen registries responded to the questionnaire of whom 44% (7/16) used the EUROCAT definition of microcephaly (a reduction in the size of the brain with a skull circumference more than 3 standard deviations (SD) below the mean for sex, age and ethnic origin), 19% (3/16) used a 2 SD cut-off, 31% (5/16) were reliant on the criteria used by individual clinicians and one registry changed criteria between 2003 and 2012. Prevalence of microcephaly in Europe was 1.53 (95% CI : 1.16-1.96) per 10,000 births with registries varying from 0.4 (95% CI : 0.2-0.7) to 4.3 (95% CI : 3.8-4.8) per 10,000 (Chi-squared =338 with 23 degrees of freedom, I2 = 93%). Registries with the 3 SD cut-off reported a prevalence of 1.74 per 10,000 (95% CI: 0.86-2.93) compared with those with the less stringent 2 SD cut-off of 1.21 per 10,000 (95% CI: 0.21-2.93). The prevalence of microcephaly would need to increase in 1 year by over 35% in Europe or by over 300% in a single registry to reach statistical significance (pConclusions: EUROCAT could detect increases in the prevalence of microcephaly due to the Zika virus of a similar magnitude to those observed in Brazil. However, due to the rarity of microcephaly and discrepant diagnostic criteria, the smaller increases expected in Europe would be unlikely to be detected. Clear diagnostic criteria for microcephaly must be adopted across Europe.

CHARGE syndrome is characterized by the variable occurrence of multisensory impairment, congenital anomalies, and developmental delay, and is caused by heterozygous mutations in the CHD7 gene. Correct interpretation of CHD7 variants is essential for genetic counseling. This is particularly difficult for missense variants because most variants in the CHD7 gene are private and a functional assay is not yet available. We have therefore developed a novel classification system to predict the pathogenic effects of CHD7 missense variants that can be used in a diagnostic setting. Our classification system combines the results from two computational algorithms (PolyPhen-2 and Align-GVGD) and the prediction of a newly developed structural model of the chromo- and helicase domains of CHD7 with segregation and phenotypic data. The combination of different variables will lead to a more confident prediction of pathogenicity than was previously possible. We have used our system to classify 145 CHD7 missense variants. Our data show that pathogenic missense mutations are mainly present in the middle of the CHD7 gene, whereas benign variants are mainly clustered in the 5' and 3' regions. Finally, we show that CHD7 missense mutations are, in general, associated with a milder phenotype than truncating mutations. Hum Mutat 33:12511260, 2012. (c) 2012 Wiley Periodicals, Inc.

Udgivelsesdato: 2010 OBJECTIVES: L1 syndrome is an X-linked recessive disorder for which we aimed to: develop a comprehensive mutation analysis system with a high rate of detection, develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and look for genotype-phenotype correlations. METHODS: The DNA of 367 referred cases was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences, and for large duplications. Clinical data for 106 patients was collected and used for statistical analysis. RESULTS: We detected 68 different mutations in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, our mutation detection rate was 66% compared to 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (odds ratio 10.4, confidence interval 3.6-30.1). The type of mutation has impact on the severity of L1 syndrome. Children with a truncating mutation died more frequently (52%) before the age of three than those with a missense mutation (8%) (p=0.02). CONCLUSIONS: We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients' clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.

What is already known about this subject • Recently, the use of selective serotonin reuptake inhibitors (SSRIs), particularly paroxetine, in pregnancy has been associated with an increased risk on specific birth defects or other adverse pregnancy outcomes. • However, the extent of SSRI use in pregnancy is largely unknown. What this study adds • In the last decade the use of SSRIs in the year preceding delivery has increased twofold. • This increase runs parallel with the increase in use of SSRIs among women of fertile age. • Paroxetine is one of the most commonly used SSRIs. • Only recently have sufficient data become available on the use of paroxetine to detect moderate increased risks for specific malformations. • The safety of SSRIs which are less frequently used is not yet established. • Case–control birth defect-monitoring systems may be helpful in providing safety and risk estimates that become more precise as data accumulate for these drugs. Aims Recent case–control studies suggest a relationship between the use of selective serotonin reuptake inhibitors (SSRIs) and the occurrence of birth defects and other adverse pregnancy outcomes. The aim was to determine the extent of the use of SSRIs before and during pregnancy and its trend over the years 1995–2004 in the Netherlands. Methods The study was performed with data from a population-based prescription database. Within this database, women giving birth to a child between 1995 and 2004 were identified. The exposure rate and 95% confidence interval (CI) were calculated as the number of pregnancies per 1000 that were exposed to an SSRI in a defined period (per trimester or in the year preceding delivery). Exposure rates were calculated for 2-year periods: 1995/1996, 1997/1998, 1999/2000, 2001/2002 and 2003/2004. Trends in exposure rates were analysed using the χ2 test for trend. Results Included were 14 902 pregnancies for which complete pharmacy records were available from 3 months before pregnancy until delivery. A total of 310 pregnancies were exposed to an SSRI in the year preceding delivery. The exposure rate increased from 12.2 (95% CI 7.0, 19.8) in 1995/1996 to 28.5 (95% CI 23.0, 34.9) in 2003/2004. Conclusion There has been a significant increase in the use of SSRIs among pregnant women in the Netherlands over the last 10 years, parallel with the increase in exposure in women of fertile age. In light of the recent warnings about the use of SSRIs in pregnancy, healthcare professionals should be careful in prescribing SSRIs to women planning a pregnancy.

