Folate, Folic Acid, and Health - moh.govt.nzfile/PHIFolicpaper.pdf · as bread, with folic acid • supplements are an effective method to get 400mcg of folic acid, but advising

Folate, Folic Acid, and Health

Table of contents Executive summary Purpose

1

Introduction

2

Neural tube defects

2

Neural tube defects and folate/folic acid

3

Response by agencies in the USA

5

Response in other countries

6

Other health outcomes affected by folic acid

! birth defects 9 ! cancers 9 ! cardiovascular disease 10 ! other health outcomes 12 Epidemiology of NTDs in NZ

13

! burden of NTDs in NZ 14 ! cost of NTDs in NZ 16 The NZ response to folic acid research

19

Folate intake of New Zealanders

22

! sources of folate 24 Methods for enhancing folate levels in the population

! diet 26 ! supplementation 27

- use of supplements 27 - sales and availability of folic acid tablets 30

! knowledge about folate/folic acid and neural tube defects 37 ! fortification 40

- cost effectiveness of folic acid fortification 40 - fortification of foods in NZ 41 - health claims 44 - knowledge about fortification in NZ 44

- level of fortification 46 - upper target level for folate 48

Dietary modelling

48

Risks from increasing folic acid intake

53

Potential toxic effects from folic acid

! multiple births and other reproductive outcomes 53 ! vitamin B12 deficiency 54 ! zinc 55 ! other potential risks 56 Monitoring health outcomes and folate levels in NZ

57

! monitoring NTDs and other birth defects 57 ! monitoring folate levels 58 Impact of folic acid supplementation and fortification policies

59

Conclusion

60

References

64

Appendices 1. Folate intake and B12 masking (reprint)

72

2. Vitamin B12 deficiency and the fortification of food with folic

acid (reprint)

76

Authors and Acknowledgements The report was originally produced in late 1999 by Dr Barry Borman, Epidemiologist, Health Funding Authority, with assistance from Sheldon Brown, to examine the relationship between folate, folic acid and health outcomes. The report was peer-reviewed by Professor Godfrey Oakley (Emory University, Atlanta, USA), who was a constant source of encouragement and enthusiasm during the writing of the report, and Associate Professor Boyd Swinburn (The National Heart Foundation, Auckland). Other major contributors to the report were: Professor Nicholas Wald (Wolfson Institute of Preventive Medicine, London, England), Dr Christopher Howson and Dr Donald Mattison (March of Dimes, White Plains, USA), Dr David Erickson (Centers for Disease Control and Prevention, Atlanta, USA), Dr Carol Bower (Western Australian Birth Defects Register, Perth, Australia), Jenny Reid (Australia and New Zealand Food Authority (ANZFA), Wellington), Kay Winegar (IMS Health, Auckland), Dr Pat Tuohy, (Child Health Adviser, Ministry of Health, Wellington), and Geoff Tempest, Professor Bob Elliott, Lyall Thurston, and Rex Jensen, of the Folate Replenishment-Plus Committee

Executive Summary

Conclusions

• Current scientific evidence fully supports the health benefits of fortifying

breads with folic acid • There is clear evidence that periconceptional consumption of adequate

amounts of folate/folic acid prevents NTDs. There is accumulating research that the risk of other birth defects and health outcomes is also reduced by folic acid

• The Food Regulations permit the voluntarily fortification of bread with folic

acid up to the level of 285mg/100g • There is no current scientific evidence of toxic effects from consuming too

much folic acid � via any diet, supplementation, or fortification • NZ women in the reproductive age group have low levels of folate • It is extremely unlikely that individuals in NZ will consume an excess of folic

acid either through diet, supplementation or fortification • the neural tube defects (NTDs), anencephaly and spina bifida, are the second

leading contributors to the health burden from birth defects • in the early 1980s two studies in England and Wales indicated that the risk of

NTDs could be reduced by periconceptional supplementation with vitamins, including the B-vitamin, folic acid. Subsequent research in a number of countries generally supported the finding

• in 1992 two randomised control trials showed that folic acid supplementation

reduced the risk of NTD recurrence and occurrence. The Centres for Disease Control and Prevention in the USA recommended that all potentially pregnant women should consume 0.4mg of folic acid every day. Women at higher risk (e.g., those who previously had an infant with a NTD) were advised to consume 4mg per day

• similar recommendations have made in a number of other jurisdictions (e.g.,

Australia, Canada, England and Wales)

Other health outcomes • recent research has indicated that folic acid may also reduce the risk of other

birth defects, including facial clefts and congenital heart disease • there is also increasing evidence that folic acid may reduce the risk from

cardiovascular disease and some forms of cancer Methods to increase folate levels • three mechanisms are available to increase folate to levels which prevent

NTDs: fortification, supplementation, and diet • fortification is the primary mechanism for improving the folate status of

women in the population. Accordingly, the FDA in the US mandated that from January 1998 all grain products had to be fortified with synthetic folic acid. Canada has adopted a similar approach and other countries are also proposing to regulate for the mandatory fortification of staple products, such as bread, with folic acid

• supplements are an effective method to get 400mcg of folic acid, but advising

women to take tablets during pregnancy is contrary to �normal� practice, many pregnancies are unplanned, and NTDs are formed (i.e., the first 28 days of gestation) before many women are aware they are pregnant

• it is extremely difficult for women to raise their level of folate sufficiently

through eating folate rich foods alone. Natural folate that occurs in food is less stable than synthetic folic acid, and has a lower bioavailability

NTDs in New Zealand • the epidemiology of NTDs shows that like a number of other countries (e.g.,

England and Wales, USA), the rate of these defects has been declining since the mid-1970s

• There is no evidence of marked differences in the risk for Maori and non-

Maori, or associations with socioeconomic status, maternal age, and parity • NZ generally has a low -moderate rate of NTDs with the rate similar to

Australia, Western Australia and parts of the USA

Folate recommendation in NZ • The Public Health Commission advised NZ women in 1994 to consume 5mg

of folic acid to reduce the risk of NTDs as well as improve their diet by consuming folate rich vegetables. The level of supplementation was the highest recommended by any country.

• In 1996, the Ministry of Health revised their recommendation to 0.8mg of folic

acid because of the advent of a low dose tablet. Folate status of NZ women • The 1997 NZ Nutrition Survey found that the usual daily median intake of

folate from food was 278mcg for males and 212 mcg for females. People living in the most deprived areas (NZDep96) and young females are likely to have inadequate intakes of folate. Half of the NZ population used vitamin and /or mineral supplements during the previous year, with the highest use among NZ European and Others and females 19-24 years.

• Another recent study found that at month 4 of their pregnancy, 49% of the

women had folate intakes less than two thirds of the Australian RDI for pregnant women at month 4 of their pregnancy. It is not known if these levels are similar to the levels during the periconceptional period and early stages of pregnancy. Almost half of the European women had taken folic acid supplements in the year before their pregnancy, compared to 10% for Maori and Pacific Island women.

Dietary modelling of folic acid • NZ data from the Australian New Zealand Food Authority (ANZFA) indicates

that it is highly unlikely that the intake of folic acid would exceed 1000mcg on a regular basis for any age-sex group.

Toxic levels of folic acid consumption • Current research shows there are no known toxic effects from the ingestion of

folic acid either by diet, supplementation or fortification. • Another concern expressed against fortification is the potential of folic acid to

mask B12 vitamin deficiency. However, a recent publication from the American Institute of Medicine states that �clear evidence of folic acid-induced neurotoxicity in humans is lacking�. Nonetheless, it is advocated that the

relationship between folic acid and B12-deficiency is considered in developing a tolerable upper intake level for folic acid intake.

• there is no relationship between increasing levels of folic acid intake and

multiple births, and adverse effects with zinc, anticonvulsants, oral contraceptives

Monitoring of health outcomes and folate levels • The NZ Birth Defects Monitoring Programme continues to monitor the

prevalence of birth defects, including NTDs, among live and stillbirths and is participating to two international studies to monitor the effect of folic acid recommendations and fortification

• The Department of Nutrition, University of Otago, has completed a

programme to collect data on folate intake and blood folate levels among women aged 20-44 years and men aged 14-19 years.

Folate, Folic Acid, and Health 1

�One of the most exciting medical findings of the last part of the 20th century is that folic acid, a simple, widely available, water-soluble

vitamin, can prevent spina bifida and anencephaly (SBA). Not since the rubella vaccine became available 30 years ago have we had a comparable opportunity for primary prevent of such common and

serious birth defects.�1

Introduction Although many aspects of infant health continue to show improvement in a number of developed and developing countries, birth defects remain major causes of infant mortality and morbidity. For example, in New Zealand the infant mortality rate between 1987 and 1996 declined from 10.1 per 1,000 livebirths to 7.3 per 1,000 livebirths. However, the proportion of infant deaths due to birth defects remained at 24%. In 1995, birth defects were the cause of 8% of infant hospitalisations, and in 1996, 19% of all fetal deaths. Results from the NZ Burden of Disease study (NZBDS)2 show that 15% of the total disability (DALYS)i in the 0-14 year age group were attributable to birth defects. Various perinatal conditions, respiratory conditions, and injury respectively accounted for 23%, 21%, and 13% of the disease burden in this age group. More than 80% of the burden from birth defects in the 0-14 year age group is borne by 0-4 year olds. The neural tube defects (NTDs) are a major group of birth defects. In 1996, 18% of perinatal deaths (stillbirths and livebirths dying in the first 7 days of life) were due to NTDs, compared to 15% attributable to congenital heart defects. Anencephaly and spina bifida comprise 90% of all NTD cases. Anencephaly is characterised by the total or partial absence of the cranial vault, the covering skin, and the brain missing or reduced to small mass. Most infants with anencephaly are stillborn and those that are liveborn usually die within hours of birth. Anencephaly often occurs in association with spina bifida. Spina bifida is a family of defects in the closure of the spinal column characterised by herniation or exposure of the spinal cord and/or meninges through an incompletely closed spine. Most infants with spina bifida are liveborn and many have associated birth defects (e.g., hydrocephalus, facial clefts). i A DALY (the �disability-adjusted life year�) represents the loss of one year of healthy life and is the sum of years lost to premature mortality and years lost to (severity-adjusted) disability - see reference 2 for a full description


Encephalocele, often also included under the term �neural tube defects�, is characterized by herniation of the brain and /or meninges through a defect in the skull. In this paper, �neural tube defects� only includes anencephaly and spina bifida. NTDs occur in the first 28 days of pregnancy, often before a mother knows she is pregnant.

