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Abstract 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.

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

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.

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

Objective To assess the agreement between medication data reported by the mother at the pregnancy booking interview and recorded by midwives in the Northern Ireland Maternity System (NIMATS) compared to dispensed prescription data recorded in the Enhanced Prescribing Database (EPD). Method As part of a larger cross-sectional study investigating the prevalence of prescriptions dispensed between the last menstrual period (LMP) and the first antenatal visit 2011-2016, this sub-study assessed the agreement between self-reported medication use recorded in NIMATS and EPD compared to NIMATS, 2015-2016. Sensitivity and specificity compared to EPD were also calculated. This shorter time period was used due to underreporting of non-supplement medications before 2015 in NIMATS. Results Between 2015-2016, there were 34,432 pregnancies to 34,096 women. In NIMATS 96.8% of women reported taking medications during early pregnancy compared to 64.3% of women having prescriptions dispensed in EPD. Folic acid (low and high-dose) was the most common medication recorded in both NIMATS (57.2%) and EPD (26.2%). Antibiotics, analgesics, antacids and anticoagulants were more commonly recorded in NIMATS but all other non-supplement medications were more common in EPD. Agreement between NIMATS and EPD ranged from 2.6% for vitamins to 87.8% for insulin. Sensitivity ranged from 2.5% for cardiac medications to 84.3% for anticoagulants. Specificity ranged from 47.6% for antibiotics to 100% for cardiac and antiviral medications. Folic acid (low and high-dose), vitamins, antibiotics and analgesics were the only medications with specificity less than 90%. Conclusion Over-the-counter medications such as low-dose folic acid, antacids and analgesics were recorded more at the maternity booking interview (NIMATS), while medications requiring prescriptions were recorded more in EPD. This is important information for determining which data source to use in future studies assessing medication use.

Objective To explore risk factors for hospital admission, and length of stay (LOS) in hospital, among children with congenital anomalies (CAs) and reference children without CAs in Europe. Method A European population-based data-linkage cohort study was conducted including children with CAs (born 1995-2014) registered in seven EUROCAT CA registries and children without CAs (reference children) living in the same geographical areas. Data on hospitalisation and LOS (1995-2015) for all children aged

Objective To establish a linked European cohort of children with congenital anomalies (CAs) to evaluate mortality and morbidity outcomes of these children up to the age of 10 years. Method EUROlinkCAT supported 22 EUROCAT population-based congenital anomaly registries in 14 countries to link their data on children with CAs to mortality, vital statistics, hospital discharge and prescription databases. All live births with a CA born 1995-2014 recorded in the registries were followed up to age 10 years or to 31st December 2015. Each registry transformed their local mortality and morbidity data to a Common Data Model (CDM) and ran centrally created syntax scripts and produced tables/outputs in a standard form for meta-analysis. Analyses were performed on 100 different congenital anomaly subgroups for children

Abstract Background The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. Methods A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. Results During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14–1.18) and 1.55 (1.53–1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33–2.47), 1.71 (1.65–1.76), 1.41 (1.35–1.47) and 1.39 (1.30–1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18–1.20) and 1.05 (1.03–1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. Conclusions The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

The risks of major congenital anomalies associated with SARS-CoV-2 vaccination in early pregnancy are not well understood. Here, the authors conduct a population-based cohort study using electronic health records from Scotland and find no evidence of an association, supporting vaccine safety in pregnancy.

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.

