open access research cancer risk with folic acid ...to cite: wien tn, pike e, wisløff t, et al....

Cancer risk with folic acid supplements:a systematic review and meta-analysis

Tale Norbye Wien,1 Eva Pike,1 Torbjørn Wisløff,1 Annetine Staff,2,3

Sigbjørn Smeland,3,4 Marianne Klemp1

ABSTRACTObjective: To explore if there is an increased cancerrisk associated with folic acid supplements givenorally.

Design: Systematic review and meta-analysis ofcontrolled studies of folic acid supplementation inhumans reporting cancer incidence and/or cancermortality. Studies on folic acid fortification of foodswere not included.

Data sources: Cochrane Library, Medline, Embaseand Centre of Reviews and Dissemination, clinical trialregistries and hand-searching of key journals.

Results: From 4104 potential references, 19 studiescontributed data to our meta-analyses, including 12randomised controlled trials (RCTs). Meta-analysis ofthe 10 RCTs reporting overall cancer incidence(N¼38 233) gave an RR of developing cancer inpatients randomised to folic acid supplements of 1.07(95% CI 1.00 to 1.14) compared to controls. Overallcancer incidence was not reported in the sevenobservational studies. Meta-analyses of six RCTsreporting prostate cancer incidence showed an RR ofprostate cancer of 1.24 (95% CI 1.03 to 1.49) for themen receiving folic acid compared to controls. Nosignificant difference in cancer incidence was shownbetween groups receiving folic acid and placebo/control group, for any other cancer type. Total cancermortality was reported in six RCTs, and a meta-analysis of these did not show any significantdifference in cancer mortality in folic acidsupplemented groups compared to controls (RR 1.09,95% CI 0.90 to 1.30). None of the observationalstudies addressed mortality.

Conclusions: A meta-analysis of 10 RCTs showeda borderline significant increase in frequency of overallcancer in the folic acid group compared to controls.Overall cancer incidence was not reported in the sevenobservational studies. Prostate cancer was the onlycancer type found to be increased after folic acidsupplementation (meta-analyses of six RCTs).Prospective studies of cancer development inpopulations where food is fortified with folic acid couldindicate whether fortification similar to supplementationmoderately increases prostate cancer risk.

INTRODUCTIONFolic acid is a synthetic form of the essentialB vitamin folate, also named folacin, pter-oylglutamic acid or vitamin B9. Folic acid is

in the human body converted to 5-methylte-trahydrofolate, which also is the form offolate found in dietary sources and is partic-ularly abundant in vegetables, fruits andgrains. Folic acid is more stable than 5-methyltetrahydrofolate, which is highly labileand sensitive to oxidation. Folate is involvedin synthesis, repair and methylation of DNA,and folate deficiency may lead to develop-mental and degenerative conditions, such asneural tube defects in developing embryosand megaloblastic anaemia at any age. Folicacid supplements are widely used to prevent

To cite: Wien TN, Pike E,Wisløff T, et al. Cancer riskwith folic acid supplements:a systematic review andmeta-analysis. BMJ Open2012;2:e000653.doi:10.1136/bmjopen-2011-000653

< Prepublication history andadditional material for thispaper are available online. Toview these files please visitthe journal online (http://bmjopen.bmj.com).

Received 19 November 2011Accepted 1 December 2011

This final article is availablefor use under the terms ofthe Creative CommonsAttribution Non-Commercial2.0 Licence; seehttp://bmjopen.bmj.com

1Norwegian KnowledgeCentre for the HealthServices, Oslo, Norway2Department of Obstetricsand Department ofGynaecology, Oslo UniversityHospital, Oslo, Norway3Institute for ClinicalMedicine, Faculty ofMedicine, University of Oslo,Oslo, Norway4Division of Surgery andCancer Medicine, OsloUniversity Hospital, Oslo,Norway

Correspondence toDr Marianne Klemp;[email protected]

ARTICLE SUMMARY

Article focus- The present systematic review aims to explore if

there is an increased cancer risk associated withfolic acid supplements given orally.

Key messages- Meta-analysis of 10 RCTs showed no benefit but

a borderline significant increase in incidence ofoverall cancer in the folic acid group compared tocontrols. Overall cancer incidence was notreported in the seven observational studies.When analysing site-specific cancers, prostatecancer was the only cancer type where anincrease in risk was shown for folic acidsupplements.

- The current study does not show any evidencefor augmented cancer risk for fertile women whoare recommended folic acid periconceptionally inorder to reduce the risk of neural tube defects.

Strengths and limitations of this study- This systematic review has been performed

with a thorough systematic search; and dataextraction and quality assessment have beenperformed by at least two independent persons.

- The limited time of follow-up of most RCTs isa limitation of our review because the time framefor cancer development might exceed the follow-up time in many RCTs.

- The highly selected population in which mostof the studies were conducted limits theapplicability to the general population andwomen of childbearing age taking folic acidpericonceptionally.

Wien TN, Pike E, Wisløff T, et al. BMJ Open 2012;2:e000653. doi:10.1136/bmjopen-2011-000653 1

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and treat folate deficiency in groups at risk and also toprevent adverse events associated with antifolate medi-cation. In Norway, folic acid is among the 10 most soldnon-prescription drugs with 17.5 defined daily doses per1000 inhabitants/day.1 Folic acid supplements may beadministered in various forms, such as tablets, mixturesor intravenously. In addition, folic acid may be added tofoods as fortification of, for example, grains and cereals.The rationale for folic acid fortification is prevention ofneural tube defects in developing embryos, and thispolicy is advocated in several countries around the world(such as in the USA and Canada) but not in Norway orin the UK.Fertile women are a large population group who are

recommended to take daily folic acid supplements,starting the month before conception and lastingthroughout the first trimester in order to preventpossible neural tube defects in developing embryos.Folate has also been widely used in patients with cardio-vascular diseases because it lowers homocysteine, whichhas been associated with increased risk of cardiovascularevents.2 Recent data from meta-analyses, however, do notshow benefit of folic acid supplementation on risk forcardiovascular events.3e5