Neural Tube Defects NTDs have been the subject of a plethora of research because they are gross malformations, usually have a high level of ascertainment, and have major impacts on infant health. The increasing use of antenatal diagnosis and screening over the last decade has resulted in considerable progress in the secondary control of NTDs. Progress in the primary prevention of the defects has been hampered by the lack of aetiological clues emerging from the research. Many studies of NTDs suffer from methodological problems (e.g., the lack of multiple case ascertainment and adjustment for the effect of possible confounding factors, using prevalence rather than incidence data).3 4 A major handicap of much of the research is that it is based on prevalence at birth rates rather than incidence data. To establish incidence rates it would be necessary to know the fate of all conceptuses5 Therefore, the effect of spontaneous abortions and terminations of pregnancy (TOPs) is generally not known, although increasingly attempts are being made to include these data in studies and monitoring programmes. The general epidemiological pattern of NTDs shows (see Elwood et al, 1992 6 for a complete review of the literature): • distinct international and intranational geographic patterns of prevalence. The

UK has traditionally reported the highest international rates, but recent data indicates areas in India, China 7, and the Middle East also have high rates. There are low to medium rates in most areas of Europe, USA, Australia, and NZ. In England and Wales, rates are higher in the north and west, and in North America on the east coast

• in many developed countries the decline in the rates of NTDs since the mid-

1970s has not always accounted for by the impact of terminations of pregnancy

• there are weak and inconsistent seasonal patterns in prevalence at birth rates


• high rates have traditionally been reported for Caucasian populations while black populations have low rates

• no causative factor has been identified in reported clusters of NTDs • an inverse relationship between the male proportion of anencephaly cases

and the prevalence rate, but only a small female predominance for spina bifida

• in areas with high prevalence rates, the rates are highest in the lowest socio-

economic categories (irrespective of how socio-economic status is measured) • when maternal age and parity effects exist they are usually U-shaped A number of aetiological factors have been investigated in relation to NTDs, but many of the studies have methodological problems (e.g., recall and ascertainment bias, difficulty in establishing levels of exposure). However: • no, or inconsistent, associations have been reported with tea drinking,

caffeine, potato consumption, recreational drugs, smoking, alcohol, maternal infections, hyperthermia, occupational exposures (e.g., visual display terminals, pesticides, solvents, plastics), various chemical elements in drinking water

• pregnancies exposed to the anti-convulsant drugs, valproic acid and

carbamazepine have a higher risk of NTDs Following an initial review of the literature, Elwood et al 8 concluded that many of the epidemiological patterns of NTDs (e.g., social class gradient, secular and seasonal trends, and some geographic variation) may have dietary determinants. The authors concluded that �one of the more viable specific hypotheses is that of folic acid deficiency although certain epidemiological features of neural-tube defects clearly are not explained by this mechanism.�

NTDs and Folate/Folic Acid In 1965 Hibbard and Smithells9 found that 69% of mothers who delivered a NTD affected infant had folate deficiency compared to 17% of mothers with normal children (mothers were matched by age, parity, time of conception and gestation). A later study reported that mothers who gave birth to infants with NTDs had lower mean first trimester levels of serum folate and red cell folate than controls.10 In the UK in the early 1980s, a non-randomised trial by Smithells 11 12 and a small randomised trial by Laurence 13 14 found the recurrence risk of NTDs was


reduced with supplementation by multivitamins, which included folic acid (table 1). However, the impact of these results was overshadowed by criticisms of the methodologies used in the studies.6 15 16 Subsequently, in the mid to late 1980s a number of case-control, cohort, and non-randomised intervention studies also reported a reduced risk of NTDs after periconceptional supplementation with multivitamins and/or folic acid.17 18 19 20 21 22 The one notable exception was the case-control study by Mills et al 23 in California and Illinois which showed no effect of supplementation on the risk of NTDs (tables 1 & 2). In July 1991 the results from a British Medical Research Council funded multicentre randomised control trial were published showing that high-dose folic acid supplements (4.0 mg per day) used by women who had a previously NTD-affected pregnancy reduced the risk of having a subsequent NTD-affected pregnancy by 70% 24 (table 1). In December 1992, Czeizel and Dudas 25 reported that in a randomised trial in Hungary the occurrence risk of NTDs was reduced with the use of 0.8mg per day of folic acid with other vitamins (table 1). Table 1: Randomised and non-randomised intervention trials of the use of vitamin supplements and NTD risk

Trial/study Place Recurrence (R) Occurrence (O)

Folic acid (FA) Multivitamin

(MV)

Daily dose of FA

supplement (mg)

Relative risk

95% confidence

interval

Randomised controlled trials

Laurence et al (1981) South Wales R FA 4 0.42 0.04-2.97MRC Vitamin Study Research Group (1991)

International R FA 4 0.29 0.10-0.74

Czeizel & Dudas (1992) Hungary O M 0.8 0.00 0.00-0.85Kirke et al (1992) Ireland R FA 0.36 0.00 0.00-10.0Combined 0.24 0.11-0.52

Non-randomised trials Smithells et al (1980, 1983) UK, several

centres R M 0.36 0.14 0.03-0.47

Vergel et al (1990) Cuba R FA 5 0.00 0.00-2.13Combined 0.12 0.04-0.41

source: Adapted from: Wald,35 CDC,38 Elwood,26 NHMRC,27 and respective studies


Table 2: Observational studies of vitamin supplementation and NTD risk Study Folic acid (FA)

multivitamin (MV) supplement

Relative risk

95% confidence

interval

Winship et al (1984) FA 0.14 0.003-1.11 Mulinare et al (1988) FA/MV 0.41 0.26-0.66 Milunsky et al (1989) FA/MV supplement 0.29 0.15-0.55

diet: folate >100mg/day 0.42 0.16-1.15 Mills et al (1989) MV/FA 0.87 0.80-1.10 Bower & Stanley (1992) FA/MV 0.11 0.01-1.33 Werler et al (1993) dietary FA 0.60 0.40-1.10 source: Adapted from: Wald,35 CDC,38 Elwood,26 , NHMRC, 27 and respective studies A variety of later studies have corroborated the finding that the periconceptual use of folic acid reduces the recurrence and occurrence risk of NTDs.28 29 30 31 32 33 During 1993-1995, the Centre for Disease Control and Prevention in the USA and the People�s Republic of China conducted a population-based intervention study of almost 250,000 women in the northern (high rates of NTD - 5-6/1,000) and southern (low NTD rates - similar to US) area of China. The results showed a 85% reduction in the risk of a NTD among women in the north who took 400mcg of folic acid daily at least 80% of the time periconceptionally, compared to 41% in the south.34 The scientific evidence emphatically shows that folic acid supplementation in the effective range of 360mcg - 4mg and increases in dietary folate prevents up to 70% of NTD 35 36 even though the mechanism of the action is still not completely known.

Response by Agencies in the USA In August 1991, the Centers for Disease Control and Prevention in Atlanta, USA, recommended that women who had a previous NTD affected pregnancy and who were planning to start a new pregnancy should consume a 4mg daily dose of folic acid from at least one month before conception through the first trimester of pregnancy.37


On 11 September 1992, the US Public Health Service issued an enhanced recommendation: 38

�All women of childbearing age in the United States who are capable of becoming pregnant should consume 0.4mg of folic acid per day for the purpose of reducing their risk of having a pregnancy affected with spina bifida or other NTDs. Because the effects of high intakes are not well known but include complicating the diagnosis of vitamin B12 deficiency, care should be taken to keep total folate consumption at <1mg per day, except under the supervision of a physician. Women who have had a previous NTD-affected pregnancy are at high risk of having a subsequent affected pregnancy. When these women are planning to become pregnant, they should consult their physicians for advice.�

In March 1996, the US Food and Drug Administration regulated that from 1 January 1998, enriched cereal grain products (e.g., flour, bread, pasta, rice etc) would be fortified with 140mcg of folic acid per 100g flour.

The Response in Other Countries Australia, Canada, China, Hungary, Ireland, New Zealand (see below), Norway, South Africa, Spain, the Netherlands, and the United Kingdom are among the countries which have also made recommendations to prevent NTDs by increasing the consumption of folic acid or naturally occurring food folatesii (see table 3). There are marked variations between the countries in the focus (e.g., all women, women planning a pregnancy), level of daily consumption (e.g., 0.4mg, 0.8mg, greater than 0.5mg), and the methods advised to increase consumption (e.g., daily supplement, folate-rich foods, a combination of both).39 Norway is one of the few countries with folic acid recommendations to advise against fortification of foods with folic acid. Supplementation and diet are thought to be sufficient to increase the folate levels of the population. The average intake for adult women is �remarkably lower than the 400 micrograms per day recommended�.40

ii �Folic acid� refers to pteroylmonoglutamic acid, a synthetic compound used in dietary supplements and fortified foods and is more readily absorbed than most naturally occurring food folates. �Folate� refers to all compounds that have the vitamin properties of folic acid; folates include folic acid and naturally occurring compounds in food


Table 3: NTD occurrence recommendations

Country Directed at all fertile women or at women planning a pregnancy

Recommended daily consumption of folates (mg)

How to achieve daily consumption

Australia planning or likely to become pregnancy

>0.5 folate-rich foods + fortified foods + 0.5mg supplement daily

Canada all not specified folate-rich foods planning >0.4/0.8iii supplement daily current status fortification of flour permitted

but not required - much of Canadian flour is fortified because millers export flour to USA

China planning >0.4 supplement daily Chile all

current status fortification of flour used for bread at 220mcg of folic acid per 100g flour starting January 2000

Denmark planning 0.4 folate-rich foods; supplement if needed

Hungary planning 0.4-1.0 supplement daily current status some voluntary fortification of

bread

Ireland women who are likely to become pregnant

>0.4 folate-rich foods + fortified foods + 0.4mg supplement daily

iii The Canadian recommendations state that women planning a pregnancy should consult their physician about folic acid supplements. In the information to physicians, it is stated that �a dose of 0.4mg daily is likely to be beneficial�, but �Individuals may choose to use doses up to 0.8mg, as the evidence for a preventive effect on occurrence is strongest at that dose�.


New Zealand planning 0.8 0.8mg tablet per day. A diet

containing extra folates around the time of conception is recommended to add to but replace daily folic acid by tablet

current status some voluntary fortification of 46 foods (including breads, breakfast cereals, food drinks) - see table 4

Norway all 0.4 folate-rich foods South Africa all 0.4 supplement daily The Netherlands planning >0.5 0.5mg supplement daily United Kingdom planning >0.4 folate-rich foods + fortified food

+ 0.4mg supplement daily

current status voluntary fortification of some cereal grain products

United States all 0.4 food and/or fortified food and/or supplements

current status All enriched cereal grain products (eg, flour, bread, pasta, rice etc) have been fortified with 140mcg of folic acid per 100g flour

source: Cornel and Erickson 1997,39 Erickson 41


Other Health Outcomes Affected by Folic Acid Birth defects There is overwhelming scientific evidence that periconceptional folate/folic acid intakes of at least 0.4mg prevents up to 70% of NTDs. Research also indicates periconceptional supplementation by folic acid or a multivitamin preparation containing folic acid, may also reduce the risk of NTD cases that have associated major defects (�multiples�),42 as well as a number of other specific birth defects such as orofacial clefts,43 44 congenital heart defects,45 46 47 limb defects,48 49 and urinary tract anomalies.46 49 50 In a population-based study, Li et al 51 showed that a periconceptional folic acid supplementation of 0.4mg/day can reduce the risk of congenital heart defect occurrence by about 36%. It estimated that 28% (36,000) of all cases of congenital heart defects (CHDs) in China could be prevented if 80% of women took 0.4mg of folic acid before their last menstrual period. A recent initial study by James et al,52 reported that folate metabolism was abnormal in mothers of children with Down syndrome. On the contrary, studies 25 49 53 54 have reported the absence of a protective relationship between the use of folic acid supplements and the risk of oral clefts and limb defects. Shaw et al 43 have cautioned that with multivitamin preparations the association may not be attributable to folic acid specifically, but may be a consequence of other multivitamin supplement components, or behaviours, that are highly correlated with the use of multivitamins containing folic acid. It is important to acknowledge that folic acid will prevent �folic acid-preventable NTDs�55 by up to 70%, but will not completely eliminate the risk of NTDs occurring. A considerably smaller number of babies will continue to be born with NTDs because both genetic and environmental factors are important contributors to the aetiology of the defects. For example, Werler et al 56 and Shaw et al 57 found that the risk of NTD was increased among obese women, independent of the effects of folate intake and folic acid supplementation.