Abstract Background The pharmacoepidemiology of the long-term benefits and harms of medicines in pregnancy and breastfeeding has received little attention. The impact of maternal medicines on children is increasingly recognised as a source of avoidable harm. The focus of attention has expanded from congenital anomalies to include less visible, but equally important, outcomes, including cognition, neurodevelopmental disorders, educational performance, and childhood ill-health. Breastfeeding, whether as a source of medicine exposure, a mitigator of adverse effects or as an outcome, has been all but ignored in pharmacoepidemiology and pharmacovigilance: a significant ‘blind spot’. Whole-population data on breastfeeding: why we need them Optimal child development and maternal health necessitate breastfeeding, yet little information exists to guide families regarding the safety of medicine use during lactation. Breastfeeding initiation or success may be altered by medicine use, and breastfeeding may obscure the true relationship between medicine exposure during pregnancy and developmental outcomes. Absent or poorly standardised recording of breastfeeding in most population databases hampers analysis and understanding of the complex relationships between medicine, pregnancy, breastfeeding and infant and maternal health. The purpose of this paper is to present the arguments for breastfeeding to be included alongside medicine use and neurodevelopmental outcomes in whole-population database investigations of the harms and benefits of medicines during pregnancy, the puerperium and postnatal period. We review: 1) the current situation, 2) how these complexities might be accommodated in pharmacoepidemiological models, using antidepressants and antiepileptics as examples; 3) the challenges in obtaining comprehensive data. Conclusions The scarcity of whole-population data and the complexities of the inter-relationships between breastfeeding, medicines, co-exposures and infant outcomes are significant barriers to full characterisation of the benefits and harms of medicines during pregnancy and breastfeeding. This makes it difficult to answer the questions: ‘is it safe to breastfeed whilst taking this medicine’, and ‘will this medicine interfere with breastfeeding and/ or infants’ development’?

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.

Abstract Background Congenital anomalies are the leading cause of perinatal, neonatal and infant mortality in developed countries. Large long-term follow-up studies investigating survival beyond the first year of life in children with rare congenital anomalies are costly and sufficiently large standardized cohorts are difficult to obtain due to the rarity of some anomalies. This study aimed to investigate the survival up to 10 years of age of children born with a rare structural congenital anomaly in the period 1995–2014 in Western Europe. Methods Live births from thirteen EUROCAT (European network for the epidemiological surveillance of congenital anomalies) population-based registries were linked to mortality records. Survival for 12,685 live births with one of the 31 investigated rare structural congenital anomalies (CAs) was estimated at 1 week, 4 weeks and 1, 5 and 10 years of age within each registry and combined across Europe using random effects meta-analyses. Differences between registries were evaluated for the eight rare CAs with at least 500 live births. Results Amongst the investigated CAs, arhinencephaly/holoprosencephaly had the lowest survival at all ages (58.1%, 95% Confidence Interval (CI): 44.3–76.2% at 1 week; 47.4%, CI: 36.4–61.6% at 1 year; 35.6%, CI: 22.2–56.9% at 10 years). Overall, children with rare CAs of the digestive system had the highest survival (> 95% at 1 week, > 84% at 10 years). Most deaths occurred within the first four weeks of life, resulting in a 10-year survival conditional on surviving 4 weeks of over 95% for 17 out of 31 rare CAs. A moderate variability in survival between participating registries was observed for the eight selected rare CAs. Conclusions Pooling standardised data across 13 European CA registries and the linkage to mortality data enabled reliable survival estimates to be obtained at five ages up to ten years. Such estimates are useful for clinical practice and parental counselling.

Abstract Background Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). Study design Pregnant women aged 15–49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. Results The prevalence of multimorbidity was 44.2% (95% CI 43.7–44.7%), 46.2% (45.6–46.8%) and 19.8% (18.8–20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8–24.6%], 23.5% [23.0–24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8–31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04–3.17] 45–49 years vs 15–19 years), multigravid (1.68 [1.50–1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44–1.76], body mass index 30+ vs body mass index 18.5–24.9) and smoked preconception (1.61 [1.46–1.77) vs non-smoker). Conclusion Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Introduction One in five pregnant women has multiple pre-existing long-term conditions in the UK. Studies have shown that maternal multiple long-term conditions are associated with adverse outcomes. This observational study aims to compare maternal and child outcomes for pregnant women with multiple long-term conditions to those without multiple long-term conditions (0 or 1 long-term conditions).Methods and analysis Pregnant women aged 15–49 years old with a conception date between 2000 and 2019 in the UK will be included with follow-up till 2019. The data source will be routine health records from all four UK nations (Clinical Practice Research Datalink (England), Secure Anonymised Information Linkage (Wales), Scotland routine health records and Northern Ireland Maternity System) and the Born in Bradford birth cohort. The exposure of two or more pre-existing, long-term physical or mental health conditions will be defined from a list of health conditions predetermined by women and clinicians. The association of maternal multiple long-term conditions with (a) antenatal, (b) peripartum, (c) postnatal and long-term and (d) mental health outcomes, for both women and their children will be examined. Outcomes of interest will be guided by a core outcome set. Comparisons will be made between pregnant women with and without multiple long-term conditions using modified Poisson and Cox regression. Generalised estimating equation will account for the clustering effect of women who had more than one pregnancy episode. Where appropriate, multiple imputation with chained equation will be used for missing data. Federated analysis will be conducted for each dataset and results will be pooled using random-effects meta-analyses.Ethics and dissemination Approval has been obtained from the respective data sources in each UK nation. Study findings will be submitted for publications in peer-reviewed journals and presented at key conferences.

