Children with Hirschsprung's disease have high morbidity in the first 5 years of life.

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

The Association of Prenatal Diagnoses with Mortality and Long-Term Morbidity in Children with Specific Isolated Congenital Anomalies: A European Register-Based Cohort Study.

OBJECTIVES: To compare 5-year survival rate and morbidity in children with spina bifida, transposition of great arteries (TGA), congenital diaphragmatic hernia (CDH) or gastroschisis diagnosed prenatally with those diagnosed postnatally. METHODS: Population-based registers' data were linked to hospital and mortality databases. RESULTS: Children whose anomaly was diagnosed prenatally (n = 1088) had a lower mean gestational age than those diagnosed postnatally (n = 1698) ranging from 8 days for CDH to 4 days for TGA. Children with CDH had the highest infant mortality rate with a significant difference (p < 0.001) between those prenatally (359/1,000 births) and postnatally (116/1,000) diagnosed. For all four anomalies, the median length of hospital stay was significantly greater in children with a prenatal diagnosis than those postnatally diagnosed. Children with prenatally diagnosed spina bifida (79% vs 60%; p = 0.002) were more likely to have surgery in the first week of life, with an indication that this also occurred in children with CDH (79% vs 69%; p = 0.06). CONCLUSIONS: Our findings do not show improved outcomes for prenatally diagnosed infants. For conditions where prenatal diagnoses were associated with greater mortality and morbidity, the findings might be attributed to increased detection of more severe anomalies. The increased mortality and morbidity in those diagnosed prenatally may be related to the lower mean gestational age (GA) at birth, leading to insufficient surfactant for respiratory effort. This is especially important for these four groups of children as they have to undergo anaesthesia and surgery shortly after birth. Appropriate prenatal counselling about the time and mode of delivery is needed.

Higher risk of cerebral palsy, seizures/epilepsy, visual- and hearing impairments, cancer, injury and child abuse in children with congenital anomalies: Data from the EUROlinkCAT study.

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

Hospital care in the first 10 years of life of children with congenital anomalies in six European countries: data from the EUROlinkCAT cohort linkage study.

OBJECTIVE: To quantify the hospital care for children born with a major congenital anomaly up to 10 years of age compared with children without a congenital anomaly. DESIGN, SETTING AND PATIENTS: 79 591 children with congenital anomalies and 2 021 772 children without congenital anomalies born 1995-2014 in six European countries in seven regions covered by congenital anomaly registries were linked to inpatient electronic health records up to their 10th birthday. MAIN OUTCOME MEASURES: Number of days in hospital and number of surgeries. RESULTS: During the first year of life among the seven regions, a median of 2.4% (IQR: 2.3, 3.2) of children with a congenital anomaly accounted for 18% (14, 24) of days in hospital and 63% (62, 76) of surgeries. Over the first 10 years of life, the percentages were 17% (15, 20) of days in hospital and 20% (19, 22) of surgeries. Children with congenital anomalies spent 8.8 (7.5, 9.9) times longer in hospital during their first year of life than children without anomalies (18 days compared with 2 days) and 5 (4.1-6.1) times longer aged, 5-9 (0.5 vs 0.1 days). In the first year of life, children with gastrointestinal anomalies spent 40 times longer and those with severe heart anomalies 20 times longer in hospital reducing to over 5 times longer when aged 5-9. CONCLUSIONS: Children with a congenital anomaly consume a significant proportion of hospital care resources. Priority should be given to public health primary prevention measures to reduce the risk of congenital anomalies.

Academic achievement at ages 11 and 16 in children born with congenital anomalies in England: A multi-registry linked cohort study.

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

Timing of Cardiac Surgical Interventions and Postoperative Mortality in Children With Severe Congenital Heart Defects Across Europe: Data From the EUROlinkCAT Study.