Cancers Daily folate supplementation may provide some protection against the development of neoplasis in ulcerative colitis.58 Women in the Nurses� Health study had a 75% lower incidence of colon cancer after consuming multivitamins, containing 0.4g of folic acid, over a 15-year period.59 Glynn et al 60 and Kato et al 61 also suggest a possible association between low folate intake and the increased risk of colon cancer (but not rectal cancer) and Ferraroni et al only with rectal cancer.62 Baron et al 63 found �modest� support for the beneficial effects of


folate on colorectal adenoma risk, while the World Cancer Research Fund 64 cautioned that the epidemiological evidence is insufficient to suggest that higher intakes of folate may decrease the risk of colorectal cancer. While no association has been found with folate intake and the overall risk of breast cancer 65 66 or the risk of early-stage breast cancer 67 there is a suggestion that the excess risk of breast cancer associated with alcohol consumption may be reduced by adequate folate intake.65 Research in South Africa 68 has suggested that an additional 0.4mg of folic acid per day could substantially reduce the incidence of oesophageal, cervical, colon, and primary liver cancers. In contrast, other reviews have concluded that high dietary folate intake �possibly has no relationship with the risk of cervical cancer� 64 69 and the �data are insufficient to make conclusions regarding the possible role of folate in reducing the risk of cancer of the lung, esophagus, or stomach.� 70 A Canadian study among the elderly, found that people with low folate levels are more likely to be demented, institutionalised, depressed and have a history of weight loss.71 Poor folate status has also been associated with impairment in word and object recall,72 and age-related hearing loss in elderly women.73 Clarke et al 74 found low blood levels of folate and vitamin B12 and elevated plasma total homocysteine levels were associated with Alzheimers disease. Cardiovascular disease There is an increasing body of research showing folic acid deficiency is associated with elevated levels of homocysteine, an independent risk factor for cardiovascular disease. Such a relationship has potentially major implications for New Zealand�s health status. Despite the death rate from cardiovascular disease declining since the 1950s, cardiovascular disease still accounts for more than 30% of all deaths and is a major component of hospital admissions. Boushey et al 75 estimated that 10% (30,000 men and 19,000 women) of mortality from coronary artery disease in the USA could be prevented by increasing, through fortification, the daily intake of folic acid by 350mcg/100g for men and 280mcg/100g for women. A subsequent meta-analysis 76 of published and unpublished randomised trials that had assessed the effects on blood homocysteine concentrations of folic acid supplements, with or without the addition of vitamins B12 or B6, found that dietary folic acid reduced blood homocysteine concentrations by 25%. There were similar effects in the range of 0.5-5mg folic acid daily. In a large prospective study of 80,082 women from Nurses� Health Study with no previous history of cardiovascular disease, it was found that the 20% who had the highest consumption of folate (94% had consumed multivitamins) had less


cardiovascular disease than the lowest 20% (7% had consumed multivitamins).77 Oakley 78 observed that inadequate blood folate, the major cause of homocysteine blood concentrations above the low, normal baseline, is unusual among those who do consume, but common among those who do not consume, multivitamin supplements. Ninety percent of those consuming multivitamins in the Framingham Heart Study original cohort had homocysteine levels above the low, normal baseline associated with adequate blood folate. 79

A case-control study by Verhoef et al 80 found that folate was the most important determinant of plasma homocysteine, even in subjects with apparently adequate nutritional status of the vitamin.

A recent population-based case-control study by Kittner et al 81 found a strong, statistically significant, inverse association between multivitamin (included 0.4mg of folic acid) use and stroke among women aged 15-44 years. Participants who developed coronary heart disease in a prospective study 82 had lower, but not statistically significant, mean plasma concentrations of folate. A retrospective cohort study in Canada 83 reported low serum levels were associated with an increased risk of fatal congenital heart disease. The Australian Diet & Heart Advisory Committee for the National Heart Foundation concluded:

�there is strong circumstantial evidence that patients with homocysteinaemia and vascular disease will benefit from treatment with folic acid, 0.5-1.0mg per day. Such treatment is safe and should be considered pending the outcome of controlled trials.�84

The Nutrition Committee of the American Heart Association has offered similar advice in a statement for healthcare professionals.85 Riddell et al 86 concluded from a recent NZ study that:

�The most appropriate means of reducing tHcy [total homocysteine] levels in individuals and population is by increasing total dietary folate from the present average intake of around 200ug/day to about 600ug/day, by the use of either folate supplements or fortified breakfast cereals.�

Despite these highly promising and accumulating results there remain a number of skeptics. To Havranek 87 �lowering homocysteine levels, through increased folate intake is a promising but unproven primary prevention strategy.� Kuller and Evans88 are more emphatically negative and dismissive of results from the current research:

�It would be pleasant to be able to put folic acid in a hamburger bun and enjoy half a pound of a juicy high-fat hamburger without worrying about


high LDL cholesterol, coronary atherosclerosis, and thrombosis. Carrots were not the panacea. Some hope that putting folic acid in bread will be the next great public health advance for cardiovascular disease.�

Other health outcomes There is an increasing volume of literature on the protective effects of folic acid in reducing the risk of a number of other health outcomes. Scholl et al 89 suggested that in low income, urban women, use of prenatal multivitamin/mineral supplements (which included 1mg of folic acid) may have the potential to diminish infant morbidity and mortality through reducing the risks of preterm delivery and low birthweight. Czeizel et al 90 found no similar association using a multivitamin containing 0.8mg of folic acid, and Stefanidis et al 91 reported no relationship between folate levels of maternal serum and gestational age at delivery or birth weight. Data from the Hungarian folic acid-NTD trial showed that the female menstrual cycle became more regular during multivitamin supplementation (including folic acid),92 but there was no increased in sexual activity.93 In addition to the unequivocal evidence that folic acid prevents NTDs, there is sufficient and accumulating scientific research to indicate that folic acid reduces the risk of a number of other adverse health outcomes.


Epidemiology of Neural Tube Defects in NZ In the 1995-96 period iv, the NZ Birth Defects Monitoring Programme (NZBDMS) reported there were • 31 cases of anencephaly (26 stillborn, 5 liveborn), a rate of 0.27 per 1,000

total births • 59 cases of spina bifida (43 liveborn, 16 stillborn), a rate of 0.51 per 1,000

total births • 90 NTD cases (48 liveborn, 42 stillborn), a rate of 0.78 per 1,000 total births In 1997-98 there were: iv

• 7 liveborn cases of anencephaly • 33 liveborn cases of spina bifida The NZ rates of anencephaly and spina bifida are almost twice as high as the rates reported from the Australian national programme and considerably higher than the rates in England/Wales and Finland (table 4). However, with the exception of the Japanese and Canadian programmes, terminations of pregnancy (TOP) account for a considerable proportion of NTD cases. For example, 83% and 68% respectively of all anencephaly and spina bifida cases in England/Wales are notified from TOP. Table 4: Rates of NTDs in selected birth defect monitoring programmes

Anencephaly Spina Bifida Total Total births Monitoring Programme no rate* no rate* no rate* Australia ('96) 40 0.16 75 0.29 115 0.45 254,978 Canada (''96) 33 0.12 156 0.55 189 0.67 283,356 England/Wales ('97) 28 0.04 48 0.07 76 0.12 645,146 Finland ('97) 5 0.08 24 0.40 29 0.49 59,565 Japan ('97) 20 0.20 35 0.35 55 0.54 100,930 New Zealand ('95-'96) 31 0.27 59 0.51 90 0.78 115,854 Norway ('96) 7 0.12 16 0.27 23 0.38 60,085 USA:Atlanta ('97) 4 0.09 13 0.30 17 0.39 43,271 *rate per 1000 total births source: NZ Birth Defects Monitoring Programme, ICBDMS Annual Report 1999 94 iv 1996 is the latest fetal death data available. The definition of a fetal death changed in late 1995 from 28 or more completed weeks of gestation to 20 weeks and/or 400g birthweight


There is currently no facility to collect data on the numbers of terminations of pregnancy carried out for NTDs. If TOPs constituted the same proportion of all cases in NZ as in Australia and Finland, the annual number of NTDs would be approximately: • 47 cases of anencephaly (3 livebirths, 12 stillbirths, 32 TOPs) • 53 cases of spina bifida (8 stillbirths, 20 livebirths, 25 TOPs) • 100 cases of NTDs of which 20 are stillborn, 23 liveborn, and 57 TOPs Data from the NZ Birth Defects Register, shows that the prevalence at birth rate of NTDs: 4 95 • is lower for Maori than nonMaori parents • is higher for females than males • is higher in the North than South Island for anencephaly, but not for spina

bifida • is lower among births to women born in countries other than the British Isles

and NZ • is not related to maternal or paternal age, parity, urban-rural place of

residence, nuptiality, social class or season of birth • has been declining since the mid-1970s 96 • is lower for NZ-born mothers than for mothers born in England/Scotland 97 Burden of NTDs in NZ NTDs are the second major category of birth defects (after congenital heart defects) and are a major component of fetal and infant death and morbidity. An alternative method of understanding the population impact of spina bifida is through the contribution to the overall �burden of disease�. This takes account of both the years of life lost to premature mortality and the years of life lost (severity-adjusted) to disability. Among 0-14 year olds, 35.5% of the total burden from birth defects is due to congenital heart defects and spina bifida (table 5). Current scientific evidence shows that the disease burden from these birth defects can be reduced by increasing the daily intake of folic acid.


Table 5: Burden of disease - birth defects, 0-14 years, 1996 Birth defect % of total

burden from birth defects

Nonchromosomal defects 41.0Congenital heart defects 20.5Spina bifida 15.0Down syndrome 10.2Urogenital defects 3.0Defects of the digestive system 1.8Facial clefts 0.4Defects of the abdominal wall 0.7Other defects 7.4Total 100.0 source: NZ Burden of Disease Study 2 Cost of NTDs Singh and Elliott 98 estimated that the 20-year cost of treating, managing and caring for one spina bifida case in NZ is about $355,060. On average there are about 20 liveborn cases of spina bifida per year resulting in a total cost over 20 years of $7,101,200. This does not include other potential costs such as the loss of parental income, special schooling needs, family stress, wheelchair, crutches, occupational therapy, GP visits etc. Waitzman et al 99 100 employed a cost-of-illness methodology to estimate the direct (includes medical, special education, and development services) and indirect (includes mortality and morbidity) costs of spina bifida and 17 other birth defects in the USA (table 6a). While health system costs in the USA are high by international standards, these data, adjusted to NZD equivalents (table 6b), show that spina bifida has the fourth highest lifetime cost from birth defects.


Table 6a: Lifetime cost of selected birth defects, USA, discounted at 5% (US$1,000s, 1992)

* double-outlet right ventricle source: Waitzman et al 99

Table 6b: NZD equivalents* of lifetime cost of selected birth defects, NZD1,000s

* 1NZD = 0.52USD ** double-outlet right ventricle source: Waitzman et al 99

Birth defect Medical Special

educationDevelopmental

services Indirect costs Total costsSpina bifida 204,512 41,672 1,781 241,324 489,289 Transposition/DORV 166,334 4,402 - 343,794 514,530 Tetralogy of fallot 185,122 3,974 - 171,390 360,486 Cleft lip or palate 97,126 17,551 2,937 578,888 696,502 Colorectal atresia 57,213 - - 162,049 219,262 Renal agenesis 24,713 - - 399,466 424,179 Lower limb reduction 16,560 11,851 - 138,656 167,067 Diagraphmatic hernia 62,772 - - 301,576 364,348 Down syndrome 278,696 293,960 95,029 1,180,068 1,847,753 Cerebral palsy 851,809 226,718 217,899 1,129,355 2,425,781

Direct Costs

New Zealand equivalent (1NZD=0.52USD)

Birth defect Medical Special

educationDevelopmental

services Indirect costs Total costsSpina bifida 393,292 80,138 3,425 464,085 940,940 Transposition/DORV 319,873 8,465 - 661,142 989,481 Tetralogy of fallot 356,004 7,642 - 329,596 693,242 Cleft lip or palate 186,781 33,752 5,648 1,113,246 1,339,427 Colorectal atresia 110,025 - - 311,633 421,658 Renal agenesis 47,525 - - 768,204 815,729 Lower limb reduction 31,846 22,790 - 266,646 321,283 Diagraphmatic hernia 120,715 - - 579,954 700,669 Down syndrome 535,954 565,308 182,748 2,269,362 3,553,371 Cerebral palsy 1,638,094 435,996 419,037 2,171,837 4,664,963