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

Objectives Preterm children are exposed to many medications in neonatal intensive care units, but little is known about the effect of prematurity on medication use throughout infancy and childhood. We examined prescriptions of cardiovascular medication (CVM), antiseizure medication (ASM), antiasthmatic medication and antibiotics issued/dispensed in the first 10 years of life for very and moderately preterm children compared with term.Design Population-based data linkage cohort study linking information from birth records to prescription records.Setting Six registries from five countries in the EUROlinkCAT study.Participants The study population included 1 722 912 children, of whom 10 820 (0.6%) were very preterm (

Objectives Asthma is the most common chronic disease in childhood, yet little is known about rates of asthma and wheezing in children with congenital anomalies. This study explored the prevalence and risk of receiving anti-asthmatic prescriptions in children with congenital anomalies compared to children without anomalies in six European regions/countries. Approach This was a EUROlinkCAT population-based linkage cohort study involving children from 0-9 years of age born between 2000-2014. Congenital anomaly data from six EUROCAT registries were linked to births data in national/vital statistics and to electronic prescription databases. Prescription/pharmacy dispensing records across regions were standardised to a Common Data Model. Anatomical Therapeutic Chemical classification codes beginning with R03 were used to identify anti-asthmatic prescriptions. Random-effects meta-analyses were performed to identify both the relative risk (RR) of receiving >1 anti-asthmatic prescription in a year relative to the reference group, and the heterogeneity of prevalence rates across registries and age group. Results A total of 5.1% of children with congenital anomalies and 4.9% of reference children were dropped from the study as they were not linked. Children with congenital anomalies (n=60,662) had a higher prevalence of >1 anti-asthmatic prescription and a significantly higher risk of being prescribed anti-asthmatics (RR=1.41, 95% CI 1.35-1.48) compared to reference children (n=1,722,912). The increased risk was consistent across all age groups. Children with congenital anomalies were more likely to be prescribed beta-2 agonists (RR=1.71, 95% CI 1.60-1.83) and inhaled corticosteroids (RR=1.74, 95% CI 1.61-1.87). Children with oesophageal atresia, diaphragmatic hernia, genetic syndromes and chromosomal anomalies had over twice the risk of being prescribed anti-asthmatics compared to reference children. Regional differences in prevalence and risk of anti-asthmatic prescriptions were identified. Conclusion Children aged 1 anti-asthmatic prescription across age group and across European regions. This study demonstrates that information on the prevalence of anti-asthmatic prescriptions issued/dispensed can be obtained through data linkage to monitor changes in prevalence over time.