BACKGROUND: The purpose of this study was to evaluate the timing of the first cardiac surgery, the number of cardiac surgeries performed, and 30-day postoperative mortality rate for children with severe congenital heart defects (sCHDs) in their first 5 years of life. METHODS AND RESULTS: This was a population-based data linkage cohort study linking information from 9 European congenital anomaly registries to vital statistics and hospital databases. Data were extracted for 5693 children with sCHDs born from 1995 to 2004. Subgroup analyses were performed for specific types of sCHD. Children with sCHDs underwent their first surgical intervention at a median age of 3.6 (95% CI, 2.6-4.5) weeks. The timing of the first surgery for most subtypes of sCHD was consistent across Europe. In the first 5 years of life, children with hypoplastic left heart underwent the most cardiac surgeries, with a median of 4.4 (95% CI, 3.1-5.6). The 30-day postoperative mortality rate in children aged <1 year ranged from 1.1% (95% CI, 0.5%-2.1%) for tetralogy of Fallot to 23% (95% CI, 12%-37%) for Ebstein anomaly. The 30-day postoperative mortality rate was highest for children undergoing surgery in the first month of life. Overall 5-year survival for sCHD was <90% for all sCHDs, except transposition of the great arteries, tetralogy of Fallot, and coarctation of the aorta. CONCLUSIONS: There were no major differences among the 9 regions in the timing, 30-day postoperative mortality rate, and number of operations performed for sCHD. Despite an overall good prognosis for most congenital heart defects, some lesions were still associated with substantial postoperative death.

Antiasthmatic prescriptions in children with and without congenital anomalies: a population-based study.

OBJECTIVES: To explore the risk of being prescribed/dispensed medications for respiratory symptoms and breathing difficulties in children with and without congenital anomalies. DESIGN: A EUROlinkCAT population-based data linkage cohort study. Data on children with and without congenital anomalies were linked to prescription databases to identify children who did/did not receive antiasthmatic prescriptions. Data were analysed by age, European region, class of antiasthmatic, anomaly, sex, gestational age and birth cohort. SETTING: Children born 2000-2014 in six regions within five European countries. PARTICIPANTS: 60 662 children with congenital anomalies and 1 722 912 reference children up to age 10 years. PRIMARY OUTCOME MEASURE: Relative risks (RR) of >1 antiasthmatic prescription in a year, identified using Anatomical Therapeutic Chemical classification codes beginning with R03. RESULTS: There were significant differences in the prescribing of antiasthmatics in the six regions. Children with congenital anomalies had a significantly higher risk of being prescribed antiasthmatics (RR 1.41, 95% CI 1.35 to 1.48) compared with reference children. The increased risk was consistent across all regions and all age groups. Children with congenital anomalies were more likely to be prescribed beta-2 agonists (RR 1.71, 95% CI 1.60 to 1.83) and inhaled corticosteroids (RR 1.74, 95% CI 1.61 to 1.87). Children with oesophageal atresia, genetic syndromes and chromosomal anomalies had over twice the risk of being prescribed antiasthmatics compared with reference children. Children with congenital anomalies born <32 weeks gestational age were over twice as likely to be prescribed antiasthmatics than those born at term (RR 2.20, 95% CI 2.10 to 2.30). CONCLUSION: This study documents the additional burden of respiratory symptoms and breathing difficulties for children with congenital anomalies, particularly those born preterm, compared with children without congenital anomalies in the first 10 years of life. These findings are beneficial to clinicians and healthcare providers as they identify children with greater morbidity associated with respiratory symptoms, as indicated by antiasthmatic prescriptions.

Risk factors for mortality in infancy and childhood in children with major congenital anomalies: A European population-based cohort study.

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

Detection and evaluation of signals associated with exposure to individual and combination of medications in pregnancy: a signal detection study protocol.

