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.

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 (77 054 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.

Pregnancy in teenagers diagnosed with type 1 diabetes mellitus in childhood: a national population-based e-cohort study.

AIMS/HYPOTHESIS: The aim of this study was to describe the characteristics and outcomes of pregnancies in a national cohort of teenage (<20 years) and young adult women (≥20 years) with and without childhood-onset (<15 years) type 1 diabetes. We hypothesised that, owing to poor glycaemic control during the teenage years, pregnancy outcomes would be poorer in teenage mothers with type 1 diabetes than young adult mothers with type 1 diabetes and mothers without diabetes. METHODS: The Brecon Register of childhood-onset type 1 diabetes diagnosed in Wales since 1995 was linked to population-based datasets in the Secure Anonymised Information Linkage (SAIL) Databank, creating an electronic cohort (e-cohort) of legal births (live or stillbirths beyond 24 weeks' gestation) to women aged less than 35 years between 1995 and 2013 in Wales. Teenage pregnancy rates were calculated based on the number of females in the same birth cohort in Wales. Pregnancy outcomes, including pre-eclampsia, preterm birth, low birthweight, macrosomia, congenital malformations, stillbirths and hospital admissions during the first year of life, were obtained from electronic records for the whole Welsh population. We used logistic and negative binomial regression to compare outcomes among teenage and young adult mothers with and without type 1 diabetes. RESULTS: A total of 197,796 births were eligible for inclusion, including 330 to girls and women with childhood-onset type 1 diabetes, of whom 68 were teenagers (age 14-19 years, mean 17.9 years) and 262 were young adults (age 20-32 years, mean 24.0 years). The mean duration of diabetes was 14.3 years (9.7 years for teenagers; 15.5 years for young adults). Pregnancy rates were lower in teenagers with type 1 diabetes than in teenagers without diabetes (mean annual teenage pregnancy rate between 1999 and 2013: 8.6 vs 18.0 per 1000 teenage girls, respectively; p < 0.001). In the background population, teenage pregnancy was associated with deprivation (p < 0.001), but this was not the case for individuals with type 1 diabetes (p = 0.85). Glycaemic control was poor in teenage and young adult mothers with type 1 diabetes (mean HbA1c based on closest value to conception: 81.3 and 80.2 mmol/mol [9.6% and 9.5%], respectively, p = 0.78). Glycaemic control improved during pregnancy in both groups but to a greater degree in young adults, who had significantly better glycaemic control than teenagers by the third trimester (mean HbA1c: 54.0 vs 67.4 mmol/mol [7.1% vs 8.3%], p = 0.01). All adverse outcomes were more common among mothers with type 1 diabetes than mothers without diabetes. Among those with type 1 diabetes, hospital admissions during the first year of life were more common among babies of teenage vs young adult mothers (adjusted OR 5.91 [95% CI 2.63, 13.25]). Other outcomes were no worse among teenage mothers with type 1 diabetes than among young adult mothers with diabetes. CONCLUSIONS/INTERPRETATION: Teenage girls with childhood-onset type 1 diabetes in Wales are less likely to have children than teenage girls without diabetes. Teenage pregnancy in girls with type 1 diabetes, unlike in the background population, is not associated with social deprivation. In our cohort, glycaemic control was poor in both teenage and young adult mothers with type 1 diabetes. Pregnancy outcomes were comparable between teenage and young adult mothers with type 1 diabetes, but hospital admissions during the first year of life were five times more common among babies of teenage mothers with type 1 diabetes than those of young adult mothers with diabetes.

Antidepressant prescriptions, discontinuation, depression and perinatal outcomes, including breastfeeding: A population cohort analysis.

