Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid

Authors: HESEKER, HELMUT - PADERBORN UNIV, GERMANY; Mason, Joel; Selhub, Jacob; Rosenberg, Irwin; Jacques, Paul

Submitted to: British Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/30/2008
Publication Date: 7/1/2009
Citation: Heseker, H.B., Mason, J.B., Selhub, J., Rosenberg, I., Jacques, P. 2009. Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid. British Journal of Nutrition. 102:173-180.

Interpretive Summary: Neural tube defects (NTDs) are relatively common congenital malformations that can lead to severe disability or even death. The causes of NTDs are multifactorial, including genetic predisposition, environmental risk factors and maternal conditions. The risk of NTDs can be reduced significantly by increasing the folate intake before and during the first 28 days after conception. Around the world, this was the rationale for the implementation of public health programs to increase the folate status of women. The limited efficacy of the campaigns to promote supplementation among women who might become pregnant has resulted in proposals for widespread mandatory fortification for all segments of the population. The US, Canada (since 1998) and Chile (since 2000) have a nutrition policy of mandatory fortification of enriched cereal-grain products with folic acid, whereas in Europe no country has yet required a mandatory folic acid fortification. At present in several European countries (e.g. Germany, Ireland, Netherland, UK), national scientific committees have recommended mandatory folic acid fortification of flour or bread, but the implementation process has not yet been established. Despite the observed beneficial effects of folic acid fortification on folate status and prevalence of NTDs, there are some suspected adverse effects. The overall experiences among countries with a fortification policy or with specific recommendations of using folic acid supplements during pregnancy, in conjunction with data from randomized controlled trials a well as from observational studies, should be used to reevaluate the possible benefits and possible detriments of folic acid fortification. The evaluation of the safety of a food fortification program requires an evaluation of segments of the population other than the primary target group (e.g. pregnant women and their offspring), who might also be effected by higher intakes of folic acid from fortified cereal-grain products. Nutrition and public health policy makers have to balance the beneficial and potential adverse effects. The aims of the present study are to 1) describe the effect of the mandatory folic acid fortification of enriched cereal-grain products on folate intake and status; 2) to review the observed effects of folic acid fortification on NTDs in the US, Canada and Chile; 3) to consider the potential impact of folic acid fortification on preventable NTDs in European countries; and 4) to review the possible consequences of increasing intakes of folic acid on health outcomes of other non-target population groups. The evaluation was based on a systematic review of the published literature and on data from birth defects registries. Countries with mandatory folic acid fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTDs. The prevalence of NTDs at birth declined to approximately 5 cases at birth/10,000 births and 7-8 cases at birth or abortion/ 10,000 births. This decline was independent of the amount of folic acid administered and reveals a ‘bottom floor-effect’ for folic acid-preventable NTDs. A transitional increase of colorectal cancer in the US and in Canada was observed soon after the fortification was implemented. Additionally an increased risk of cognitive defects cannot be excluded in elderly people with poor vitamin B 12 status and higher intake of folic acid. Our findings indicate that not all cases of neural tube defects are preventable by increasing folate intake. The relative decline depends on the initial NTD rate and the folate status of the population. Countries with NTD prevalence close to the observed floor may have much smaller reductions in NTD rates with folic acid fortification than commonly predicted. Additionally potential adverse effects of other vulnerable population groups have to be taken seriously. P

Technical Abstract: The objective of this study was to evaluate the beneficial effects of different levels of folic acid administration on the prevalence of neural tube defects, with a concurrent assessment of other potential benefits or adverse effects. The evaluation was based on a systematic review of the published literature and on data from birth defects registries. Countries with mandatory folic acid fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTDs. The prevalence of NTDs at birth declined to approximately 5 cases at birth/10,000 births and 7-8 cases at birth or abortion/ 10,000 births. This decline was independent of the amount of folic acid administered and reveals a ‘bottom floor-effect’ for folic acid-preventable NTDs. A transitional increase of colorectal cancer in the US and in Canada was observed soon after the fortification was implemented. Additionally an increased risk of cognitive defects cannot be excluded in elderly people with poor vitamin B and reveals a ‘bottom floor-effect’ for folic acid-preventable NTDs status and higher intake of folic acid. Not all cases of neural tube defects are preventable by increasing folate intake. The relative decline depends on the initial NTD rate and the folate status of the population. Countries with NTD prevalence close to the observed floor may have much smaller reductions in NTD rates with folic acid fortification than commonly predicted. Additionally potential adverse effects of other vulnerable population groups have to be taken seriously. Policy decisions concerning fortification programs must factor into account all the evidence of risks to all vulnerable groups.