STUDY QUESTION: What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? METHODS: This was a population based, observational study using data on 11,353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. SUMMARY ANSWER AND LIMITATIONS: Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10,000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. WHAT THIS STUDY ADDS: In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. FUNDING, COMPETING INTERESTS, DATA SHARING: The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.

Birth Registry Mainz Model Childrens Hospital University Medical Center Johannes Gutenberg University Mainz Germany

Center for Human Genetics Institut de Recherche Scientifique en Pathologie et en Génétique Charleroi Belgium

Children's University Hospital of Zagreb Clinical Hospital Sisters of Mercy Zagreb Croatia

CNR Institute of Clinical Physiology and Tuscany Registry of Congenital Defects Gabrielle Monasterio Foundation Pisa Italy

Department of Health Information and Research Guardamangia Malta

Department of Health Sciences University of Leicester Leicester UK

Department of Medical Genetics University of Medical Sciences Poznan Poland

Department of Public Health Health Service Executive South Ireland

EUROCAT Central Registry Centre for Maternal Fetal and Infant Research Institute of Nursing Research University of Ulster Newtownabbey UK

EUROCAT Northern Netherlands Registry University of Groningen University Medical Center Groningen Department of Genetics Groningen Netherlands

Health Service Executive Dublin Ireland

Hospital Lillebaelt Kolding Denmark

Institute of Health and Society Newcastle University Newcastle UK

Instituto Nacionale de Saude Dr Ricardo Jorge Lisbon Portugal

Malformation Monitoring Centre Saxony Anhalt Medical Faculty Otto von Guericke University Magdeburg Germany

Medical Birth Registry of Norway Norwegian Institute of Public Health and Department of Global Public Health and Primary Care University of Bergen Bergen Norway

Medical University of Graz Graz Austria

National Institute for Health and Welfare Helsinki Finland

National Institute of Health Development Department of Hungarian Congenital Abnormality Registry and Surveillance Budapest Hungary

National Perinatal Epidemiology Unit University of Oxford Oxford UK

National Registry of Congenital Anomalies of the Czech Republic Department of Medical Genetics Thomayer University Hospital Prague Czech Republic

Obstetrical Perinatal and Pediatric Epidemiology Research Team Center for Biostatistics and Epidemiology INSERM U1153 Maternité de Port Royal 75014 Paris France

Provincial Institute for Hygiene Antwerp Belgium

Public Health Department HSE South Lacken Kilkenny Ireland

Public Health Division of Gipuzkoa Instituto BIO Donostia Basque Government CIBER Epidemiología y Salud Pública CIBERESP San Sebatian Spain

Public Health Wales Swanseaa UK

Registro IMER IMER Registry Center for Clinical and Epidemiological Research University of Ferrara Ferrara Italy

Service de Genetique Medicale Maternite CHUV Lausanne Switzerland

University Hospitals Southampton Faculty of Medicine and Wessex Clinical Genetics Service Southampton UK

BMJ. 2015 Nov 24;351:h6198. doi: 10.1136/bmj.h6198. PubMed

BMJ. 2016 Feb 16;352:i763. doi: 10.1136/bmj.i763. PubMed

BMJ. 2016 Feb 16;352:i769. doi: 10.1136/bmj.i769. PubMed

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Prevention of Neural Tube Defects in Europe: A Public Health Failure