Ten-Year Survival of Children With Congenital Anomalies: A European Cohort Study

OBJECTIVES: To investigate the survival up to age 10 for children born alive with a major congenital anomaly (CA). METHODS: This population-based linked cohort study (EUROlinkCAT) linked data on live births from 2005 to 2014 from 13 European CA registries with mortality data. Pooled Kaplan-Meier survival estimates up to age 10 were calculated for these children (77054 children with isolated structural anomalies and 4011 children with Down syndrome). RESULTS: The highest mortality of children with isolated structural CAs was within infancy, with survival of 97.3% (95% confidence interval [CI]: 96.6%–98.1%) and 96.9% (95% CI: 96.0%–97.7%) at age 1 and 10, respectively. The 10-year survival exceeded 90% for the majority of specific CAs (27 of 32), with considerable variations between CAs of different severity. Survival of children with a specific isolated anomaly was higher than in all children with the same anomaly when those with associated anomalies were included. For children with Down syndrome, the 10-year survival was significantly higher for those without associated cardiac or digestive system anomalies (97.6%; 95% CI: 96.5%–98.7%) compared with children with Down syndrome associated with a cardiac anomaly (92.3%; 95% CI: 89.4%–95.3%), digestive system anomaly (92.8%; 95% CI: 87.7%–98.2%), or both (88.6%; 95% CI: 83.2%–94.3%). CONCLUSIONS: Ten-year survival of children born with congenital anomalies in Western Europe from 2005 to 2014 was relatively high. Reliable information on long-term survival of children born with specific CAs is of major importance for parents of these children and for the health care professionals involved in their care. Full article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2021-053793 Faculty of Medical Sciences, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom; Unit of Epidemiology of Rare diseases and Congenital Anomalies, Institute of Clinical Physiology, National Research Council, Pisa, Italy; Fondazione Toscana Gabriele Monasterio, Pisa, Italy; Population Health Research Institute, St George’s, University of London, London, United Kingdom; Pediatric Department, Hospital Lillebaelt, Kolding, Denmark; Faculty of Life & Health Sciences, Ulster University, Northern Ireland, United Kingdom; Rare Diseases Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, Valencia, Spain; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Malta Congenital Anomalies Registry, Directorate for Health Information and Research, Tal-Piet a, Malta; Information Services Department, THL Finnish Institute for Health and Welfare. Helsinki, Finland; Obstetrical, Perinatal and Pediatric Epidemiology Research Team (EPOP e), INSERM-INRA, Universit e de Paris, Center of Research in Epidemiology and Statistics (CRESS), Paris, France; Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway; Center for Clinical and Epidemiological Research, University of Ferrara, Ferrara, Italy; Faculty of Health and Life Science, Swansea University, Swansea, United Kingdom; Public Health Wales, Swansea, United Kingdom; and Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom WHAT’S KNOWN ON THIS SUBJECT: Survival beyond infancy in children born with common congenital anomalies (CAs) has been reported by individual studies, but long-term survival estimates for children with a wide range of specific CAs using standardized population-based multicenter data are lacking. WHAT THIS STUDY ADDS: This population-based linked cohort study from 13 regions within 9 European countries (EUROlinkCAT) provided reliable survival estimates up to age 10 for children with specific isolated and nonisolated structural CAs that are important for clinical practice and counseling. To cite: Glinianaia SV, Rankin J, Pierini A, et al. Ten-Year Survival of Children With Congenital Anomalies: A European Cohort Study. Pediatrics. 2022;149(3):e2021053793 PEDIATRICS Volume 149, number 3, March 2022:e2021053793 ARTICLE D ow naded rom http://publications.aap.org/pediatrics542/peds.2021-053793/1261028/peds_2021053793.pdf by gest on 18 Feruary 2022 Congenital anomalies (CAs) are a major cause of perinatal, neonatal, and infant mortality in high-income countries, including the United States and Western European countries. Their contribution to mortality in children <5 years and in older children is also significant. Evidence from a 15-year time trend analysis (2001–2015) of preventable child mortality in 34 members of the Organization for Economic Co-operation and Development, including the United States, Canada, Japan, Australia, New Zealand, and Europe, showed that congenital heart defects (CHDs) were the second leading cause of mortality in infancy (<1 year), the leading cause of mortality in children aged 1 to 4 years, and the third cause in older children (5–14 years old). Globally, after a reduction of child mortality because of communicable diseases, the relative contribution of CAs to child mortality is increasing. Despite the global decline in infant and child mortality, a large variation in child death rates exists between countries, including Western Europe. Because of considerable length and costs of long-term follow-up studies, there is less research on survival beyond the first year of life, particularly for rare types of CAs. We found no published studies from Western Europe that summarized and compared survival of children with specific CAs aged beyond 1 year. Given that the significantly increased mortality of children born with CAs compared with the general population is not restricted to infancy, this research is of major public health importance. This multicenter, population-based, linked cohort European study aimed to investigate the survival up to age 10 of children born with a major CA from 2005 to 2014 by linking data on live births from 13 European Surveillance of Congenital Anomalies (EUROCAT) registries to mortality data. This study was part of the EUROlinkCAT project that aimed to investigate the survival, morbidity, and educational outcomes of European children born with major CAs by linking live births with CAs to electronic administrative, health care, and education databases.

