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Wheat flour fortification and human healthHelena Pachón, Food Fortification Initiative and Emory University, USA
BURLEIGH DODDS SERIES IN AGRICULTURAL SCIENCE
http://dx.doi.org/10.19103/AS.2021.0087.23© The Authors 2021. This is an open access chapter distributed under a Creative Commons Attribution 4.0 License (CC BY)
Wheat flour fortification and human healthHelena Pachón, Food Fortification Initiative and Emory University, USA
1 Introduction 2 Statusofwheatflourfortification 3 Howthehumanhealthimpactofwheatflourfortificationismeasured 4 Examplesofhealthoutcomesassociatedwithwheatflourfortification
that have been studied 5 Additional considerations when assessing the health impact of wheat
flourfortification 6 Healthimpactresultsobservedfromwheatflourfortificationstudies 7 Summary 8 Future trends in research 9 Where to look for further information 10 References
1 IntroductionThe objective of this chapter is to review evidence of the human health impact ofwheatflourfortification.
1.1 What is wheat flour fortification?
Food fortification is the addition of nutrients to foods while they are beingprocessed(WHOandFAO2006).Alsoknownasenrichment,foodfortificationis a unique intervention in health circles because it is delivered by the private sector in contrast to most public-health interventions that are implemented by thepublicsector.Forwheatflour,fortificationoccursinamillafterpartsofthewheat kernel areground to flour: theendosperm in refinedwhite flour andthebran,germandendosperminwhole-grainflour(BauernfeindandDeRitter1991). Small concentrations of nutrients, usually vitamins and minerals, are addedtothisflourinthemills.Wheatflourcanbefortifiedinlarge,industrial-sized mills or in small, non-industrialized mills. This chapter will focus on
Wheat flour fortification and human health Wheat flour fortification and human health
Wheat flour fortification and human health2
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large-scale industrial fortificationofwheat flourwheremostof theevidenceandsuccesswithflourfortificationisobserved.
Withafewexceptions,mostnutrientscanbeaddedtowheatflourthroughfortification(WHOandFAO2006).Nutrients in theouter layersof thewheatkernelthatwereremovedduringmillingcanbeaddedtowheatflourthroughfortification.TheBvitaminsthiamin,riboflavinandniacinareexamplesofthis(BauernfeindandDeRitter1991);addingthesenutrientsbacktoflourthroughfortificationisknownasrestitutionorrestoration.Nutrientscanbeaddedbackat thesame, lowerorhigher levels thanpresent in thekernel.Nutrients thatarenotnaturallyfoundinthewheatkernelcanalsobeaddedtoflourthroughfortification.VitaminB12isanexampleofthis(USDA2020).
Nutrients are usually added through fortification coupled with anotheringredient(s). For example, iron can be added in the form of ferrous sulfate orsodium ironethylenediaminetetraacetate (NaFeEDTA) (WHO2009); theseforms are known as fortificants or fortification compounds. Niacin can beadded in the form of niacinamide, nicotinic acid or nicotinamide (WHO and FAO 2006). Because nutrients are added to flour to benefit human health,forms that are better absorbed by the human body (i.e. more bioavailable) are preferred.Theymaybecostlierthanlesswell-absorbedforms(e.g.NaFeEDTAcomparedwithelectrolyticiron);however,lessneedstobeaddedofthemorebioavailableformtohaveacomparablehealthbenefit(Hurrellet al.2010).
There are different reasons why some nutrients or fortificants are nottypicallyaddedtowheatflourthroughfortification.Forbioavailabilitypurposes,anotherfoodmaybeabetterchoicetoaddthenutrientto;thisisthecasewithvitaminA.VitaminArequiresfatforabsorption;oil,margarineandbutterarebetteroptionsforfortifyingbecausetheyarelipidrich.VitaminAcanbeaddedtoflour;however,itisacostlyingredientbecauseoftheprocessingrequiredto encapsulate the vitamin so it can be mixed into flour (WHO and FAO2006).Afortificantmayinterferewiththetechnologicalprocessingorsensorycharacteristicsofthefoodmadewithfortifiedflour.Forexample,ferroussulfatecan cause rancidity in high-fat foods (WHO and FAO 2006). For these foods, a lessreactiveironcompoundmaybeusedinflourfortification.
1.2 Why fortify wheat flour?
Manycountrieswithmandatoryfortificationdocumenttheirreasonforfortifyingwheatflour(Markset al.2018). It is toaddressawidespreadhealthproblemcausedbyanutrientdeficiency(ies)inthepopulation,suchasirondeficiency,anemia and neural tube defects.
Thereasonwheatflour ischosentofortify isbecauseitmeetstwobasiccriteria. First, food made with wheat flour (such as bread, noodles, pasta)is consumed by a large proportion of the population trying to be reached.
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Wheat flour fortification and human health 3
Second,mostoftheworld’swheatflourisproducedinlarge-scale, industrialmills (FFI 2020). This is important because large-scale fortification is easierfor industry to implement and for the government to monitor compared with small-scalefortification(WHOandFAO2006).
2 Status of wheat flour fortificationThestatusofwheatflourfortificationcanbeorganizedbythreenon-mutuallyexclusive categories: countries with foundational documents that establish a wheat flour fortification program; countries with documented performanceof existing flour fortification programs; and countries without fortificationprograms which have the potential to benefit fromwheat flour fortification.CountrystatisticsonthesethreecategoriesofflourfortificationcanbefoundattheGlobalFortificationDataExchangewebsite(FortificationData.org).Thischapter will focus on a subset of countries with ‘foundational documents’ – thosewithlegislationthatmandatesorallowsvoluntaryfortificationandthosewithstandardsforwheatflourfortification–anddocumentedperformanceoftheirflourfortificationprograms.
2.1 Countries that mandate wheat flour fortification
As of February 10, 2020, 83 countries have legislation that effectively mandates thefortificationofwheatflour(GlobalFortificationDataExchange2020a).Thismeansthecountryhas‘documentation[which]indicatesthatfortificationofallor some of the food is compulsory or required’. These countries are shown in green in Fig. 1.
Figure 1 Countriesingreenarethosewithlegislationthathastheeffectofmandatingwheatflourfortificationwithoneormorenutrients(GlobalFortificationDataExchange2020a).Countries in yelloware those confirmed tonothavemandatory legislationofwheatflour.Countriesingreyarethoseunlikelytohavemandatoryfortificationofwheatflour;however,thisinformationhasnotbeenconfirmedbyanin-countrycontact.
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Countries with mandatory wheat flour fortification share the followingcharacteristics:
• FollowingtheUnitedNations’2018regionaldesignation(UnitedNationsStatisticsDivision2020),25areintheAfricaRegion,35areintheAmericasregion, 16 in the Asia region, three are in the Europe region and four in Oceania.
• Sixteen are low-income countries, 29 are lower-middle-income countries, 25 are upper-middle-income countries and 13 are high-income countries pertheWorldBank’s2017designation(WorldBank2020).
• Sixteencountriesalsohavemandatoryfortificationofmaizeflour(GlobalFortificationDataExchange2020a).
2.2 Countries that allow voluntary fortification of wheat flour
AsofFebruary10,2020,14countrieshave ‘officialdocumentationand/orafoodstandardthatprovidesguidanceorregulationsforfortificationbutdoesnot have the effect ofmandating or requiring fortification’, that is, voluntaryfortificationofwheatflour (GlobalFortificationDataExchange2020a).Thesecountries are shown in blue in Fig. 2.
2.3 Countries with standards for wheat flour fortification
Standardsaredocumentsthat‘indicatestandardizedfortificationlevelsofthefoodvehicleinquestionwithoneormorenutrients’(GlobalFortificationDataExchange 2020b). Among the 97 countries with mandatory or voluntary wheat flour fortification, the Global Fortification Data Exchange has standards for91. Table 1 lists the nutrients that are included in these 91 standards (Global
Figure 2 Countries in blue have voluntary wheat flour fortification with one ormorenutrients (GlobalFortificationDataExchange2020a).Countries in yellowdonothavevoluntaryfortificationofwheatflour.
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Wheat flour fortification and human health 5
Fortification Data Exchange 2020b). Overall, standards include up to fourdifferent minerals and eight different vitamins.
Mostcountriesincludeiron,folicacid,thiamin,riboflavinandniacinintheirstandards for wheat flour fortification. Thirty one or fewer countries includezinc,calcium,vitaminA,vitaminB12,vitaminB6,vitaminDorseleniumintheirstandards.
3 How the human health impact of wheat flour fortification is measured
The remainder of the chapter will center on health improvements observed fromlarge-scalefortificationofwheatflour,eitheraloneorincombinationwithmaizeflour.
Therearetwotypesofstudies toassess if foodfortificationhasahealthimpact.Thefirstareefficacystudieswhichtellusthe‘extenttowhich[fortification]producesabeneficialresultunderidealconditions’(Sametet al.2008).Usually,efficacyisbasedontheresultsofrandomizedcontrolledtrials.Incomparison,effectiveness studies estimate the extent to which fortification producesa beneficial result ‘when deployed in the field in the usual circumstances’.Evidenceisneededfromefficacystudiestoensurethatfortificationcanhaveabeneficialimpact.Additionally,effectivenessstudiesreportifthesebenefitsareobserved when programs are implemented under real-life conditions.
This chapter will focus on effectiveness trials. This is because there is good evidence fromefficacy trials that ifpeopledeficient inanutrientconsumea
Table 1 Among 91 countries with mandatory or voluntary wheat flour fortification whosestandards are available, the nutrients and amounts that are listed in fortification standards(GlobalFortificationDataExchange2020b)
Nutrient Numberofcountries Amount (mg/kg)
Iron 89 15–120Folicacid(vitaminB9) 73 0.1–5.11Thiamin(vitaminB1) 66 1.25–10Riboflavin(vitaminB2) 64 1.3–6.6Niacin(vitaminB3) 64 6.7–60Zinc 31 12.5–101.3Calcium 23 1.28–2,400VitaminA 20 0.62–10VitaminB12 20 0–0.04VitaminB6 14 2.0–6.5VitaminD 7 0.01–0.02Selenium 1 0.21
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food fortifiedwith thatnutrient, theirnutrientstatuswill improveaswill theirhealth (e.g. Muthayya et al. 2012; Black et al. 2012).What is less known ishowfortificationoperatesunderreal-lifeconditionssuchaswhenitisofferedthrough a government’s social program or it is provided through the open market.
4 Examples of health outcomes associated with wheat flour fortification that have been studied
Generally speaking, when people consume a nutrient provided from any source (such as a non-fortified food, a fortified food, a supplement), theywill experience an increase in their bodies’ levels of that nutrient. This improvement in nutritional status can in turn improve functional outcomes: ‘nutrient-dependent physiological functions’ that can be measured (Solomons and Allen 1983). For example, we expect that when people consume folic acid from any source, it will increase their blood folate levels (Fig. 3). In women of childbearing age, this will lead to a reduction in neural tube defects, a functional outcome.
Specific to fortified wheat flour, researchers have assessed its role inaffectingbiologicalmarkersandfunctionaloutcomes;allof theseresultswillbe reviewed in this chapter.
4.1 Biological markers of nutritional status
Biologicalmarkersofnutritionalstatuscanbemeasuredinaminimallyinvasiveway frombiologicalfluidsand tissuessuchasblood,urineandhair (Gibson1990). In assessing the impact of wheat flour fortification in effectivenessstudies, only blood and breast milk samples have been taken (Table 2).