Direct Costs


Based on the data from Waitzman et al 99 the lifetime cost of each case of spina bifida is estimated to be NZD565,000 (table 7), more than for the major congenital heart defects such as tetralogy of fallot and transposition of the great vessels, abdominal wall defects, and cleft lip or palate. Table 7: Lifetime cost per case of birth defects, United States (1992) and NZD equivalent Cost per case ($,000s) Birth defect USD (1992) NZD* Truncus arteriosus 505 971 Cerebral palsy 503 967 Down syndrome 451 867 Single ventricle 344 662 Spina bifida 294 565 Transposition/DORV** 267 513 Tetralogy of fallot 262 504 Renal agenesis 250 481 Diagraphmatic hernia 250 481 Lower limb reduction 199 383 Omphalocele 176 338 Tracheoesophageal fistula 145 279 Colorectal atresia 123 237 Gastroschisis 108 208 Cleft lip or palate 101 194 Upper limb reduction 99 190 Urinary obstruction 84 162 Atresia, small intestine 75 144 * 1NZD = 0.52USD ** double-outlet right ventricle source: Waitzman et al 99


The NZ Response to Folic Acid Research

On page 2 of the 10 January 1993 issue of the NZ �Sunday Times� 101 an article under the heading �Green vegie diet to avoid birth defects� noted: • �pregnant women are being advised to eat plenty of green, leafy vegetables to

reduce the risk of their baby being born handicapped�. • �The Health Department plans to send a circular to general practitioners

advising them to encourage pregnant patients to boost their intake of folic acid�

• the Department�s principal medical officer of health said that �the abundance

of vegetables in New Zealand meant there was no need to recommend "pills and potions" to pregnant women. Instead they should simply ensure they ate plenty of green vegetables, lightly steamed rather than cooked, and salads.�

The results of the UK MRC trial 24 were promoted by Dixon and Murray,102 in the 10 March 1993 issue of NZ Medical Journal and by Elwood 103 in the 28 July issue of the NZ Herald. In September, the Public Health Commission (PHC) v produced a letter to health professionals entitled �Reducing the chances of spina bifida by taking folic acid.�104 A public statement was made recommending that all women planning a pregnancy should take a daily supplement of folic acid per day. Only 5mg tablets were available on the NZ market. Women were also advised to improve their diet by increasing the consumption of green vegetables. Additional features of �the overall prevention plan for spina bifida and neural tube defects� were for the PHC and the Ministry of Health to: • obtain approval of a lower dose folic acid tablet • investigate whether and to what extent the food supply should be fortified with

folic acid In June 1995, health professionals 105 and the public 106 107 were informed of the availability of a �low dose� 0.8mg folic acid tablet �to help prevent spina bifida in planned pregnancies�. Women were advised that �diet alone does not provide sufficient folic acid� and �to take daily folic acid by tablet�. The PHC undertook to investigate �other avenues for increasing folic acid intake� noting the �Addition of folate to manufactured foods deserves serious consideration as this could contribute to a reduction in the incidence of spina bifida and other conditions.� 108

v The Public Health Commission was disestablished in 1994 and its functions taken over by the Ministry of Health (policy and monitoring) and the Regional Health Authorities (purchasing)


In 1995, the PHC recommended that �spina bifida incidence among livebirths be reduced one-third below the 1993 incidence level by 1997.� 108 The target was elaborated in the 1995 edition of �Progress on Health Outcome Targets�: 109

�To reduce by 30 percent the prevalence of spina bifida among livebirths from 0.42 per 1,000 livebirths in 1993 to 0.29 per 1,000 livebirths by the year 1997.�

Two important points were made in the accompanying commentary: • �At the current rate of decline [of spina bifida] the target will be easily

achieved� • �Fortification of food with folic acid will be considered by the Ministry of Health

in 1995 as a way to reduce the risk of spina bifida in unplanned pregnancies� The �National Plan of Action for Nutrition�, published in 1995, observed: �Most nutrition professionals in New Zealand have supported the view that all New Zealanders can obtain the nutrients they need through the appropriate food choices (apart from folic acid, iodine and fluoride).� 110 Subsequent developments in NZ�s response to the scientific research on the relationship between folic acid and NTDs have been: 1996

• Singh and Elliott 98 recommend a �Folate Replenishment-Plus Programme� to fortify all flour with folate

• Kellogg launches its entire range of cereals with added folic acid onto the

New Zealand and Australian market with the �Folate added� logo on the packaging

1997 • in January/February Sanitarium adds folic acid to the breakfast cereal

�Weetbix� at a level of 333mg/100g • the flourmilling industry through its research trust is approached to lend

support to the proposal to fortify all flour with folic acid

• the Folate Replenishment-Plus Committee formed to coordinate and promote the fortification of flour with folic acid. Membership comprises health professionals, representatives of the milling and baking industry and NZCCS, a nutritionist, an epidemiologist, and a public relations


consultant. Funding was initially provided by the NZ Flourmillers� Research Trust and subsequently by NZCCS

1997-98 • Folate Replenishment-Plus Committee undertakes a consultation and

communications campaign and begins discussions with the Ministry of Health about the folate fortification of flour to the level of 285mcg/100g

1998 • The Baking Industry Research Trust commission Bourn and Newton, from

the Department of Consumer Sciences, University of Otago to produce a report on �Consumer Attitudes on the Fortification of New Zealand Bakery Products� 111

• based on feedback from consultation, the Folate Replenishment-Plus

Committee modifies its proposal to only fortify bread, rather than flour, at the level of 140mcg/100g and discussions begin with the NZ Association of Bakers

• The Australia New Zealand Food Authority (ANZFA) launches the folate

health claim and continues negotiations with the corporate and business community

• Sanitarium progressively adds folic acid to other products such as �Hi

Bran/Soya Linseed�, �Marmite� and �Light & Tasty�

• in November, Kellogg conducts research on folate awareness

1999 • in March, Kellogg launches a campaign about the benefits of folate to

health generally and specifically in reducing the risk of NTDs • the Ministry of Health and ANZFA fund University of Otago to collect

baseline data on folate intake and blood folate levels among women of child-bearing age and teenage boys

• in June, Watson and McDonald 122 release a report on �Nutrition during

Pregnancy�

• in June, Kellogg repeats its previous research on folate awareness

• in August, publication of results from the �1997 National Nutrition Survey� 113


• in September, Sanitarium announces at nutrition conference in Auckland that four products in Australia and two in New Zealand will carry the ANZFA folate health claim

• late 1999 - Champion, New Zealand�s leading supplier of flour and bakery

pre-mixes, adds folic acid to all its improvers, concentrates and yeast-raised bakery mixes at the recommended levels. To coincide with this initiative, a leading supermarket retailing group applies for registration from ANZFA to add folic acid to all bread made at its in-store bakeries using Champion�s bakery mixes and concentrates with added folic acid.

Folate Intake of New Zealanders The current NZ Recommended Daily Intake (RDI) of folate is 200mcg per day for non-pregnant adults and 400mcg per day for women of childbearing age 112. As previously noted the Ministry of Health also recommends that women planning a pregnancy should take an additional daily supplement of folic acid to reduce the risk of NTDs. The 1997 the National Nutrition Survey 113 found that the usual daily median intake of folate from food was 242mcg (males 278mcg, females 212mcg) (table 8). In comparison, the median intake in the 1991 survey 114 was less than 170mcg, but the increase could represent a change in folate intake as well as differences in the methods used in the two surveys. In 1997, median folate intakes for males ranged from 256mcg (65+ year age group) to 286mcg (25-44 year age group) and for females from 194mcg (15-18 year age group) to 222mcg (45-64 year age group). Males and females living in NZDep96 115 quartile IV areas had lower levels of intake (268mcg and 201mcg respectively) than those living in the highest quartile I areas (287mcg and 227mcg respectively). Comparing results from the 1991 and 1997 surveys shows the median intake for boys aged 15-18 years increased 27%, compared to more than 45% in the other age groups. Among women, the median intakes in the 15-18 and 19-24 year age groups increased 28% and 14% respectively, compared to 43% for 25-44 years, and more than 51% in the oldest age groups.


Table 8: Usual folate intake by ethnic, gender, age group

Usual folate intake (mcg)

50th percentile

Ethnic group / gender

Age group (yrs)

1991 1997 1997 -inadequate

intake (%) *NZ 15+ 170 242 7.1Male 15-18 218 277 2.8

19-24 187 272 3.4 25-44 192 286 1.6 45-64 192 278 0.8 65+ 176 256 1.0 Total 192 278 1.3

Female 15-18 151 194 22.2 19-24 171 195 21.2 25-44 149 213 13.4 45-64 147 222 9.8 65+ 140 217 9.2 Total 151 212 13.1

Maori Male 15-24 226 8.7

25-44 283 2.5 45+ 260 1.0 Total 273 2.3

Female 15-24 194 28.6 25-44 207 18.4 45+ 196 26.0 Total 198 23.0

Other Male 15-24 291 1.7

25-44 290 0.8 45+ 272 1.5 Total 282 1.7

Female 15-24 197 18.7 25-44 215 11.5 45+ 222 9.5 Total 215 11.5

*calculated by probability analysis source: 1997 National Nutrition Survey, 113 1991 National Nutrition Survey 114


In 1997, the prevalence of inadequate intake was reported to be higher among: • females than males (irrespective of age) (table 8) • NZ Maori females and males than NZ European and Others (table 8) • females living in areas the lowest quartile of NZDep96 compared to those

living in quartile I areas • females aged 15-24 years (21.2-22.2%) compared with females aged 45+

years (9.2-9.8%) (table 8) However, the authors caution that �the prevalence of inadequate intake is likely to be overestimated� because of the difficulty in determining folate levels in foods and that the requirements have been set to maintain liver stores. 113 Sources of folate According to the 1997 National Nutrition Survey,113 vegetables are the principal source of dietary folate in most age groups (table 9). The exceptions are breakfast cereals (16%) for males aged 15-24 years, while vegetables and bread contribute similar proportions (15%) of dietary folate for females aged 15-18 years.


Table 9: Major sources of dietary folate, by gender and age group

Major sources of folate (%) Age group (yrs)

Vegetables Bread* Breakfast cereals

Fruits Potatoes and kumara

NZ population

15+ 18 13 11 8 8

Male 15-18 13 12 16 5 11 19-24 12 11 16 6 10 25-44 18 14 10 6 8 45-64 18 14 10 6 8 65-74 24 12 12 6 8 75+ 18 14 14 8 9 Total 17 13 12 6 9

Female 15-18 15 15 10 9 8 19-24 20 12 9 11 8 25-44 18 13 11 9 7 45-64 22 13 10 10 6 65-74 22 13 10 11 6 75+ 22 12 13 10 6 Total 20 13 10 10 6

* includes rolls and speciality breads source: 1997 National Nutrition Survey 113

Methods of Enhancing Folate Levels in The Population

Three strategies are available to increase the folate levels sufficiently to prevent NTDs: diet, supplementation, and fortification. The first two approaches are selective by focusing primarily on women who are planning a pregnancy, while fortification is a population based strategy. Diet A NZ study 122 of the diet of pregnant women at four and seven months found less than half of the women had changed their eating habits since they became pregnant. Maori and Pacific Island women ate less fruit and vegetables, the major source of dietary folate, and bread and cereals than European women. Women in the lower occupational categories ate bread and cereals less often


than the other groups. However, the report provides no indication of the relevance of these data to the mothers� diet at the time when NTDs are formed. It is not feasible to expect a woman to increase her folate level through diet alone. As highlighted by Skeaff and Mann,116 the folate-NTD relationship is:

�the first well documented public health situation where the amount of nutrient required to prevent the nutrient-related condition is more than can be practically eaten in the diet by choosing foods wisely.�

Wald and Bower 117 noted that for a woman to receive an extra 0.4mg of folic acid each day she would have to �consume over eight glasses of orange juice, 10 servings of broccoli, three servings of brussel sprouts, or appropriate combinations of such foods.� Elwood 118 estimated that 100g of fresh green cabbage, a good source of folate, contains only about 90mcg of active folic acid. The bioavailability of food folate is about 50%.70 Therefore, Cuskelly et al 119 found that dietary advice and consumption of extra folate as natural food folates were �ineffective in optimising folate status.� In contrast, serum folate doubled with supplements and fortified foods. The authors concluded: �that advice to women to consume folate-rich foods as a means to optimise folate status is misleading.� Improving all aspects of maternal diet, especially among adolescent mothers,120 should be regarded as a fundamental part of public health practice. While it is commendable to encourage women to consume more folate-rich foods, such a strategy alone will have little impact on preventing NTDs. Supplementation The second strategy for the prevention of NTDs is through the use of dietary supplements,vi either specifically folic acid or a multivitamin containing folic acid. The bioavailability of synthetic folic acid ranges from about 100% for supplements taken on an empty stomach to 85% when consumed with a meal.70 An economic analysis in the USA,121 estimated that folic acid supplementation would reduce annual hospital charges for NTDs and congenital heart defects respectively by USD73-89m and USD1047-1135m.