Objectives Education outcomes predict life chances; however disabilities and concurrent learning difficulties are often barriers to school performance. Low educational achievement is also linked with socio-economic deprivation. We aimed to quantify the association of these factors with education outcomes by ages 12 and 17 for children in Wales (UK). Approach We linked health, socio-economic and education data for children born after 1997 in Wales, registered with any one of 17 isolated congenital anomalies. Children were included if they had known education outcomes at ages 12 (n=9,223) and 17 (n=4524). A reference population comprised children born similarly but without anomalies, also having education records at 12 (n=261,827) and 17 (n=4,524). Multinomial logistic regressions determined the likelihood of attainment in compulsory subjects by age 12 and of attaining five GCSE qualifications by age 17. We adjusted for socio-economic status by using free school meal eligibility (household deprivation) and area-based indices of deprivation. Results We identified 14 and 11 isolated anomalies that reduced the likelihood of achieving educational standards by ages 12 and 17 respectively. Educational achievements were lower for children with Down syndrome, Turner syndrome, hydrocephalus and limb reduction defects, particularly at age 12, indicating that children with anomalies may catch-up with their peers. While children with anomalies were less likely to achieve five GCSEs by age 17, there was no difference in the grades of those who did so. Deprivation, particularly at household level, further reduced the likelihood of education success. At age 17, household deprivation reduced 3-fold the odds of achieving any five GCSEs grades A*-C. Conclusions Children with congenital anomalies from the most deprived communities and households are at particular risk of low education achievement. To realise their potential, these children should be identified from medical records at an early age and offered targeted educational support as soon as possible and at every opportunity.

Objectives Advances in surgical management strategies have substantially reduced fatality from congenital heart defects (CHD). Decreased infant mortality might be expected, consequentially to result in greater morbidity in older children due to complications later in childhood and adolescence. This study aims to evaluate the use of cardiovascular medication (CVM) as an indicator of disease burden in children born with CHD in the first 10 years of life.Design Population-based cohort study.Setting Six population-based registries from the European Surveillance of Congenital Anomalies (EUROCAT) network participated. Data from live born children with major congenital anomalies (CA) born from 2000 to 2014 were linked to prescription databases. Four groups of children were analysed: CA, CHD, severe CHD (sCHD) and ventricular septal defect (VSD) without sCHD. Live born children without CA were included as reference group.Participants We obtained data on 61 038 children born with a CA, including 19 678 with CHD, 3392 with sCHD, 12 728 children with VSD without sCHD, and 1 725 496 reference children.Results Children born with sCHD were the most likely to receive a CVM prescription (42.9%, 95% CI, 26.3 to 58.5) in the first year of life compared with 13.3% (6.7 to 22.0) of children with any CHD, 5.9% (3.7 to 8.7) of children with any CA and 0.1% (0.0 to 0.1) of reference children. Medication was less likely to be prescribed after the first year of life for sCHD; 18.8% (14.8 to 23.1) for children 1–4 years and 15.8% (12.0 to 20.1) 5–9 years. Children with sCHD were most likely to receive a diuretic (36.4%, 18.6 to 54.5), an antihypertensive (6.9%, 3.7 to 11.3) or a beta-blocker (5.5%, 2.9 to9.2).Conclusion Almost half of all children with sCHD were prescribed CVM in their first year of life. For all four groups of children with anomalies, the proportion of children with a CVM prescription decreased with age.

To examine the prevalence, determinants and attitude towards herbal medication (HM) use in the first trimester of pregnancy in Cameroon women. Between March to August 2015, we surveyed 795 pregnant women attending 20 randomly selected urban or rural hospitals in South West Cameroon on first trimester orthodox medication (OM) and HM use. Data was obtained by interviews using structured questionnaires. First trimester HM use was reported by 293 (36∙9%) women, 76% of whom used it in combination with OM. The most frequent indication for taking HM was prevention/treatment of anaemia (26∙3%). The HM were usually self-prescribed (33∙3%) or by family (56∙2%), and obtained from the woman's own garden (69∙3%). Twenty percent of women believed that HM was always safe to take in pregnancy, compared to 69.3% for OM. Intake of HM was significantly influenced by women's opinion on OM or HM safety-the odds of taking HM was 3 time higher among women who were unsure about the safety of OM (AOR: 3∙0, 95%CI = 1∙5-6∙1), while women who thought HM were never safe or who were unsure about its safety, were 91% or 84% respectively less likely to take HM compared to women who believed HM were always safe. We identified a high prevalence of HM use and concomitant use with OM, strongly influenced by women's perception of HM and OM safety. These findings indicate the need for WHO to specifically address safety in pregnancy in its policy to integrate traditional medicine use into existing healthcare systems in Africa.