Folateprovidedthroughthefortificationcompound,folicacid,isthemoststudiednutrientaddedtofortifiedflour.Severalbiologicalmarkershavebeenassessed such as the concentration of plasma or serum folate and red blood cellfolate;thesewereusedtoquantifytheprevalence(orpercentage)offolatedeficiencyandwhencombinedwithhemoglobin,todeterminetheprevalence
Consume folic acid Increase red bloodcell folate
Reduce neural tubedefects
Figure 3 Arepresentationofhowfortificationwithanutrientsuchasfolicacidcanleadtoimprovement in a biological marker of that nutrient such as red blood cell folate. In turn, an increase in red blood cell folate can lead to improvement in a functional outcome: for example, a reduced risk of neural tube defects.
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Wheat flour fortification and human health 7
offolate-deficiencyanemia.Foriron,zincandvitaminB12addedtowheatflour,studies assessed their impact on biological markers, as well (Table 2).
4.2 Functional outcomes
The impact of wheat flour fortification on several functional outcomes wasstudied (Table 2). For example, positive functional outcomes evaluated were reductions in neural tube defects and anemia while negative functional
Table 2 Biologicalmarkersofnutritionalstatusandfunctionaloutcomesassessedinstudiesofwheatflourfortification’simpactonhumanhealth
Nutrientprovidedthroughfortification
Biologicalmarkersofnutritional statusa Functional outcomesa
Folate FolatedeficiencyFolate-deficiencyanemiaHigh homocysteinePlasma/serum folatePlasma/serum homocysteineRed blood cell folate
AnemiaCancerCognitive functionCongenital heart diseaseCoronary heart diseaseHypersensitivity MaskingofvitaminB12deficiencyMyocardial infarctionOrofacial cleftsNeuraltubedefectsStrokeThyroid- and diabetes-related disorders
Iron BodyironstoresPlasma/serum ferritinIrondeficiencyIron-deficiencyanemiaSoluble transferrin receptor
Anemia
Zinc Plasma/serum zincZincdeficiency
Noneassessed
VitaminB12 BreastmilkvitaminB12Plasma/serumvitaminB12VitaminB12deficiency
Noneassessed
Multiple Hemoglobin Anemiab
a Some of the markers of nutritional status measure the concentration of nutrients or other constituents in the blood or breastmilk. Some of the markers of nutritional status and most of the functional outcomes refer to the prevalence (or percentage) of people who have the condition. The functional outcomes refer to the incidence (or number of people newly diagnosed with the condition), prevalence (or percentage of people who have the condition) or deaths (or number of people who die due to the condition). bSomestudiesassessedtheeffectoffortificationwithmultiplenutrientsontheprevalenceofanemia,withoutevaluatingthecontributionoffortificationinimprovingnutrient-specificbiologicalmarkersofnutritionalstatus(forexample,Assunçãoet al.2007).
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outcomesassessedweremaskingofvitaminB12deficiencyandan increasein cancer incidence (Table 2). Some of these outcomes are described further.
4.2.1 Neural tube defects
Neural tube defects are a type of congenital anomaly that affects thedevelopment of a baby’s spine and brain while in utero(Avaglianoet al.2018).It is estimated that between 213 800 and 322 000 babies are born with neural tubedefectsaroundtheworldeveryyear(Blencoweet al.2018).Forhealthyspine and brain development, the neural tube must close by 28 days after conception (vanGoolet al.2018); thisdevelopmentalmilestone in the fetusoccursbeforemostwomenknowtheyarepregnant(Martinezet al.2018).
Thetwomostcommonformsofneuraltubedefectsarespinabifidaandanencephaly (Avaglianoet al.2018).Spinabifida iswhenthebaby’sspine isnotformedcorrectly.Spinabifidacanbetreated,butitcannotbecured,andindividualswithspinabifidahavevaryingdegreesofpermanentdisabilityforthe rest of their lives. Anencephaly is when the brain is not formed correctly. All babies with anencephaly die in utero or shortly after birth.
With adequate folate status in women before conception, a healthy neural tubeformsinthefetus(Martinezet al.2018).FolicacidisaformofvitaminB9thatiswellabsorbedbythebody.Itcanbeprovidedinpillformorasafortificationcompound (IOM 1998). Folic acid consumed by women before conception andinthefirstfewweeksafterconceptionpreventsaround70%ofthesebirthdefects (Czeizel andDudás1992;MRCVitaminStudyResearchGroup1991).For this reason, women capable of becoming pregnant are recommended to increase their folic acid intake by consuming supplements with folic acid, foods fortifiedwithfolicacidandfoodsrichinfoodfolates(aformofvitaminB9thatthebody does not absorb as well as it absorbs folic acid) (Institute of Medicine 1998).
4.2.2 Anemia
Anemia is ‘a condition in which the number of red blood cells or the hemoglobin concentration within them is lower than normal’ (WHO 2020). An estimated 800 million women and preschool children worldwide have anemia (Stevens et al. 2013). In public-health practice, anemia is determined by measuringhemoglobin levels in blood (Chaparro and Suchdev 2019). If the value is below a cut-off, a person is considered to be anemic. Anemia has multiple causes, both nutritional andnon-nutritional innature.Dietarydeficiencies in thenutrientsiron,copper,zinc,folate,vitaminB12,riboflavin,vitaminB6,thiamin,vitaminAand vitamin E – which contribute to hemoglobin synthesis – can cause anemia (KraemerandZimmermann2007).Non-nutritional causesofanemia includemalaria,hemoglobindisorderssuchasthalassemiaandchronicinflammation(Chaparro and Suchdev 2019).
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Wheat flour fortification and human health 9
The prevalence of anemia can only be reduced if the causes of the anemia are addressed. In some world regions, there are both nutritional and non-nutritional causes of anemia (Kassebaum et al. 2014). In these cases,fortificationwithnutrients involved inhemoglobinsynthesiscanonly reducetheoccurrenceofanemiaifthereisadeficiencyinthesenutrientsinthediet.
4.2.3 Masking of vitamin B12 deficiency
Aconcernemergedinthemid-1900srelatedtobothfolateandvitaminB12.Folatedeficiencyindependentlycausesmegaloblasticanemia;thatisanemiawhere the red blood cells are larger than normal (IOM 2000). Vitamin B12deficiency also independently causes megaloblastic anemia. Additionally,vitaminB12deficiencycausespotentiallyirreversibleneurologicalconditionssuch as ‘memory loss, disorientation and frank dementia’.
ThemaskingofvitaminB12deficiencyoccursinaspecificsituationwhereapersonhasmegaloblasticanemiaduetovitaminB12deficiencyonly(Berry2019). This is often observed in older adults who are unable to absorb vitamin B12fromthedietaswellastheydidwhentheywereyounger(Allenet al.2018).In these individuals, if folic acid is provided, the anemia is corrected. However, ifvitaminB12isnotprovided,vitaminB12deficiencycanpersistandwith it,potentially irreversible neurological conditions.
When folic acid corrects megaloblastic anemia while not treating the underlyingvitaminB12deficiency,itisknownas‘folicacidmaskingofvitaminB12deficiency’.FortificationwithfolicacidmaymaskvitaminB12deficiency.
4.2.4 Cancer
Folic acid is reported tobothprevent and cause cancer (Smith et al. 2008).Specifically,folicacid‘mayprotectagainsttheinitiationofcancer,butfacilitatethe growth of preneoplastic [pre-cancerous] cells’. The cancer research conducted with folic acid has mainly focused on folic acid delivered through large-dose supplements, and not lower-dose food fortification. Evidence ofwheatflourfortificationwithfolicacidcausingcancerisreviewedinthischapter.
5 Additional considerations when assessing the health impact of wheat flour fortification
Thereareseveralchallengeswithassessingthehealthimpactoffoodfortificationprogramsthrougheffectivenessstudies.Thefirstfiveoftheseissuescanaffecttheinterpretationoftheresearchresults;thelastissueistoaddressthepaucityof such data from countries that implement fortification programs. Potentialsolutions for overcoming these challenges are noted.
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5.1 Lack of a control group
Because large-scale fortification is often implemented under a nationalmandate, it rarely offers an opportunity to have a randomly selected control group thatdoesnotget fortification foraperiodof time.The lackof suchagroupmakes itdifficult to infercausality for fortification (Victoraet al.2004).Thus,wecannotstatewithcertaintythatfortificationcausesanimprovementina health outcome.
For example, using two national surveys from Costa Rica, researchers observed therewasa lowerprevalenceof irondeficiency, anemiaand iron-deficiency anemia in children in 2008 comparedwith 1996 (Martorell et al.2015).Between the twosurveys,maizeflourandmilkweremandated tobefortified with iron, and the iron compound used to fortify wheat flour waschangedtoafortificantthatthebodyabsorbswell(i.e.ferrousfumarate).Isitplausiblethatfortificationcontributedtothehealthimpactobserved?
The investigators generated a program-impact pathway of various factors inCostaRica’sfoodfortificationprogram(Fig.4)(Martorellet al.2015).First,theyassessedwhethertherewasapotentialtobenefitfromfoodfortification.Theyconcludedtherewasapotentialtobenefitbecausemicronutrientdeficiencieswerepresentin1996(27%ofchildrenwereirondeficient).Next,theyassessedifafortificationpolicyhadbeencreatedandlegislationpassed.Theanswerwasyes.Then,theyassessedifbioavailablefortificantsweremandated.Theanswerwasalsoyes.Next,theydeterminediffoodswerefortifiedatmandatedlevels.
Figure 4 Programimpactpathwaydevelopedbyresearcherstodeterminetheplausibilityoffoodfortificationimprovinghealthoutcomes(Martorellet al.2015).
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Wheat flour fortification and human health 11
Theyobtaineddatafromthegovernmentregulatoryagencythatconfirmedthatall246wheatfloursamplesobtainedinbakeriesoveraone-yearperiodmetorexceededtheironcontentrequiredbylaw.After,theyevaluatediffortifiedfoods were consumed in adequate amounts. They analyzed dietary data andestimated that fortified foodscontributed49%of children’sdietary ironrequirement. Finally, they assessed the public health impact and saw a reduction inbiologicalmakersandafunctionaloutcome.TheaffirmativeresponsestoallofthesequestionssuggestthatitisplausiblethatfoodfortificationwithironinCosta Rica contributed to the health impacts observed.
This type of complementary, program-related information can be presented foranyprogramtoargueforfortification’scontributiontohealthimpacts.Forexample, program decision makers can compile and triangulate information generated through government monitoring, such as compliance with fortification(SmarterFuturesnodate).Unfortunately,thistypeofinformationisrarelypresentedineffectivenessstudies(Pachónet al.2015).
5.2 Challenges of using birth defects registry data
The following experience from Peru highlights the importance of verifying electronic birth defects registry information with a review of clinical records, to minimize misclassification errors. In 2012, Ricks et al. (2012) publishedanarticle thatevaluated the impactonneural tubedefects (NTDs)ofwheatflourfortificationwithfolicacidwhichwasdecreedinPeruin2005.TheirworkshowednoreductioninNTDsinalargematernityhospitalinLima,afterfolic-acid fortification of wheat flour began; the pre-fortification NTD estimates(18.4/10 000 live and still births) were from 2004 to 2005 and the post-fortificationNTDestimates(20.0/10000liveandstillbirths)werefrom2007to2008.ElectronicregistrydatawereusedtogeneratetheNTDestimates.
Tarqui-Mamani (2013) wrote a letter to the editor of the journal that published Ricks’ paper. Tarqui-Mamani’s research team used the same data as Ricks;however,theyreviewedclinicalchartsandfoundthat32.9%ofcasesintheelectronicregistrynotedasNTDswereinfactothercongenitalanomalies.ThissuggeststhattheRicks’paperoverestimatedthenumberofNTDcasesinboththepre-andpost-fortificationperiods.