vi A dietary supplement is �an edible substance in a controlled dose which is intended to supplement the intake of those substances normally derived from food� (Nutrition Taskforce. Food for Health. The Report of the Nutrition Taskforce to the Department of Health. Wellington: Department of Health, 1991)


use of supplements The 1997 National Nutrition Survey 113 found that 51% of the NZ population (59% of females, 42% of males) were regular or occasional users of vitamin and/or mineral supplements during the last year (table 9). Only 23% of Pacific Island women used these supplements, compared to 46% of Maori women and 63% of �Other� women (table 10) Three percent of the women aged 25-44 years in the �Other� ethnic group consumed folic acid supplements in the last year. Table 9: Vitamin and mineral supplement use in the last year, by gender and age group

Consumption frequency % of population consuming Gender Age group

(yrs) Regular* Occasional** Multivitamins

&/or mineralFolic acid

NZ 15+ 28 23 19 1 Male 15-18 19 36 17 0

19-24 18 33 15 0 25-44 21 26 16 0 45-64 22 13 10 0 65-74 21 4 8 0 75+ 19 5 13 0 Total 21 21 14 0

Female 15-18 29 37 16 0 19-24 33 36 32 0 25-44 37 27 27 2 45-64 36 20 24 0 65-74 35 15 16 1 75+ 26 8 11 0 Total 34 25 24 1

* used any supplement at least once per week, during the last year ** used any supplement no more than three times per month, during the last year *** the use of any supplement, regular or ocassional source: source: 1997 National Nutrition Survey 113


Table 10: Vitamin and mineral supplement use in the last year, by ethnic group, females Consumption

frequency % of population consuming

Ethnic group Age group (yrs)

Regular* Occasional** Multivitamins &/or mineral

Folic acid

Maori 15-24 22 20 9 0 25-44 29 25 20 1 45+ 22 14 18 0 Total 25 21 16 0 Pacific Island 15-24 10* 12* 6+ 0+ 25-44 11 14 9 0 45+ 12* 8* 11+ 0+ Total 11 12 9 0 Other 15-24 35 43 31 0 25-44 39 29 29 3 45+ 35 17 20 0 Total 37 26 26 1 * used any supplement at least once per week, during the last year **used any supplement no more than three times per month, during the last year *** the use of any supplement, regular or occasional + limited sample size source: source: 1997 National Nutrition Survey 113 There are caveats with these data. �Regular� and �occasional� users take a supplement �at least once a week� and �three times per month� respectively, but folic acid must be taken daily to prevent NTDs. There is no indication of the amount of folic acid included in either the multivitamin or folic acid specific supplements. Watson and McDonald 122 found that 37% of 504 pregnant female volunteers in the northern half of the North Island had taken folic acid supplement in the year before their pregnancy (table 11). Almost half of �European� women used a supplement compared to 10% of Maori and 9% of Pacific Island women. Among European and Pacific Island women consumption of multivitamin supplements were considerably lower than the consumption of folic acid supplements. The authors noted: �there was some anecdotal evidence Pacific Island women were being warned off all pills during pregnancy, which includes folic acid.� The use of folic acid also increased with higher occupation category and increasing education level and income. It is not clear from the study report what effect recall bias may have on the results, and the relevance of diet and nutrition data at months 4 and 7 of pregnancy compared to the time of conception and the first 28 days of gestation (when NTDs occur). There is also no indication about


the frequency of supplement use in the year before the pregnancy or the amount of folic acid in the various supplements. Table 11: Women taking multivitamin and folic acid supplements in the year before pregnancy Supplement use in the year before

pregnancy Multivitamin Folic acid Ethnic group no % no % European 43 12.1 173 48.6 Maori 10 10.0 10 10.0 Pacific 1 2.6 4 8.7 Total 54 10.8 187 37.1 source: adapted from Watson and McDonald 122 A nationwide mail survey in 1998 111 found 69% of females and 49% of males had taken some form of dietary supplement (there was no indication of type of supplement) during the previous year. The highest proportions of weekly supplement takers were in the youngest age groups. The proportion of older respondents taking supplements at least once a week was less than in the younger age groups. Despite the methodological limitations of these NZ studies, there are indications that NZ women are not taking sufficient folic acid by supplementation to prevent NTDs. sales and availability of folic acid tablets In the period 1991 to 1996, annual unit sales of folic acid in NZ,123 which will be an underestimate of the true level of supplementation, declined by 24% from 172,300 to 130,013 (figure 1). The peaks of sales each year generally occurred in March-April and there is some evidence that the major announcements on folic acid stimulated a small sales reaction. Annual sales increased 4% in 1997, and 7% in 1998, with peak sales occurring in November-December. There is some evidence of more consistent purchasing of folic acid tablets since July 1995, when the second recommendation was issued by the Ministry of Health and the so-called �low dose� 0.8mg folic acid tablet became available. Folic acid is available on the NZ market from folic acid specific tablets of 300mcg, 800mcg, and 5mg, and multivitamin tablets with levels of folic acid ranging from 30mcg to 350mcg (table 12). Most multivitamin tablets will not provide sufficient daily folic acid to prevent NTDs. In contrast, multivitamin tablets in the USA usually include 400mcg of folic acid. The annual cost of folic acid specific supplements in NZ is about NZD30-40.


Table 12: Sample of folic acid supplements available in NZ, November 1999 Manufacturer Brand Multivitamin

(MV) or folic acid (FA)

Amount of folic acid

Number of

tablets

Cost Comment or any health statement on accompanying

packing Healtheries Multivitamin & minerals MV nil Healtheries Teenage multi MV 130mcg Healtheries Senior multi MV 100mcg Healtheries Womens multi MV 300mcg 30 10.30 Healtheries Womens multi MV 300mcg 60 17.05 Healtheries Folic acid FA 300mcg 60 5.35 "Recommended prior to and

during pregnancy for health cell development"

Red Seal Womens multi MV 300mcg 30 9.25 Red Seal One-a-day multi MV 100mcg 30 5.25 Red Seal Total multi MV 30mcg 30 7.75

Kordels Womens multi MV 300mcg 30 12.95 Kordels Megatime MV 300mcg 60 21.95 Kordels Teentime MV 125mcg 60 16.95

Natural nutrition Womens mega vita-min MV 200mcg 50 22.95 Natural nutrition Nutritent care for women

on the pill MV 200mcg 30 14.95


Nature's Own Folic acid FA 300mcg 100 8.75 "Useful for normal health pregnancies"

Blackmores Folic acid FA 300mcg 90 9.95 "May reduce the risk of having

a child withg spina bifida/neural tube dfefects if

taken prior to and during pregnancy"

Blackmores Womens multi MV 300mcg 50 17.95

Thompsons Folic acid FA 300mcg 80 9.95 Thompsons Femmefit MV 300mcg 60 19.95 Thompsons Multifort MV 300mcg 60 18.80

Abbott Iron-folic acid Iron+FA 350mcg 30 5.95 Bio-organics Ultra MV 25mcg 30 17.80

Folic Acid obtained from pharmachist

Folic acid FA 800mcg 120 9.95 no questions were asked or advice given

Folic Acid obtained from pharmachist

Folic acid FA 5mg 120 8.50 no questions were asked or advice given


Figure 1: Unit sales of folic acid in New Zealand, 1991 to June 1999

source: IMS HEALTH, New Zealand Phamaceutical Index, June 1999

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

J J J J J

J

J

J

J

months and years

1991 1992 1993 1994 1995 1996 1997 1998 1999

J= January

unit sales

MRC studypublished

1st PHC recommendation

0.8mg tabletadvertised


Knowledge about folate and NTDs Integral to increasing the intake of dietary folate and the use of supplements is the level of knowledge that health professionals and the public have about the benefits of improving folate levels. A number of studies have investigated the awareness of folic acid among populations, changes in diet or supplement use, the impact of mass media campaigns and the usefulness of other information sources. For example: • in Toronto in 1994 124 only 13% of mothers of spina bifida infants were aware

of relation between folic acid and NTDs and they did not take folic acid supplements. A sample of �well educated, English speaking women�, in Ontario during 1997-98 showed 63% were aware of the need for preconceptional folic acid, but only one third took vitamin supplements before conception 125

• in Ireland, traditionally an area with high international rates of NTDs, only 16%

of women were taking folic acid despite a mass media campaign. 126 Marriage and planned pregnancy were predictors of folic acid knowledge, compared to planned pregnancy advice given before pregnancy and relative affluence as predictors of periconceptional use127

• specifically in Dublin, 63% of women were aware of folic acid, but this

knowledge was associated with higher social class and education and only 3% of women were actually taking supplements 128

• 41% of female undergraduate students were aware of the need to increase

folate intake 129 • a South American study 130 found that 40% of women claimed to have taken

vitamins during pregnancy, but only half were actually found to have taken vitamins. Minerals and other products had often been mistaken for vitamins. None of the mothers who took vitamins did so preconceptionally, 14% knew the benefits of taking folate, but only 2% correctly identified folate rich foods

• in Glasgow, 57% of women took supplements during their pregnancy, but only

21% did so before conception. 131 The most important reason for not taking supplements was the lack of awareness of the benefits, with unplanned pregnancy, younger age, and previous pregnancies being other reasons

• in Israel, 6% of 920 women interviewed had heard of folic acid and 38% had

taken it132


• in a study in Atlanta, 133 the location of the Center for Disease Control and Prevention, found than 80% of low income, predominantly minority women did not take supplements preconceptionally, 57% had heard about folate, and 30% could list folate rich food sources.

• among Latinos and African Americans in inner city Hartford, 11% of

respondents identified folic acid as capable of preventing NTDs, and more than 80% did not know which foods were folate rich, and the intake of fruit and vegetables was low 134

• in Western Australia, most women were not taking folic acid supplements

before they became pregnant (the critical time), but there was an increase in the number taking supplements in the first trimester 135

• Brandenburg et al 136 found that 60% of women were taking folic acid

supplements, but only 25% were using it periconceptionally • in the south of England, 32% of pregnant women used supplements

containing folic acid before conception, but young age, smoking and low education attainment were predictors of failure to use folic acid before conception.168 Previous reports 137 138 139 140 from elsewhere in England also found that women had poor knowledge of folic acid and a low level of supplementation

• pregnant women attending an inner city practice were no more aware of the

relationship between folic acid and NTDs than non-pregnant women in contrast to women attending a suburban practice 141

• surveys before the 1996 Victorian Folate Campaign in Australia found that

78% of women knew the term �folate� or �folic acid�, 42% did not know what it was, 12% knew folate prevents NTDs, 40% knew folate should be taken periconceptionally, and 4% were taking a folate supplement 142

• a 1998 national sample survey of women 143 in the US reported:

- 68% had heard or read about folic acid (52% in 1995) - awareness was lowest among 18-24 year olds and those with less

than high school education - 13% knew that folic acid prevents birth defects - 7% knew that folic acid should be taken before pregnancy - 32% were taking a daily vitamin supplement containing folic acid

• only about 2% of women in a sample from teaching practices in Northeastern

Ontario knew that folic acid supplementation before conception prevents NTDs 144


Results from studies reporting on the sources of information about folic acid and NTDs show: • in Ontario, the media were the principal source of information before

conception and doctors after 125 • in Glasgow, the major sources of information on folic acid supplement use for

pregnant women were GPs, magazines, and books 131 • a random sample of Canadian physicians 145 showed that only 14% knew the

correct timing of folic acid supplements • less affluent women in Ireland used their GP more as a source of information

and advice than more affluent women 127 • in Dublin, the majority of women found out about folic acid from lay sources

(eg, friends and media) 146 • doctors were the major source of information in Western Australia 150 • a small survey in England in 1995 139 found that only 43% of GPs correctly

knew the correct dose and duration of folic acid needed to prevent NTDs • in 1998 in the USA,143 31% of women of childbearing age obtained

information about folic acid from books and magazines, 23% from radio or television, and 19% from health care providers

• in Southwestern Virginia, television and healthcare providers were the two

leading sources of information about folic acid 147 • Bonin et al 144 found variability about knowledge of folic acid supplementation

between 22 teaching practices in Northeastern Ontario • among women attending two GP practices in the UK, magazines and

newspapers were the major source of information. 141 Only a third of patients mentioned health professions as a source of information

• in Leiden, 148 18% of GPs thought they were insufficiently informed about folic

acid recommendations, 58% sometimes forgot to inform the women about folic acid, and 66% thought it contributed to the medicalisation of the pregnancy

Mass media campaigns are often used to increase public awareness and use of folic acid. Evaluations of some of the campaigns show:


• following mass media campaigns in the Netherlands in 1995 149 and Ireland in 1996-97,126 the awareness of women about folic acid increased more than 76% and usage of folic acid more than doubled. However, in the Netherlands the socioeconomic differences in awareness persisted.