BackgroundCongenital anomalies are a leading cause of childhood morbidity, but little is known about the long-term outcomes.ObjectiveTo 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).MethodsEuropean 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, Results99,416 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.ConclusionsChildren 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.

Background Studies on medication safety in pregnancy are increasingly focusing on child neurodevelopmental outcomes. Establishing neurodevelopmental safety is complex due to the range of neurodevelopmental outcomes and the length of follow-up needed for accurate assessment. The aim of this study was to provide an inventory of European data sources for use in pharmacoepidemiologic studies investigating neurodevelopment following maternal medication exposure. Method The EUROmediSAFE inventory of data sources in Europe for evaluating perinatal and long-term childhood risks associated with in-utero exposure to medication was updated by contacting colleagues across 31 European countries, literature review and internet searches. Included data sources must record at least one neurodevelopmental outcome and maternal medication use in pregnancy must be available, either in the data source itself or through linkage with another data source. Information on the domain of neurodevelopment, measure/scale used and the approach to measurement were recorded for each data source. Results Ninety data sources were identified across 14 countries. The majority (63.3%) were created for health surveillance and research with the remaining serving administrative purposes (21.1% healthcare databases,15.6% other administrative databases). Five domains of neurodevelopment were identified—infant development (36 data sources,13 countries), child behaviour (27 data sources, 10 countries), cognition (29 data sources, 12 countries), educational achievement (20 data sources, 7 countries), and diagnostic codes for neurodevelopmental disorders (42 data sources, 11 countries). Thirty-nine data sources, in 12 countries, had information on more than one domain of neurodevelopment. Conclusion This inventory is invaluable to future studies planning to investigate the neurodevelopmental impact of medication exposures during pregnancy. Caution must be used when combining varied approaches to neurodevelopment outcome measurement, the age of children in the data source, and the sensitivity and specificity of the outcome measure selected should be borne in mind.

Aim To establish the prevalence of prescriptions dispensed in early pregnancy by maternal age and area deprivation, for women who gave birth in Northern Ireland (NI) 2011–2016. Study design Population-based linked cohort study. Methods The NI Maternity System (NIMATS) database was used to identify all births to resident mothers in NI between 2011 and 2016. Prescriptions dispensed between the last menstrual period (LMP) and the first antenatal care visit (mean 10.7 weeks) (2010–2016) were extracted from the Enhanced Prescribing Database (EPD) which records all prescriptions dispensed by pharmacists in NI. EPD data were linked to NIMATS using the mother’s Health and Care Number. Maternal deprivation based on the NI Multiple Deprivation Measure 2017 was linked using the mother’s postcode. Results The cohort included 139,687 pregnancies resulting in live or stillbirths to 106,206 women. A medication was dispensed in 63.5% of pregnancies, and in 48.7% of pregnancies excluding supplements (vitamins, iron, and folic acid). Folic acid was the most commonly dispensed medication (33.1%). Excluding supplements, the mean number of medications was 1.1, with 4.2% having ≥5 medications. The most common non-supplement medications were antibiotics (13.1%), antiemetics (8.7%), analgesics (6.9%), hormonal medications (6.9%) and antidepressants (6.1%). Younger women (Conclusion Half of all pregnant women in NI were dispensed a non-supplement medication between LMP and the first antenatal care visit. Younger and older mothers and those living in the most deprived areas were more likely to have medications dispensed. More antidepressants were dispensed in areas of social deprivation.