In 2013, Tarqui-Mamani was part of a research team that reported their analysis of the same electronic registry data as Ricks, but after having double-checked the clinical charts (Sanabria Rojas et al. 2013). They reported ondata collected in longer pre- (2001–2005) and post-fortification periods(2006–2010). The birth prevalence of NTDs that they reported in both thepre-fortification (2005: 13.6/10000) and post-fortification (2010: 7.6/10000)periods were lower than what Ricks reported, suggesting again, that Ricks misclassified congenital anomalies asNTDs.The Sanabria results indicate a
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lowerprevalenceofNTDsinthepost-fortificationperiodcomparedwiththepre-fortificationperiod.
5.3 Selecting an outcome indicator that is only responsive to the nutrients added through fortification
As noted earlier for anemia, there are many factors that together or in isolation cancauselowhemoglobinlevels;theseincludenutritionalandnon-nutritionalcauses. When anemia is the sole outcome studied to measure the impact of a nutritioninterventionsuchasfortification,onecanneverbecompletelysureifthe change (or lack of change) was due to the nutrients delivered. It is preferable to select an outcome that is directly and exclusively changed in the human body becauseofaparticularnutrientthatisprovidedthroughfortification.Examplesof such outcomes are the biological markers described previously (Table 2).
5.4 Allowing sufficient time before measuring outcomes
There are two main reasons why a minimum amount of time is needed between the start of fortification program implementation and the measurementof health outcomes. One is that programs need sufficient time to ensure aconsistent supplyof adequately fortified food reaches the targetpopulation(SmarterFuturesnodate).Millsthathaveneverfortifiedneedtimetopurchaseand install feeders, purchase vitamins and minerals, purchase bags with new nutrient labels, train mill staff in adding nutrients and testing for this addition, and in documenting the fortification process during all shifts. At the sametime, governments need time to train inspectors in auditing mill activities and integrating inspectionsfor fortification intoexistingprotocolsandschedules.Additionally,theremaybeseveralmonthsbetweentheproductionofflourandits appearance in the market for consumers or in mass-produced products that useflourasaningredient.Anotherreasonisthatsomebiologicalmarkersandmost functional indicators require a longer period of time before their presence canbemeasured in the humanbody.Neural tubedefects aremeasured atthe end of a nine-month pregnancy period and cancers can take decades to manifest (Keum and Giovannucci 2014).
For programs that are evaluated ‘too soon’ after initiation, a lack of impact can be due to either of the aforementioned reasons or to the program being ineffective(e.g.wrongfoodwaschosentobefortified;wrongnutrients,levelsor fortification compounds selected). In Brazil, the first published studiesthat assessed hemoglobin levels and the prevalence of neural tube defects (NTDs)showednodifferencebetweenthepre-andpost-fortificationperiods(Table 3), whereas later studies did observe higher hemoglobin levels and lowerprevalenceofNTDsinthepost-fortificationperiod.
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Wheat flour fortification and human health 13
For these reasons, it is prudent to measure program-performance informationsuchasthepercentageofflourproducedthatisadequatelyfortified(i.e.compliance)andthepercentageofpeopleconsumingadequatelyfortifiedflour(i.e.coverage)beforeembarkingonanimpactevaluation.Programsthatarenotdeliveringadequatelyfortifiedfoodtomostofthetargetpopulationareunlikelytoseeahealthimpact;inthosecases,programperformanceshouldbeimproved before assessing impact.
5.5 Unethical to conduct randomized controlled studies for some outcomes
A randomized controlled trial would unequivocally answer the question ‘does consumptionoffolicacid-fortifiedflourbypregnantwomencauseareductioninneuraltubedefects?’However,becauseithasbeenestablishedthatfolicaciddeliveredtopregnantwomen(inasupplement)reducesthefirstoccurrenceand recurrence of neural tube defects, it would be unethical to conduct such a trial where a group of pregnant women would knowingly be deprived of folic acid (Oakley 2009). For this reason, only observational studies, like those described in this chapter, can be ethically completed. Conclusions from these studies can be strengthened with program-performance data as noted earlier.
5.6 Impact evaluation surveys can be costly
Becausestand-alone,fortificationimpactevaluationsurveyscanbecostly,onesolutionistouseexistingdatatoassessthehealthimpactofflourfortification.
Table 3 StudiesfromBrazilthatreportedhemoglobinlevelsandneuraltubedefectsbeforeandafterfortificationofwheatandmaizeflour
Study Outcome Results
Assunçãoet al.2007
Hemoglobin Hemoglobin levels are the same in pre- and post-fortificationperiods
Fujimoriet al.2011 Hemoglobin Hemoglobin levels higher in the post- than pre-fortificationperiod
Assunçãoet al.2012
Hemoglobin Hemoglobin levels higher in the post- than pre-fortificationperiod
Pachecoet al.2009 Neuraltubedefects NTDprevalenceisthesame in pre- and post-fortificationperiods
López-Cameloet al.2010
Neuraltubedefects PrevalenceofonetypeofNTDisthesame in pre-andpost-fortificationperiods:totalspinabifida;prevalenceoftwotypesofNTDslower in thepost-fortificationthanpre-fortificationperiod:anencephaly, cephalocele
Pacheco Santos et al.2016
Neuraltubedefects NTDprevalencelowerinpost-fortificationthanpre-fortificationperiod
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Forexample, inJune2004,wheatandmaizeflour fortificationwith ironandfolic acid became mandatory in Brazil (Global Fortification Data Exchange,2020c). Researchers based in the city of Recife were interested in determining ifthefortificationmandatehadanimpactonthenumberofbabiesbornwithneuraltubedefects(Pachecoet al.2009).
Brazil has a National Information System on Live Births (Pacheco et al.2009). The information in this system was used to determine if a child was born in Recife with a neural tube defect. The researchers then counted the number ofbabiesbornwithneuraltubedefectsbeforefortificationbecamemandatoryandafterfortificationbecamemandatory.
This research project did not require primary data collection by the researchers.Theywereabletouseexistingdatatoassessiffortificationhadahealthimpact.ThisandthestudyfromCostaRica(Martorellet al.2015)providea valuable lesson. Existing data, such as national nutrition surveys and live births registries,canbeusedtoestimatethehealthimpactofflourfortification.
Another solution for minimizing the cost of evaluating health impact is toaddfortification-relevantquestionstoexistingdata-collectionsystems.Forinstance,forthe2014DemographicandHealthSurveyconductedinCambodia,decision makers added a micronutrient module for the first time (NationalInstitute of Statistics et al. 2015). This allowed for nationally representativeinformation to be available for several biological markers of nutrient status: iron,vitaminA,vitaminD,calcium, folate,vitaminB12and iodinestatus.Theresources required to add blood and urine sampling to existing surveys, such as this one, are substantially lower than paying for a stand-alone survey to exclusivelymeasurethehealthimpactoffoodfortification.
6 Health impact results observed from wheat flour fortification studies
Researchers have employed different study designs to assess if wheat flourfortificationaffectsanyofthehealthoutcomesdescribedinTable2:biologicalmarkers of nutritional status and functional outcomes (both positive and negative). What follows are the trends observed from these studies (Figs. 5–7).
Nutrientsandhealthoutcomesstudied:
• Folic acid is the nutrient added to fortified wheat flour that was moststudied,followeddistantlybyiron,vitaminB12andzinc.
• Numerous health outcomes were studied. For folic acid, these can begrouped into the following categories: folate status (including folate deficiencyand folate-deficiencyanemia),neural tubedefects (includingvarious sub-types), cancer (including breast, colorectal and pediatric
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Wheat flour fortification and human health 15
cancers), homocysteine status (including high homocysteine), orofacial clefts, heart health (coronary heart disease, stroke, myocardial infarction) and others (vitamin B12 deficiency masking, congenital heart disease,cognitive function, hypersensitivity, and thyroid- and diabetes-related disorders).
• Health outcomes studied for added iron included iron status, iron deficiencyandiron-deficiencyanemia.
• Health outcomes studies for vitamin B12 and zinc were status anddeficiencybiomarkers.
• Hemoglobin and anemia, biomarkers potentially linked to multiple nutrients, were also studied.
0%10%20%30%40%50%60%70%80%90%
100%
Health�Outcomes�Assessed�after�Flour�Fortification�with�Folic�Acid
Improved Made�no�difference Worsened
Folate status (n
=21)
Folate deficiency
(n=19)
Folate-deficiency
anemia (n=1)
Homocysteine st
atus (n=4)
High homocysteine (n
=2)
Neural tube defects
(n=47)
Anencephaly (
n=2)
Spina bifida (n=8)
Non-spina bifida neural tu
be defect (n=1)
Cephalocele (n
=1)
Encephaloce
le (n=1)
Cancer (n
=1)
Breast ca
ncer in
cidence
(n=6)
Breast ca
ncer d
eath (n=1)
Colon cance
r incid
ence (n
=7)
Colon cance
r death (n
=4)
Colon cance
r hosp
ital d
ischarge (n
=1)
Neuroblastoma (n
=1)
Wilms' T
umor (n=1)
Acute lym
phoblastic l
eukemia (n
=1)
Hepatoblastoma (n
=1)
Embryonal c
ancer (n
=1)
Brain cance
r (n=1)
Vitamin B12 deficie
ncy maski
ng (n=3)
Congenital h
eart dise
ase (n
=1)
Coronary heart d
isease
death (n=1)
Stroke
death (n=2)
Myoca
rdial infarct
ion (n=2)
Cognitive fu
nction (n
=2)
Hyperse
nsitivit
y (n=1)
Thyroid- a
nd diabetes-related diso
rders (n=1)
Non-syndromic c
left lip with
or with
out cleft p
alate (n=1)
Total orofacia
l clefts
(n=1)
Cleft lip with
or with
out cleft p
alate (n=1)
Cleft palate (n
=1)
Non-syndromic o
rofacial c
lefts (n
=1)
Non-syndromic c
left palate (n
=1)
Figure 5 Asummaryofresearchonallhealthoutcomesassessedafterflourfortificationwith folic acid: fortification improved, worsened ormade no difference in the healthoutcome. The number in parentheses reflects the number of analyses conducted. Ifstudies reported overall results only, the number reflects the number of studies. Ifa study reported results by different population groups (e.g. women, children), the numberreflectsthenumberofpopulationgroups.‘Folatestatus’asreflectedinserum,plasmaorredbloodcelllevels.‘Folatedeficiency’asreflectedinserum,plasmaorredblood cell levels below a cutoff. ‘Plasma homocysteine concentration increases when inadequate quantities of folate are available to donate the methyl group that is required to convert homocysteine to methionine’ (Institute of Medicine 1998). Serum or plasma homocysteinelevelsaboveacutoffreflectfolatedeficiency.For‘coloncancerincidence,death and hospital discharge’, this may refer to colon cancer alone or to colorectal cancer. Hypersensitivity outcomes include ‘asthma, allergy and atopic disease, wheeze, hypersensitivitytest,eczemaandfoodallergy’(NationalToxicologyProgram2015).
Wheat flour fortification and human health16
Published by Burleigh Dodds Science Publishing Limited, 2021.
Results from the most studied outcomes:
• The most studied outcomes were neural tube defects, cancer, folate status,folatedeficiency,anemia,irondeficiency,ironstatus,hemoglobinandiron-deficiencyanemia.
• Exceptfor iron-deficiencyanemia,mostanalysesshowedimprovementsinallof theseoutcomesafter fortification.Forexample, casesofneuraltube defects and cancers overwhelmingly decreased and levels of folate andironinbiomarkersincreasedafterfortification.
