Folic acid fortification and congenital heart disease

BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b1144 (Published 13 May 2009) Cite this as: BMJ 2009;338:b1144
  1. Helena M Gardiner, senior lecturer and director of perinatal cardiology1,
  2. Jean-Claude Fouron, professor of fetal cardiology2
  1. 1Faculty of Medicine, Imperial College at Queen Charlotte’s and Chelsea and the Royal Brompton Hospitals, London W12 0NN
  2. 2CHU Sainte-Justine, Montreal H3T 1C5, QC, Canada
  1. helena.gardiner{at}imperial.ac.uk

    More effective interventions are needed to target women of child bearing age

    In the linked study (doi:10.1136/bmj.b1673), Ionescu-Ittu and colleagues investigate whether the 1998 government policy for mandatory fortification of flour and pasta products with folate reduced the prevalence of severe congenital heart disease at birth in Quebec, Canada.1 In 1997 the Teratology Society recommended folic acid supplementation to reduce the risk of neural tube defects through the fortification of staple foods. The aim was to ensure that 95% of women of child bearing age received 0.4 mg folic acid daily, with an additional 0.4 mg for those planning a pregnancy.2 Although the potential role of folic acid in the prevention of neural tube defects was reported as early as 1980, public health campaigns resulted in preconception supplementation in only a third of pregnant women.3

    The fortification policy was influenced by a Hungarian trial that reported a 90% reduction in primary neural tube defects in pregnancies supplemented by periconceptional multivitamins containing 0.8 mg folic acid.4 Canada initiated mandatory food fortification in 1998, and fortification of wheat flour is currently practised in 67 countries (47 in response to national mandates or regional requirements), but it has not been adopted in Europe.5 Folate is an important cofactor in homocysteine metabolism, and supplementation may reduce congenital malformations, including congenital heart disease, stroke, and coronary heart disease. Folate antagonists may increase congenital heart disease, particularly ventricular septal defect and conotruncal malformations.6 Because congenital heart disease accounts for a third of infant deaths from malformations in industrialised countries and treatment is costly, complex, and unavailable to many children, primary prevention is vital.7

    Ionescu-Ittu and colleagues assessed the effect of fortification with folic acid food on the prevalence of severe congenital heart disease in 1.3 million births between 1990 and 2005. They identified 2038 cases and compared changes in birth prevalence before and after fortification. Although they found no changes during the nine years before fortification, they found a 6% drop in the following seven years and concluded that mandatory fortification reduces severe congenital heart disease.1

    Such studies raise important questions about whether food fortification is an effective strategy, and what its effect might be. Firstly, are the current levels of fortification sufficient to significantly reduce the rates of congenital malformations? In one Canadian study, only 14% of women of child bearing age had folate concentrations that protect against neural tube defects after food fortification alone.8 Recommendations have therefore called for increased fortification and additional supplementation with periconceptual folic acid and vitamins.9

    Secondly, does fortification reduce the prevalence of severe congenital heart disease? Ionescu-Ittu and colleagues recorded cases from the physicians’ claims database and Quebec death registry when severe congenital heart disease was documented as the main cause of death. An important factor is the antenatal detection rate for congenital heart disease during this period. Any change in live birth prevalence of a malformation must take into account changes in the detection rate at screening and rates of termination of pregnancy. Both these rates are high for neural tube defects in most European countries, which results in a low live birth prevalence of 11-14%.10 In contrast, antenatal detection of congenital heart disease is low (about 30%), and termination of pregnancy rates have fallen for all but the most severe forms of disease. Unpublished data from St Justine Hospital’s cardiac unit, which serves half of the Quebec population, show a 5% increase (from 20% to 25%) in the antenatal diagnosis of severe congenital heart disease between the pre-fortification and post-fortification periods. Termination of pregnancy for congenital heart disease remained stable at about 40%, so antenatal diagnosis could account for a 2% reduction in birth prevalence after fortification and reduce the effect of food fortification to 2.6-4%.

    Population based studies have shown a year by year variation in congenital heart disease.11 This, and the heterogeneity of congenital heart disease, make it difficult to ascribe causality and assess a potential gene-environment interaction—for example, the effects of no folate supplementation in families with single polymorphic mutations at nucleotide 677 of the MTHFR gene.12

    Thirdly, is food fortification harmful to some people? Few European countries have implemented fortification and have cited unknown health risks and freedom of choice as the reasons for this decision. Although cognitive function is improved by lowering homocysteine concentrations, as long as vitamin B12 status is normal, this must be monitored in vulnerable groups, such as elderly people. Folate may play a dual role in cancer; low doses seem protective, but time trend analyses in countries with food fortification have shown an increased risk of colorectal and breast cancer, particularly in those receiving a higher dose of 1 mg/day. Firm evidence of its effects on cardiovascular diseases is awaited. It may also have adverse effects in the unborn baby. Theoretically the epigenetic regulation of DNA through methylation may be influenced by folate and vitamin B12 availability and hence may affect the expression of oncogenes or tumour suppressor genes in offspring supplemented in utero. However, research confirming this has not yet been published.

    Mandatory food fortification has reduced the prevalence of neural tube defects by about 9%, and Ionescu-Ittu and colleagues describe modest reductions in congenital heart disease.1 5 Substantial reductions in malformations have been reported only from additional periconceptual supplementation.4

    As the population becomes more obese, rates of type 2 diabetes increase and nutritional habits remain poor, and the prevalence of congenital heart disease may increase. So, rather than considering fortification targeted at populations, should we find more effective interventions to target women of child bearing age?


    Cite this as: BMJ 2009;338:b1144



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