Masking of vitamin B12 deficiency, with risk of irre-versible nerve damage, is a well-known risk associatedwith folic acid supplementation, especially in the olderpopulation.6 In general, however, folic acid supplemen-tation has been considered safe. Foods containing folatepossibly decrease the risk of several cancers.7 Folate isinvolved in the synthesis of nucleotides and amino acids,including methonine. In folic acid deficiency, theprimary intracellular methyl donor S-adenosylmethio-nine is reduced, and synthesis, methylation and repair ofDNA are hampered and the resulting DNA instabilityincreases the risk of cancer development.8 9 Over thepast years, however, there have been rising concerns thatfolic acid supplementation actually could increase therisk of cancer, as animal and human studies have indi-cated that high folate status might promote progressionof preneoplastic and undiagnosed neoplastic lesions.10 11

A combined analysis from 200912 of two Norwegianrandomised controlled clinical trials,13 14 with extendedpost-trial follow-up, demonstrated an increased inci-dence of cancer among patients taking folic acid forhomocysteine reduction as secondary prevention ofcardiovascular events.The aim of the present systematic review was to

investigate whether folic acid supplement given orallyincreases cancer incidence and cancer mortality inhumans. Risks associated with folic acid fortification offoods are beyond the scope of this review.

METHODSWe conducted a systematic review and several meta-analyses of existing literature, following the methodsrecommended in the PRISMA statement for reportingsystematic reviews and meta-analyses of studies that

evaluate healthcare interventions.15 The methods of theanalyses and inclusion criteria were prespecified andpublished in a protocol available at the web pages of theNorwegian Knowledge Centre for the Health Servicesand are available as online supplementary materials.16

Eligibility criteriaWe included systematic reviews, randomised controlledtrials (RCTs) and controlled observational studies(caseecontrol and cohort studies) that assessed cancerincidence and/or cancer mortality in any populationtaking folic acid supplements $0.4 mg/day by oral routefor any indication. Folic acid could be taken with orwithout other B vitamins and compared with any control.We excluded studies where folic acid was given as part ofhigh-dose cytostatic regimen of cancer treatment. Thefolic acid dose cut-off of $0.4 mg/day was set in order tocompare doses considered to have clinical relevanceacross groups and studies.

Literature searchTo identify all relevant published reports, we performeda systematic literature search using medical subjectheadings (MeSH) and free-text search terms for folate,folic acid, cancer and neoplasm. We searched thefollowing electronic databases and web pages frominception to present: Embase, Ovid Medline, CochraneLibrary, Centre for Reviews and Dissemination, NHSevidence, Clinical evidence and ISI Web of Knowledge,AHRQ, INAHTA, SBU, DACEHTA and FINOHTA. Thesearches were conducted in March 2010, with supple-mentary searches in Embase, Medline and CochraneLibrary on 6 May 2010. A filter for controlled studies wasused in order to reduce number of hits.17 There were nolimits by language, and non-English papers with a rele-vant English abstract were translated. The full searchstrategy including the search terms for the variousdatabases is supplied at the web pages of the NorwegianKnowledge Centre for the Health Services.18 In addition,we manually searched reference lists of review articlesand conducted limited updated non-systematic literaturesearches in the same electronic databases up to 31January 2011. For ongoing studies, we searchedWHO’s International clinical trials registry platform andhttp://www.clinicaltrials.org, up to 10 February 2011.Study authors were not contacted for additionalnon-published data.

Data extraction and quality assessmentAll citations identified by the search process werescreened by two reviewers independently (TNW and EP)to determine if they met the eligibility criteria. Possiblerelevant articles were retrieved in full text. To avoidmissing studies due to inconsistent vocabulary (folicacid/folate), citations on dietary folate were alsoretrieved in full text and assessed.The quality of the included studies was assessed inde-

pendently by two reviewers (TNW and EP) using theCochrane Collaboration’s tool for Risk of Bias

2 Wien TN, Pike E, Wisløff T, et al. BMJ Open 2012;2:e000653. doi:10.1136/bmjopen-2011-000653

Cancer risk with folic acid supplements


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assessment19 for RCT’s and checklists for cohort andcaseecontrol studies.20 The quality of the end points wasassessed by the same two reviewers using GRADE.21

Study data were extracted using standardised tables bythree authors independently (TNW, EP and TW) andwere always extracted from the intention-to-treat popu-lations. Any disagreements between the independentassessments of the reviewers in literature selection, dataextraction and quality assessment were dissolved bydiscussion or by a fourth reviewer (MK).

Statistical analysesWhen feasible, we pooled data by meta-analyses withCochrane Collaboration software (RevMan5) and usedrandom-effects model calculating RRs with 95% CIs. Fortrials with factorial design, we compared all groups thatreceived folic acid supplements $0.4 mg/day withgroups that did not. Analyses were conducted for bothcrude data and adjusted data when possible. For RCT’s,analyses of crude data are presented in this article, andfor observational data, adjusted analyses are presented.In our analyses of adjusted data, we used the analyseswith the most explanatory variables if there were alter-natives. These analyses were combined using genericinverse variance in RevMan5. Sensitivity analyses werepredefined for population characteristics such as sex,age, body mass index, comorbidity and risk factors forcancer such as smoking habits and characteristics ofintervention such as dose and time of exposure and timeto outcome assessment, that is, time of follow-up. Asindividual patient data were not available, sensitivityanalyses were performed at trial level.