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Health�Outcomes�Assessed�after�Flour�Fortificationwith�Multiple�Nutrients�or�Iron
Improved Made�no�difference Worsened
Hemoglobin (n=11)
Anemia (n=19)
Iron st
atus: ferrit
in (n=7)
Iron st
atus: soluble tra
nsferrin
receptor (n
=2)
Iron st
atus: body ir
on stores (n
=2)
Iron deficie
ncy (n=6)
Iron deficie
ncy: lo
w ferrit
in (n=7)
Iron deficie
ncy: high so
luble
transfe
rrin re
ceptor (
n=2)
Iron deficie
ncy: lo
w body
iron st
ores (n=2)
Iron-deficie
ncy anemia (n
=6)
Figure 6 Asummaryofresearchonhealthoutcomesassessedafterflourfortificationwithmultiplenutrientsoriron:fortificationimproved,worsenedormadenodifferenceinthehealthoutcome.Thenumberinparenthesesreflectsthenumberofanalysesconducted.Ifstudiesreportedonlytheoverallresults,thenumberreflectsthenumberofstudies.Ifastudy reported results by different population groups (e.g. women, children), the number reflectsthenumberofpopulationgroups.Hemoglobinlevelandprevalenceofanemiacanbeaffectedbymultiplenutrients;theycanalsobeaffectedbynon-nutritionalfactorssuchasmalariainfection.‘Irondeficiency’asdefinedbytheauthors.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 17
• Fewanalyses showed thathealthoutcomesworsenedafter fortification.Thiswasthecaseforcancer, folatedeficiency,anemia,hemoglobinandiron-deficiency anemia. That is, the cases of cancer, folate deficiency,anemiaand iron-deficiencyanemia increasedand levelsofhemoglobindecreasedafterfortification.
• Conflictingresultsforcancermaybeexplainedbythedifferenceinyearssincefortificationwasinitiated(e.g. increasedincidenceofcoloncancerafter fortification is suggested by studies published in the 2000s; the
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
B12 status:plasma(n=2)
B12 status:breastmilk
(n=1)
B12deficiency:
plasma(n=2)
B12deficiency:breastmilk
(n=1)
Zinc status(n=3)
Zincdeficiency
(n=3)
Health Outcomes Assessed after Flour Fortification with Vitamin B12 or Zinc
Improved Made no difference Worsened
Figure 7 A summaryof researchonhealthoutcomesassessedafter flour fortificationwithvitaminB12orzinc:fortificationimproved,worsenedormadenodifferenceinthehealthoutcome.Thenumberinparenthesesreflectsthenumberofanalysesconducted.If studies reportedoverall resultsonly, thenumberreflects thenumberofstudies. Ifastudy reported results by different population groups (e.g. women, children), the number reflectsthenumberofpopulationgroups.
Wheat flour fortification and human health18
Published by Burleigh Dodds Science Publishing Limited, 2021.
opposite is observed in studies published in the 2010s) or by the sample sizeinstudies(e.g.increasedbreastcancerincidenceafterfortificationisobserved in studieswith sample sizes<2000; studies thatobservednodifferenceoradecreasedincidenceafter fortificationhavesamplesizes>2000 and going into the millions).
• Conflicting results for hemoglobin, anemia and iron-deficiency anemia(i.e. some studies show improvements and some show worsening after fortification) may be explained by (1) the existence of non-nutritionalcausesofanemiawhichcannotbeaddressedbyfortification,(2)nutritionalcausesofanemianotaddressedbyfortificationbecausealimitednumberof nutrientswere added through fortification and (3) levelsof nutrientsorfortificationcompoundsusedinfortificationdonotfollowinternationalguidelines.
Results from other outcomes:
• All remaining outcomes had data from four or fewer analyses: folate-deficiencyanemia,homocysteinestatus,highhomocysteine,vitaminB12deficiency masking, congenital heart disease, coronary heart disease,stroke, myocardial infarction, cognitive function, hypersensitivity, thyroid- anddiabetes-relateddisorders,orofacialclefts,vitaminB12status,vitaminB12deficiency,zincstatusandzincdeficiency.
• Cautiously, outcomes with two to four analyses suggest the following relationshipwithfortification.
• Homocysteine status, high homocysteine, stroke death, myocardial infarction,orofacialclefts,vitaminB12status,vitaminB12deficiency,zincstatusandzincdeficiencytrendtowardimprovementafterfortification.
• Vitamin B12 deficiency masking and cognitive function trend towardsshowingnodifferencebeforeandafterfortification.
• Noneoftheoutcomeswithtwo,threeorfouranalysesshowaworseningofhealthafterfortification.
6.1 Results from studies in individual countries that assessed health outcomes before and after fortification
‘Before and after’ studies are those where health outcomes are measuredbeforefoodfortificationisimplementedinacountryandthenafter.Here,thebeforeorpre-fortificationperiodisconsideredthecontrolgroupfortheafterorpost-fortificationperiod.Health informationcanbecollectedonthesameindividuals,ortherecanbedifferentindividualsinthepre-fortificationperiodandthepost-fortificationperiod.Whatfollowsarestudiesconductedinsinglecountries.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 19
6.1.1 Results from studies where the same individuals were measured before and after fortification
Studieswherethesameindividualsweremeasuredbeforeandafterfortificationin a single country are summarized in Table 4. One example is from Chile with red blood cell folate data from the same women of reproductive age (Hertrampf et al.2003).Women’sbloodwastakenbeforeinitiationoffortificationofwheatflourwithfolicacidanditwastaken12monthsafterfortificationhadstarted.Inthesewomen,redbloodcellfolatelevelswere290 + 102nmol/Linthepre-fortificationperiodandincreasedto707 + 179nmol/Linthepost-fortificationperiod.Redbloodcellfolatelevelsincreasedwithin12monthsafterfortificationstarted,suggestingthatfortificationofwheatflourwithfolicacidimprovedabiological marker of folate status.
Sometimes, pre- and post-fortification studies may not show clearimprovements in nutrient status. For example, South Africa experienced an improvementinthenutritionalstatusofonenutrientaddedthroughfortification(i.e. folic acid which was further supported by reductions in neural tube defects (Sayedet al.2008))butnotinanothernutrientaddedthroughfortification(i.e.iron)(Modjadjiet al.2007).TheresultsfromtheModjadjistudysuggestedthatanironcompoundmorebioavailablethantheelectrolyticironspecifiedinthecountrystandardcouldbewarranted(UNICEFandFoodFortificationInitiative2004).
6.1.2 Results from studies where different individuals were measured before and after fortification
Studieswheredifferentindividualsweremeasuredbeforeandafterfortificationin a single country are summarized in Table 5 for neural tube defects and Table 6 for other health outcomes.
A study from Iran included neural tube defect data collected from different babies(Abdollahiet al.2011)(Table5).Theresearchersreportedneuraltubedefectsbeforefortificationofwheatflourwithfolicacid(years2006–2007)andafterfortification(2007–2008).Therewere31.6and21.9neuraltubedefectsper10 000 live and still births between the time periods, respectively, pointing to a 31%reductioninneuraltubedefectsafterfortificationofwheatflourwithfolicacid.Wheatflour fortificationwith folicacid improveda functionaloutcome;thiswasaconsistentfindinginallcountrieswhichstudiedneuraltubedefects.
In Cameroon, women and pre-school children’s nutritional status was measuredbeforeandafterinitiationofoilfortificationwithvitaminAandwheatflourfortificationwithmultiplenutrients:folicacid,iron,vitaminB12andzinc(Engle-Stoneet al.2017) (Table6).PlasmavitaminB12 levelswerehigher inwomenandchildreninthepost-fortificationperiodthaninthepre-fortificationperiod; the same was true for breastmilk vitamin B12 levels in lactating
Wheat flour fortification and human health20
Published by Burleigh Dodds Science Publishing Limited, 2021.
Tabl
e 4 Healthoutcomeresultsfrom
studiesw
herethesameindividualsw
eremeasuredbeforeandafterw
heatflourfortificationa
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ecIn
divi
dual
s stu
died
Resu
lts
Chi
leHirschet al.2002
dFo
lic a
cid
Serumfolate;folate
deficiency
Old
er a
dults
(wom
en a
nd m
en)
Hig
her s
erum
fola
te le
vels
in
thepost-fortificationthanpre-
fortificationperiod;prevalence
offolatedeficiencylowerinpost-
fortificationthanpre-fortification
perio
dC
hile
Hertrampfet al.2003
Folic
aci
dSerumfolate;red
bloodcell(RBC
)folate;low
serum
folate,low
RBC
folate
Wom
en o
f chi
ldbe
arin
g ag
eHigherserum
andRBC
folate
levelsinthepost-fortificationthan
pre-fortificationperiod;prevalence
oflowserumandRBC
folatelower
inpost-fortificationthanpre-
fortificationperiod
Iran
Sadighiet al.2008
Irone
Serumferritin;
hemoglobin;low
serumferritin;
anem
ia;iron-
deficiencyanem
ia
Wom
en o
f chi
ldbe
arin
g ag
eNodifferencebetweenthepre-
andpost-fortificationperiodsfor
serumferritinandhemoglobin;no
diffe
renc
e be
twee
n th
e pr
e-an
d post-fortificationperiodsinthe
prev
alen
ce o
f low
seru
m fe
rriti
n,
anem
iaandiron-deficiencyanemia
Sout
h Af
ricaa
Modjadjiet al.2007
Iron
Serumferritin;low
seru
m fe
rriti
nW
omen
of c
hild
bear
ing
age
Nodifferenceinserumferritin
leve
ls be
twee
n pr
e- a
nd p
ost-
fortificationperiods;nodifference
in p
reva
lenc
e of
low
seru
m fe
rriti
n betweenpre-andpost-fortification
perio
ds
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 21
Sout
h Af
ricaa
Modjadjiet al.2007
Folic
aci
dSerumfolate;RBC
folate;low
serum
folate;low
RBC
folate
Wom
en o
f chi
ldbe
arin
g ag
eHigherserum
andRBC
folate
levelsinthepost-fortificationthan
pre-fortificationperiod;prevalence
oflowserumandRBC
folatelower
inpost-fortificationthanpre-
fortificationperiod
Sout
h Af
ricaa
Modjadjiet al.2007
Mul
tiple
fHem
oglobin;low
hem
oglo
bin
Wom
en o
f chi
ldbe
arin
g ag
eH
ighe
r hem
oglo
bin
leve
ls in
thepost-fortificationthanpre-
fortificationperiod;nodifference
in p
reva
lenc
e of
low
hem
oglo
bin
betweenpre-andpost-fortification
perio
dsUSA
aEnquobahrieet al.2012
Folic
aci
dSerumfolate;serum
ho
moc
yste
ine
Adol
esce
nts
Hig
her s
erum
fola
te a
nd
hom
ocys
tein
eg lev
els i
n th
e po
st-
fortificationthanpre-fortification
perio
dUSA
aStolzenberg-Solomonet al.
2006;Linet al.2008;Stevens
et al.2010;Houghtonet al.
2019
a,b
Folic
aci
dBreastcancer
Wom
en 3
0–55
yea
rs (H
ough
ton
et al.2019a),32–53years
(Houghtonet al.2019b),
45yearsorolder(Linet al.
2008
), 50
–74
year
s (St
even
s et al.2010),55–74years
(Stolzenberg-Solomonet al.
2006
)
Hig
her b
reas
t can
cer i
ncid
ence
inthepost-fortificationthan
pre-fortificationperiod(Linet al.
2008;Houghtonet al.2019b);h
no d
iffer
ence
in b
reas
t can
cer
inci
denc
e be
twee
n pr
e- a
nd p
ost-
fortificationperiods(Stolzenberg-
Solomonet al.2006;Stevenset al.