• in Western Australia: 150

- the promotion of folic acid supplements to prevent NTDs during 1992-95, resulted in 70% of GPs offering folic acid supplements to women planning a pregnancy, 56% of GPs and 82% of pharmacists knowing the recommended dose of 0.5mg, and an 88% increase in sale of 0.5mg of folic acid

- it was estimated that 68% of women of child-bearing age in Western Australia knew of the association between folic acid and NTDs compared with 8% before the campaign

- women who had seen the promotional pamphlet were seven times more likely than women who had not seen the pamphlet to know increasing folic acid intake prevents NTDs

• in southwestern Virginia there were considerable increases in the awareness

and knowledge of the benefits of folic acid following a year-long community information campaign aimed at the women of childbearing age in 1997

Therefore, most women are still not aware that folic acid prevents NTDs, the use of folic acid is still low, and women who do take supplements are usually not taking them periconceptionally. Mass media campaigns can increase awareness, but these need to be sustained over a period of time. Fortification The preceeding evidence from NZ and overseas clearly shows that improving the folate status of a population to a level sufficient to prevent NTDs can only be achieved through a population approach. The effective change in dietary habits and use of supplements is dependent on a number of factors such as patient education, availability and cost of foods, access to care, access to medication, compliance and acceptability of taking supplements in pregnancy, availability and accuracy of advice given to women. In many cases, these requirements are most problematic for those in the lower or more disadvantaged socio-economic groups. It has been estimated 151 that in the UK, GPs would have to give advice during 35,714 consultations about contraception or 111,428 general medical consultations to prevent one neural tube defect. The estimate assumes that women plan their pregnancies, attend for consultations, remember and wish to comply with the advice given, and can afford folate supplementation.


Another major impediment to improving folic acid intake through supplementation is the high proportion of pregnancies which are unplanned. A number of studies have shown that women were consuming supplements after the critical time of NTD formation. In many countries it is estimated that about 40% of pregnancies are unplanned, in contrast to the Netherlands where 90% of pregnancies are planned.149 There are no data on the proportion of unplanned pregnancies in NZ. As a surrogate measure, rate of teenage pregnancy in NZ has declined over the last ten years, but it is still of the highest in the developed world 152 Because diet and supplementation have major deficiencies as delivery mechanisms, food fortification vii has been proposed as the population strategy for improving folate status and preventing NTDs. Fortification is simple, does not require behavioural change or active intervention, and is in the public domain. Skeaff and Mann 116 identified �the key principal of fortification is that the amount of nutrient added to the food supply should be only as much as is needed to produce the desired effect while minimising any risk of toxicity to the target and non-target populations.� Cost effectiveness of folic acid fortification A number of studies have shown that fortification with folic acid is a highly effective delivery mechanism for increasing the folate status of a population. An extensive economic analysis in the USA 100 153 concluded that fortification of cereal grains �would probably have economic benefits that significantly exceed the costs under a wide range of assumptions.� It was estimated that US consumers would spend USD132,000 on supplements to avert one NTD case, compared to USD92,500 for low-level fortification (140mcg/100g) and USD65,500 for high-level fortification (350mcg/100g). Singh and Elliot 98 have estimated that preventing one spina bifida birth per year in NZ will pay for the entire costs of fortifying 236,000 tonnes of flour milled annually at 100mcg/35g ($201,780). Supplementation using folic acid tablets was estimated to cost about $30 per year per women capable of childbearing. Therefore, the total annual cost of fortification equates to the cost of 6,726 women taking folic supplements. In the 1996 Census there were 833,730 women aged 15-44 years. The NHMRC 27 in Australia estimated that each year fortification would produce savings of AUD$2,315,289 and acknowledged this would be an underestimate.

vii Fortification is the addition of nutrients to food �for the purpose of improving the quality of food or as a way of helping to improve the nutritional status of a population or a sector of the population.� source: Ministry of Health. Food and Nutrition Guidelines for Health Children Aged 2-12 Years: A Background Paper. Wellington: Ministry of Health, 1997


Fortification of foods in NZ The introduction of a fortification programme requires the availability of a legislative regulation and the provision for health claims to be placed on food products. In accordance with The Food Regulations 1984, Amendment no 12 (1995/305), the allowable folate fortification level in NZ since January1996 is 100mcg per 35g of white flour and pasta, and 50g of breads. In 1998, 46 viii foods available in NZ had been fortified with folic acid, 50% of which were breakfast cereals, and 21 were produced by Kelloggs (Aust) Pty Ltd (table 13). The earliest date that a product had been fortified was 1 January 1980 (Healtheries KLB6 Slimming Formula - 320.00mcg/100g). Three of the four breads had been fortified (200mcg/100g) since 1 March 1996. Table 13: Total number of foods fortified with folic acid in NZ in 1998 Food no

fortified Breads 4 Breakfast cereals 23 Extracts of meat, yeast, or vegetables

1

Food drinks 15 Supplement bar 3 Total 46 source: NZ Therapeutic Database The overall level of fortification varies from 40mcg/100g (�Up & Go�) to 2000mcg/100g (�Marmite�), but in bread and breakfast cereals the range is from 166.70mcg/100g to 333.30mcg/100g (table 14).

viii The summary in the publication from the NZ Therapeutic Database lists 48 foods available in 1998 which had been fortified; details are only given for 46 products - no details are given for the 2 fortified fruit juices


Table 14: Fortified foods available in NZ, 1998 Food Company Brand Product Amount Date

fortified Breads Allied Foods Co Ltd Norths Extra Fibre White 200.00mcg/100g 1/03/1996 Swiss Grain 200.00mcg/100g 1/03/1996 Wholemeal 200.00mcg/100g 1/03/1996 Tip Top Mighty White 200.00mcg/100g 1/10/1998 Breakfast cereals Kelloggs (Aust) Pty Ltd Kelloggs All-bran 222.20mcg/100g 1/12/1996 All Bran Soy 'N' Fibre 222.20mcg/100g 1/08/1998 Bran Flakes 333.00mcg/100g 1/01/1998 Coco Pops 166.70mcg/100g 1/12/1996 Corn Flakes 333.00mcg/100g 1/12/1996 Crispix 167.00mcg/100g 1/06/1997 Crunchy Nut Corn Flakes 166.70mcg/100g 1/12/1996 Froot Loops 166.70mcg/100g 1/12/1996 Frosties 166.70mcg/100g 1/12/1996 Golden Wheats 333.00mcg/100g 1/06/1997 Honey Rice Bubbles 167.00mcg/100g 1/06/1997 Just Right 222.00mcg/100g 1/12/1996 Just Right Grains 222.00mcg/100g 1/10/1998 Mini-wheats - Apricot 333.30mcg/100g 1/12/1996 Mini-wheats -

Blackcurrent 333.30mcg/100g 1/12/1996

Mini-wheats - Strawberry 333.30mcg/100g 1/12/1996 Nutri-grain 166.70mcg/100g 1/12/1996 Rice Bubbles 166.70mcg/100g 1/12/1996 Special K 333.30mcg/100g 1/12/1996 Sultana Bran 222.00mcg/100g 1/12/1996 Sustain 222.00mcg/100g 1/12/1996 Sanitarium The Health

Food Co

Sanitarium Light 'N' Tasty 333.30mcg/100g 1/11/1997 Weetbix 100.00mcg/100g 1/03/1997


Extracts of meat, yeast, or vegetables

Sanitarium The Health Food Co

Sanitarium Marmite 2000.00mcg/100

g 1/07/1998

Food drinks

Healtheries of NZ Ltd Healtheries KLB6 Slimming Formula

- Creamy Vanilla 320.00mcg/100g 1/01/1980

KLB6 Slimming Formula - Luscious Strawberry

320.00mcg/100g 1/01/1980

KLB6 Slimming Formula Rich - Chocolate

320.00mcg/100g 1/01/1980

Vitaplan - Bountiful Berry 55.00mcg/100g 1/02/1995 Vitaplan - Classic

Chocolate 55.00mcg/100g 1/02/1995

Vitaplan - Vital Vanilla 55.00mcg/100g 1/02/1995 Heinz Wattie's

Australasia

Complan Complan Banana 55.00mcg/100g 14/02/1996 Complan Chocolate 55.00mcg/100g 14/02/1996 Complan Double

Chocolate 55.00mcg/100g 14/02/1996

Complan Strawberry 55.00mcg/100g 14/02/1996 Complan Vanilla 55.00mcg/100g 14/02/1996 Sanitarium The Health

Food Co

Sanitarium Up & Go - Banana 40.00mcg/100g 1/10/1998 Up & Go - Cocoa Malt 40.00mcg/100g 1/10/1998 Up & Go - Original Malt 40.00mcg/100g 1/10/1998 Smithkline Beecham Consumer Healthcare Horlicks Malted Food Drink 160.00mcg/100g 1/12/1996 Supplement bar


New Image International K-28Plus K-28Plus Blueberry 167.00mcg/100g 1/01/1998 K-28Plus Chocolate 167.00mcg/100g 1/01/1998 K-28Plus Vanilla 167.00mcg/100g 1/01/1998 source: NZ Therapeutic Database

Health claims Previously in Australia and NZ, the use of health claims ix about foods on product labels and associated advertising had been prohibited under the Australian and New Zealand Food Regulations. However, from November 1998 to February 2000, ANZFA is piloting a health claim communicating the benefits of folate to help reduce the prevalence of neural tube defects. The Medicines Act was amended in December 1998 to permit the use of a folate health claim. By July 1999, ANZFA had approved the use of the folate health claim on more than 100 products (28 primary foods and 72 processed foods) which contained at least 40mcg of folate. However, up to May 1999, no NZ food company or association had sought approval to carry the claim, and �interviews with key informants in NZ confirmed a low level of interest in the folate health claim�.154 Consumer knowledge about, and reaction to, fortification in NZ In the Netherlands,149 64% of pregnant women preferred to take folic acid in fortified food rather than by tablet irrespective of the level of education. Despite publicity, the increase in the availability of fortified products in NZ, and differences in study design, two surveys indicate little change in the awareness about fortification in NZ. In a mail survey in 1998 111, 56% of the respondents claimed they had heard about fortification, compared to 52% in a Ministry of Health telephone survey in 1994.155

In 1998, 111 more females (49%) than males (41%) knew about bread fortification, but there were no differences in awareness across the age groups. The major sources of information for those that knew about fortification were breakfast cereal packets (50%), other food packets (42%), television advertisements (39%) and newspapers/magazines (34%) It was also found that 62% of female and 53% of male respondents thought it was very to extremely important to have a choice of buying bakery products with or without added folic acid.

ix health claims are messages which make a direct link between eating certain foods as part of people�s diet and reducing the risk of a specific disease (ANZFA)