RESULTSLiterature search and characteristics of included studiesThe literature search retrieved 4104 citations, andadditionally 31 citations were identified through manualsearches of reference lists and limited updated searches.Fourteen articles from the literature search and sevenarticles from the manual search, together covering 19studies, were included (figure 1). The 19 includedstudies represented 12 RCTs and seven observationalstudies (six cohort studies and one caseecontrol study).Details of the included RCTs are given in table 1 and ofthe observational studies in table 2. All RCTs wereperformed between 1994 and 2008, except for one study,a 36-year follow-up of an RCT of folic acid given inpregnancy, starting in 1966.29 30 Baseline dietary data inthe observational studies were collected between 1984and 1986 in the Nurses’ Health Study and HealthProfessionals Follow-up Study36 and up to 2000e2002 inthe VITamins And Lifestyle (VITAL) Cohort Study.34 38

Seven RCTs were performed in populations withcardiovascular disease or high-risk groups for cardiovas-cular disease, three were in populations with a history ofcolorectal adenoma, one in a population with atrophicgastritis and one was performed in pregnant women.Except for a cohort study in patients with ulcerative

colitis,35 the populations in the observational studieswere not selected by any morbidity criteria but wererather cohorts/caseecontrol studies selected by livingarea or profession. All folic acid supplements wereadministered as tablets, and in many of the RCTs givenin combinations with other interventions (table 1). TwoRCTs (NORVIT13 and WENBIT14 with a median of 40and 38 months treatment, respectively) reported cancerdata of an additional 38 months post-trial observationalfollow-up in a combined analysis published in 2009.12 Wehave in our meta-analysis used data from the combinedanalysis stratified by trial but refer to the original publi-cations13 14 and count these studies (NORVIT andWENBIT) as two RCTs. Two RCTs, HOST24 and VISP,25

did not report cancer data in the original publications,but such data are provided in a recent meta-analysis fromwhich we have extracted cancer data.3

When available, analyses were performed on adjusteddata in addition to crude data. These analyses gave thesame conclusions. For the RCTs, we present crude datain text and figures (adjusted data are available at the webpages of the Norwegian Knowledge Centre for theHealth Services18).

Ongoing studiesOur search for ongoing and unpublished studies withthe search word ‘folic acid’ detected 1642 studies inWHO’s International clinical trials registry platform and245 trials in the http://ClinicalTrials.gov database. Onlytwo of these trials met our eligibility criteria includingcancer as predefined outcome. One is an ongoing Dutchstudy of vitamin B12 and folic acid supplementation for

Figure 1 Process of study selection. RCT, randomisedcontrolled trial.




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Table

1CharacteristicsofincludedRCTs

Study

Participants

N:total(N

tot),

folicacid

(Nint);country

Populationcharacteristics

intervention/controlgroup:

sex(%

females);

agein

years

(mean±SD);

characteristics;%

smokers

Intervention/control

Tim

eoftreatm

ent/

follow-upmonths

Outcomes

Logan(2008)2

2

(ukCAP)

Ntot:939,Nint:470;UK,

Denmark

%F:39/42;meanage:5869/

5869;colorectaladenoma*;

%smokers:notreported

Folic

acid

0.5

mg/day

6aspirin/placebo6

aspirin

36y/36

Totalandsite-specific

cancerincidence

Wu(2009)23

Ntot:672,Nint:338;USA

%F:61/62;meanage:6567/

6667;colorectaladenoma*;

%smokers:7/7

Folic

acid

1mg/day/placebo

Mean64/64+

upto

12


cancerincidence

Cole

(2007)1

1

(AFPPS)

Ntot:1021,Nint:516;

USA,Canada

%F:36/36;meanage:

57610/57610;colorectal

adenoma*;

%smokers:15/14

Folic

acid

1mg/day

6aspirin/placebo6

aspirin

Mean33+mean

42z/75


cancerincidence

Jamison(2007)2

4

(HOST)/Clarke(2010)3


%F:2/2;meanage:65612/

66612;chronic

renal

disease;%

smokers:21/19

Folic

acid

40mg/day

+vitB12+B6/placebo

Median38/38

Totalcancerincidence

Toole

(2004)2

5

(VISP)/Clarke(2010)3

Ntot:3680,Nint:1827;USA,

Canada,Scotland

%F:38/37;meanage:

66611/66611;cardiovascular

disease;%

smokers:18/16

Folic

acid

2.5

mg/day

+vitB6+vitB12/folic

acid

20mg+vitB6+vitB12

Mean20/20

Totalcancerincidence

Zhang(2008)2

6

(WAFACS)


%F:100/100;meanage:


disease;%

smokers:11/12

Folic

acid

2.5

mg/day

+vitB12+B6/placebo

Mean88/88


cancerincidenceand

mortality

Ebbing(2009)12

(WENBIT

14+

NORVIT

13)x

Ntot6837,Nint3411;Norw

ay

%F:23/24;meanage:63611/

62611;cardiovasculardisease;

%smokers:38/41

Folic

acid

0.8

mg/day

+vitB126vitB6/placebo

6vitB6

Median39/77


cancerincidenceand

mortality

Lonn(2006)27

(HOPE-2)

Ntot:5522,Nint:2758;Europe,

Canada,USA

%F:29/28;meanage:


disease;%

smokers:11/12

Folic

acid

2.5

mg/day

+vitB12+B6/placebo

Mean60/60


cancerincidenceand

mortality

SEARCH

(2010)28

Ntot12064,Nint6033;UK

%F:17/17;meanage:

6469{;

cardiovasculardisease;

%smokers:12/12

Folic

acid

2mg/day

+vitB12/placebo

Mean80/80


cancerincidence/total

cancermortality

Charles(2004)2

9/

Charles(2005)30

Ntot:2462,Nint:485;Scotland

%F:100/100;meanage:

2665/2666;pregnancy;

%smokers:45/46

Folic

acid

5mg/

day/placebo

Inpregnancy/36years

Totalandbreast

cancermortality

Zhu(2003)3

1Ntot:98,Nint:44;China

%F:41/30;meanage

57612/57611;atrophic

gastritis;

%smokers:notreported

Folic

acid

20mg/day

firstyear,20mgtwice

weekly

secondyear

+vitB12/placebo

12+12/m

ean73

Gastrointestinal

cancerincidence

*Colorectaladenoma:history

ofcolorectaladenoma(removedbefore

randomisation).

yReportedas3years,nomeangiven.

zCole’s

studytreatm

ent:firstperiodfolic

acid

6aspirin

versusplace

bo6

aspirin,seco

ndperiodfolic

acid

versusplacebo.

xEbbing’s

studyis

acombinedanalysiswithprolongedfollow-upoftwoRCTs1314andwecountthem

astwoRCTs.

{SEARCH

studymeanagegivenfortotalparticipants.

RCT,randomisedcontrolledtrial.