2010;Houghtonet al.2019a)
(Con
tinue
d)
Wheat flour fortification and human health22
Published by Burleigh Dodds Science Publishing Limited, 2021.
USA
aGibsonet al.2011
Fola
tei
Colo
rect
al c
ance
r in
cide
nce
Adul
ts 5
0–71
yea
rsLowercolorectalcancerincidence
with
hig
her f
olat
e in
take
in th
e post-fortificationperiod,thistrend
was
not
obs
erve
d in
the
pre-
fortificationperiod
RBC,redbloodcell
a Wheatflourw
astheonlygrainfortifiedwithoneorm
orenutrientsinmostcountries.Wheatandmaizeflourw
asfortifiedwithnutrientsinSouthAfricaandtheUSA
(inadditiontorice);theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbediscernedwiththisstudy.
b Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
c Som
e of
the
heal
th o
utco
mes
mea
sure
the
conc
entra
tion
of n
utrie
nts o
r oth
er co
nstit
uent
s in
the
bloo
d or
bre
astm
ilk a
nd so
me
refe
r to
the
prev
alen
ce (i
.e. p
erce
ntag
e of
peo
ple
who
hav
e th
e co
nditi
on),
the
inci
denc
e (i.
e. n
umbe
r of p
eopl
e ne
wly
dia
gnos
ed w
ith th
e co
nditi
on),
or d
eath
s (i.
e. n
umbe
r of p
eopl
e w
ho d
ie d
ue to
the
cond
ition
). d EventhoughthetitleofthisarticlereferstomaskingofvitaminB12deficiency,theauthorspresentednodatathatcouldsupportorrefutemaskingofB12deficiency
byfortificationwithfolicacid(Hirschet al.2002).
e WheatflourinIranisfortifiedwithtwonutrientsthatcontributetohem
oglobinsynthesis:ironandfolicacid(Sadighiet al.2008).
f Asreportedinthearticle,SouthAfricafortifiedwheatandmaizeflourw
ithfolicacid,iron,vitaminA,thiam
in,riboflavin,niacin,pyridoxineandzinc;manyofwhich
can
cont
ribut
e to
hem
oglo
bin
synt
hesis
. g T
he h
omoc
yste
ine
resu
lts a
re th
e op
posit
e of
wha
t is
expe
cted
. Whe
n fo
late
leve
ls ar
e ad
equa
te, h
omoc
yste
ine
leve
ls ar
e us
ually
low
(Ins
titut
e of
Med
icin
e 19
98).
Theauthorssuggestthatinadolescence,thereisatrendtowardanincreaseinhom
ocysteinelevelswhichwasnotaffectedbyfortification(Enquobahrieet al.2012).
h Thi
s res
ult i
s the
opp
osite
of w
hat i
s exp
ecte
d.
i Folatefromanysource:foodsnaturallyrichinfolate,supplem
entscontainingfolicacidandfolicacid-fortifiedfood(Gibsonet al.2011).
Tabl
e 4 Healthoutcomeresultsfrom
studiesw
herethesameindividualsw
eremeasuredbeforeandafterw
heatflourfortificationa
(Con
tinue
d)
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ecIn
divi
dual
s stu
died
Resu
lts
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 23
Tabl
e 5 Resultsforneuraltubedefectsasthehealthoutcomefromstudieswheredifferentindividualsweremeasuredbeforeandafterwheatflour
fortificationa
Coun
trySt
udy
Nutrient
bH
ealth
ou
tcom
ec In
divi
dual
s stu
died
Resu
lts
Arge
ntin
aLópez-Cameloet al.2010;
Bidondoet al.2015;
Sargiottoet al.2015
Folic
aci
dNeuraltube
defe
cts
Livebirthsandstillbirths
weighing500 gormore
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiod
Aust
ralia
Bottoet al.2006;Hilder
2016
Folic
aci
dNeuraltube
defe
cts
Livebirths,stillbirthsand
term
inat
ions
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiodd
Brazila
Pachecoet al.2009;
López-Cameloet al.2010;
PachecoSantoset al.2016
Folic
aci
dNeuraltube
defe
cts
Livebirths(allstudies)and
stillbirthsweighing500 gor
more(López-Cam
eloet al.
2010;PachecoSantoset al.
2016
)
PrevalenceoftwotypesofN
TDslow
erin
post-fortificationthanpre-fortificationperiod:
anencephaly,cephalocele(López-Cam
elo
et al.2010);
no d
iffer
ence
in p
reva
lenc
e of
one
type
of
NTDbetweenthepre-andpost-fortification
periods:totalspinabifida(López-Cam
eloet al.
2010);
nodifferenceinNTDprevalencebetween
post-fortificationandpre-fortificationperiods
(Pachecoet al.2009);prevalenceofN
TDs
lowerinpost-fortificationthanpre-fortification
period(PachecoSantoset al.2016)
Cana
daRayet al.2002;Bottoet al.
2006
Folic
aci
dNeuraltube
defe
cts
Livebirths,stillbirthsand
term
inat
ions
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiod
(Con
tinue
d)
Wheat flour fortification and human health24
Published by Burleigh Dodds Science Publishing Limited, 2021.
Chi
leCastillaet al.2003;López-
Cameloet al.2005,2010;
Corralet al.2006;Nazer
et al.2007;Cortéset al.
2012;NazerandCifuentes
2013
Folic
aci
dNeuraltube
defe
cts
Livebirths(allstudies)and
stillbirthsweighing500 g
ormore(Castillaet al.2003;
López-Cameloet al.2005,
2010;Corralet al.2006;
Nazeret al.2007;Cortés
et al.2012;Nazerand
Cifu
ente
s 201
3)
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiod
Cost
a Ri
caa
Tacs
an C
hen
and
Asce
ncio
Rivera2004;Barboza
ArgüelloandUmañaSolís
2011;BarbozaArgüello
et al.2015
Folic
aci
dNeuraltube
defe
cts
Livebirths(allstudies)and
stillbirthsweighing500 g
or m
ore
(Tac
san
Che
n an
d AscencioRivera2004;
BarbozaArgüelloand
UmañaSolís2011;Barboza
Argüelloet al.2015)
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiode
Iran
Abdo
llahi
et a
l. 20
11Fo
lic a
cid
Neuraltube
defe
cts
Livebirthsandstillbirths
weighing500 gormore
with
a g
esta
tiona
l age
of
20 w
eeks
or m
ore
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiod
Tabl
e 5 Resultsforneuraltubedefectsasthehealthoutcomefromstudieswheredifferentindividualsweremeasuredbeforeandafterwheatflour
fortificationa
(Con
tinue
d)
Coun
trySt
udy
Nutrient
bH
ealth
ou
tcom
ec In
divi
dual
s stu
died
Resu
lts
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 25
Peru
Rickset al.2012;Sanabria
Rojaset al.2013;Tarqui-
Mam
aniet al.2016
Folic
aci
dNeuraltube
defe
cts
Livebirthsandstillbirths
(Rickset al.2012;Sanabria
Rojaset al.2013);livebirths
(Tarqui-M
amaniet al.2016)
NodifferenceintheprevalenceofN
TDs
betweenpost-fortificationandpre-fortification
periods(Rickset al.2012);prevalenceofN
TDs
lowerinpost-fortificationthanpre-fortification
period(SanabriaRojaset al.2013);prevalence
ofspinabifidalowerinpost-fortificationthan
pre-fortificationperiod(Tarqui-M
amaniet al.
2016);nodifferenceintheprevalenceof
anen
ceph
aly
and
ence
phal
ocel
e be
twee
n post-fortificationandpre-fortificationperiods
(Tarqui-M
amaniet al.2016)
Sout
h Af
ricaa
Sayedet al.2008
Folic
aci
dNeuraltube
defe
cts
Livebirthsandstillbirths
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiod
USA
aHoneinet al.2001;CDC
2004;Bottoet al.2006
Folic
aci
dNeuraltube
defe
cts
Livebirths(Honeinet al.
2001
)Livebirths,stillbirthsand
terminations(Bottoet al.
2006);livebirths,stillbirths,
term
inat
ions
, and
feta
l de
aths
f (CDC2004)
PrevalenceofN
TDslow
erinpost-fortification
thanpre-fortificationperiod
NTDs,neuraltubedefects
a Wheatflourwastheonlygrainfortifiedwithfolicacidinmostcountries.WheatandmaizeflourwerefortifiedwithfolicacidinBrazil,CostaRica(inadditiontoriceand
milk),SouthAfricaandtheUSA(inadditiontorice);theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbediscernedwiththisstudy.
b Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
c In
this
tabl
e, th
e he
alth
out
com
e re
fers
to th
e pr
eval
ence
(or p
erce
ntag
e) o
f liv
ebirt
hs, s
till b
irths
, fet
al d
eath
s an
d/or
term
inat
ions
affe
cted
by
a ne
ural
tube
def
ect
suchasspinabifidaoranencephaly.
d AustraliaexperienceddecreasesintheprevalenceofNTDsw
henthecountrywentfromnofortificationtovoluntaryfortification(Bottoet al.2006)andfrom
voluntary
tomandatoryfortification(Hilder2016).
e Wheatflourw
asthefirstfoodmandatedtobefortifiedwithfolicacidinCostaRica.Withtheadditionofsubsequentfoodsmandatedtobefortifiedwithfolicacid
(maizeflour,milk,rice)andwithanincreaseinthefolicacidlevelsinwheatflour(from1.5 mg/kgto1.8 mg/kg),NTDscontinuedtodecrease(BarbozaArgüelloand
UmañaSolís2011).
f ‘Fet
al d
eath
refe
rs to
the
spon
tane
ous i
ntra
uter
ine
deat
h of
a fe
tus a
t any
tim
e du
ring
preg
nanc
y. Fe
tal d
eath
s lat
er in
pre
gnan
cy (a
t 20
wee
ks o
f ges
tatio
n or
mor
e,
or28weeksorm
ore,forexample)arealsosometimesreferredtoasstillbirths.’(CDC2020).
Wheat flour fortification and human health26
Published by Burleigh Dodds Science Publishing Limited, 2021.
women.Consistentwiththesefindings,theprevalenceoflowplasma(womenandchildren) andbreastmilk (women) vitaminB12 levelswas lower inpost-fortificationthanpre-fortificationperiod.ThesevitaminB12resultssuggestthatwheatflourfortificationwithvitaminB12improvednutritionaloutcomesinthecountry.
Results for the nutritional status of folic acid, zinc and hemoglobin/anemia also suggested that fortificationwas adequately implemented inCameroon.For iron, three indicators of nutritional status were measured: plasma ferritin, soluble transferrin receptor and body iron stores. These were used to measure the prevalence of low plasma ferritin and high-soluble transferrin receptors (bothmarkersofirondeficiency);togetherwithhemoglobin,plasmaferritinwasusedtocalculatetheprevalenceofsimultaneousirondeficiencyandanemia.Most of these measures pointed toward improvements in iron status for women and children except for the prevalence of low plasma ferritin (women) and iron-deficiencyanemia(womenandchildren)whichwasnotdifferentbetweenthepre-andpost-fortificationperiods.