Introduction Congenital anomalies (CAs) are a major cause of infant mortality, childhood morbidity and long-term disability. Over 130 000 children born in Europe every year will have a CA. This paper describes the EUROlinkCAT study, which is investigating the health and educational outcomes of children with CAs for the first 10 years of their lives.Methods and analysis EUROCAT is a European network of population-based registries for the epidemiological surveillance of CAs. EUROlinkCAT is using the EUROCAT infrastructure to support 22 EUROCAT registries in 14 countries to link their data on births with CAs to mortality, hospital discharge, prescription and educational databases. Once linked, each registry transforms their case data into a common data model (CDM) format and they are then supplied with common STATA syntax scripts to analyse their data. The resulting aggregate tables and analysis results are submitted to a central results repository (CRR) and meta-analyses are performed to summarise the results across all registries. The CRR currently contains data on 155 594 children with a CA followed up to age 10 from a population of 6 million births from 1995 to 2014.Ethics The CA registries have the required ethics permissions for routine surveillance and transmission of anonymised data to the EUROCAT central database. Each registry is responsible for applying for and obtaining additional ethics and other permissions required for their participation in EUROlinkCAT.Dissemination The CDM and associated documentation, including linkage and standardisation procedures, will be available post-EUROlinkCAT thus facilitating future local, national and European-level analyses to improve healthcare. Recommendations to improve the accuracy of routinely collected data will be made.Findings will provide evidence to inform parents, health professionals, public health authorities and national treatment guidelines to optimise diagnosis, prevention and treatment for these children with a view to reducing health inequalities in Europe.

We investigated the role of maternal environmental factors in the aetiology of congenital heart disease (CHD). A population-based case-control study (242 CHD cases, 966 controls) was conducted using an iPad questionnaire for mother with linkage to maternity and first trimester prescription records. Risk of CHD was associated with low maternal education (OR adjusted for confounders 1.59; 95% confidence interval [CI], 1.02-2.49), pregestational diabetes (OR 4.04; 95% CI 1.00-16.28), self-reported maternal clotting disorders (adjOR 8.55, 95%CI 1.51-48.44), prescriptions for the anticlotting medication enoxaparin (adjOR 3.22, 95%CI 1.01-10.22) and self-reported vaginal infections (adjOR 1.69, 95%CI 1.01-2.80). There was no strong support for the hypothesis that periconceptional folic acid supplements have a protective effect, but there was a protective effect of frequent consumption of folate rich fruits (adjOR 0.64, 95%CI 0.47-0.89). Compared to the most common pre-pregnancy dietary pattern, CHD risk was associated with a poor diet low in fruit and vegetables (adjOR 1.56, 95%CI 1.05-2.34). Mothers of cases reported more pregnancy related stress (adjOR 1.69; 95% CI 1.22-2.34) and multiple stressors (adjOR 1.94, 95%CI 0.83-4.53). We found no supportive evidence for CHD risk being associated with obesity, smoking, depression or antidepressant use in this population. Our findings add to the previous evidence base to show potential for public health approaches to help prevent CHD in future by modifying environmental factors. Independent confirmation should be sought regarding elevated CHD risk associated with maternal blood clotting disorders and their treatment, since we are the first to report this.

Abstract Background There is a paucity of epidemiological data on medication use in pregnancy in Cameroon. Methods Between March and August 2015, 795 pregnant women attending 8 urban and 12 rural hospitals in Cameroon for antenatal (ANC) or other care were interviewed on first trimester medication use using structured questionnaires. Multivariate logistic regression was used to analyse the association of 18 sociodemographic factors with medication use. Results A total of 582 (73.2%) women took at least one orthodox (Western) medication during the first trimester, 543 (68.3%) women a non-pregnancy related orthodox medication, and 336 (42.3%)women a pregnancy related orthodox medication. 44% of the women took anti-infectives including antimalarials (33.6%) and antibiotics (20.8%).The other most common medications were analgesics (48.8%) and antianaemias (38.6%). Sulfadoxine/pyrimethamine, contraindicated in the first trimester of pregnancy, was the most commonly used antimalarial(13% of women).0.2% of women reported antiretroviral use. Almost 80% of all orthodox medications consumed by women were purchased from the hospital. 12.8% of the women self-prescribed. Health unit and early gestational age at ANC booking were consistent determinants of prescribing of non-pregnancy related, pregnancy related and anti-infective medications. Illness and opinion on the safety of orthodox medications were determinants of the use of non-pregnancy related medications and anti-infectives. Age and parity were associated only with non-pregnancy related medications. Conclusion This study has confirmed the observations of studies across Africa indicating the increasing use of medications during pregnancy. This is an indication that access to medicine is improving and more emphasis now must be placed on medication safety systems targeting pregnant women, especially during the first trimester when the risk of teratogenicity is highest.