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.

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 beta(2)-agonists compared with nonchromosomal control registrations. Odds of exposure to salbutamol were similar. Nonsignificant ORs of exposure to inhaled beta(2)-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 beta(2)-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 beta(2)-agonists for cleft palate and gastroschisis and found a potential new signal for renal dysplasia associated with combined long-acting beta(2)-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.

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. Published 2005 Wiley-Liss, Inc.

BackgroundThis 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. Birth Defects Research (Part A) 100:260-269, 2014. (c) 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 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.

This retrospective cohort study was planned to determine whether recommendations to take folic acid have in fact lessened the risk of neural tube defects. Recommendations typically include eating a healthy diet and takingfolic acid supplements when planning pregnancy or throughout the childbearing years. In a few countries, including the United States, flour is fortified so that much of the population will receive at least a small supplemental amount of folic acid. Many governments promote the use of supplements because folic acid is inexpensive, safe, and easy to use. The authors acquired information on more than 13 million births from 13 birth defects registries in Norway that monitored rates of neural tube defects from 1988 to 1998. Cases of anencephaly and spina bifida totaled 8636. Rates of defects were stable during the 10-year monitoring interval in most areas. There were no evident changes in rates of defects after local recommendations were issued. Comparable findings were obtained when analyzing anencephaly and spina bifida separately and combined. Folic acid use in Europe is, in general, low; in Norway, it is approximately 10%. In China, intensive educational efforts and a high rate of planned pregnancies probably are responsible for the effectiveness of a public health campaign to promote the use of folic acid supplements. Rates of folic acid use generally follow economic and educational trends. Fortifying flour with folic acid holds promise for delivering some folic acid to a large part of the population, crossing social and economic barriers. Blood folate levels have increased rapidly where this practice is followed. It is estimated that thousands of neural tube defects occurring since 1992 could have been prevented.

Item does not contain fulltext BACKGROUND: In case-control studies that assess associations between medication use and birth defects, detailed information on type of medication and timing of use is essential to prevent misclassification. However, data on the accuracy of recall of medication use during pregnancy are scarce. OBJECTIVE: The aim of this study was to validate a self-administered questionnaire to assess prescription medication use in the 3 months before and during pregnancy. METHODS: This validation study was embedded in Eurocat Northern Netherlands, a population-based birth defects registry that covers 10% of all births in The Netherlands. The questionnaire was validated among 560 mothers of infants with major birth defects registered from 1 January 2009 through 30 June 2010 by comparing it with a reference standard consisting of pharmacy data which were checked for compliance by maternal interviews. Sensitivity and specificity were calculated to quantify validity for any prescription medication use, groups of medications and individual medications. In addition, we determined whether maternal characteristics influenced disagreement between the questionnaire and the reference standard using logistic regression analyses. RESULTS: The sensitivity for any prescription medication use was 0.57, ranging between 0.07 (dermatological corticosteroids) and 0.83 (antihypertensives) for medication groups, and between 0.00 (naproxen) and 0.73 (salbutamol) for individual medications. Overall, specificity was high (0.93-1.00). Smoking during pregnancy and completing the questionnaire>2 years after delivery were associated with increased disagreement between the questionnaire for prescription medication use and the reference standard. CONCLUSIONS: The validity of the self-administered questionnaire for prescription medication use during pregnancy was moderate to poor for most medications and disagreement differed by some maternal characteristics. As many epidemiological studies use similar questionnaires to assess medication use these studies may need additional data sources such as pharmacy records or prescription databases for medication use next to self-reported methods. Also, previous knowledge on the effect of questionnaire design should be taken into account.