The same study design was used to investigate potential negative health impactsof fortification (Table6). Inone study conducted in theUSA,researchers surmised that people with low vitamin B12 deficiency and noanemiawhoconsumedgrains (i.e.wheatflour,maizeflourandrice) fortifiedwithfolicacidcouldbeatriskofdevelopingvitaminB12deficiency(Qiet al.2014).Inotherwords,sincefolicacidisprovidedthroughgrainfortificationintheUSA,theseindividualswillnotdevelopanemia.However,sincevitaminB12isnotprovidedthroughgrainfortificationintheUSA,theymaydevelopvitaminB12deficiency.TheresearchersassessediftheprevalenceofolderadultswithvitaminB12deficiencyandnoanemiachangedbetweenpreandpost folic-acidfortificationperiods.IffolicacidwasmaskingvitaminB12deficiency,onewouldexpectanincreaseinthepost-fortificationperiodintheprevalenceofvitaminB12deficiencyandnoanemiainthesameadults.Therewasnochangeintheprevalencefromthepre-tothepost-fortificationperiod,suggestingtherewasnomaskingofvitaminB12deficiencybygrainfortificationwithfolicacid.
6.2 Results from trend studies in individual countries that assessed health outcomes multiple times after fortification
When information on a health outcome is available for many years after fortificationhasstarted,trendstudiescanbecompleted(Table7).Forexample,SaudiArabiabeganvoluntarywheatflourfortificationwithfolicacidandothernutrients in 2001 (Safdar et al. 2007). Investigators had information on thenumberofbabiesbornwithneuraltubedefectsfor3yearsbeforefortificationstarted (~15, 30 and 20 per 10 000 births, respectively) and for 5 years after fortificationstarted(~15,12,10,10and9per10000births,respectively).The
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 27
Tabl
e 6 Resultsforhealthoutcomesotherthanneuraltubedefectsfromstudieswheredifferentindividualsweremeasuredbeforeandafterw
heatflour
fortificationa
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ec In
divi
dual
s st
udie
dRe
sults
Aust
ralia
Brow
net al.
2011
Folic
aci
dSerumfolate;red
bloodcell(RBC
)folate;low
serum
folate;low
RBC
fo
late
Bloodsamples
anal
yzed
in a
pu
blic
hos
pita
l’s
labo
rato
ry
Higherserum
folateandRBC
folatelevelsinthepost-fortificationthan
pre-fortificationperiod;prevalenceoflowserumfolateandlowRBC
folatelowerinpost-fortificationthanpre-fortificationperiodinwom
en
and
child
ren
Aust
ralia
Beckettet al.
2017
Folic
aci
dPl
asm
a homocysteine;
high
homocysteine;
serumfolate;low
serumfolate;RBC
fo
late
Wom
en a
nd m
en
65 y
ears
or o
lder
Higherserum
folateandRBC
folatelevelsinthepost-fortificationthan
pre-fortificationperiod;
low
er p
lasm
a ho
moc
yste
ined l
evelsinthepost-fortificationthanpre-
fortificationperiod;
prev
alen
ce o
f hig
h ho
moc
yste
ine
leve
ls (h
yper
hom
ocys
tein
emia
)d and
lowserumfolatelowerinpost-fortificationthanpre-fortificationperiod
Brazila
Brittoet al.2014
Folic
aci
dSerumfolate;red
bloo
d ce
ll fo
late
Preg
nant
w
omen
, chi
ldre
n,
adol
esce
nts,
adul
ts, e
lder
ly
Hig
her s
erum
fola
te a
nd re
d bl
ood
cell
fola
te le
vels
in th
e po
st-
fortificationthanpre-fortificationperiodinallagegroups
Brazila
Assu
nção
and
Santos2007;
Assunçãoet al.
2007;Costa
et al.2009;
Fujim
oriet al.
2011
, Ass
unçã
o et al.2012
Iron
Hem
oglo
bin
(Assunçãoet al.
2007
, Fuj
imor
i et al.2011;
Assunçãoet al.
2012);anem
ia(all
stud
ies)
Chi
ldre
n le
ss
than
6 y
ears
(Assunçãoet al.
2007,2012;
Costaet al.2009)
Preg
nant
wom
en
(Fujimoriet al.
2011
)
Nodifferenceinhem
oglobinlevels(Assunçãoet al.2007);
higherhem
oglobinlevelsinpost-fortificationthanpre-fortification
period(Fujimoriet al.2011);
lowerhem
oglobinlevelsinpost-fortificationthanpre-fortification
period(Assunçãoet al.2012);
prevalenceofanemiahigherinpost-fortificationthanpre-fortification
(Assunçãoet al.2007,2012);e
prevalenceofanemialowerinpost-fortificationthanpre-fortification
(Costaet al.2009;Fujimoriet al.2011)f
(Con
tinue
d)
Wheat flour fortification and human health28
Published by Burleigh Dodds Science Publishing Limited, 2021.
Cam
eroo
nEn
gle-
Ston
e et al.2017
gFo
lic a
cid
Plasmafolate;
low
pla
sma
fola
teW
omen
of
child
bear
ing
age,
chi
ldre
n 12
–59
mon
ths
Higherplasmafolatelevelsinthepost-fortificationthanpre-fortification
periodinwom
enandchildren;
prevalenceoflow
plasmafolatelowerinpost-fortificationthanpre-
fortificationperiodinwom
enandchildren
Cam
eroo
nEn
gle-
Ston
e et al.2017
gIro
nPlasmaferritin;
solu
ble
trans
ferr
in
receptor;body
ironstores;low
plasmaferritin;
high
solu
ble
trans
ferr
in
receptor;iron-
deficiencyanem
ia
Wom
en o
f ch
ildbe
arin
g ag
eH
ighe
r pla
sma
ferr
itin
leve
ls an
d bo
dy ir
on st
ores
in th
e po
st-
fortificationthanpre-fortificationperiod;
lowersolubletransferrinreceptorlevelsinthepost-fortificationthan
pre-fortificationperiod;
h no
diffe
renc
e in
pre
vale
nce
of lo
w p
lasm
a ferritinandiron-deficiencyanem
iabetweenpost-fortificationandpre-
fortificationperiod;
prev
alen
ce o
f hig
h-so
lubl
e tra
nsfe
rrin
rece
ptor
and
low
bod
y iro
n storeslowerinpost-fortificationthanpre-fortificationperiod
Cam
eroo
nEn
gle-
Ston
e et al.2017
gIro
nPlasmaferritin;
solu
ble
trans
ferr
in
receptor;body
ironstores;low
plasmaferritin;
high
solu
ble
trans
ferr
in
receptor;iron-
deficiencyanem
ia
Chi
ldre
n 12
–59
mon
ths
Hig
her p
lasm
a fe
rriti
n le
vels
and
body
iron
stor
es in
the
post
-fortificationthanpre-fortificationperiod;
lowersolubletransferrinreceptorlevelsinthepost-fortificationthan
pre-fortificationperiod;
h
nodifferenceinprevalenceofiron-deficiencyanemiabetweenpost-
fortificationandpre-fortificationperiod;
prevalenceoflow
plasmaferritinlowerinpost-fortificationthanpre-
fortificationperiodinchildren;
prev
alen
ce o
f hig
h so
lubl
e tra
nsfe
rrin
rece
ptor
and
low
bod
y iro
n storeslowerinpost-fortificationthanpre-fortificationperiod
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ec In
divi
dual
s st
udie
dRe
sults
Tabl
e 6 Resultsforhealthoutcomesotherthanneuraltubedefectsfromstudieswheredifferentindividualsweremeasuredbeforeandafterw
heatflour
fortificationa
(Con
tinue
d)
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 29
Cam
eroo
nEn
gle-
Ston
e et al.2017
gVitaminB12
Plas
ma
vita
min
B12;breastmilk
vitaminB12
(wom
enonly);
prev
alen
ce lo
w
vitaminB12;
prev
alen
ce lo
w
brea
stm
ilk v
itam
in
B12(wom
enonly)
Wom
en o
f ch
ildbe
arin
g ag
e, c
hild
ren
12–5
9 m
onth
s
Hig
her p
lasm
a (w
omen
and
chi
ldre
n) a
nd b
reas
tmilk
(wom
en) v
itam
in
B12levelsinthepost-fortificationthanpre-fortificationperiod;
prev
alen
ce o
f low
pla
sma
(wom
en a
nd c
hild
ren)
and
bre
astm
ilk
(wom
en)vitaminB12lowerinpost-fortificationthanpre-fortification
perio
d
Cam
eroo
nEn
gle-
Ston
e et al.2017
gZi
ncPlasmazinc;
low
pla
sma
zinc
Wom
en o
f ch
ildbe
arin
g ag
e, c
hild
ren
12–5
9 m
onth
s
Higherplasmazinclevelsinthepost-fortificationthanpre-fortification
periodinwom
enandchildren;
prevalenceoflow
plasmazinclowerinpost-fortificationthanpre-
fortificationperiodinwom
enandchildren
Cam
eroo
nEn
gle-
Ston
e et al.2017
gM
ultip
leHem
oglobin;
anem
iaW
omen
of
child
bear
ing
age,
chi
ldre
n 12
–59
mon
ths
In w
omen
and
chi
ldre
n, n
o di
ffere
nce
in h
emog
lobi
n le
vels
betw
een
thepost-fortificationandpre-fortificationperiod;
prevalenceofanemialowerinpost-fortificationthanpre-fortification
perio
d in
wom
en, n
o di
ffere
nce
in p
reva
lenc
e of
ane
mia
in p
ost-
fortificationandpre-fortificationperiodinchildren
Cana
daRayet al.2003;
Liuet al.2004
Folic
aci
dSe
rum
fola
te (R
ay
et al.2003;Liu
et al.2004);RBC
folate(Liuet al.
2004);plasma
hom
ocys
tein
e (Liuet al.2004);
folatedeficiency
(Rayet al.2003)
Wom
en 6
5 ye
ars
and
olde
r (Ra
y et al.2003),
wom
en 1
9–44
ye
ars a
nd
wom
en a
nd m
en
65 y
ears
and
older(Liuet al.
2004
)
Inwom
enandolderadults:higherserum
andRBC
folatelevels
inthepost-fortificationthanpre-fortificationperiod,lowerplasma
homocysteinelevelsinthepost-fortificationthanpre-fortification
period;
inwom
en65yearsandolder:prevalenceoffolatedeficiencylowerin
post-fortificationthanpre-fortificationperiod
Cana
daMasonet al.
2007
Folic
aci
dIn
cide
nce
of
colo
rect
al c
ance
rAl
l age
sIncidenceofcolorectalcancerhigherinpost-fortificationthanpre-
fortificationperiode
(Con
tinue
d)
Wheat flour fortification and human health30
Published by Burleigh Dodds Science Publishing Limited, 2021.
Chi
leHirschet al.
2009
Folic
aci
dH
ospi
tal
disc
harg
e du
e to
co
lon
canc
er
Patie
nts
disc
harg
ed fr
om
publ
ic o
r priv
ate
hosp
itals
Follo
win
g th
e se
cula
r tre
nd, h
ighe
r hos
pita
l disc
harg
es d
ue to
col
on
cancerinthepost-fortificationthanpre-fortificationperiodi
Cost
a Ri
caa
Tacs
an C
hen
and
Asce
ncio
Ri
vera
200
4
Folic
aci
dSerumfolate;
folatedeficiency
Wom
enIn
urb
an a
nd ru
ral a
reas
: hig
her s
erum
fola
te le
vels
in th
e po
st-
fortificationthanpre-fortificationperiod;
inurbanandruralareas:prevalenceoffolatedeficiencylowerinthe
post-fortificationthanpre-fortificationperiod
Cost
a Ri
caaMartorellet al.
2015
Iron
Serumferritin;
hemoglobin;
irondeficiency;
iron-deficiency
anem
ia;anemia
Chi
ldre
n 1–
7 ye
ars
Higherserum
ferritinandhemoglobininthepost-fortificationthan
pre-fortificationperiod;
prevalenceofirondeficiency,iron-deficiencyanem
iaandanemialower
inthepost-fortificationthanpre-fortificationperiod
Cost
a Ri
caaMartorellet al.