Introduction The Baby Hearts study aimed to investigate risk and protective factors for congenital heart disease (CHD), and to investigate the health behaviours of a representative sample of pregnant women in Northern Ireland. Objectives We describe and evaluate the population-based case-control design enhanced with data linkage to administrative health data. Methods Cases (mothers of babies with CHD, n=286) were recruited following diagnosis prenatally or postnatally. Controls (mothers of babies without CHD, n=966) were recruited at 18-22 weeks gestation, from all women attending each maternity unit during a designated month. Hybrid data collection methods were used, including a self-administered iPad/postal questionnaire, and linkage to maternity and prescription records. Results Refusal rates were low (8%). iPad questionnaire completion at clinic or home visit had high acceptability whereas postal questionnaires were poorly returned leading to a further 9-10% loss of eligible cases/controls. In total, 61% of eligible cases and 68% of eligible controls were recruited, closely representative of the Northern Ireland population, with no evidence of selection bias. Of those recruited, 97% gave consent for linkage to medical records. Thirty-three percent of women had an unplanned pregnancy and 76% suspected they were pregnant by 5 weeks gestation, with no significant differences between cases and controls. There was considerable discordance between self-report, maternity and prescription records regarding medications obtained/taken in the first trimester, but no evidence of differences between cases and controls that would indicate substantial recall bias. Although there was high concordance between self-report and maternity records regarding folic acid supplementation, cases had significantly lower concordance than controls. Conclusions Our results suggest hybrid data collection approaches are a useful way forward for aetiological studies to reduce responder burden and address and estimate recall bias, and that the Baby Hearts study protocol is suitable for replication in other populations, modified to the local context.

Background Over 130,000 children are born in Europe every year with congenital anomalies which are a major cause of infant mortality, childhood morbidity and long-term disability. A European data linkage study (EUROlinkCAT) aims to investigate the health and educational outcomes of children up to 10 years of age with congenital anomalies, born between 1995 and 2014. While congenital anomaly data including information on potential risk factors are standardised across the EUROCAT network, information on mortality, morbidity and educational outcomes are not. Objective To create a common data model that transforms key variables in local databases to standardised formats enabling data on health and educational outcomes to be pooled and analysed across multiple registries. Method Twenty-two EUROCAT registries in fourteen countries are participating in the study. Each registry records uniformly coded data on cases of congenital anomaly registered in their local population using the EUROCAT Data Management Program. The registries will link their congenital anomaly data to their local mortality, hospital discharge, prescriptions and educational data. The linked individual case data cannot leave the local institution or “safe haven” environment, therefore verification and validation of all derived variables, data transformations and proxy variables must be performed locally. Findings Creating a common data model is challenging as there are diverse coding classification systems, languages, healthcare and educational systems in Europe. As with many administrative datasets, the common data model is based on coded data rather than the often richer “free text” information. Conclusion The use of administrative datasets across Europe enables pooling of data on rare outcomes and allows hypotheses on the health and education of children to be investigated. However, a common data model must be applied to ensure that data from multiple sites conform to a standard format.