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Table

2Characteristicsofincludedobservationalstudies

Study

Participants

N:folic

acid

group(N

folic),

controls

(Nctrl);country

Population

characteristics;case/

control;sex;age

years;%

smokers

Dailyintakeoffolicacid

supplement/control

Tim

eoftreatm

ent

Outcome

A.Characteristicsoftheincludedcaseecontrolstudy

Freudenheim

(1996)3

2Nfolic:192,Nctrl:313;USA

Premenopausalwomen

$40years

diagnosedwith

breastcancer/frequency-

matchedonbasis

ofage

andcounty,randomly

selectedfrom

motor

vehiclesrecords;%

smokers:notreported

Folic

acid

$0.4

mg/no

folic

acid

supplement

In-personinterviewsabout

usualdietin

theperiod

2years

before

theinterview

Breastcancer

incidence

Study

Totalnumberofpersons

withcancer/totalnumber

inthecohort,folicacid

group(‡0.4

mg)(N

folic),

controls

(Nctrl),country

Population

characteristics;sex;

ageyears;%

smokers

Dailyintakeof

folicacid

supplement/control

Tim

eoftreatm

ent/

follow-upyears

Outcomes

B.Characteristicsoftheincludedcohort

studies

Stolzenberg-Solomon

(2006)3

3(PLCO)

691womenwithbreast

cancer/25400women;

Nfolic:67143person-years,

Nctrl:46652person-years;

USA

Womenfrom

theProstate,

Lung,Colorectal,and

OvarianCancerScreening

Trialcohort;meanage:63

(55e74);%

smokers:not

reported

Folic

acid

$0.4

mg/no

folic

acid

Currentor2years

ago/m

edian4.9

years

Breastcancer

incidence

Maruti(2009)3

4(VITAL)

743womenwithbreast

cancer/35023women;

Nfolic:notreported*,

Nctrl:notreported*;

USA

Postm

enopausalwomen

from

theVITaminsAnd

Lifestyle

Study;meanage:

62(50e76);%

smokers:

notreported

Folic

acid

$0.4

mg/no

folic

acid

Mean10years/m

ean

5years

Breastcancer

incidence

Lashner(1997)3

5Fourpersonswith

colorectalcancer/97

persons;Nfolic:39,

Nctrl:58;USA

High-riskpatients

with

ulcerativecolitis;both

sexes;age:w30;%

smokers:w

7%

Folic

acid:0.4

mgfrom

multivitamin

or1mg

from

sole

supplement/no

folic

acid

Atleast6months/until

detectionofcanceror

date

oflastsurveillance

colonoscopy

Colorectalcancer

incidence

Skinner(2004)36

326personswith

pancreaticcancer/

125480persons;Nfolic:

219771person-years,

Nctrl:1287823person-

years;USA

Womenfrom

theNurse’s

HealthStudy,age:51.767

andmenfrom

theHealth

Professionals

Follow-up

Study,age:54.9610;

%smokers:women:

22%,men:9%

Folsyre

$0.4

mg/

<0.3

mgfolic

acid

for

men<0.2

mgforwomen

0to

$10years/14years

Pancreaticcancer

incidence Continued




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preventing fractures in older people, with cancer assecondary outcome.39 The other is a prolonged post-trialfollow-up of the Norwegian studies WENBIT andNORVITup to 2014,40 for which we have data up to 2007included in our analysis.12

Excluded studiesTwo hundred and twenty-five studies judged to be rele-vant from screening of title/abstract were excluded afterfull-text examination. List of excluded articles is avail-able at the web pages of the Norwegian KnowledgeCentre for the Health Services.18 Eighty-nine studieswere excluded due to missing or too low folic acidsupplement intervention, that is, the study did notreport data on folic acid supplements, only on dietaryfolate (83 studies) or supplement dose was below0.4 mg/day (six studies). In 95 studies, data wereincomplete by either no dose specification on folic acidsupplementation or lacking cancer outcome data forfolic acid supplements (eg, risk was given for total folateintake, not for folic acid per se). Additionally, 41 studieswere excluded due to other reasons, such as lack ofa control group or lacking data on cancer developmentor mortality.

Methodological qualityGenerally, the risk of bias in the included RCTs was low.All the RCTs, except two, had low risk of bias, that is, theyhad adequate sequence generation, allocation conceal-ment, blinding and follow-up. The two remaining trialshad high29 and unclear31 risk of bias, respectively, mainlydue to inadequate or unclear reporting of sequencegeneration and allocation concealment. These two trialsreported data on cancer mortality29 and gastrointestinalcancer,31 not on overall cancer incidence, and thus donot influence our overall estimate for this end point.The quality of the evidence for the individual end pointswas evaluated by use of GRADE. The outcomes from theRCTs generally had high quality for cancer incidence(high for total, colorectal, lung and prostate cancers;and moderate for breast cancer). For cancer mortality,the quality ranged from very low (breast), low (colorectaland prostate) to moderate (total and lung cancermortality). The most common reason for lower qualitywas the very low number of events. The quality of theoutcomes from the observational studies varied from lowto very low.

Cancer incidenceThe pooled effect estimates from 10 RCTs11 13 14 22e28

reporting total cancer incidence with folic acid supple-mentation versus placebo were borderline significantwith an RR of 1.07 (95% CI 1.00 to 1.14) (figure 2A). Atotal of 3515 incident cancers were detected among38 233 participants. No heterogeneity across studies wasdetected in the analysis (I2¼0%). The funnel plot of thisanalysis seemed symmetrical (figure 2B); hence, we haveno indication of publication bias based on this analysis.Sensitivity analyses on trial level (table 3) showed

Table

2Continued

Study

Totalnumberofpersons

withcancer/totalnumber

inthecohort,folicacid

group(‡0.4

mg)(N

folic),

controls

(Nctrl),country

Population

characteristics;sex;

ageyears;%

smokers

Dailyintakeof

folicacid

supplement/control

Tim

eoftreatm

ent/

follow-upyears

Outcomes

Oaks(2010)37(PLCO)

266personswith

pancreaticcancer/

109175persons;Nfolic:

notreportedy;