From 23%-49% of respondents had no opinion about a number of statements on fortification (table 14), including 49% who �neither agreed nor disagreed� that �folate should be added to bread.� Males over 55 years of age disagreed more than 15-24 year olds with the statement that �folate should be added to bread�. On the contrary, younger males disagreed more about getting �too much vitamin/mineral by eating foods with added vitamins and minerals�. Both males and females aged 55-74 years tended to disagree more than 15-24 year olds with the statement �eating foods with added vitamins and minerals would help me to have a healthy diet�. Table 14: Level of agreement with statements about vitamins and minerals (mean and standard deviation)* Mean (standard deviation) Statement Females Males Total Healthy people can get all the vitamins and minerals they need from food

3.4 (1.0) 3.6 (0.9) 3.5 (1.0)

Where there is a choice, I prefer to eat foods with vitamins and minerals added to them

3.2 (0.9) 3.0 (1.0) 3.1 (0.9)

Folate should be added to bread 3.2 (0.9) 3.0 (0.9) 3.1 (0.9) It is unnatural to add vitamins and minerals to foods

2.8 (1.0) 2.8 (1.0) 2.8 (1.0)

I can get too much of a vitamin/mineral by eating foods with added vitamins and minerals

2.9 (1.0) 2.9 (1.0) 2.9 (1.0)

Eating foods with added vitamins and minerals would help me to have a healthy diet

3.3 (1.0) 3.2 (1.0) 3.3 (1.0)

*scale: 1=strongly disagree; 5=strongly agree source: Bourn and Newton 111


Level of fortification Critical to the acceptance and success of a fortification programme is determining the appropriate level of fortification. After much debate 55 156 157 158 159 and reviewing several possible concentrations of fortification up to 350mcg/100g (five times the replacement level or level of wheat before milling), the US FDA regulated that the fortification level would be at 140mcg/100g (twice the replacement level) of all enriched cereal grain products (eg, flour, bread, pasta, rice etc). The level of fortification proposed by the Folate Replenishment-Plus Committee (140mcg/100g) is the same as regulated by the US FDA and implemented on January 1, 1998. Modelling by the Centers for Disease Control (Fig 2) has shown that: • fortifying flour with 350mcg/100g would increase average intake by about

0.25mg per day, leaving about 30% of women with total folate intakes below 0.4mg/day. 158 Total folate consumption of all sources (diet, supplements, and fortification) would be more than 1mg for 15% of the population

• fortifying at 140mcg/100g of flour would increase average daily intake of

women in the reproductive age group by about 1mcg and have only modest effect on NTD rates

On the basis of recent data, Oakley180 (appendix 3) has even suggested that the concentration of folic acid in fortified grains can be safely increased to 3.5mg or higher up to almost 7mg/kg grain. The March of Dimes (appendix 4) and the American College of Preventive Medicine advocate increasing the fortification level in the USA to at least 350mcgs, but the American College of Medical Genetics 160 supports an increase to 280mcg/100g of grain. The American Academy of Pediatrics,161 simply �encourages efforts at devising a program of food fortification to provide all women a daily intake of 400ug of folic acid.� while the Teratology Society 162 recommended fortification to a level that �will provide 0.4mg of folic acid each day to at least 95% of women in the reproductive age group.� After a careful examination of the literature, the Institute of Medicine (IOM) clearly stated in 1998: 70

�to reduce the risk of neural tube defects for women capable of becoming pregnant, the recommendation is to take 400 µg of synthetic folic acid daily, from fortified foods and/or supplements, in addition to consuming food folate from a varied diet.�


The vital difference between the IOM recommendation and the FDA deliberations is that the former stipulated 400mcg of synthetic folic acid in addition to folate from a diet. In contrast, the FDA only considered 400mcg of folate from all sources. Figure 2: Percentage of women aged 19 to 50 years with mean daily intake of total folate greater than or equal to specified amount, by grain fortification level (mcg/100g).

source: Oakley G. In: Willett W. Nutritional Epidemiology; New York: Oxford University Press, 1998


Upper target for folate In 1994, the Australian NHMRC Expert Panel on Folate Fortification Committee adopted 1000mcg a day as an upper target on intake of natural and synthetic folate for all population groups. 27 Dietary modelling indicated that with the proposed level of voluntary fortification, x females aged 25-34 years would be consuming a mean folate intake of 500mcg a day, with intakes of about 290mcg a day and 730mcg a day at the 10th and 90th percentiles respectively. Males in the same age group would, respectively, consume 710mcg, 410mcg and 1040mcg folate a day. It was concluded: �Even women who take folate supplements should have total folate intakes below the 1000mcg upper target�. The Institute of Medicine 70 has set an upper limit of 1000mcg of synthetic folic acid per day.

Dietary modelling Data is available from two dietary modelling exercises in NZ. The Australian and New Zealand Food Authority (ANZFA) has recently carried out dietary modelling of potential folate intakes from NZ diets containing folate-fortified supplementary foods. Two scenarios were modelled (each with three options): • scenario 1 assumes only the current market proportions of folate-fortified

products within each permitted category (table 11) • scenario 2 assumes all breads, breakfast cereals and fruit juice (not fruit

drinks) are fortified to the maximum permitted amount of folate (table 12) Fortified fruit juice was included in the models to allow for the product to appear on the local market in response to the initiative to pilot the folate-neural tube defect health claim. Males aged 15-18 and 19-24 years in scenario 2 are the only group who could potentially exceed the upper intake level of 1000mcg of synthetic folic acid (table 12). However, this would necessitate an extremely high intake from all breads, breakfast cereals and fruit juice which have been fortified to the maximum permitted level. ANZFA concluded from their modelling that:

x 50% RDI per reference quantity of: flour, savoury biscuits, break, breakfast cereals, past, rice, yeast extracts, and fruit and vegetable juices. ANZFA, 1999


�the results of both models show that at both mean and high levels of consumption of supplementary foods, the risk of chronic excessive synthetic folic acid intake (greater than 1mg synthetic folic/day) is minimal from today�s folate-fortified food supply, and very low from an even more folate-fortified food supply. The safety of the Authority�s recommendation is further assured because of the overestimates built into the model assumptions�.

A recent NZ study by Bourn and Newton 111 163 for the Baking Industry Research Trust, estimated that (table 13): • of women aged 25-44 years:

- 10% would consume over 400mcg of folate per day if flour was fortified at 140mg/100g

- about half would consume 400mcg of folate per day if all bread was directly fortified at 70mcg/35g slice

- about 10% would consume over 400mcg folate/day if half of bread consumed was fortified at 70mcg/35g slice

• males would have higher folate intakes because of greater consumption

of breads and cereals The authors concluded that it �seems unlikely that the majority of women in the child-bearing age group will consume the additional 400µg folate/day, unless the appearance of health claims on labels has a significant impact on food purchases.� The Institute of Medicine, 70 which set an upper limit of 1000mcg of synthetic folic acid per day, concluded from dietary modelling in the US that with current fortification levels and �� assuming regular use of an over-the-counter supplement that contains folic acid (ordinarily 400µg per dose), it is unlikely that intake of folic acid would exceed 1,000µg on a regular basis for any of the gender or life-stage groups.�


Table 11: ANZFA modelling: scenario 1 for New Zealanders who might consume fortified bread, breakfast cereals and juice

Male Female Male Female Male Female Male Female Male Female Options 15-18yrs 15-18yrs 19-24yrs 19-24yrs 25-44yrs 25-44yrs 45-64yrs 45-64yrs 65+yrs 65+yrs Folate intake from diet containing mean intake of some fortified breakfast cereals and fruit juice, and high intake fortified (100mcg/200mL) beverage supplements and high intake fortified bread

859 454 708 464 649 410 525 399 467 329

Maximum amount of added folic acid (from above scenario covering high intake fortified beverage supplements and high intake fortified bread)

587 292 502 292 400 252 308 243 276 173

Upper 'safe' intake of added folic acid (mcg/day) 800 800 1000 1000 1000 1000 1000 1000 1000 1000 assume * 25% of breads and 100% breakfast cereals and 30% fruit juice are fortified to maximum permitted levels * all dry beverage flavourings fortified at 1000mcg/g source: ANZFA 1999


Table 12: ANZFA modelling: scenario 2 for New Zealanders who regularly consume fortified bread, breakfast cereal and juice

Male Female Male Female Male Female Male Female Male Female Options 15-18yrs 15-18yrs 19-24yrs 19-24yrs 25-44yrs 25-44yrs 45-64yrs 45-64yrs 65+yrs 65+yrs Folate intake from diet containing mean intake of some fortified breakfast cereals and fruit juice, and high intake fortified (100mcg/200mL) beverage supplements and high intake fortified bread

1417 794 1266 804 1110 664 910 671 778 566

Maximum amount of added folic acid (from above covering high intake fortified beverage supplements and high intake fortified bread)

1145 632 1060 632 861 506 693 515 587 410

Upper 'safe' intake of added folic acid (mcg/day) 800 800 1000 1000 1000 1000 1000 1000 1000 1000 assume * 100% breads and 100% breakfast cereals and 100% fruit juice are fortified to maximum permitted levels * all dry beverage flavourings fortified at 1000mcg/100g source: ANZFA 1999


Table 13 :Estimated dietary folate intakes for the 25-44 year age group

Folate (mcg/day) Percentiles

Gender Estimated folate intake from 10 50 90 Female

fortified breads (140mcg folate/100g flour) plus cereals and dietary folate intake

128 252 432

fortified breads (all bread 70mcg folate/35g slice) plus cereals and dietary folate intake

193 403 584

fortified breads (50% bread 70mcg folate/35g slice) plus cereals and dietary folate intake

141 281 462

Male

fortified breads (140mcg folate/100g flour) plus cereals and dietary folate intake

162 354 625

fortified breads (all bread 70mcg folate/35g slice) plus cereals and dietary folate intake

227 505 920

fortified breads (50% bread 70mcg folate/35g slice) plus cereals and dietary folate intake

175 382 675

source: Bourn and Newton 111 163


Risks from Increasing Folic Acid A major objection to fortification of a staple food (e.g., bread) with folic acid is that all members of society are exposed to folic acid in larger amounts than is usual. However, there are instances in public health where fortification has been effective to prevent rickets (vitamin D), goiter (iodine) and dental caries (fluoride). Rubella immunisation is offered to both boys and girls although the benefit accrues to the pregnant women. A number of potential risks have been identified from increasing the level of folate, both individually and on a population basis. A traditional view is that diet should be a sufficient source of nutritients and improvement in diet should be sufficient without recourse to other means such as supplements. As noted above, the bioavailability of food folate is considerably less than synthetic folic acid and women in the reproductive age would have to consume larger amounts of folate rich foods to obtain the same bioavailability from synthetic folic acid. Moreover, there have been a number of examples in the history of health where advice and/or techniques promoted in one era were subsequently shown to be deterimental to an individual�s health. There is no current evidence to indicate that the consumption of synthetic folic acid above 1mg per day is harmful. There are indications that the tolerable safety level may extend to 7mg. However, it is impossible to give a 100% assurance that folic acid is totally and completely safe. It is also inappropriate to give such an assurance because the quest for absolute safety and certainty will negate most public health programmes and in folic acid, not enable the prevention of up to 70% of NTDs.

