Fsanz Summary of Emerging Evidence on Health Outcomes

7/29/2019 Fsanz Summary of Emerging Evidence on Health Outcomes

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MANDATORY FOLIC ACID FORTIFICATION SUMMARY OF EMERGING

EVIDENCE ON HEALTH OUTCOMES

KEY POINTS

Based on all available scientific evidence, adding folic acid to bread in Australia and NewZealand is safe for the whole population.

Food Standards Australia New Zealand (FSANZ) is continuing to carefully monitor,review and report on scientific research on folic acid and health outcomes. Since themandatory requirement was developed in 2007, no new evidence has emerged that changes

FSANZs original conclusion that mandatory fortification with folic acid is safe. Folic acid is added to flour in many countries, with two thirds of the worlds population

having access to folic acid fortified flour. For over 10 years, the United States and Canadahave had mandatory fortification of flour with folic acid and have found this to be aneffective way of reducing neural tube defects (NTDs).

FOLIC ACID AND HEALTH OUTCOMES

There are studies currently looking at the possible protective and adverse effects of folicacid on types of health conditions, including cancer, stroke, mental function in the elderly,

and some types of other birth defects. However, the only proven scientific evidence is thatfolic acid protects against NTDs.

FSANZ has continued to review the results of randomised controlled trials as they arereported. These have included a number of large trials administering folic acid with otherB vitamins to test the hypothesis that folic acid will reduce the incidence of heart diseaseand stroke. A number of these large randomised trials are testing doses of folic acid up totwenty times (2000-5000g) higher than the average amount being added under mandatoryfortification. The average folic acid added through mandatory folic acid fortification will

be 150g.

This is a brief review of the emerging evidence on folic acid and health outcomes since thedevelopment of the Standard in 2007.

FOLIC ACID AND BIRTH OUTCOMES

Neural Tube Defects

There is convincing evidence that increasing intakes of folic acid can reduce the incidenceof NTDs.

The level of fortification in Australia is expected to prevent between 14 and 49 NTDs in the300-350 affected pregnancies each year when combined with existing voluntaryfortification permissions and current levels of supplement usage.


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In New Zealand mandatory fortification is expected to prevent between 4 to14 NTDs peryear in the 70-75affected pregnancies each year when combined with existing voluntaryfortification permissions and current levels of supplement usage.

FSANZ estimates the cost saving from the yearly prevention of NTDs in Australia to be$AUD125 million and $NZD39 million New Zealand (including still births andterminations).

Emerging evidence suggests that deficient or inadequate maternal vitamin B12 status is alsoassociated with a significantly increased risk for NTDs (Molloy et al, 2009). Thishighlights that other factors, in addition to folic acid, may also be important in preventing

NTDs.

Twinning

The observation of increased twinning was made some years ago and was noted inFSANZs Final Assessment Report. The genetics of various diseases and their possible

interaction with folic acid or any other compound is still unknown.

Spontaneous Preterm Birth

Pre-conception folate (folic acid) supplementation was recorded in a cohort of 34,480pregnant women participating in a Down syndrome screening study (Bukowski et al.,2009). The authors report that pre-conceptional folate supplementation for 1 year or morewas associated with a 70% decrease in risk of spontaneous preterm delivery between 20and 37 weeks compared to women not taking a folate supplement. As this study is anobservational study the results may be subject to confounding factors.

Congenital Heart Defects

A time trend analysis in Canada (Lonescu-Ittu et al., 2009) reported that in the 7 yearsfollowing mandatory folic acid fortification implementation there was a significantdecrease of 6% each year in the prevalence of severe congenital birth defects.

It should be noted that other risk factors for severe congenital heart defects were notmeasured which may confound the results. The authors also had to rely on data from theUS to establish a lag time between the announcement of the policy and its implementation,as there was a lack of this data in Canada.

FOLIC ACID AND CANCER RISK

The risk of folic acid promoting cancer was canvassed exhaustively by FSANZ during thestandards development process.

Based on all of the available evidence, FSANZ concluded that there is no apparent risk topublic health and safety, including cancer. FSANZ consulted with scientific experts bothnationally and internationally who supported this conclusion.

However, FSANZ is continuing to monitor and assess any new evidence that might ariseand have formed a group of experts to assist with this.

Below is a brief summary of studies investigating folic acid intake and cancer riskpublished since the development of the standard.