INTRODUCTION: Considering the high prevalence of polypharmacy in pregnant women and the knowledge gap in the risk-benefit safety profile of their often-complex treatment plan, more research is needed to optimise prescribing. In this study, we aim to detect adverse and protective effect signals of exposure to individual and pairwise combinations of medications during pregnancy. METHODS AND ANALYSIS: Using a range of real-world data sources from the UK, we aim to conduct a pharmacovigilance study to assess the safety of medications prescribed during the preconception period (3 months prior to conception) and first trimester of pregnancy. Women aged between 15 and 49 years with a record of pregnancy within the Clinical Practice Research Datalink (CPRD) Pregnancy Register, the Welsh Secure Anonymised Information Linkage (SAIL), the Scottish Morbidity Record (SMR) data sets and the Northern Ireland Maternity System (NIMATS) will be included. A series of case control studies will be conducted to estimate measures of disproportionality, detecting signals of association between a range of pregnancy outcomes and exposure to individual and combinations of medications. A multidisciplinary expert team will be invited to a signal detection workshop. By employing a structured framework, signals will be transparently assessed by each member of the team using a questionnaire appraising the signals on aspects of temporality, selection, time and measurement-related biases and confounding by underlying disease or comedications. Through group discussion, the expert team will reach consensus on each of the medication exposure-outcome signal, thereby excluding spurious signals, leaving signals suggestive of causal associations for further evaluation. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Independent Scientific Advisory Committee, SAIL Information Governance Review Panel, University of St. Andrews Teaching and Research Ethics Committee and Office for Research Ethics Committees Northern Ireland (ORECNI) for access and use of CPRD, SAIL, SMR and NIMATS data, respectively.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Educational achievement of children with selected major congenital anomalies and associated factors: a Finnish registry-based study.

BACKGROUND: Children with major congenital anomalies may be at risk of poor educational outcomes. We aimed to evaluate the educational achievement of children born with major congenital anomalies compared with children without major congenital anomalies in relation to sociodemographic factors. METHODS: We performed a registry-based study including 401 544 children in Finland, graduates of the compulsory school who applied to secondary education. We used health data from the Finnish Register of Congenital Malformations for children born from 1995 to 2002 linked with education data from the Finnish Ministry of Education and Culture. We used generalized linear regression to compare the mean grade differences of children with specific major congenital anomalies and 'All anomalies' subgroup (major congenital anomalies, chromosomal syndromes, and multiple anomalies) with reference children. RESULTS: Children with major congenital anomalies were less likely to apply for further education than reference children (88.0% vs. 96.8%; odds ratio = 4.13; 95% confidence interval, 3.92-4.36). For most non-chromosomal congenital anomalies, children born with congenital anomalies had similar educational achievement to the reference children. For the 'All anomalies' subgroup, children with congenital anomalies had lower educational achievement than reference children. Among children with congenital anomalies, male sex, lower maternal educational levels and younger maternal age were associated with lower educational achievement. CONCLUSIONS: For children applying to further education, most non-chromosomal congenital anomalies were not associated with lower educational achievement. Nevertheless, efforts are needed to improve educational achievement in children with major congenital anomalies associated with maternal sociodemographic background.

Creating a population-based cohort of children born with and without congenital anomalies using birth data matched to hospital discharge databases in 11 European regions: Assessment of linkage success and data quality.

Linking routinely collected healthcare administrative data is a valuable method for conducting research on morbidity outcomes, but linkage quality and accuracy needs to be assessed for bias as the data were not collected for research. The aim of this study was to describe the rates of linking data on children with and without congenital anomalies to regional or national hospital discharge databases and to evaluate the quality of the matched data. Eleven population-based EUROCAT registries participated in a EUROlinkCAT study linking data on children with a congenital anomaly and children without congenital anomalies (reference children) born between 1995 and 2014 to administrative databases including hospital discharge records. Odds ratios (OR), adjusted by region, were estimated to assess the association of maternal and child characteristics on the likelihood of being matched. Data on 102,654 children with congenital anomalies were extracted from 11 EUROCAT registries and 2,199,379 reference children from birth registers in seven regions. Overall, 97% of children with congenital anomalies and 95% of reference children were successfully matched to administrative databases. Information on maternal age, multiple birth status, sex, gestational age and birthweight were >95% complete in the linked datasets for most regions. Compared with children born at term, those born at ≤27 weeks and 28-31 weeks were less likely to be matched (adjusted OR 0.23, 95% CI 0.21-0.25 and adjusted OR 0.75, 95% CI 0.70-0.81 respectively). For children born 32-36 weeks, those with congenital anomalies were less likely to be matched (adjusted OR 0.78, 95% CI 0.71-0.85) while reference children were more likely to be matched (adjusted OR 1.28, 95% CI 1.24-1.32). Children born to teenage mothers and mothers ≥35 years were less likely to be matched compared with mothers aged 20-34 years (adjusted ORs 0.92, 95% CI 0.88-0.96; and 0.87, 95% CI 0.86-0.89 respectively). The accuracy of linkage and the quality of the matched data suggest that these data are suitable for researching morbidity outcomes in most regions/countries. However, children born preterm and those born to mothers aged <20 and ≥35 years are less likely to be matched. While linkage to administrative databases enables identification of a reference group and long-term outcomes to be investigated, efforts are needed to improve linkages to population groups that are less likely to be linked.