Potential toxic effects from folic acid multiple births and other reproductive outcomes The Hungarian randomised control trial of folic acid and the occurrence of the NTDs 25 found a higher rate of multiple births after periconceptional multivitamin supplementation.90 164 165 166 In contrast, a recent analysis of UK data 167 from the MRC Vitamin Study 24 and the Prospective Study of Nutrition, Smoking and Pregnancy Outcome 168 provided no evidence that folic acid supplementation is associated with an increased rate of twinning. The higher rate of conceptions after preconceptional multivitamin supplementation compared with a placebo-like trace element supplementation was explained by a 5% shorter time in the achievement of conception.169


vitamin B12 deficiency To some, 170 171 the major fear from fortification is the so-called �masking� effect of folic acid. Folic acid may correct the anaemia due to vitamin B12 deficiency, thereby delaying the diagnosis and treatment of the deficiency, and increasing the risk of permanent neurological damage by allowing the complications to progress. To ensure that fortification was safe for all people the FDA restricted the level of fortification to 140mcg/100g primarily because:156

�One in five people [aged] 65 to 95 lack sufficient vitamin B12, a deficiency that can cause pernicious anemia. Extra folic acid can mask the symptoms of the condition, which may lead to permanent nerve damage if left untreated.�

Appendices 1 172 and 2 173 provide an evaluation of the issue of folic acid and B12 deficiency. There is overwhelming evidence that �folic acid is intrinsically safe�. 174 For example: • Oakley et al 175 have noted there have been no controlled published studies

showing that folic acid consumption resulted in correcting the anaemia and delaying the diagnosis of vitamin B12 deficiency

• �folic acid even in a full therapeutic dose (eg, 4 or 5mg/d) will neither cause

nor accelerate neurological deterioration in pernicious anemia� 174 • �there may be more elderly people with biochemical folate deficiency than

vitamin B12 deficiency� 172 • �the recommended dose [0.4-0.8mg] will not mask the hematological features

of pernicious anemia� 176 • �a dose of 0.4 to 0.8 mg per day is considered safe for general use� 35 • �there are no known reports of neurological illness induced by folate

fortification of staple foods in countries where this is practised� 27 • aggravation of the B12 neuropathy is rare in the US, despite 40% of adults

taking vitamin supplements 177 • the cause of the neuropathy is B12 deficiency, not folic acid, even in high

dose and it is diagnosed in the absence of anaemia 35. Therefore any effect


folate has in delaying the onset of anaemia does not mask or delay the diagnosis of neuropathy 27

• the side-effects of food fortification with folic acid are hypothetical and

avoidable 174 Wald and Bower 178 concluded that:

� Concern over the presence or absence of an accompanying macrocytosis or anaemia is misplaced � The haematological effect of folic acid in pernicious anaemia should not be used as a reason for failure to implement adequate folic-acid fortification for prevention of neural tube defects.�

To Bower and Wald: 173

�Potential diagnosis problems with vitamin B12 deficiency should be a reason to ensure that patients with B12 deficiency are being diagnosed in a timely fashion and treated appropriately, not a reason to delay or discourage public health strategies to prevent neural tube defects.�

After a careful review of the literature, Dickinson174 stated �that the current prejudice against universal folic acid fortification of food is based on anecdotal and scientifically invalid evidence, and that the benefits outweigh the risks... folic acid is not a neurological poison.� The Teratology Society 179 believe there is only a �theoretical risk� of folic acid fortification delaying the diagnosis of pernicious anemia which is �clearly outweighed by the demonstrable benefit of fortification.� Fortification with vitamin B12 has been suggested 175 180 181 as a solution to the lingering, and unfounded, concerns over the potential for harm from folic acid doses greater than 1mg. Keane et al 182 recommended the use of folic acid-fortified milk in the regular diet of the elderly population to overcome folic acid deficiency which is common about elderly and results in anaemia, dementia, and many neurological sequelae. The Institute of Medicine 70 has recommended daily allowance (RDA) for adults 50 years and older of 2.4mcg of synthetic B12 which can only be obtained from fortified foods or B12-containing supplements. In August 1996, the US FDA 183 184 received a citizens petition requesting:


• every food that was to be fortified with folic acid also be fortified with a specified amount of vitamin B12 (a minimum 25 micrograms per 100 grams of the folic-fortified foods)

Herbert and Bigaouette 184 estimated that implementation of this petition would prevent B12 deficiency, 20% of all heart attacks, 40% of all thrombotic strokes, and 60% of all peripheral venous thrombosis, and save billions of health care dollars. Bronstrup et al 185 also suggested B12 cofortification or supplementation to reduce homocyseine levels. zinc There has been debate about supplemental folic acid intake having an adverse affect on intestinal zinc absorption 186 187 188 189 190. After reviewing the literature, the Institute of Medicine 70 concluded in 1998 that �folic acid supplementation has either no effect on zinc nutrition or an extremely subtle one.� For example, in the MRC trial 24 there was minimal difference between the zinc levels for cases and controls. Hambidge et al 191 concluded that �periconceptional folic acid supplements do not compromise the zinc status of the mother or the embyro with respect to zinc intake.� other potential risks In 1998 the Institute of Medicine 70 evaluated the potential for folate interactions with nutrients, other food components, and drugs and found : • no reports demonstrate that the intake of other nutrients increases or

decreases the requirement for folate • certain forms of fibre (eg, wheat bran) may decrease the bioavailability of

certan forms of folate under some conditions, but many forms of fibre had no adverse effects

• survey data of chronic alcoholics suggest that inadequate intake is a major

cause of the folate deficiency observed in chronic alcohol users • low intake rather than an increased requirement may account for the poorer

folate status of smokers • routine use of low doses of nonsteroidal anti-inflammatory drugs has not been

reported to impair folate status • no definitive conclusions can be drawn about the adverse effects of

anticonvulsants on folate status.


• methotrexate is a folic acid antagonist frequently used successfully in the treatment of some nonneoplastic diseases (eg, rheumatoid arthritis, psoriasis, asthma, primary biliary cirrhosis, and inflammatory bowel disease). When patients are also given high-folate diets or supplemental folate, there is a significant reduction in toxic effects with no reduction in drug efficacy. It is recommended that patients undergoing chronic methotrexate therapy for rheumatoid arthritis increase folate consumption

• oral contraceptive use has not been reported to influence folate status A review of the Hazardous Substances Data Bank 192 shows: • oral folic acid is not toxic to man even with doses as high as 15mg per day,

and there have been no substantiated reports of side effects • allergic reactions to folic acid preparations have been rarely reported and

have included erythma, rash, itching, general malaise, and bronchospastic respiratory difficulty

• adverse gastrointestinal and central nervous system effects have been rarely

reported in patients receiving 15mg of folic acid daily for one month

Monitoring of health outcomes and folate levels in NZ To maximise the prevention of folic acid-preventable birth defects requires a passive population strategy that assures that all, or almost all (more than 90%) of women of reproductive age consume 400mcg of synthetic folic acid per day. Until such a strategy is implemented, the following monitoring and research would assist in increasing the number of women consuming the requisite level of folic acid daily: • monitoring changes in the relative risks of birth defects in relation to the

promotion and implementation of prevention policies • investigating the extent to which available evidence has modified and factors

which have promoted or impeded the use of folic acid or multivitamin supplements among women of childbearing age

• determining additional factors that promote or impede change in the use of

folic acid or multivitamin supplements • what recommendations and advisories have been issued or are being

developed to promote the use of folic acid or multivitamin supplements


• clarifying the factors considered by the public health authorities when deciding if and how to promote such recommendations

Monitoring NTDs and other birth defects NZ Birth Defects Monitoring Programme (NZBDMS) , which has been operating since 1980, will continue to monitor the prevalence at birth of the NTDs as well as other birth defects. The NZBDMS routinely collects data on all livebirths born in, or admitted to, a public hospital. Quarterly and annual tables are submitted to the International Clearinghouse for Birth Defects Monitoring Systems in Rome and also supplied to a number of people in NZ. These livebirth data are annually supplemented with stillbirth data. The major deficiency in the current ascertainment is the absence of data on terminations of pregnancy (TOP). However, a joint study with Dr Joanne Dixon, Geneticist, Capital Coast Health, is investigating various methods in which TOP data can be included in the NZBDMS. Currently, if the presence of a birth defect is the reason for the TOP, the specific defect(s) does not have to be specified on the form. The NZBDMS is participating in two international studies monitoring the impact of folic acid recommendations: • Biomed project (PL 963969): NTDs and Primary Prevention Strategies

(Funded by the European Union). Twenty-four birth defect registries and monitoring programmes are participating in this study which has the objectives:

- to investigate the reasons why different countries, working from the

same published data, adopted different policies (or none) regarding the primary prevention of NTDs through the use of folic acid

- to determine the extent to which such policies (or lack) are being implemented

- to determine time trends in NTD prevalence in the same countries during the period likely to be influenced by such policies (or absence of policy)

- to determine whether different strategies have been associated with different time trends in NTD prevalence

The study will be completed in 2001 • Prevention Strategies based on periconceptional folic acid supplementation

(Funded by the Centers for Disease Control and Prevention, USA). Twenty programmes are involved in this study which has the following objectives:


• to describe and compare public health policies regarding the use of folic acid or multivitamin supplements for the primary prevention of NTDs and other birth defects

• evaluate the extent to which current public health policies are being

implemented and explore the factors involved in the compliance and acceptance of such policies

• compare the prevalence of NTDs, oral clefts, cardiac defects, and limb

defects before and after the initiation of folate prevention strategies

The project will be completed in 2002. Monitoring folate levels The Ministry of Health and ANZFA are funding a project by the University of Otago to establish baseline data among women aged 20-44 years (n=210) and boys aged 14-19 years (n=140) on: 193 • folate status, using dietary and biochemical assessment, for monitoring the

impact of the folate health claim • knowledge, attitudes and behaviours about the folic acid and the health claim Draft results from the study are scheduled for release by the end of November 1999. The Ministry has expressed a wish to implement a folate monitoring programme.

Impact of folic acid supplementation and fortification policies An international study conducted over 1987-mid-1996 found that changes in the time trend of NTDs were not due to the introduction of national policies of folate supplementation 194 Since the 1992 folic acid recommendation in the UK,195 the number of folic acid prescriptions dispensed and preparations sold over the counter increased considerably.196 However, there has been no concomitant change in the incidence of NTDs (since the early 1970s), either nationally or regionally. 197 Explanations include incorrect use of the supplement and the limited impact of a health education campaign which reinforce the need for a fortification programme. 198


Since fortification in the USA, NTD rates in North Carolina have shown little change, 199 but elsewhere folate levels have risen since fortification. 200 201

The lack of visible evidence of a decline in NTD rates since folic acid recommendations were made and fortification commenced should not detract

from continuing efforts to increase the intake of folic acid. Oakley 202 has argued strongly that such is likely to be the result of �the failure to implement effective

programs for protection against folic acid-preventable birth defects.�


Conclusion There is no scientific evidence that the fortification of bread with synthetic folic acid at the level of 140mcg/100g presents any risk to any group in the NZ population. Dietary modelling in NZ and the USA indicates that it is highly unlikely that the intake of folic acid would exceed 1,000mcg (the upper threshold) on a regular basis for any age-gender groups. The NZ programmes for monitoring the effect of a fortification programme on health outcomes are of similar standard to those elsewhere. However, there is currently no provision to monitor the folate status of the population. However, it is not certain that fortification at 140mcg/100g will be sufficient to prevent NTDs occurring. Modelling data from the USA indicates that the proposed level of fortification will still require women to take supplements as well as generally improving their diet. There can be no doubt that implementing the proposal to fortify some breads to 140mcg/100g should only be viewed as a first step towards: • increasing the level of fortification to at least the level permitted by the Food

Regulations (285mcg/100g - see appendices 3,4,5) • encouraging manufacturers to increase the level of folic acid fortification in

breakfast cereals • regulating folic acid fortification A fortification programme, will not only assist in preventing NTDs but also offer other advantages without risk: 27 • the folate status of the NZ population, regardless of age, gender, ethnic

group, and socio-economic status • folate intakes will be increased without a change of dietary behaviour or

having to remember to take supplements • folic acid will be provided in a continuous and passive manner • folate deficiency in the elderly would be corrected • current evidence indicates that improving folate status could reduce the risk of

other major health outcomes such as cardiovascular disease and colorectal cancer. Riddell et al 86 concluded that in NZ:


�Fortification with folic acid, recommended primarily to reduce the risk of congenital malformation may also help to reduce cardiovascular risk.�


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Folate, Folic Acid, and Health - moh.govt.nzfile/PHIFolicpaper.pdf · as bread, with folic acid • supplements are an effective method to get 400mcg of folic acid, but advising