Nctrl:

notreportedy;

USA

Menandwomenfrom

the

Prostate,Lung,Colorectal,

andOvarianCancer

ScreeningTrial;age:

55e74;%

smokers:not

specifiedforthe

supplementgroup

Folic

acid

$0.4

mg

daily/nofolic

acid

Currentor2years

ago/m

edian6.5

years

Pancreaticcancer

incidence

Slatore

(2008)38(VITAL)

521personswithlung

cancer/77721;Nfolic:

21619,Nctrl:24394;USA

Menandwomenfrom

VITaminsAndLifestyle

Study;casesecontrolsz;

%females:43/52;age:

6767/6267;%

smokers:30/8

Folic

acid

$0.4

mg

daily/nofolic

acid

Mean10years/m

ean:

4years

Lungcancer

incidence

*Atotalof32023womenin

thecohortwere

distributedoverfourquartile

withrespectto

intake.

yAtotalof109175personsin

thecohortwere

distributedoverfourquartileswithrespectto

intake.

zThewhole

cohortof77721personswere

distributedoverfourquartileswithrespect

tointake.




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borderline increased risk of cancer development afterfolic acid supplementation in the four studies including>70% of men (RR 1.08, 95% CI 1.00 to 1.16) and in thetwo studies including >30% of current smokers (RR1.19, 95% CI 1.02 to 1.38). Sensitivity analysis oncomorbidity by separating studies in populations witha history of adenoma from populations with cardiovas-cular disease did not yield significant increased risk fordeveloping cancer with folic acid supplementation ineither group. Distributions of age and body mass indexwere very similar between the studies; thus, sensitivityanalysis on study level by those factors was not feasible.Due to lacking data, we were not able to perform sensi-tivity analyses on alcohol consumption, family history ofcancer or physical activity. Sensitivity analyses on folicacid dosage showed increased risk in the four studies,with a dose from 0.4 to 1 mg (RR 1.21, 95% CI 1.06 to

1.38) but not in those with folic acid doses above 1 mg.Folic acid exposure time of <60 months did not yieldsignificant risk differences between the groups. Longerfollow-up time, however, yielded borderline statisticalsignificant increased cancer risk in the folic acidsupplemented group, with an RR of 1.09 (95% CI 1.00 to1.18) in the six studies with >60 months of follow-up.Folic acid supplements given in coadministration withother B vitamins12 24e28 did not show any significantdifference between the groups. When administeredtogether with aspirin,11 22 a borderline significantincreased risk was shown in the folic acid groupscompared to the control groups (RR 1.43, 95% CI 1.00to 2.03). Two of the RCTs24 26 were done in the USA afterintroduction of fortification. Sensitivity analysis of thosetwo showed no significant difference between the groups(table 3).

Figure 2 Randomised controlled trials that compare folic acid supplements $0.4 g/day with placebo/control treatment withrespect to total cancer incidence. (A) Forest plot showing meta-analysis. (B) Funnel plot of effect estimates plotted against SEs(on a reversed scale).




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Meta-analysis of the seven observational studiesincluding all cancer types reported showed no differencein cancer incidence between the group taking folic acidsupplements and abstainers (six cohort studies gave anRR of 1.03, 95% CI 0.92 to 1.16; and one caseecontrolstudy an RR of 0.96, 95% CI 0.54 to 1.68).In RCTs reporting incident cancer type, prostate

cancer was the most common cancer type. In sixRCTs13 14 23 27 28 41 with 25 738 male participants, 349incident cases of prostate cancer were found among12 867 participants in the folic acid groups and 283 casesamong 12 871 participants in the control groups (RR1.24, 95% CI 1.03 to 1.49) (figure 3). None of theincluded observational studies reported on prostate

cancer. No statistically significant augmented cancerincidence risk was shown in the meta-analyses of inci-dence of any other cancer types in RCTs or observationalstudies. This included meta-analyses of RCTs of cancerof the breast (RR 0.86, 95% CI 0.65 to 1.14, threeRCTs),23 26 27 colon and rectum (RR 1.00, 95% CI 0.83 to1.21, nine RCTs),11 12 22 23 26e28 31 haematologicalcancers (RR 1.16, 95% CI 0.76 to 1.78, four RCTs),12 26 28

lung (RR 1.11, 95% CI 0.92 to 1.33, six RCTs)12 23 26e28

and pancreas cancer (RR 1.50, 95% CI 0.42 to 5.31,analysis of one RCT).26 Correspondingly, none of theobservational studies showed any difference in cancerincidence between the groups32e38 as shown for breastcancer (RR 1.02, 95% CI 0.75 to 1.39, two cohortstudies32 34; and 0.96, 95% CI 0.54 to 1.68, one caseecontrol study32), lung cancer (RR 0.99, 95% CI 0.79 to1.24, one cohort study38), pancreas cancer (RR 1.12,95% CI 0.90 to 1.40, two cohort studies36 37) and colonand rectum cancer (RR 0.45, 95% CI 0.05 to 3.92, onecohort study35).

Cancer mortalityTotal cancer mortality was reported in six RCTs,13 14 26e29

with a total of 1134 cancer-related deaths among 32 327participants. With the exception of one study in pregnantwomen,29 30 all studies were performed in populations ofpatients with cardiovascular disease. The pooled effectestimate of all studies (figure 4A) showed no significantincrease in cancer mortality in folic acid groupscompared to controls (RR 1.09, 95% CI 0.92 to 1.30).Sensitivity analysis on trial level showed increased risk forcancer mortality after folic acid supplementation instudies with >30% of smokers (RR 1.38, 95% CI 1.10 to1.72). This subgroup included 9299 participants from thecombined analysis of two Norwegian RCTs12 (NORVIT13

and WENBIT14) after folic acid supplementation assecondary prevention of cardiovascular events and froma Scottish follow-up study29 30 after folic acid supple-mentation in pregnancy. Sensitivity analyses on sex, age,comorbidity, dose folic acid or time of follow-up did notyield significant risk increase in any group.