WHAT'S KNOWN ON THIS SUBJECT: Survival beyond infancy in children born with common congenital anomalies (CAs) has been reported by individual studies, but long-term survival estimates for children with a wide range of specific CAs using standardized population-based multicenter data are lacking.
WHAT THIS STUDY ADDS: This population-based linked cohort study from 13 regions within 9 European countries (EUROlinkCAT) provided reliable survival estimates up to age 10 for children with specific isolated and nonisolated structural CAs that are important for clinical practice and counseling.
Congenital anomalies (CAs) are a major cause of perinatal, neonatal, and infant mortality in high-income countries, including the United States and Western European countries. [1][2][3][4] Their contribution to mortality in children <5 years 5,6 and in older children 7 is also significant. Evidence from a 15-year time trend analysis (2001)(2002)(2003)(2004)(2005)(2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015) of preventable child mortality in 34 members of the Organization for Economic Co-operation and Development, including the United States, Canada, Japan, Australia, New Zealand, and Europe, showed that congenital heart defects (CHDs) were the second leading cause of mortality in infancy (<1 year), the leading cause of mortality in children aged 1 to 4 years, and the third cause in older children (5-14 years old). 8 Globally, after a reduction of child mortality because of communicable diseases, the relative contribution of CAs to child mortality is increasing. 6,9,10 Despite the global decline in infant and child mortality, 9,11 a large variation in child death rates exists between countries, including Western Europe. 12 Because of considerable length and costs of long-term follow-up studies, there is less research on survival beyond the first year of life, particularly for rare types of CAs. We found no published studies from Western Europe that summarized and compared survival of children with specific CAs aged beyond 1 year. Given that the significantly increased mortality of children born with CAs compared with the general population is not restricted to infancy, 13,14 this research is of major public health importance.
This multicenter, population-based, linked cohort European study aimed to investigate the survival up to age 10 of children born with a major CA from 2005 to 2014 by linking data on live births from 13 European Surveillance of Congenital Anomalies 15,16 (EUROCAT) registries to mortality data. This study was part of the EUROlinkCAT project that aimed to investigate the survival, morbidity, and educational outcomes of European children born with major CAs by linking live births with CAs to electronic administrative, health care, and education databases. 17

Setting and Population
Initially, 21 population-based EUROCAT registries agreed to participate in the EUROlinkCAT project. 17 Three registries were unable to obtain linked data within the given time frame, whereas the data linkage in 3 other registries was not considered of sufficient quality. 18 An additional registry (Belgium: Antwerp) was not included in this analysis because it did not provide death data beyond infancy and for some specific CAs because of their country's restrictions on releasing small numbers. Survival of children from the only EUROCAT registry in Eastern Europe (Ukrainian OMNI-Net) was considerably lower compared with all other registries. Because childhood mortality is higher in Eastern than in Western Europe, 19 and because OMNI-Net was the only registry from Eastern Europe, it was decided to limit the analysis to Western European registries.
All live-born children with a major CA born between January 1, 1995, and December 31, 2014, recorded in the 13 registries were linked to mortality sources up to the child's 10th birthday or to December