The burden of disease for children born alive with Turner syndrome-A European cohort study.

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

Ethics and legal requirements for data linkage in 14 European countries for children with congenital anomalies.

INTRODUCTION: Linking healthcare data sets can create valuable resources for research, particularly when investigating rare exposures or outcomes. However, across Europe, the permissions processes required to access data can be complex. This paper documents the processes required by the EUROlinkCAT study investigators to research the health and survival of children with congenital anomalies in Europe. METHODS: Eighteen congenital anomaly registries in 14 countries provided information on all the permissions required to perform surveillance of congenital anomalies and to link their data on live births with available vital statistics and healthcare databases for research. Small number restrictions imposed by data providers were also documented. RESULTS: The permissions requirements varied substantially, with certain registries able to conduct congenital anomaly surveillance as part of national or regional healthcare provision, while others were required to obtain ethics approvals or informed consent. Data linkage and analysis for research purposes added additional layers of complexity for registries, with some required to obtain several permissions, including ethics approvals to link the data. Restrictions relating to small numbers often resulted in a registry's data on specific congenital anomalies being unusable. CONCLUSION: The permissions required to obtain and link data on children with congenital anomalies varied greatly across Europe. The variation and complexity present a significant obstacle to the use of such data, especially in large data linkage projects. Furthermore, small number restrictions severely limited the research that could be performed for children with specific rare congenital anomalies.

Causes of death in children with congenital anomalies up to age 10 in eight European countries.

BACKGROUND: Congenital anomalies (CAs) increase the risk of death during infancy and childhood. This study aimed to evaluate the accuracy of using death certificates to estimate the burden of CAs on mortality for children under 10 years old. METHODS: Children born alive with a major CA between 1 January 1995 and 31 December 2014, from 13 population-based European CA registries were linked to mortality records up to their 10th birthday or 31 December 2015, whichever was earlier. RESULTS: In total 4199 neonatal, 2100 postneonatal and 1087 deaths in children aged 1-9 years were reported. The underlying cause of death was a CA in 71% (95% CI 64% to 78%) of neonatal and 68% (95% CI 61% to 74%) of postneonatal infant deaths. For neonatal deaths the proportions varied by registry from 45% to 89% and by anomaly from 53% for Down syndrome to 94% for tetralogy of Fallot. In children aged 1-9, 49% (95% CI 42% to 57%) were attributed to a CA. Comparing mortality in children with anomalies to population mortality predicts that over 90% of all deaths at all ages are attributable to the anomalies. The specific CA was often not reported on the death certificate, even for lethal anomalies such as trisomy 13 (only 80% included the code for trisomy 13). CONCLUSIONS: Data on the underlying cause of death from death certificates alone are not sufficient to evaluate the burden of CAs on infant and childhood mortality across countries and over time. Linked data from CA registries and death certificates are necessary for obtaining accurate estimates.

Survival, hospitalisation and surgery in children born with Pierre Robin sequence: a European population-based cohort study.