Table 3 Sensitivity analyses on study level of population,intervention and time to outcome assessment

Sensitivity analysis on study level RR (95% CI)

All 1.07 (1.00 to 1.14)<70% men11 22 23 25 26 1.05 (0.90 to 1.23)>70% men12 24 27 28 1.08 (1.00 to 1.16)<30% smokers11 23e28 1.05 (0.98 to 1.12)>30% smokers12 1.19 (1.02 to 1.38)<15% smokers23 26e28 1.04 (0.97 to 1.13)>15% smokers11 12 24 25 1.12 (0.93 to 1.35)History of colorectaladenoma11 22 23

1.28 (0.95 to 1.72)

History of cardiovasculardisease12 24e28

1.06 (0.99 to 1.13)

0.4e1 mg folic acid/day11 12 22 23 1.21 (1.06 to 1.38)>1 mg folic acid/day24e28 1.03 (0.96 to 1.11)<5 years exposure12 22 24 25 1.10 (0.97 to 1.23)>5 years exposure11 23 26e28 1.06 (0.97 to 1.17)<5 years follow-up22 24 25 0.95 (0.78 to 1.17)>5 years follow-up11 12 23 26e28 1.09 (1.00 to 1.18)Folic acid given in combinationwith other B vitamins12 24e28

1.06 (0.99 to 1.13)

Folic acid given with aspirin11 22 1.43 (1.00 to 2.03)Folic acid given in countrieswith fortification24 26

0.95 (0.81 to 1.13)

Figure 3 Forest plot of randomised controlled trials that compare folic acid supplements $0.4 g/day with placebo/controltreatment with respect to prostate cancer incidence.




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All meta-analyses of mortality of site-specific cancershad results that were not statistically significant in RCTs(data available at the web pages of the NorwegianKnowledge Centre for the Health Services18). None ofthe observational studies addressed mortality.

DISCUSSIONIn the present systematic review, a meta-analysis of 10RCTs showed a borderline significant incidence increaseof overall cancer in the folic acid group compared tocontrols. Overall cancer incidence was not reported inthe seven observational studies. However, meta-analysisof the seven observational studies including all cancertypes reported showed no difference in cancer incidencebetween the group taking folic acid supplements andabstainers.In sensitivity analyses, we identified four subgroups

where folic acid supplementation increased cancerincidence and/or cancer mortality. These subgroupsconsisted of studies with a dose of folic acid from 0.4 mgto 1 mg/day, studies with >30% of smokers, studies with>70% of men and studies with a follow-up longer than5 years. Whether smoking, gender, follow-up time or anyother unreported reasons are the factors that contributeto this adverse effect of folic acid has not been studied.

Comparison with other studiesOur finding of no benefit, but a possible adverse effectfrom folic acid supplementation on cancer incidence isin line with reported results of studies on other nutrientsupplements, including vitamin E, b-carotene (vitamin-Aprecursor) or selenium; all showing no or an adverseeffect of supplementation in controlled clinical trials oncancer development.42 43 A recent meta-analysis of folicacid supplements by Clarke and coworkers, in the‘B-Vitamin Treatment Trialists’ Collaboration’3 withindividual patient data, found no increased cancer risk inany subgroups. Our analysis differs from Clarke’s bybeing a systematic review, thus including more studies(five more RCTs and seven observational studies) andby including more diverse populations than the sevenB-vitamin trials in populations with cardiovascular diseaseincluded in the Clarke’s study. In two studies includedboth in Clarke’s meta-analysis and in ours, NORVIT and

WENBIT, we included data from the combined analysiswith longer follow-up time published in 200912; whereasClarke et al only use cancer data from the originalpapers13 14 with a shorter follow-up. When assessingpossible harm, a longer follow-up time is beneficial inorder to discover more potential cancer cases, as anaugmented cancer risk after folic acid intervention maynot be confined to a short post-trial time period.In our sensitivity analyses of the RCTs, the studies with

the largest proportions of smokers showed an increasedrisk of cancer incidence and cancer mortality associatedwith folic acid supplements. Smoking is a well-known riskfactor for many cancers. Furthermore, unlike folatesupplements, folate from diet seems to be protective forcancer development.7 Many smokers have poor dietaryhabits, and folate intake has been shown to be inverselyassociated with smoking duration.44 Recently, the Euro-pean Prospective Investigation into Cancer and Nutri-tion, a large observational study, found a lower risk ofdeveloping lung cancer in former and current smokerswithin the highest quartile of serum folate compared tothe lowest (OR 0.68, 95% CI 0.51 to 0.90).45 No effectwas apparent in never-smokers (OR 0.84, 95% CI 0.43 to1.65) or for colorectal cancer risk.46 Interestingly, and inline with a possible adverse effect of folic acid supple-mentation, another report from the European Prospec-tive Investigation into Cancer and Nutrition studysuggests a U-shaped relationship between plasma folateand risk of pancreatic cancer in both men and women,with highest risk for the lowest and highest serumquintile levels.47

A large Swedish prospective study found that pancre-atic cancer risk was reduced in people with diets rich infolate from foods but not from supplements.48 This is inline with other observational studies indicating a source-specific effect of folates with dietary folate beingprotective and folic acid supplements possibly beingharmful or having no effect with respect to cancerrisk.49e52 In one of the RCTs included in our analysis,41

folic acid supplementation of 1 mg/day increased therisk of prostate cancer, while higher dietary folate andplasma folate levels among non-users of vitaminsupplements were associated with decreased risk ofprostate cancer.53

Figure 4 Forest plot of randomised controlled trials that compare folic acid supplements $0.4 g/day with placebo/controltreatment with respect to total cancer mortality.