Data Linkage
The EUROCAT registries have ethics permissions and procedures for routine surveillance, data collection, and transmission of anonymized data to a central database, according to national guidelines. Twelve CA registries sought local ethics approvals or other permissions to link their data with local mortality sources; 1 registry (Norway) obtained permission to use data they had already linked.
Registries linked their CA data to either national/vital statistics or to mortality records only. Linkage to national and vital statistics provided information on the vital status of all linked children (dead or alive) and, hence, a measure of successful linkage. Conversely, only registered deaths could be ascertained from mortality records; that is, children without death certificates were assumed to be alive, although it could have been a linkage failure. A detailed description of the linkage process and results is provided elsewhere. 18 Data were only included in this paper from those registries where the linkage success was >85% for all years; for 5 registries, it was $99%.

Classification of Congenital Anomalies and Definitions
All major CAs were coded using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision 20 or 9th Revision, and categorized by CA group and subgroup (the organ system affected and the individual disorder) following the EUROCAT guidelines. 21 Children with only minor anomalies, defined in EUROCAT as those with lesser medical, functional, or cosmetic consequences for the child (eg, clinodactyly), were not included. 22 For each CA subgroup, all children with the specified anomalies were included and those with an isolated anomaly only were identified, resulting in 2 groups for analysis: "All" and "Isolated." An isolated CA was defined as a structural CA in one organ system only or as part of a known sequence (eg, renal agenesis with pulmonary hypoplasia). A child classified as having an isolated anomaly may be included in >1 anomaly subgroup within the same organ system (eg, esophageal atresia and anal atresia). The EUROCAT hierarchical computer algorithm for classification of major CAs was used 23,24 without a manual clinical review of the identified potential multiple CAs. This article is focused on relatively common structural CAs in live births (live birth prevalence $1 per 10 000) and Down syndrome as the most common chromosomal anomaly (Supplemental Table 4). 17

Statistical Analysis
In addition to the standardized EUROCAT variables, 17 a common data model was developed to standardize the local variables obtained from linkage. This enabled centrally written syntax scripts for checking the linkage quality and for the analysis of mortality data to be run by all registries. 17 The statistical analysis consisted of 2 stages. First, the probability of survival at specific ages (7 days, 28 days, 3 months, 6 months, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 years) was calculated for each CA subgroup using Kaplan-Meier survival analysis, which takes into account the censoring of the data that occurred mainly because of the end of follow-up being December 31, 2015. This analysis was performed on individual case data by the registries locally using the centrally written syntax script. Registries then uploaded the Kaplan-Meier survival estimates with 95% confidence intervals (CIs), the number at risk, and the number of deaths at each age for each CA subgroup to the Central Results Repository at Ulster University, United Kingdom, using a secure Web platform. No individual case data were uploaded. The second stage involved pooling these data by meta-analysis to produce projectwide estimates.