Periconceptional folic acid has been associated with a reduced risk of neural tube defects, but findings on its effect in oral clefts are largely inconclusive. This case-control study assesses the effects of periconceptional folic acid on cleft risk, using complementary data from the Dutch Oral Cleft Registry and a population-based birth defects registry (Eurocat) of children and foetuses born in the Northern Netherlands between 1997 and 2009. Cases were live-born infants with non-syndromic clefts (n = 367) and controls were infants or foetuses with chromosomal/syndromal (n = 924) or non-folate related anomalies (n = 2,021). We analyzed type/timing/duration of supplement use related to traditional cleft categories as well as to their timing (early/late embryonic periods) and underlying embryological processes (fusion/differentiation defects). Consistent supplement use during the aetiologically relevant period (weeks 0-12 postconception) was associated with an increased risk of clefts (adjusted odds ratio 1.72, 95 % confidence interval 1.19-2.49), especially of cleft lip/alveolus (3.16, 1.69-5.91). Further analysis systematically showed twofold to threefold increased risks for late differentiation defects-mainly clefts of the lip/alveolus-with no significant associations for early/late fusion defects. Effects were attributable to folic acid and not to other multivitamin components, and inclusion of partial use (not covering the complete aetiologically relevant period) generally weakened associations. In conclusion, this study presents several lines of evidence indicating that periconceptional folic acid in the Northern Netherlands is associated with an increased risk of clefts, in particular of cleft lip/alveolus. This association is strengthened by the specificity, consistency, systematic pattern, and duration of exposure-response relationship of our findings, underlining the need to evaluate public health strategies regarding folic acid and to further investigate potential adverse effects.

Contains fulltext : 89586.pdf (Publisher’s version ) (Closed access) AIMS: To investigate the potentially protective of periconceptional folic acid use on the risk of congenital heart defects (CHDs) relative to other non-folate related malformations. METHODS AND RESULTS: We analysed data from a large regional register of birth defects (EUROCAT-Northern Netherlands), over a 10 year period (1996-2005) for a case-control study. The cases were mothers who had delivered infants with isolated or complex heart defects, without any related syndrome or genetic abnormality (n = 611). We used two control groups; one from the EUROCAT database and another from the general population. The registry controls consisted of mothers of children with a known chromosomal or genetic defect, and with infants with other non-folate related congenital malformations (n = 2401). Additional folic acid was taken as a single supplement or as a multivitamin containing folic acid in a dose of >or=400 microg daily. Mothers who had used folate antagonists or who had diabetes, and mothers of children with oral clefts, hypospadias, limb reduction- or neural tube defects, were excluded from both groups. Potentially confounding factors of periconceptional folic acid use in relation to CHD were explored, including baby's birth year, maternal body mass index, education, maternal age at delivery of index baby, smoking behaviour, and alcohol use during pregnancy. Periconceptional folic acid use revealed an odds ratio (OR) of 0.82 (95% CI 0.68-0.98) for all types of CHD relative to other malformations. The estimated relative risk for CHDs of additional folic acid use compared with the general population was comparable [OR 0.74 (95%CI 0.62-0.88)]. Subgroup analysis showed an OR of 0.62 (95% CI 0.47-0.82) for isolated septal defects. The proportions of the potential confounders between mothers of case and control infants did not differ significantly. CONCLUSION: Our results support the hypothesis that additional periconceptional folic acid use reduces CHD risk in infants. Use of periconceptional folic acid supplements was related to approximately 20% reduction in the prevalence of any CHD. Given the relatively high prevalence of CHD worldwide, our findings are important for public health. 01 februari 2010

Eurocat is a network of population based registers of congenital anomalies in Europe covering about a quarter of the birth population in 19 countries (http://www.eurocat.ulster.ac.uk/). We surveyed registries with regard to the requirement for informed consent and its implementation.1 We sent a questionnaire on ethics and confidentiality developed by the Eurocat Working Group to 35 registries in 2003 and updated June 2004; 29 registries from 15 countries replied (table). Eight registries reported experience of opt-in informed consent. View this table: National legislation on informed consent for congenital anomaly and other clinical registers Five registries depend on medical records and notification from clinicians. One experienced a fall in registration (less than 10 written consents in the entire year in which opt-in consent was instituted, compared with 249 cases in the year before opt-in) such that an exemption was negotiated enabling a switch to opt-out consent. Currently 0.1% of parents opt out. A second registry, in which notifying clinicians ask for consent by post, is permitted to keep a reduced, anonymous set of documentation on cases without consent (about 18%). A third registry gives administrative help for clinicians obtaining consent …