2015
VitaminsA
,B1,B2,B9,
B12,E
Min
eral
s iro
n, zi
ncf
Hem
oglobin;
anem
iaW
omen
15–
45
year
sHigherhem
oglobinlevelsinthepost-fortificationthanpre-fortification
period;prevalenceofanemialowerinthepost-fortificationthan
pre-fortificationperiod
Fiji
NationalFood
andNutrition
Cent
re 2
012
Folic
aci
d,
iron,
nia
cin,
riboflavin,
thia
min
, zin
c
Serumferritin;
hemoglobin;
serumfolate;
serumzinc;low
serumferritin;
anem
ia;low
serumfolate;low
se
rum
zinc
Wom
en o
f ch
ildbe
arin
g ag
eH
ighe
r ser
um fe
rriti
n, h
emog
lobi
n, se
rum
fola
te a
nd se
rum
zinc
leve
ls inthepost-fortificationthanpre-fortificationperiod;
prev
alen
ce o
f low
seru
m fe
rriti
n, a
nem
ia, l
ow se
rum
fola
te a
nd lo
w
serumzinclowerinpost-fortificationthanpre-fortificationperiod
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ec In
divi
dual
s st
udie
dRe
sults
Tabl
e 6 Resultsforhealthoutcomesotherthanneuraltubedefectsfromstudieswheredifferentindividualsweremeasuredbeforeandafterw
heatflour
fortificationa
(Con
tinue
d)
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 31
Iran
Abdollahiet al.
2011
Folic
aci
dSerumfolate;
plas
ma
homocysteine;
lowserumfolate;
high
pla
sma
hom
ocys
tein
e
Wom
en o
f ch
ildbe
arin
g ag
eHigherserum
folatelevelsinthepost-fortificationthanpre-fortification
period;
lowerplasmahomocysteinelevelsinthepost-fortificationthanpre-
fortificationperiod;
j
prev
alen
ce o
f low
seru
m fo
late
and
hig
h pl
asm
a ho
moc
yste
ine
low
er in
post-fortificationthanpre-fortificationperiod
Iran
Sadighiet al.
2009
Ironk
Serumferritin;
hemoglobin;low
serumferritin;
anem
ia;iron-
deficiencyanem
ia
Wom
en o
f ch
ildbe
arin
g ag
eHigherserum
ferritinlevelsinthepost-fortificationthanpre-fortification
perio
d, lo
wer
hem
oglo
bin
leve
lse inthepost-fortificationthanpre-
fortificationperiod;
prevalenceoflow
serumferritinlowerinpost-fortificationthanpre-
fortificationperiod;prevalenceofanemia
e andiron-deficiencyanemia
e higherinpost-fortificationthanpre-fortificationperiod
USA
aCDC2003;
Dietrichet al.
2005;Pfeiffer
et al.2012,
2019
Folic
aci
dSe
rum
fola
te (a
ll studies);
RBCfolate(all
studies);low
se
rum
fola
te
(Dietrichet al.
2005;Pfeiffer
et al.2012);
lowRBC
folate
(Dietrichet al.
2005;Pfeiffer
et al.2012)
Chi
ldre
n (P
feiff
er
et al.2012,2019)
Adults(Dietrich
et al.2005;
Pfeifferet al.
2012
, 201
9)Ad
ult w
omen
(CDC2003)
Higherserum
andRBC
folatelevelsinthepost-fortificationthanpre-
fortificationperiod;
prevalenceoflow
serumfolateandlowRBC
folatelowerinpost-
fortificationthanpre-fortificationperiod
USA
aMillset al.2003;
Qiet al.2014
Folic
aci
dM
aski
ng o
f vitaminB12
deficiency
Old
er a
dults
with
bo
th lo
w v
itam
in
B12status(or
vitaminB12
deficiency)and
no a
nem
ia (o
r m
acro
cyto
sislb
)
Prevalenceoflow
vitaminB12statusandnoanem
iathesamein
thepre-andpost-fortificationperiods;noevidenceofm
asking;m
prevalenceofvitaminB12deficiencyandnoanem
ia(orm
acrocytosis)
thesame(orlow
er)inpost-fortificationthanpre-fortificationperiod;no
evid
ence
of m
aski
ngm
(Con
tinue
d)
Wheat flour fortification and human health32
Published by Burleigh Dodds Science Publishing Limited, 2021.
USA
aMasonet al.
2007
Folic
aci
dIn
cide
nce
of
colo
rect
al c
ance
rAl
l age
sIncidenceofcolorectalcancerhigherinpost-fortificationthanpre-
fortificationperiode
Venezuelaa
Layrisseet al.
1996
, 200
2Iro
nmSe
rum
ferr
itin
(bothstudies);
low
seru
m fe
rriti
n (bothstudies);
anem
ia (b
oth
studies);iron-
deficiencyanem
ia
(Layrisseet al.
1996
)
Chi
ldre
n an
d ad
oles
cent
sHigherserum
ferritinlevelsinthepost-fortificationthanpre-fortification
period(bothstudies);prevalenceoflowserumferritinandanem
ia
lowerinpost-fortificationthanpre-fortificationperiod(Layrisseet al.
1996);nodifferenceinprevalenceoflowserumferritinoranemiain
post-fortificationandpre-fortificationperiod(Layrisseet al.2002);no
differenceinprevalenceofiron-deficiencyanemiainpost-fortification
andpre-fortificationperiod(Layrisseet al.1996)
NTDs,neuraltubedefects;RBC
,redbloodcell
a Wheatflourw
astheonlygrainfortifiedwithoneorm
orenutrientsinmostcountries.Wheatandmaizeflourw
erefortifiedwithnutrientsinBrazil,CostaRica(in
additiontoriceandmilk),theUSA(inadditiontorice)andVenezuela;theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbe
disc
erne
d w
ith th
is st
udy.
b Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
c Som
e of
the
heal
th o
utco
mes
mea
sure
the
conc
entra
tion
of n
utrie
nts o
r oth
er co
nstit
uent
s in
the
bloo
d or
bre
astm
ilk a
nd so
me
refe
r to
the
prev
alen
ce (i
.e. p
erce
ntag
e of
peo
ple
who
hav
e th
e co
nditi
on),
the
inci
denc
e (i.
e. n
umbe
r of p
eopl
e ne
wly
dia
gnos
ed w
ith th
e co
nditi
on),
or d
eath
s (i.
e. n
umbe
r of p
eopl
e w
ho d
ie d
ue to
the
cond
ition
).d ‘
Plas
ma
hom
ocys
tein
e co
ncen
tratio
n in
crea
ses w
hen
inad
equa
te q
uant
ities
of f
olat
e ar
e av
aila
ble
to d
onat
e th
e m
ethy
l gro
up th
at is
requ
ired
to co
nver
t hom
ocys
tein
e to
met
hion
ine’
(Ins
titut
e of
Med
icin
e 19
98).
Whe
n fo
late
leve
ls ar
e hi
gh, h
omoc
yste
ine
leve
ls ar
e us
ually
low
and
the
prev
alen
ce o
f peo
ple
with
hig
h ho
moc
yste
ine
leve
ls (e
.g. h
yper
hom
ocys
tein
emia
) are
usu
ally
low
. e T
his r
esul
t is t
he o
ppos
ite o
f wha
t is e
xpec
ted.
f Thepost-fortificationprevalenceofanemiawascom
paredtothepre-fortificationprevalenceofanemiaforpreschoolchildren(1)inthesamesoutheastregionofthe
coun
try a
s wel
l as (
2) o
ther
regi
ons o
f the
cou
ntry
. The
resu
lts w
ere
the
sam
e.
g For
this
stud
y fro
m C
amer
oon,
adj
uste
d re
sults
are
pre
sent
ed (n
ot u
nadj
uste
d re
sults
). h Adecreaseinsolubletransferrinreceptorlevelsreflectanimprovem
entinironstatus.
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ec In
divi
dual
s st
udie
dRe
sults
Tabl
e 6 Resultsforhealthoutcomesotherthanneuraltubedefectsfromstudieswheredifferentindividualsweremeasuredbeforeandafterw
heatflour
fortificationa
(Con
tinue
d)
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 33
i Theupw
ardtrendinChilemirrorstheincreaseindeathsduetocoloncancerevidentfrom1990to2003(Donosoet al.2006)–precedingtheintroductionof
fortificationwithfolicacidinthecountryin2000.
j Adecreaseinhom
ocysteinelevelsreflectsanimprovem
entinfolatestatus.
k WheatflourinIranisfortifiedwithtwonutrientsthatcontributetohem
oglobinsynthesis:ironandfolicacid(Sadighiet al.2008).
l Mac
rocy
tosis
mea
ns e
nlar
ged
red
bloo
d ce
lls.
mIftheprevalenceofindividualswithvitaminB12deficiency(orlow
vitaminB12status)andnoanem
ia(ornomacrocytosis)increasedbetweenthepreandpostfolic-
acidfortificationperiods,thatwouldbeevidenceoffortificationwithfolicacidmaskingofvitaminB12deficiency.
n WheatandmaizeflourinVenezuelaarefortifiedwithothernutrientsthatcontributetohem
oglobinsynthesis:iron,vitaminA,thiam
inandriboflavin(Layrisseet al.1996).
Wheat flour fortification and human health34
Published by Burleigh Dodds Science Publishing Limited, 2021.
60% reduction in neural tubedefects frompre- to post fortificationperiodssuggests that wheat flour fortification with folic acid improved a functionaloutcome.
The same study design was used to investigate potential negative health impacts of fortified food, such as cancer. Vollset et al. (2013) collated thenumberofcolorectaldeathsper100000populationintheUSAfrom1950to2010.Inthecountry,voluntaryfortificationofbreakfastcerealswithfolicacidbegan in 1973 andmandatory fortification of grainswith folic acid becameeffectivein1998. If fortificationwithfolicacidacceleratesdeathfromcancer,cancer deaths from 1973 (or 1998) until 2010 should increase. The data show the opposite trend for women and men: during this 60-year period, there was a declineincolorectalcancerdeaths.Theseresultssuggestthatfortificationwithfolic acid does not cause cancer deaths.
6.3 Results from cross-sectional studies in individual countries that assessed health outcomes and fortification exposure simultaneously
Cross-sectional studies are another type of design that can inform the health impact of a fortification program. Cross-sectional means that informationwas collected at one point of time only. These studies are especially useful in caseswherenopre-fortification information isavailable, so it isnotpossibleto complete a before-and-after study. Three countries have completed such studies (Table 8).
One example is from Oman where a one-time, cross-sectional survey was conducted in2004 (Grimmet al.2012).FerritinandC-reactiveproteinwereassessed in non-pregnant women of childbearing age. This information was usedtocalculatethepercentageofwomenwithirondeficiency,abiomarkerofironstatus.Familieswereaskedhowmuchwheatflourtheyconsumedintheprevious two months and the total number of individuals living or working in thehouseholdduringthistime.Additionally,wheatfloursamplesweretakenfromhomesandanalyzedforthepresenceoffortificantiron.Thisinformationwasusedtocalculate themonthlypercapitaconsumptionof fortifiedwheatflour.