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It has been speculated that folate may be beneficial inprimary prevention of cancer, but potentially harmful inthe presence of early cancer.10 Accordingly, the anti-folate methotrexate is an effective cytostatic drug used inthe standard therapy of several cancer types. Weperformed sensitivity analyses for the folic acid supple-mented population with a history of adenomas and thepopulations without such a history. This analysis showedno significant increased risk of colorectal cancer ineither group. It should be noted, however, that we do nothave data to support or weaken the interesting hypoth-esis of timing of folate supplementation as beingimportant. The relative short latency time from exposure(folate supplementation) to cancer developmentreported from the recent Norwegian randomised trials12

suggests an effect on late carcinogenesis, as this shorttime indicates that a precancer situation might havebeen present during the intervention period.In our sensitivity analyses of the RCTs, the studies with

dose interval 0.4e1 mg/day were associated witha higher risk of cancer development than studies withdoses above 1 mg/day, with RRs of 1.21 (95% CI 1.06 to1.38) and 1.03 (95% CI 0.96 to 1.11), respectively. Oursystematic search had no dose limitation and thusallowed us to search for all dose ranges, although oureligibility criteria specified doses $0.4 mg/day. Weidentified no RCTs, but 11 observational studies withdoses below 0.4 mg/day reporting cancer incidence,thus allowing us post hoc to evaluate a possibledoseeresponse pattern of observational studiesincluding doses below 0.4 mg/day. Six of these studieswere already included in our review, as they alsocontained groups with daily intakes $0.4 mg,32e34 36e38

and five were excluded from our main analyses due todaily dose of folic acid below 0.4 mg.49 50 54e56 Noincreased risk was found in the meta-analyses of dosesbelow 0.4 mg/day, with RR of 1.07 (95% CI 0.92 to 1.26)for the cohort studies33 34 36e38 49 50 54 56 and 1.17 (95%CI 0.58 to 2.33) for the caseecontrol studies.32 55 Hence,our analyses did not indicate any doseeresponse patternbetween folic acid dose and cancer incidence.The reason for the increased risk in the dose interval

0.4e1 mg/day has not been elucidated in our study, andwe cannot exclude that other characteristics of theseparticular studies may be confounders. Although thesmokers are randomised and evenly distributed betweenfolic acid and placebo groups, one might speculate thata possible harmful effect of folic acid on smokers will bemore evident in studies with more smokers.A high alcohol intake is associated with higher inci-

dence of several cancer types, including premenopausaland postmenopausal breast cancer.7 Folate intake orblood folate do not seem to influence breast cancer risk,but adequate folate may reduce the increased risk asso-ciated with alcohol consumption.57 A similar associationbetween alcohol consumption and folate intake isreported in a prospective cohort study from the Nurses’Health Study on oral cancer risk in women.58 The effect

of alcohol consumption on cancer development afterfolic acid supplementation was not possible to evaluatein the present study, due to restricted information in theoriginal publications on alcohol intake.When different cancer sites were assessed in our study,

prostate cancer was the only cancer type found in thepooled analysis to have a significant risk increase afterfolic acid supplementation. There was some heteroge-neity between the studies (I2¼17%), with one of thetrials, AFPPS41 being an outlier compared to the otherstudies with an RR of 2.68 (95% CI 1.27 to 5.66).However, the increased risk remained even if omittingthis study from the pooled effect estimate (RR 1.19, 95%CI 1.01 to 1.39, I2¼0%). In line with our results, a recentmeta-analysis on serum folate and prostate cancer59

concluded that high serum folate concentrations wereassociated with increased prostate cancer risk. We mayspeculate on a specific effect of folic acid on prostatetissue rather than on cancer development in general dueto differences in tissue and cell sensitivity to folic acideffects. Such potential tissue- and cell-specific differ-ences in folic acid effects on cell biology need to befurther explored in order to generate a molecularunderstanding for such a possible diverse tissue effect.The major group recommended taking folic acid

supplements today is women in childbearing age beforeand in the first trimester of pregnancy in order to preventneural tube defects in the offspring. Only one of thestudies in our review was performed in a population ofpregnant women, the 36-year post-trial follow-up after anRCT in Scottish women taking folic acid in pregnancy.29

This study of Charles et al showed a significant increasedrisk for total cancer mortality (RR 1.70, 95% CI 1.06 to2.72) in pregnant women with folic acid supplementa-tion, in the group taking the highest dosage of folic acid,5 mg/day, but not in the 0.2 mg group (RR 1.20, 95% CI0.71 to 2.02). However, in our meta-analysis of total cancermortality, where the study of Charles et al was analysedtogether with five other studies, no significant increase intotal mortality was showed (RR 1.09, 95% CI 0.92 to 1.30).The 5 mg daily dose far exceeds the folic acid supple-mentation dosage recommended today for the femalefertile population (0.4 mg/day). It is worth noticing alsothat the proportion of smokers in the study of Charleset al was high (>40%), which reflects smoking habits inthe 1960s when the study was performed. Another studyassessing cancer effects after folic acid supplements inpregnancy showed a reduced risk of childhood leukaemia(acute lymphoblastic leukaemia) in the offsprings.60 Thisstudy was, however, not included in our present analysis,as folic acid supplement dose was not specified.The folic acid recommendations in order to reduce

risk of fetal neural tube development are poorly followedby fertile women, as few women start folic acid intakeprior to pregnancy.61 62 Several countries, such asCanada and the USA, have started fortification of foodsin order to increase periconceptional folic acid intake,aiming at reducing the incidence of neural tube defects.




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This food fortification strategy has been shown to effi-ciently reduce the incidence of open neural tube defectsin Canada.63 Other countries, such as Norway64 and theUK, have not chosen this general food fortificationstrategy, mainly due to the unknown effects ofaugmented folic acid intake on the general populationoutside the target group of fertile women, such asmasking of vitamin B12 deficiency in the older popula-tion and a possible risk of cancer development. Longi-tudinal studies on cancer development in countries thathave introduced fortification of foods with folic acidcould indicate whether fortification has similar risk ofcancer as what seems to be the case for folic acidsupplements. At present, there are no studies indicatingthat the current recommendation of folic acid supple-mentation (with the present recommended moderatedosages) to fertile women has any negative effects on thewoman’s or the offspring’s future health.Folic acid may alternatively be administered as 5-

methyltetrahydrofolate, as in the SU-FOL.OM3-trial,65

where patients in France with a history of ischaemicheart disease were randomised to either receive B vita-mins (5-methyltetrahydrofolate, vitamin B6 and vitaminB12 or placebo) and u-3 fatty acids or placebo in a 232factorial design. Mean duration of supplementation andof follow-up was 4.7 years. In this study, allocation toB-vitamins did not have any significant effect on cancerincidence (HR 1.19, 95% CI 0.88 to 1.60). Adding thisstudy to our meta-analysis of total cancer incidencewould, however, not change the conclusions, witha pooled effect estimate (RR 1.08, 95% CI 1.01 to 1.14).