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Colon Cancer

Prior to gazettal of the FSANZ Standard, the results of Lonn et al(2006) were known. Thisstudy reported a non-significant increase in total cancer, colo-rectal, breast and prostatecancers. Another large cardiovascular trial did not report any cancer data.

Since then, 4 large cardiovascular trials (up to 12,000 people randomised for up to 7 years)have reported their cardiovascular outcomes but only one has reported any data for colo-rectal cancer to date. In this study there was a non-significant decrease in colo-rectalcancer in those receiving folic acid and B vitamins (Zhang et al, 2008). A large study(8,000 people) examining the effect of folic acid on stroke rates, which includes

participants from Australia and New Zealand ,is scheduled to complete data collection inmid-2009.

Three smaller trials have been conducted (100- 1000 people). Of these, the two trials inpeople with colon adenomas (Cole et al, 2007 Logan et al2008) have reported lower ratesof colo-rectal cancer in those receiving folic acid.

Without knowing what the as-yet unreported data from the large cardiovascular trials is, itis not possible to conclude whether folic acid is associated with a decrease, an increase orhas no effect on colo-rectal cancer incidence.

Colo-rectal adenoma studies

Cole et al(2007) reported a small, non-significant increase in the recurrence of colonadenomas associated with folic acid intakes. There was a higher increase in advancedadenoma which was significant only in the subset who chose to continue to participate for4-6 years. It was noted that those given folic acid had had larger adenomas removed beforethe trial started and so may have been more prone to having additional adenomas than the

people in the placebo group.

A 2008 study from the UK in 939 men and women who had had all bowel polyps removed,found a slightly higher rate of new adenomas (not significant) but no difference in the rateof advanced adenomas in those given folic acid compared to placebo (Logan et al, 2008).

In these two studies, there was a lower rate of colo-rectal cancer in those who received folicacid than those who received placebo (up to 27% lower).

In contrast, a small trial investigating folic acid supplementation and the recurrence ofcolorectal adenomas in 94 subjects with adenomatous polyps (Jaszewski et al., 2008)reported a significant reduction in the recurrence of adenomas in the subjects receiving the

folic acid supplement (5mg/day) compared to the placebo. This was only observed insubjects under the age of 70 years.

Time Trend Studies

Mason et al(2007) reported increased rates of colorectal cancer rates in the United Statesand Canada between 1986-2002. They suggest this trend may be due to folic acidfortification which was mandated in 1996 and fully in place in 1998 in the United States.


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In contrast, in 2007, the United States National Cancer Institute reported no significantchange in cancer trends coinciding with the introduction of mandatory folic acidfortification, when they analysed the same dataset as Mason et al., 2007.(http://progressreport.cancer.gov/doc_detail.asp?pid=1&did=2007&chid=73&coid=720&mid=#trends).

A study in Chile analysed hospital discharge data for colon cancer during the periods of1992-6 and 2002-4 concluding that the higher rate of discharge in the second periodcoincided with the introduction of folic acid fortification in 2000 (Hirsch et al., 2009).However the study does not include data from the period when folic acid fortification wasintroduced. The International Classification of Disease coding also changed at that timeand this might affect the validity of the results.

In Australia and New Zealand, the Department of Health and Ageing has engaged theAustralian Institute of Health and Welfare to implement the Australia Health MinistersAdvisory Council endorsed monitoring framework for the mandatory fortification of foodwith folic acid. The purpose of this work is to coordinate monitoring of folate levels in the

Australian and New Zealand populations to establish baseline data and enable assessmentof the effectiveness of mandatory fortification with folic acid. It is also intended to monitorfor adverse health effects.

Prostate cancer

The focus of the Cole et al(2007) study was the recurrence of colorectal adenomas,however an increase in the incidence of prostate cancer was observed. This mainly occurredin the folic acid supplement group, where 24 cases were reported compared to only 9 casesin the placebo group.

A more recent report by Figueirdo et al(2009) provides further detail on the male subjectsinvestigated in the Cole et al(2007) study. This current study followed 643 (baseline) menover 10 years. It should be noted that there was a large drop out after the sixth year ofstudy. During this time only one more case of prostate cancer was noted in the folic acidgroup and none in the placebo group.

Lonn et al(2006) reported a much smaller, non-significant increase in prostate cancer inthose randomised to folic acid and other B vitamins. Lonn et al(2006) used a higher doseof folic acid than did Cole et al(2007).