Meta-Analysis
The Kaplan-Meier survival estimates were combined in a random-effects meta-analysis to estimate the overall survival for each CA subgroup by modifying a method proposed by Combescure et al. 25 Combescure proposed the random-effects metaanalysis of survival curves by using the DerSimonian and Laird multivariate procedure 26 on arc-sine transformations of the conditional survival probabilities with a continuity correction of 0.25. However, when analyzed by individual CA subgroups, low numbers of cases in each registry and relatively low death rates for certain CA subgroups resulted in 100% survival for all registries for certain age years. By applying the method above, the model estimated a decrease in survival at these ages despite no deaths occurring, resulting in an underestimation of the overall survival. We therefore applied 3 adaptations. Firstly, instead of using the fixed continuity correction of 0.25 within the arcsine transformation, a variable continuity correction equal to 1/n (the number of children alive at the start of the period) was used. This allowed the continuity correction to shrink with increasing sample sizes, while simultaneously reducing the overweighting of high survivals when sample sizes are small, which occurs because of the multivariate meta-analytic technique. This reduced the bias introduced into the country-level estimates when their samples sizes were $6 children. Secondly, data were excluded from the analysis if there were <6 children alive with the specified anomaly in a registry at a certain age. This was required because even the variable 1/n continuity correction still introduced bias for sample sizes <6. Thirdly, if no deaths occurred in any of the registries after a certain age, the overall survival for the remaining ages was imputed as the survival rate for the previous time period. This is a logical assumption because no deaths had been observed. In scenarios where there were no deaths in any registry during specific ages (eg, ages 3 and 4), but deaths did occur in later time periods, the meta-analyses were run on a reduced number of time points to limit the prevalence of the "no death" time periods. In these scenarios, instead of the 9 yearly time points, 2-10 average survival was calculated between ages 1 to 5 and 6 to 10. This preserved the use of all the data but reduced the number of time points in which continuity corrections would introduce significant bias. All metaanalyses were performed using R software.
Sensitivity analyses were performed excluding each registry in turn to determine if the overall survival estimates differed significantly.

Comparison of 10-Year Survival Between Different Congenital Anomaly Groups
Four independent categories of children with Down syndrome were analyzed: those without associated CHD or digestive system anomaly, those with only a CHD, those with only a digestive system anomaly, and those with both (other, less common associated CAs were not considered). The 10-year survival estimates for each registry were analyzed using a random-effects meta-analysis comparing the 3 Down syndrome groups with an associated CHD and/or digestive system anomaly with the group without any of these CAs.
Ten-year survival estimates with 95% CI for Isolated and for All groups were plotted for selected CAs. No formal statistical tests were performed because the All group included children in the Isolated group.
Stata v16 (StataCorp LLC, 2019) was used for the above comparisons.   Table 2 also shows survival for children with Down syndrome (n 5 4011) with or without CHD or digestive system anomaly. Compared with the highest 10-year survival in children with Down syndrome without associated CHD or digestive system anomaly of 97.6% (95% CI: 96.5%-98.7%), survival was significantly lower when Down syndrome was associated with any CHD but not digestive system anomaly (P < .001), with any digestive system anomaly but not CHD (P 5 .018), and with both CHD and digestive system anomaly (P < 0.001).

RESULTS
In the sensitivity analysis, the pooled survival estimates were robust to the exclusion of data from individual registries for most specific CAs (within ±2.5%, but mostly within ±1%), except for severe microcephaly (Wales registry: 5.7%) and HLH (Finland registry: 3.6%) (Supplemental Table 5).  Table 3, for "any CA," although 80% of live births were in children with isolated CAs, only 47.5% of deaths occurred in these children, indicating the higher survival in children with an isolated CA (96.9%, Table 2) compared with All CA (94.8%, Table 3). The proportions of children with isolated CAs in all live births and all deaths differed by CA severity, being more similar for severe CAs (eg, HLH, atrioventricular septal defect, diaphragmatic hernia). This indicates that, for these anomalies, the death is most likely related to that specific CA, whereas in other CAs with large differences in proportions, the death is related to the associated anomalies and karyotype defect.
Survival curves are shown for children with more common The number of live births or deaths for "any isolated anomaly" is not equal to the sum of those for each CA subgroup because some CAs may belong to >1 CA subgroup; for example, an individual CHD may also be associated with severe CHD, and any isolated anomaly may include other subgroups not listed in this table. The survival estimate of 100% at 1 week for 2 CA subgroups is because of rounding to 1 decimal place. The number of deaths from the Netherlands: Northern registry were rounded to 0 or 5 because of small number restrictions and therefore were not included in the numbers of live births and deaths but were included in the survival estimates. ASD, atrial septal defect; AVSD, atrioventricular septal defect. a For each anomaly subgroup, all children with the specified anomalies were included, and those with an isolated anomaly only were identified. An isolated CA is defined as a structural CA in 1 organ system only or if coexisting anomalies were a consequence of a single primary anomaly. b Reduction in the size of the brain with a head circumference >3 SDs below the mean for sex, gestational age, and ethnic origin (EUROCAT definition 41 ). c Severe CHD included the following CHD subgroups: common arterial truncus, double outlet right ventricle, transposition of great vessels, single ventricle, atrioventricular septal defect, tetralogy of Fallot, pulmonary valve atresia, triscuspid atresia and stenosis, Ebstein anomaly, hypoplastic right heart, aortic valve atresia/stenosis, mitral valve anomalies, HLH, coarctation of aorta, aortic atresia/interrupted aortic arch, total anomalous pulmonary venous return (see the corresponding International Statistical Classification of Diseases and Related Health Problems codes in Supplemental Table 4 and Morris et al 17 for more rare CHD). selected CAs from different organ systems in the Isolated and All groups, clearly demonstrating the higher survival for children in the Isolated group (Fig 1).