OBJECTIVE: To evaluate survival, hospitalisations and surgical procedures for children born with Pierre Robin sequence (PRS) across Europe. DESIGN: Multicentre population-based cohort study. SETTING: Data on 463 live births with PRS from a population of 4 984 793 from 12 EUROCAT congenital anomaly registries. METHODS: Data on children with PRS born 1995-2014 were linked electronically to data on mortality, hospitalisations and surgical procedures up to 10 years of age. Each registry applied a common data model to standardise the linked data and ran common syntax scripts to produce aggregate tables. Results from each registry were pooled using random-effect meta-analyses. MAIN OUTCOME MEASURES: Probability of survival, proportion of children hospitalised and undergoing surgery, and median length of hospital stay. RESULTS: The majority of deaths occurred in the first year of life with a survival rate of 96.0% (95% CI 93.5% to 98.5%); 95.1% (95% CI 92.7% to 97.7%) survived to age 10. In the first year of life, 99.2% (95% CI 95.0% to 99.9%) of children were hospitalised with a median stay of 21.4 days (95% CI 15.6 to 27.2), and 67.6% (95% CI 46.6% to 81.8%) underwent surgery. In the first 5 years of life, 99.2% of children underwent a median of two surgical procedures. Between ages 5 and 9, 58.3% (95% CI 44.7% to 69.7%) were hospitalised with a median annual stay of 0.3 days. CONCLUSIONS: Children with PRS had high mortality and morbidity with long hospital stays in the first year of life, and almost all had surgery before 5 years of age. Survival improved after infancy with fewer hospitalisations after age 5. This study provides reliable estimates of the survival and morbidity of children with PRS for families and healthcare providers.

Ten-year survival of children with trisomy 13 or trisomy 18: a multi-registry European cohort study.

OBJECTIVE: To investigate the survival to 10 years of age of children with trisomy 13 (T13) and children with trisomy 18 (T18), born 1995-2014. DESIGN: Population-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. SETTING: 13 regions in nine Western European countries. PATIENTS: 252 live births with T13 and 602 with T18. MAIN OUTCOME MEASURES: Survival 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. RESULTS: Survival 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. CONCLUSIONS: This 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.

Prevalence of polypharmacy in pregnancy: a systematic review.

OBJECTIVES: The use of medications among pregnant women has been rising over the past few decades but the reporting of polypharmacy has been sporadic. The objective of this review is to identify literature reporting the prevalence of polypharmacy among pregnant women, the prevalence of multimorbidity in women taking multiple medications in pregnancy and associated effects on maternal and offspring outcomes. DESIGN: MEDLINE and Embase were searched from their inception to 14 September 2021 for interventional trials, observational studies and systematic reviews reporting on the prevalence of polypharmacy or the use of multiple medications in pregnancy were included.Data on prevalence of polypharmacy, prevalence of multimorbidity, combinations of medications and pregnancy and offspring outcomes were extracted. A descriptive analysis was performed. RESULTS: Fourteen studies met the review criteria. The prevalence of women being prescribed two or more medications during pregnancy ranged from 4.9% (4.3%-5.5%) to 62.4% (61.3%-63.5%), with a median of 22.5%. For the first trimester, prevalence ranged from 4.9% (4.7%-5.14%) to 33.7% (32.2%-35.1%). No study reported on the prevalence of multimorbidity, or associated pregnancy outcomes in women exposed to polypharmacy. CONCLUSION: There is a significant burden of polypharmacy among pregnant women. There is a need for evidence on the combinations of medications prescribed in pregnancy, how this specifically affects women with multiple long-term conditions and the associated benefits and harms. TWEETABLE ABSTRACT: Our systematic review shows significant burden of polypharmacy in pregnancy but outcomes for women and offspring are unknown. PROSPERO REGISTRATION NUMBER: CRD42021223966.

Prescriptions for insulin and insulin analogues in children with and without major congenital anomalies: a data linkage cohort study across six European regions.

