Study questions: Does the proportion of neural tube defects (NTDs) in which there are co-occurring anomalies of other systems vary by geographical area and time in Europe between 1980 and 2015? Which group of factors, e.g., sex, age, family history, condition at discovery, and prenatal screening during pregnancy that potentially affect ascertainment of isolated NTD cases and co-occurring anomalies, are associated with the presence of these anomalies? Methods: Data on fetuses or births with NTDs recorded in 28 European Surveillance of Congenital Anomalies (EUROCAT) registries operating throughout or during a part of the period 1980-2015, were obtained and analysed. Information on the corresponding denominators of total births for each registry were compiled, comprising approximately 15.7 million births. We developed algorithms to classify NTDs that occurred as part of certain recognized genetic and unknown etiology syndromes, isolated NTD cases (either with no other anomaly reported or only an anomaly considered to be secondary to the NTD), and NTDs not occurring as part of recognized syndromes but with one or more co-occurring anomalies. We assessed factors that could impact ascertainment of isolated NTD cases and NTD cases with co-occurring anomalies. We also conducted a sensitivity analysis to evaluate the effect of family history and consanguinity on NTD outcomes. Lastly, we reported on the prevalence of NTDs across Eastern, Western, Northern, and Southern Europe as defined by the World Bank. Results: A total of 14,703 fetuses or births with NTDs were recorded in the EUROCAT registries. The total number of births (live and stillbirths) that occurred during the periods when the EUROCAT registries were operating was 15.7 million. The overall prevalence at birth of NTDs in Eastern Europe was 11.6 per 10,000 births, in Western Europe 11.0 per 10,000 births, in Northern Europe 10.5 cases per 10,000 births and in Southern Europe 6.7 per 10,000 births. The most prevalent genetic syndromes were chromosomal anomalies, particularly trisomy 18. The most common secondary anomaly was Arnold-Chiari syndrome which occurred mostly with spina bifida. The most prevalent associated anomalies were limb defects, followed by congenital heart defects, abdominal wall, and urinary system defects. We found anencephaly to be most prevalent in isolated NTD cases without secondary anomalies and spina bifida in secondary anomalies and most of the co-occurring anomalies. For factors that could affect ascertainment, we found that birth type, birth weight, family history, maternal and paternal age (≥30 years) were risk factors for isolated NTD cases and for co-occurring anomalies. Lastly, approximately 48% of NTDs occurred in Northern Europe, followed 29% in Western Europe, 16% in Southern Europe, and 7.6% in Eastern Europe. Conclusion: In the absence of folate fortification, isolated NTD cases showed higher prevalence than NTDs with co-occurring anomalies over the past 35 years across Europe. This research suggests that Europe should develop and implement policies and guidelines for folate fortification to help prevent simpler NTD cases. Further research and data are needed for newer EUROCAT registries to predict trends and prevalence of NTDs. Contribution and involvement: This project was done in collaboration with the experts from the School of Epidemiology and Public Health (SEPH) and dysmorphologists that provided support with regards to NTD classification. AB spearheaded the development of the research protocol and thesis manuscript with funding and support from JL and TR. Evaluation of the output of cases from the algorithm was provided to AB by JL, TR, JE, FB, AN, EB, ML, and the EUROCAT Joint Research Centre.

Neural tube defects (NTD) result from the failure of the neural tube to close properly very early in gestation. A child born with an NTD may experience an early death or life-long disability. In the 1990s, the critical role of folic acid in the prevention of NTDs was confirmed and as a strategy to increase blood folate concentrations of women of childbearing age, folic acid fortification programs were mandated in Canada and the US. However, this change impacted the entire population not just women of childbearing age and not everyone may benefit from the increased folate intake. The objective of this research was to investigate the impact of higher intakes of folates on the mortality rates of children with acute lymphoblastic leukemia (ALL) and the risk of colorectal cancer (CRC) in adult populations. To address the impact in children with ALL, a comparison of the mortality rates between the pre- and post-fortification time periods in Ontario was performed using data from the Pediatric Oncology Group of Ontario. A second comparison between the mortality rates in these children in non-folic acid fortifying countries and the US was also completed. These analyses suggest that folic acid fortification is not negatively impacting mortality. With respect to CRC, one systematic review and two meta-analyses were conducted investigating folate intake and the risk of CRC or adenoma recurrence. The first analysis, in observational studies, compared high versus low folate intake and the risk of CRC. The second examined folate intake within the various polymorphisms of the methylene tetrahydrofolate reductase enzyme. The final study examined the impact of supplementation of 1 milligram or more per day of folic acid and the risk of colorectal adenoma recurrence in those adults with a history of colorectal adenomas. The findings from the completed observational studies suggest that there is an associated risk reduction in colorectal cancer from the intake of higher levels of folates. The investigations into the impact of the folic acid fortification program suggest that the program is not associated with having a negative impact on mortality of children with ALL or on the risk of colorectal cancer.

Neural tube defects (NTD) result from the failure of the neural tube to close properly very early in gestation. A child born with an NTD may experience an early death or life-long disability. In the 1990s, the critical role of folic acid in the prevention of NTDs was confirmed and as a strategy to increase blood folate concentrations of women of childbearing age, folic acid fortification programs were mandated in Canada and the US. However, this change impacted the entire population not just women of childbearing age and not everyone may benefit from the increased folate intake. The objective of this research was to investigate the impact of higher intakes of folates on the mortality rates of children with acute lymphoblastic leukemia (ALL) and the risk of colorectal cancer (CRC) in adult populations. To address the impact in children with ALL, a comparison of the mortality rates between the pre- and post-fortification time periods in Ontario was performed using data from the Pediatric Oncology Group of Ontario. A second comparison between the mortality rates in these children in non-folic acid fortifying countries and the US was also completed. These analyses suggest that folic acid fortification is not negatively impacting mortality. With respect to CRC, one systematic review and two meta-analyses were conducted investigating folate intake and the risk of CRC or adenoma recurrence. The first analysis, in observational studies, compared high versus low folate intake and the risk of CRC. The second examined folate intake within the various polymorphisms of the methylene tetrahydrofolate reductase enzyme. The final study examined the impact of supplementation of 1 milligram or more per day of folic acid and the risk of colorectal adenoma recurrence in those adults with a history of colorectal adenomas. The findings from the completed observational studies suggest that there is an associated risk reduction in colorectal cancer from the intake of higher levels of folates. The investigations into the impact of the folic acid fortification program suggest that the program is not associated with having a negative impact on mortality of children with ALL or on the risk of colorectal cancer.