DISCUSSION
This linked cohort study using population-based data on live births from 2005 to 2014 (n 5 96 263 out of a birth population of 4 218 786) among 13 CA registries in Western Europe provided survival estimates for children up to age 10. The pooled 10-year survival was >90% for the majority of isolated CA subgroups (27 of 32), with considerable variation in survival among specific CAs of different severity. Presence of associated anomalies considerably reduced survival in children with specific CAs. For children with Down syndrome, the 10-year survival was significantly higher for children without associated CHD or digestive system anomalies, compared with children with these anomalies.
Survival of children born with specific isolated CAs was higher in our study for spina bifida, CHDs, orofacial clefts, esophageal atresia, anorectal atresia or stenosis, diaphragmatic hernia, abdominal wall defects, and limb reduction defects compared with published population-based studies from Europe, the United States, and Australia, 27-33 and 2 systematic reviews. 14,34 The higher survival is expected, as first, the published studies cover earlier birth cohorts and survival has improved over time partly because of improvements in prenatal diagnosis and consequent increases in terminations of pregnancy for more severe CAs

19.4
The number of live births or deaths for "any anomaly" is not equal to the sum of those for each CA subgroup because some CAs may belong to >1 CA subgroup; for example, an individual CHD may also be associated with severe CHD, and any anomaly may include other subgroups not listed in this table. The number of deaths from the Netherlands: Northern registry were rounded to 0 or 5 because of small number restrictions and therefore were not included in the numbers of live births and deaths but were included in the survival estimates. ASD, atrial septal defect; AVSD, atrioventricular septal defect.
a For each anomaly subgroup, all children with the specified anomalies were included and those with an isolated anomaly only were identified. An isolated CA is defined as a structural CA in 1 organ system only or if coexisting anomalies were a consequence of a single primary anomaly.
b Reduction in the size of the brain with a head circumference >3 SDs below the mean for sex, gestational age, and ethnic origin (EUROCAT definition 41 Five-and 10-year survival of children with Down syndrome was also higher in our study compared with earlier studies 28,38-40 and comparable to more recent ones. 30,41,42 Presence of associated CHD in children with Down syndrome is an acknowledged risk factor for reduced long-term survival, 14,39-43 although a significant improvement in survival of these children over time was recently reported. 14 This European study also reports a significantly reduced survival of children with Down syndrome associated with CHD and/or digestive system anomalies compared with those without.

Strengths
This study has several strengths. We used high-quality data from specialist population-based registries of CAs that were linked to official mortality data sources, including data from national and vital statistics for 11 of 13 registries. Standardized approaches to data collection, coding, and classification in EUROCAT registries were enhanced by standardization of linked mortality data, creation of standardized syntax scripts, and generation of combined data sets and analytic results. This enabled the establishment of a large cohort of children with CAs in 13 regions of 9 Western European countries, increasing statistical power for the analysis of specific CAs and, thereby, the reliability of our findings. We developed a novel meta-analytic approach of analyzing survival data from several small samples to reduce bias arising as a result of the use of more standard techniques, which rely on the asymptotic

FIGURE 1
Survival estimates (with 95% CI) of children with selected subgroups of congenital anomalies for "Isolated" and "All" groups in 13 EUROCAT registries in 9 Western European countries, 2005 to 2014. For each anomaly subgroup, all children with the specified anomalies were included and those with an isolated anomaly only were identified, resulting in 2 groups for analysis: All and Isolated with a specified CA. An isolated CA is defined as a structural CA in 1 organ system only or if coexisting anomalies were a consequence of a single primary anomaly.
properties of estimates from larger samples.