OBJECTIVES: To explore associations between exposure to antidepressants, their discontinuation, depression [medicated or unmediated] and preterm birth [<37 and <32 weeks], small for gestational age (SGA) [<10th and <3rd centiles], breastfeeding [any] at 6-8 weeks. METHODS: Design: A population-based cohort study. Setting: The Secure Anonymised Information Linkage [SAIL] databank in Wales, linking maternal primary care data with infant outcomes. Participants: 107,573, 105,331, and 38,725 infants born 2000-2010 with information on prematurity, SGA and breastfeeding respectively, after exclusions. Exposures: Maternal antidepressant prescriptions in trimesters 2 or 3, discontinuation after trimester 1, recorded diagnosis of depression [medicated or unmediated] in pregnancy. Methods: Odds ratios for adverse pregnancy outcomes were calculated, adjusted for smoking, parity, socio-economic status, and depression. RESULTS: Exclusive formula feeding at 6-8 weeks was associated with prescriptions in trimesters 2 or 3 for any antidepressants (adjusted odds ratio [aOR] 0.81, 95% confidence intervals 0.67-0.98), SSRIs [aOR 0.77, 0.62-0.95], particularly higher doses [aOR 0.45, 0.23-0.86], discontinuation of antidepressants or SSRIs after trimester 1 (aOR 0.70, 0.57-0.83 and 0.66, 0.51-0.87), diagnosis of depression aOR 0.76 [0.70-0.82), particularly if medicated (aOR 0.70, 0.58-0.85), rather than unmedicated (aOR 0.87, 0.82-0.92). Preterm birth at <37 and <32 weeks' gestation was associated with diagnosis of depression (aOR 1.27, 1.17-1.38, and 1.33, 1.09-1.62), particularly if medicated (aOR 1.56, 1.23-1.96, and 1.63, 0.94-2.84); birth at <37 weeks was associated with antidepressants, (aOR 1.24, 1.04-1.49]. SGA <3rd centile was associated with antidepressants (aOR 1.43, 1.07-1.90), and SSRIs (aOR 1.46, 1.06-2.00], particularly higher doses [aOR 2.10, 1.32-3.34]. All adverse outcomes were associated with socio-economic status and smoking. IMPLICATIONS: Exposure to antidepressants or depression increased risks of exclusive formula feeding at 6-8 weeks, and prescription of antidepressants was associated with SGA <3rd centile. Prescription of antidepressants offers a useful marker to target additional support and additional care before and during pregnancy and lactation.

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark.

BACKGROUND: Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP). METHODS AND FINDINGS: Three population-based EUROCAT congenital anomaly registries- Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010)-were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06-2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03-1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99-1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were not statistically significant. The dose-response relationship between severe CHD and SSRI dose (meta-regression OR 1.49, 1.12-1.97) was consistent with SSRI-exposure related risk. Analyses in Wales suggested no associations between anomalies and diagnosed depression. CONCLUSION: The additional absolute risk of teratogenesis associated with SSRIs, if causal, is small. However, the high prevalence of SSRI use augments its public health importance, justifying modifications to preconception care.

Improving Information on Maternal Medication Use by Linking Prescription Data to Congenital Anomaly Registers: A EUROmediCAT Study.

INTRODUCTION: Research on associations between medication use during pregnancy and congenital anomalies is significative for assessing the safe use of a medicine in pregnancy. Congenital anomaly (CA) registries do not have optimal information on medicine exposure, in contrast to prescription databases. Linkage of prescription databases to the CA registries is a potentially effective method of obtaining accurate information on medicine use in pregnancies and the risk of congenital anomalies. METHODS: We linked data from primary care and prescription databases to five European Surveillance of Congenital Anomalies (EUROCAT) CA registries. The linkage was evaluated by looking at linkage rate, characteristics of linked and non-linked cases, first trimester exposure rates for six groups of medicines according to the prescription data and information on medication use registered in the CA databases, and agreement of exposure. RESULTS: Of the 52,619 cases registered in the CA databases, 26,552 could be linked. The linkage rate varied between registries over time and by type of birth. The first trimester exposure rates and the agreements between the databases varied for the different medicine groups. Information on anti-epileptic drugs and insulins and analogue medicine use recorded by CA registries was of good quality. For selective serotonin reuptake inhibitors, anti-asthmatics, antibacterials for systemic use, and gonadotropins and other ovulation stimulants, the recorded information was less complete. CONCLUSION: Linkage of primary care or prescription databases to CA registries improved the quality of information on maternal use of medicines in pregnancy, especially for medicine groups that are less fully registered in CA registries.

A case study of the Secure Anonymous Information Linkage (SAIL) Gateway: a privacy-protecting remote access system for health-related research and evaluation.

With the current expansion of data linkage research, the challenge is to find the balance between preserving the privacy of person-level data whilst making these data accessible for use to their full potential. We describe a privacy-protecting safe haven and secure remote access system, referred to as the Secure Anonymised Information Linkage (SAIL) Gateway. The Gateway provides data users with a familiar Windows interface and their usual toolsets to access approved anonymously-linked datasets for research and evaluation. We outline the principles and operating model of the Gateway, the features provided to users within the secure environment, and how we are approaching the challenges of making data safely accessible to increasing numbers of research users. The Gateway represents a powerful analytical environment and has been designed to be scalable and adaptable to meet the needs of the rapidly growing data linkage community.