Strengths and limitations of the studyOur review has several strengths. Our thorough system-atic search makes it plausible that we have retrieved allrelevant studies and can be assured not to miss impor-tant data. However, not all studies could be included inour meta-analyses due to unreported outcomes or doseof folic acid in supplements. The data extraction hasbeen performed by individual reviewers and thencontrolled by others, which also strengthens our trust inthis review. Additionally, most of the RCTs included areof high methodological quality, with a low risk of bias.This generally implies that we can be quite confidentthat the different study groups were randomisedadequately and that the result from the studies can betrusted. Also, in some of the included studies, cancercases found shortly after initiation of the study wereexcluded since it would be biologically implausible thatthese cases were related to the intervention.The limited time of follow-up of most RCTs is a major

limitation of our review because the time frame forcancer development might exceed the follow-up time inmany RCTs. Actually, this review may be too conservativeregarding estimating the long-term cancer risk associ-ated with folic acid supplementation since regularlyRCTs have a short follow-up time. This is also supportedby our sensitivity analysis where the subgroup of studies

with the longer follow-up time showed borderlineincrease in cancer risk with folic acid supplements,whereas the studies with shorter follow-up did not.However, when we add observational studies to broadenthe evidence base and lengthen follow-up time, we donot find any additional risk difference between thegroups.Another limitation of our study is the lack of infor-

mation on dietary patterns in the studied populations asthe effect of supplements may vary according to thefolate status of the population, for example, theproportion that are folate deficient. However, this is notthought to vary within one single study (RCTs) but mayvary between studies and countries. In one of the RCTs,11

baseline dietary data were supplied in a separate paper,53

and although it showed an inverse association betweenhigh dietary intake and colorectal adenoma in theplacebo group, thus indicating a protective effect, noassociation between dietary folate and colorectaladenoma was shown in the folic acid-supplementedgroup. The authors interpreted this as a beneficial effectof folate supplementation compared to deficiency butlimited to some point of sufficiency, where increasesprovide no additional benefit. Our analysis mayemphasise the need for pooling all relevant evidenceinto meta-analyses when appropriate and not trying tointerpret conflicting results only based on one singleRCT.Another important limitation of our review is the

selected populations in which the RCTs were performed,thus the findings may not be applicable to the popula-tion in general. Most participants included were treatedin secondary prevention of adenomas and cardiovasculardisease and may have increased cancer risk, for example,smoking is a common risk factor for cancer andcardiovascular disease. The one study with pregnantwomen had a higher proportion of smokers than isreported today.66 Effects of folic acid supplementationmay vary among different subgroups, as demonstratedon trial level in our analysis. Our conclusions arebased on RCTs with a low risk of bias, and randomisationof participants should minimise the problem ofconfounding.We performed only regular meta-analyses and analysed

sensitivity by dividing the results into groups. A moresophisticated way of investigating impact of differentpossible factors is to perform meta-regression.19

However, this is not recommended if <10 studies areincluded.19 Furthermore, we could not perform sensi-tivity analyses on some other variables that would be ofinterest, for instance on shorter periods of folic acidexposure that is more common in pregnancy.More studies assessing cancer risk in the only popula-

tion where folic acid supplementation is shown to bebeneficial today (periconceptionally to fertile women toprevent neural tube defects) would have strengthenedthe analysis. However, the one long-term follow-upafter such folic acid supplementation29 did not find an




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elevated mortality rate for any cancer (total cancers andbreast cancer analysed separately) following the lowsupplementation dosage of 0.2 mg daily.Our review has not addressed dietary folate, and we

cannot conclude on a possible ‘source-specific’ effect. ACochrane review under preparation is addressing thisissue.67

Conclusions and policy implicationsA meta-analysis of 10 RCTs showed a borderline signifi-cant increase in incidence of overall cancer in the folicacid group compared to controls. Overall cancer inci-dence was not reported in the seven observationalstudies. Longer follow-up than in ordinary RCTs mightbe needed to confirm this finding of a possible border-line significant increase in overall cancer incidence inthe folic acid group compared to controls. Our analysisidentified a very moderate, although statistically signifi-cant, elevated risk of prostate cancer after folic acidsupplementation. A major limitation of our study is thehighly selected population in which most of the studieswere conducted (to prevent clinical events in heartdisease patients), and the findings might not be appli-cable to the major groups currently recommended totake folic acid supplements, that is, women of child-bearing age. Longitudinal studies on cancer develop-ment in countries that have introduced fortification offoods with folic acid, such as in the USA and Canada,could indicate whether fortification similar to supple-mentation moderately increases prostate cancer risksimultaneously with the positive effect of reducingneural tube defects.

Acknowledgements We thank research librarian Ingrid Harboe for herassistance in the literature searches and Ingvil von Mehren Sæterdal andInger Natvig Norderhaug for their critical review of the protocol.

Funding This work was supported by the Norwegian Knowledge Centre for theHealth Services.

Competing interests All authors have completed the Unified CompetingInterest form, http://www.icmje.org/coi_disclosure.pdf (available on requestfrom the corresponding author), and declare no competing interests for thesubmitted work.

Ethics approval This is a systematic review not requiring approval.

Contributors All authors contributed to the design of the systematic review,analysis and interpretation of the data. All authors had full access to all thedata and take responsibility for the integrity of the data and the accuracy of theanalysis. TNW, EP and TW extracted the data from the included studies. TNWdrafted the manuscript, and the other authors critically reviewed themanuscript.

Provenance and peer review Not commissioned; externally peer reviewed.

Data sharing statement An extended version of this report in Norwegian isavailable at the web pages of the Norwegian Knowledge Centre for the HealthServices www.nokc.no. Appendices to the extended report including searchstrategy, tables of included and excluded studies, data analyses on crude andadjusted data and GRADE files are available in English.

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