Limitations
We were not able to include as many registries as originally planned because of barriers to gaining ethical approval, low linkage quality, or lack of survival data beyond 1 year. Despite relatively high linkage success, lack of 100% linkage in all registries may have resulted in an overestimate of the survival because of missed deaths. An overestimate of the pooled survival for children with severe microcephaly revealed by the sensitivity analysis after exclusion of the Wales registry may be because of a less stringent definition of severe microcephaly in Wales (<5th percentile instead of EUROCAT definition of <À3 SD). 44,45 Higher survival of children with HLH in Finland may be because of higher prenatal detection rates, resulting in improved survival after the full implementation of the national ultrasound screening program from 2010. 46,47 The classification of CA into isolated and multiple CA was computerbased only, without manual expert review of the potential multiple CA cases, which could have resulted in some isolated CAs being misclassified as multiple CAs. 23 No formal comparison of 10-year survival among the isolated and nonisolated CAs could be performed because the Isolated and All groups were not mutually exclusive.
The participating registries do not cover all births in Western European countries, but we consider our results to be representative of Western Europe.

CONCLUSIONS
The accuracy of estimated long-term survival of children born with specific CAs is ensured by the use of common protocol for data collection, standardization, quality control, and registry-specific statistical analyses, as well as the development of the novel meta-analytic approach.
Reliable information on long-term survival of children born with specific CAs is of major importance for counseling parents facing a prenatal diagnosis of CA, families living with a child affected by a CA, and for the health professionals involved in their care. The timely diagnosis of associated anomalies is essential for parental counseling because of their association with reduced survival. The geographical coverage should be widened in future European studies to produce findings that are more representative and generalizable for all of Europe.

ACKNOWLEDGMENTS
We thank EUROlinkCAT contributors to this paper for their work on the project (data linkage and standardization, running syntax scripts): Dr Glinianaia contributed to development of study methods, including data standardization and linkage, developed the statistical analysis plan, performed the descriptive analysis, interpreted the results, drafted the initial manuscript, and reviewed and revised the manuscript; Dr Rankin conceptualized and designed the study, contributed to obtaining funding, supervised the work, contributed to interpretation of the results, and reviewed and revised the manuscript; Dr Pierini conceptualized and designed the study, contributed to obtaining funding, contributed to interpretation of the results, and critically reviewed the manuscript for important intellectual content; Dr Coi and Ms Santoro contributed to the data analysis and interpretation of the results, and critically reviewed the manuscript for important intellectual content; Dr Tan contributed to development of study methods, including data standardization and data linkage, development of the statistical analysis plan, writing the analysis programs, data analysis and interpretation of the results, and critically reviewed the manuscript for important intellectual content; Ms Reid wrote analysis programs and contributed to data analysis, interpretation of the results, and critically reviewed the manuscript for important intellectual content; Dr Garne contributed to obtaining funding, development of study methods, including data standardization, data linkage, and interpretation of the results, and critically reviewed the manuscript for important intellectual content; Dr Loane contributed to obtaining funding, was responsible for data standardization and management of data linkage by the participating data providers, contributed to data analysis and interpretation of the results, and critically reviewed the manuscript for important intellectual content; Dr Given contributed to development of study methods, including data standardization, data linkage, and interpretation of the results, and critically reviewed the manuscript for important intellectual content; Drs Cavero-Carbonell, de Walle, Gatt, Gissler, Khoshnood, Klungsøyr, Urhøj, Zurriaga, Ms Heino, Ms Lelong, Ms Neville, Ms