Prevention of neural tube defects with folate

In 1979, when there was concern about birth defects in the offspring of Vietnam veterans exposed to Agent Orange (but no comprehensive information on birth defects in Australia), Jane Seward and Fiona Stanley were awarded a Commonwealth grant to establish a birth defects register in Western Australia (WA). The register, the first of its kind in the country, began in 1980 (Fig. 1). Staff of the birth defects register in Western Australia, 1981. Left to right: Fiona Stanley, Jan Payne, Jane Seward, Carol Bower and Linda Watson. The publication of the paper by Smithells et al. in 1981,1 which strongly suggested that maternal periconceptional vitamin supplementation reduces the risk of neural tube defects, provided the stimulus to undertake the fledgling register's first research project – a case control study of folate intake and neural tube defects.2 The WA study was the first to show a protective effect of dietary folate for neural tube defects,3 and, along with other observational and randomised controlled studies in the early 1990s, it helped confirm that adequate maternal folate intake before and in early pregnancy reduces the risk of neural tube defects by around 70%.4-6 This conclusion largely substantiated Elwood's rather bold statement in 19837: ‘If it is confirmed that a reduction of over 80% in the risk of these severe congenital defects can be produced by a widely available and inexpensive nutritional supplement, this is one of the great medical advances of the century’. Great medical advances need to be put into practice for their potential to be realised. In Australia, as in other countries, national recommendations for the use of folic acid supplements to prevent neural tube defects were produced.8 In 1992, in WA, we established the first health promotion programme in Australia to inform health professionals and women of childbearing age about folate for the prevention of neural tube defects and to encourage the use of periconceptional folic acid supplements.9 Further programmes followed in other states10, 11 and, to a lesser extent, nationally. Evaluation of these activities showed high recognition of the programme materials, increased knowledge and practice among health professionals, increased sales of folic acid supplements, increased knowledge among women of childbearing age and increased use of periconceptional folic acid supplements.9, 10, 12-14 However, the neural tube closes very early in pregnancy (by the end of the sixth week after the last menstrual period), and almost half of all pregnancies are unplanned,15 so it is not surprising that only 50% of women, at best, take folic acid supplements periconceptionally.16 Hence, there is considerable appeal to fortifying a staple food with folic acid, offering some protection to most pregnancies. In 1995, in Australia, voluntary fortification of some foods (breads, breakfast cereals, flour, savoury biscuits, pasta, yeast extracts, fruit and vegetable juices, and meal replacements) with folic acid was approved,17 and fortification began in 1996. Prior to this time, folic acid was not an allowable additive to foods in Australia. An evaluation of voluntary fortification in 2001 found that relatively few foods had been fortified (104 by 1999, mostly different types of breakfast cereals).18 The information collected by the WA Register was used to monitor trends in neural tube defects over this time19 and showed a 30% fall following the health promotion and voluntary fortification interventions (Fig. 2), and similar falls were observed in South Australia and Victoria.20, 21 This reduction was considerably less than the 70% in the meta-analysis of the randomised controlled trials. A further case control study (1997–2000) based on the WA Register showed that 28% of women took ≥200 μg daily of folic acid supplements periconceptionally, just over half obtained more than 100 μg of folic acid from (voluntarily) fortified foods daily, and knowledge of the link between folate and neural tube defects was associated with a 60% reduction in the risk of neural tube defects.22 An analysis of data for the controls (a random sample of women giving birth) showed that those who did not take ≥200 μg of periconceptional folic acid supplements daily were more likely to be younger, unmarried, a public patient or having their first baby, to have a high school education only, not to have planned their pregnancy, to have recognised their pregnancy later than 7 weeks gestation, to smoke, to drink more than their usual amount of alcohol on any occasion in the first 3 months of pregnancy and not to engage in any exercise in early pregnancy. No such associations were seen for women who ate ≤100 μg of folic acid from fortified foods.23 Neural tube defects in Western Australia, 1980–2010. Data from the WA Register of Developmental Anomalies. , live births; , TOP; , total. A, introduction of the promotion of folic acid supplement use; B, introduction of the voluntary fortification of some food with folic acid; C, introduction of the mandatory fortification of flour with folic acid; TOP, termination of pregnancy. Furthermore, early research from the Register had found that neural tube defects in Aboriginal infants were 40% more common compared with non-Aboriginal infants,24 and follow-up analyses showed that while the occurrence of neural tube defects fell following health promotion and voluntary fortification for non-Aboriginal infants, there was no such change for Aboriginal infants, such that for the period 1996–2000, neural tube defects were almost twice as common in Aboriginal infants.25 More recent unpublished Register data confirm that this is still the case. Clearly, the promotion of periconceptional folic acid supplement use was not reaching all segments of the target population equally, and while no inequality was observed for voluntary fortification, it was only reaching about half the target population. This evidence, coupled with the success of mandatory fortification overseas (e.g. United States,26 Canada27 and Chile28), led to the consideration of mandatory fortification in Australia and New Zealand. Following an assessment process that began in 2004,29 final approval was reached in 2007, and a 2-year lead-in time was provided, such that fortification with folic acid of wheat flour for bread making became mandatory in Australia in September 2009.30 In New Zealand, the Minister for Food Safety delayed the commencement of mandatory fortification a few months before it was to take effect because of industry and consumer concerns. Mandatory fortification has been reconsidered in New Zealand and rejected. An enhanced voluntary bread fortification program, in collaboration with the bread industry, is being planned instead.31 A programme of monitoring mandatory fortification has been established in Australia,32 and an increase in population levels of serum and red cell folate has already been demonstrated.33 It is now almost time to be able to evaluate whether this has affected the incidence of neural tube defects. Unfortunately, this will need to be based on data from only three states (South Australia, Victoria and WA) because the other jurisdictions have limited ascertainment of terminations of pregnancy for fetal anomaly (the majority of neural tube defects are now prenatally diagnosed, and the pregnancy is terminated).34 The importance of Stanley's foresight in establishing a birth defects register in WA (now called the WA Register of Developmental Anomalies) with a high level of case ascertainment and in ensuring it was used for research, as well as her commitment to identifying inequalities in health and translating research into action, is exemplified by the work on folate and neural tube defects. Perhaps, more than a decade into the 21st century, we will soon be able to assess whether one of the great medical advances of the 20th century has been successfully translated into practice. Thank you to Fiona Stanley for her support, mentoring and encouragement, and to all the wonderful people with whom we have both had the privilege of working.

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