Background The Northern Ireland (NI) Baby Hearts study aimed to investigate risk factors for congenital heart defects (CHD), and to investigate the health behaviours of a representative sample of NI pregnant women. Methods We performed a case-control study with hybrid data collection methods, including self-administered iPad questionnaire or postal questionnaire, information held in maternity records and linkage to prescription records. Cases (n=286) were recruited following diagnosis prenatally or postnatally, controls (n=966) were recruited during recruitment months in each maternity unit at 18-20 weeks gestation. Findings Refusal rates for questionnaire completion were low (7-8%). Among those recruited, consent for access and linkage to medical records was high (98%). Recruitment of both cases and controls was closely representative of the NI population in terms of age, area of residence and deprivation. There was considerable discordance between self-report questionnaires, maternity records and prescription records regarding medications taken in the first trimester, and between self-report questionnaires and maternity records regarding behaviours such as preconceptional folic acid, pregnancy planning, and smoking. However, there were no differences between cases and controls that would indicate recall bias. Conclusions Our results suggest that hybrid data collection approaches are a useful way forward for aetiological studies.

Background There is great potential to use routinely collected patient health records for research if the quality of data is sufficient for this purpose. Objective To assess the accuracy of information on medications and maternal diseases reported by the mother and recorded in the NI Maternity System (NIMATS) database compared to electronic prescriptions issued by the General Practitioner and recorded in the Enhanced Prescribing Database (EPD). Method A cross-sectional data linkage validation study was conducted through the Honest Broker Service. The NIMATS database, EPD and NI Multiple Deprivation Measure (MDM) were linked for all births in NI with a pregnancy booking interview between 1st April 2010 and 30th June 2016. Information on medications and illnesses recorded in NIMATS were compared to prescription data recorded in EPD. Findings Between April 2010 and June 2016, 139,687 pregnant women were linked to EPD and the NIMDM. In NIMATS, 94.4% (131,909) of women reported taking medications in the first trimester of pregnancy compared to 63.5% (88,693) in the EPD. The most common exposures in both databases were vitamins, folic acid and iron. Use of some medications varied by maternal age for example antibiotics were more common among younger mothers while cardiac medications were more common among older mothers. Excluding vitamins, folic acid and iron, 27.2% (14,786) of pregnancies with a medication recorded in NIMATS had a current disease recorded compared to 30.3% (20,574) of those in EPD. Conclusions Medication exposure rates differ depending on the data source used. NIMATS includes over-the-counter and hospital prescribed medications but may be subject to maternal recall bias. The EPD records prescribed medications but it is unknown if the woman took these. For both NIMATS and EPD, less than a third of pregnancies with a medication exposure have a disease recorded suggesting under recording of maternal disease in NIMATS.

BACKGROUND:Surveillance of congenital anomalies is important to identify potential teratogens. METHODS:This study analysed the prevalence of 61 congenital anomaly subgroups (excluding chromosomal) in 25 population-based EUROCAT registries (1980-2012). Live births, fetal deaths and terminations of pregnancy for fetal anomaly were analysed with multilevel random-effects Poisson regression models. RESULTS:Seventeen anomaly subgroups had statistically significant trends from 2003-2012; 12 increasing and 5 decreasing. CONCLUSIONS:The annual increasing prevalence of severe congenital heart defects, single ventricle, atrioventricular septal defects and tetralogy of Fallot of 1.4% (95% CI: 0.7% to 2.0%), 4.6% (1.0% to 8.2%), 3.4% (1.3% to 5.5%) and 4.1% (2.4% to 5.7%) respectively may reflect increases in maternal obesity and diabetes (known risk factors). The increased prevalence of cystic adenomatous malformation of the lung [6.5% (3.5% to 9.4%)] and decreased prevalence of limb reduction defects [-2.8% (-4.2% to -1.5%)] are unexplained. For renal dysplasia and maternal infections, increasing trends may be explained by increased screening, and deceases in patent ductus arteriosus at term and increases in craniosynostosis, by improved follow up period after birth and improved diagnosis. For oesophageal atresia, duodenal atresia/stenosis and ano-rectal atresia/stenosis recent changes in prevalence appeared incidental when compared with larger long term fluctuations. For microcephaly and congenital hydronephrosis trends could not be interpreted due to discrepancies in diagnostic criteria. The trends for club foot and syndactyly disappeared once registries with disparate results were excluded. No decrease in neural tube defects was detected, despite efforts at prevention through folic acid supplementation.