Given the number of large trials that have not yet described their prostate cancer outcomesthese results should be interpreted with caution. A number of trials are underway to test the

hypothesis that higher intakes of folic acid might reduce the risk of cardiovascular disease,which are also collecting information on side effects, such as cancer.

Breast cancer

Overall the combined studies suggest a non significant slight reduction in breast cancer. As noted above, Lonn et al(2006) reported a non-significant increase in breast cancer in

those who received folic acid plus other B vitamins. This trial had only a small number ofwomen.

In 2008, Zhang et alreported a non-significant decrease in breast cancer in womenrandomised to folic acid and other B vitamins in a trial of 5,400 US women followed for 7years. No other study has reported any data relating to breast cancer to date.


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FOLIC ACID AND HEART DISEASE

Stroke and Heart disease

A meta-analysis by Bazzano et al(2006) found no significant effect on cardiovasculardisease. A meta-analysis of trials published prior to April 2007 reported a significant 18%

reduction in stroke (Wang et al, 2007) in those randomised to folic acid. However severaltrials that were much larger than any included in these meta-analyses have been publishedsince then and have not reported the same level of effect on stroke.

In addition, several large trials investigating folic acid and cardiovascular disease arecurrently taking place that are yet to publish their results. These randomised controlledtrials will also provide more useful data to confirm or refute the possible association withvarious cancers and folic acid intakes.

UNMETABOLISED FOLIC ACID

Unmetabolised folic acid in plasma and immune system

During the standards development process, FSANZ investigated the potential forunmetabolised folic acid circulating in the blood to be a health risk. FSANZ concluded thatthe link between unmetabolised circulating folic acid and adverse health effects has not

been substantiated. Consequently, the health significance of this remains uncertain.

The study by Sweeney et al(2009) investigated circulatory unmetabolised folic acid in 70adults and 20 new born babies following widespread uptake of voluntary fortification

permissions for folic acid. . Low levels of unmetabolised circulating folic acid werepresent in the majority of subjects. The authors conclude that mandatory fortificationwould further increase these levels. They note that the health consequences of

unmetabolised circulating folic acid are unknown but suggest the potential for folic acid tomask pernicious anaemia and possibly accelerate the growth of existing cancers.

The study by Troen et al. (2006) describes a relationship between the presence ofunmetabolised folic acid and one particular type of cell involved in immunity and whichcan kill cancer cells. As the test of immunity and unmetabolised folic acid levels weredone on the same sample of blood, it is not possible to determine which occurred first.

FOLIC ACID AND RHEUMATOID ARTHRITIS

Arabelovic et al. (2007) examined the amount of methotrexate used by 36 patients withrheumaroid arthritis between 1988-1997 and noted an increase in dosage. There are other

important considerations when assessing the usefulness of drugs, such as side effects. Forexample, van Ede et al. (2001) randomised 434 patients with rheumatoid arthritis to receiveeither placebo or 1-2 mg folic acid per day in addition to their methotrexate in a double-

blind study. After 48 weeks, 38% of those receiving placebo had discontinued takingmethotrexate owing to side effects whereas only 17% of those receiving folic acid had tocease taking methotrexate. This study also reported that methotrexate dosage was higher inthose receiving folic acid compared to placebo.


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FOLIC ACID AND COGNITIVE FUNCTION

Durga et al. (2007) tested vitamin B12 with or without 800g folic acid versus placebo in818 people who did not have vitamin B12 deficiency over 3 years. Those who receivedvitamin B12 plus folic acid had less cognitive loss (a good outcome) that those who

received vitamin B12 alone. The possibility that folic acid may affect neurological function in people with vitamin B12

deficiency dates back to the 1940s when pernicious anaemia was being treated with liver (itwas before vitamin B12 had been purified; we now know that liver contains vitamin B12).Patients with pernicious anaemia given 15-20 mg folic acid, without liver, experienced a

progression of their neurological problem (Meyer, 1947). One interpretation of this findingis that vitamin B12deficiency will continue to progress unless vitamin B12 is given; anotherhypothesis is that very high doses of folic acid exacerbates the consequence of vitamin B 12deficiency. As there has never been a properly conducted controlled trial, the hypothesis(folic acid exacerbates the neurological effects of vitamin B12 deficiency) continues to becited.


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Fsanz Summary of Emerging Evidence on Health Outcomes