Are children with major congenital anomalies more likely to develop diabetes requiring insulin therapy, as indicated by prescriptions for insulin, than children without congenital anomalies? The aim of this study is to evaluate prescription rates of insulin/insulin analogues in children aged 0-9 years with and without major congenital anomalies. A EUROlinkCAT data linkage cohort study, involving six population-based congenital anomaly registries in five countries. Data on children with major congenital anomalies (60,662) and children without congenital anomalies (1,722,912), the reference group, were linked to prescription records. Birth cohort and gestational age were examined. The mean follow-up for all children was 6.2 years. In children with congenital anomalies aged 0-3 years, 0.04 per 100 child-years (95% CIs 0.01-0.07) had > 1 prescription for insulin/insulin analogues compared with 0.03 (95% CIs 0.01-0.06) in reference children, increasing ten-fold by age 8-9 years. The risk of > 1 prescription for insulin/insulin analogues aged 0-9 years in children with non-chromosomal anomalies (RR 0.92, 95% CI 0.84-1.00) was similar to that of reference children. However, children with chromosomal anomalies (RR 2.37, 95% CI 1.91-2.96), and specifically children with Down syndrome (RR 3.44, 95% CIs 2.70-4.37), Down syndrome with congenital heart defects (RR 3.86, 95% CIs 2.88-5.16) and Down syndrome without congenital heart defects (RR 2.78, 95% CIs 1.82-4.27), had a significantly increased risk of > 1 prescription for insulin/insulin analogues aged 0-9 years compared to reference children. Female children had a reduced risk of > 1 prescription aged 0-9 years compared with male children (RR 0.76, 95% CI 0.64-0.90 for children with congenital anomalies and RR 0.90, 95% CI 0.87-0.93 for reference children). Children without congenital anomalies born preterm (< 37 weeks) were more likely to have > 1 insulin/insulin analogue prescription compared to term births (RR 1.28, 95% CIs 1.20-1.36). CONCLUSION: This is the first population-based study using a standardised methodology across multiple countries. Males, children without congenital anomalies born preterm and those with chromosomal anomalies had an increased risk of being prescribed insulin/insulin analogues. These results will help clinicians to identify which congenital anomalies are associated with an increased risk of developing diabetes requiring insulin therapy and allow them to reassure families of children who have non-chromosomal anomalies that their risk is similar to that of the general population. WHAT IS KNOWN: • Children and young adults with Down syndrome have an increased risk of diabetes requiring insulin therapy. • Children born prematurely have an increased risk of developing diabetes requiring insulin therapy. WHAT IS NEW: • Children with non-chromosomal anomalies do not have an increased risk of developing diabetes requiring insulin therapy compared to children without congenital anomalies. • Female children, with or without major congenital anomalies, are less likely to develop diabetes requiring insulin therapy before the age of 10 compared to male children.

Hospital Length of Stay and Surgery among European Children with Rare Structural Congenital Anomalies-A Population-Based Data Linkage Study.

Little is known about morbidity for children with rare structural congenital anomalies. This European, population-based data-linkage cohort study analysed data on hospitalisations and surgical procedures for 5948 children born 1995-2014 with 18 rare structural congenital anomalies from nine EUROCAT registries in five countries. In the first year of life, the median length of stay (LOS) ranged from 3.5 days (anotia) to 53.8 days (atresia of bile ducts). Generally, children with gastrointestinal anomalies, bladder anomalies and Prune-Belly had the longest LOS. At ages 1-4, the median LOS per year was ≤3 days for most anomalies. The proportion of children having surgery before age 5 years ranged from 40% to 100%. The median number of surgical procedures for those under 5 years was two or more for 14 of the 18 anomalies and the highest for children with Prune-Belly at 7.4 (95% CI 2.5-12.3). The median age at first surgery for children with atresia of bile ducts was 8.4 weeks (95% CI 7.6-9.2) which is older than international recommendations. Results from the subset of registries with data up to 10 years of age showed that the need for hospitalisations and surgery continued. The burden of disease in early childhood is high for children with rare structural congenital anomalies.