The researchers then completed a dose-response analysis and found that the prevalence of iron deficiency was lowest in women whose householdsconsumedthehighestamountoffortifiedwheatflour:26.8%comparedwith38.8%.Theseresultsareinthedirectiononewouldexpectifflourfortifiedwithiron is being produced and consumed in the country. While the study design does not allowone to conclude that fortification caused a reduction in irondeficiency,theresultssuggestthatfortificationiscontributingtoimprovingtheiron status of women in Oman.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 35
Tabl
e 7 Resultsfrom
trendstudiesw
herehealthoutcomesweremeasuredmultipletimesafterw
heatflourfortificationbegana
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ec In
divi
dual
s stu
died
Resu
lts
Cana
daPersadet al.2002;
DeWalset al.2003;
Liuet al.2004;De
Walset al.2007
Folic
aci
dNeuraltubedefects
Livebirths,stillbirths
and
term
inat
ions
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
Cana
daFrenchet al.2003;
Gruppet al.2011
Folic
aci
dPe
diat
ric c
ance
rsC
hild
ren
less
than
17years(Frenchet al.
2003
)C
hild
ren
less
than
4years(Gruppet al.
2011
)
Prev
alen
ce o
f neu
robl
asto
ma
and
Wilm
s’ tumorlowerinpost-fortificationthan
pre-fortificationperiod;nodifferencein
the
prev
alen
ce o
f acu
te ly
mph
obla
stic
le
ukem
ia, h
epat
obla
stom
a, e
mbr
yona
l ca
ncer
s or b
rain
can
cers
bet
wee
n po
st- a
nd
pre-fortificationperiods
Cana
daIonescu-Ittuet al.
2009
Folic
aci
dCo
ngen
ital h
eart
dise
ase
Livebirths,stillbirths
Prev
alen
ce o
f con
geni
tal h
eart
dise
ased
lowerinpost-fortificationthanpre-
fortificationperiod
Cana
daYanget al.2006
Folic
aci
dSt
roke
dea
thAd
ults
40
year
s of a
ge
and
olde
rDecreaseindeathsfromstrokewasgreater
inthepost-fortificationperiod(−5.4%
annually)thanpre-fortificationperiod
(−1.0%
annually)
Jord
anAm
arin
and
Obe
idat
20
10Fo
lic a
cid
Neuraltubedefects
Livebirths
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
Om
anAlasfooret al.2010
Folic
aci
dSpinabifidae;non-spina
bifidaneuraltubedefects
fLivebirths
Prevalenceofspinabifidalowerinpost-
fortificationthanpre-fortificationperiod;
no d
iffer
ence
in th
e pr
eval
ence
of o
ther
, non-spina-bifidaNTDsbetweenpost-and
pre-fortificationperiods
(Con
tinue
d)
Wheat flour fortification and human health36
Published by Burleigh Dodds Science Publishing Limited, 2021.
Saud
i Ara
biaSafdaret al.2007
Folic
aci
dNeuraltubedefects
Livebirths
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
Tanz
ania
aNooret al.2017
Folic
aci
dPlasmafolate;
folatedeficiency
Wom
enH
ighe
r pla
sma
fola
te le
vels
in th
e po
st-
fortificationthanpre-fortificationperiod;
prevalenceoffolatedeficiencylowerin
post-fortificationthanpre-fortification
perio
dUSA
aVollsetet al.
2013;Keumand
Giovannucci2014;
Siegelet al.2019
Folic
aci
dCo
lore
ctal
can
cer i
ncid
ence
(K
eum
and
Gio
vann
ucci
2014;Siegelet al.2019)and
mortality(Vollsetet al.2013;
Keum
and
Gio
vann
ucci
2014;Siegelet al.2019);
brea
st c
ance
r inc
iden
ce a
nd
mortality(Siegelet al.2019)
All a
ges a
nd se
xes
(Siegelet al.2019)
Adults(Vollsetet al.
2013;Keumand
Gio
vann
ucci
201
4)
Inci
denc
e of
col
orec
tal c
ance
r dec
reas
ed
for w
omen
(fro
m 1
998
to 2
008)
, men
(fro
m
1998to2015)(Siegelet al.2019)andall
adul
ts (f
rom
197
5 to
200
9) (K
eum
and
Giovannucci2014);
inci
denc
e of
bre
ast c
ance
r dec
reas
ed fo
r wom
en(from1999to2004)(Siegelet al.
2019);
deat
h fro
m c
olor
ecta
l can
cer d
ecre
ased
in
wom
en a
nd m
en (f
rom
195
0 to
201
0)
(Vollsetet al.2013);
deat
h fro
m c
olor
ecta
l can
cer d
ecre
ased
in
bla
ck a
nd w
hite
wom
en a
nd m
en (f
rom
19
75 to
200
9) (K
eum
and
Gio
vann
ucci
2014);
deat
h fro
m c
olor
ecta
l can
cer d
ecre
ased
in
wom
en (f
rom
197
5 to
201
6) a
nd m
en (f
rom
1987to2016)(Siegelet al.2019);
deat
h fro
m b
reas
t can
cer d
ecre
ased
in
wom
en(from1990to2016)(Siegelet al.
2019
)
Coun
trySt
udy
Nutrient
bH
ealth
out
com
ec In
divi
dual
s stu
died
Resu
lts
Tabl
e 7 Resultsfrom
trendstudiesw
herehealthoutcomesweremeasuredmultipletimesafterw
heatflourfortificationbegana
(Con
tinue
d)
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 37
USA
aMathewset al.2002;
Williamset al.2002,
2005
, 201
5
Folic
aci
dNeuraltubedefects
Livebirths(allstudies),
still
birt
hs (W
illia
ms
et al.2002,2015),
feta
l dea
thsg (
Will
iam
s et al.2002,2005)and
term
inat
ions
(Will
iam
s et al.2002,2005,2015)
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
(Mathewset al.2002;W
illiamset al.
2002);forHispanicandnon-Hispanic
whites:prevalenceofNTDslow
erinpost-
fortificationthanpre-fortificationperiod
(Williamset al.2005);fornon-Hispanic
blac
ks: n
o di
ffere
nce
in p
reva
lenc
e of
NTDsbetweenpost-fortificationandpre-
fortificationperiods(W
illiamset al.2005)
USA
aYanget al.2006
Folic
aci
dSt
roke
dea
thAd
ults
40
year
s of a
ge
and
olde
rDecreaseindeathsfromstrokewasgreater
inthepost-fortificationperiod(−2.9%
annually)thanpre-fortificationperiod
(−0.3%
annually)
a Wheatflourw
astheonlygrainfortifiedwithfolicacidinmostcountries.Wheatandmaizeflourw
erefortifiedwithfolicacidinTanzaniaandtheUSA(inadditionto
rice);theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbediscernedwiththisstudy.
b Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
c Som
e of
the
heal
th o
utco
mes
mea
sure
the
conc
entra
tion
of n
utrie
nts o
r oth
er co
nstit
uent
s in
the
bloo
d or
bre
astm
ilk a
nd so
me
refe
r to
the
prev
alen
ce (i
.e. p
erce
ntag
e of
peo
ple
who
hav
e th
e co
nditi
on),
the
inci
denc
e (i.
e. n
umbe
r of p
eopl
e ne
wly
dia
gnos
ed w
ith th
e co
nditi
on),
or d
eath
s (i.
e. n
umbe
r of p
eopl
e w
ho d
ie d
ue to
the
cond
ition
). d S
ever
e co
ngen
ital h
eart
defe
cts
stud
ied
wer
e as
follo
ws:
‘tet
ralo
gy o
f Fal
lot,
endo
card
ial c
ushi
on d
efec
ts, u
nive
ntric
ular
hea
rts, t
runc
us a
rterio
sus,
or tr
ansp
ositi
on
com
plex
es’ (
Ione
scu-
Ittu
et a
l. 20
09).
e Spinabifidaisatypeofneuraltubedefect.
f Theotherneuraltubedefectsthatwerenotspinabifidawerenotspecified(Alasfooret al.2010).
g ‘Fe
tal d
eath
refe
rs to
the
spon
tane
ous i
ntra
uter
ine
deat
h of
a fe
tus a
t any
tim
e du
ring
preg
nanc
y. Fe
tal d
eath
s lat
er in
pre
gnan
cy (a
t 20
wee
ks o
f ges
tatio
n or
mor
e,
or28weeksorm
ore,forexample)arealsosometimesreferredtoasstillbirths.’(CDC2020).
Wheat flour fortification and human health38
Published by Burleigh Dodds Science Publishing Limited, 2021.
Tabl
e 8 Resultsfrom
cross-sectionalstudiesinindividualcountriesthatassessedhealthoutcomesandfortificationexposuresimultaneously.
Coun
trySt
udy
Nutrient
aH
ealth
out
com
eb In
divi
dual
s stu
died
Resu
lts
Om
anGrim
met al.
2012
Iron
Irondeficiency
Wom
en o
f ch
ildbe
arin
g ag
ePrevalenceofirondeficiencylowerinwom
enwhose
householdsconsumedthemostfortifiedwheatflour
com
pare
d w
ith h
ouse
hold
s who
pur
chas
ed th
e le
ast
fortifiedflour
Colo
mbi
aFothergillet al.
2019
Iron
Lowserumferritin
Wom
en o
f ch
ildbe
arin
g ag
e C
hild
ren
2–4
and
5–12
ye
ars
Prev
alen
ce o
f low
seru
m fe
rriti
n di
d no
t diff
er b
y intakeofwheatflour-containingfoods
Colo
mbi
aFothergillet al.
2019
Folic
aci
d, ir
on,
riboflavin,thiam
inAn
emia
Wom
en o
f ch
ildbe
arin
g ag
eC
hild
ren
2–4
and
5–12
ye
ars
Prev
alen
ce o
f ane
mia
was
low
est i
n ch
ildre
n 2–
4 ye
ars w
ho w
ere
in th
e hi
ghes
t qua
rtile
for i
ntak
e of
wheatflour-containingfoods;prevalenceofanemia
didnotdifferbyintakeofwheatflour-containing
food
sc for
wom
en a
nd c
hild
ren
5–12
yea
rsUzbekistan
Hundet al.
2013
dIro
nIro
n de
plet
ione
Wom
en o
f ch
ildbe
arin
g ag
ePr
eval
ence
of i
ron
depl
etio
n di
d no
t diff
er b
y householdpossessionofflourthatshouldbe
fortifiedfandbreadthatshouldbefortified
Uzbekistan
Hundet al.
2013
dFo
lic a
cid
Folatedeficiency
Wom
en o
f ch
ildbe
arin
g ag
ePrevalenceoffolatedeficiencywashigherin
householdspossessingflourthatshouldbe
fortified;
f,gprevalenceoffolatedeficiencywaslower
in h
ouse
hold
s pos
sess
ing
brea
d th
at sh
ould
be
fortified
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 39
Uzbekistan
Hundet al.
2013
dFo
lic a
cid,
iron
, riboflavin,thiam
in,
zinc
Anem
iaW
omen
of
child
bear
ing
age
Prev
alen
ce o
f ane
mia
did
not
diff
er b
y ho
useh
old
possessionofflourthatshouldbefortifiedf
and
breadthatshouldbefortified
a Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
b So
me
of t
he h
ealth
out
com
es m
easu
re t
he c
once
ntra
tion
of n
utrie
nts
or o
ther
con
stitu
ents
in t
he b
lood
or
brea
stm
ilk a
nd s
ome
refe
r to
the
pre
vale
nce
(i.e.
pe
rcen
tage
of p
eopl
e w
ho h
ave
the
cond
ition
), th
e in
cide
nce
(i.e.
num
ber o
f peo
ple
new
ly d
iagn
osed
with
the
cond
ition
), or
dea
ths (
i.e. n
umbe
r of p
eopl
e w
ho d
ie
due
to th
e co
nditi
on).
c Wheat-flourcontainingfoodsincludesfoodssuchasbread,pastaandcookies;thefortificationstatusoftheflourusedtomakethesefoodscouldnotbeconfirmed
(Fothergillet al.2019).
d TheunpublishedreportbyNorthrop-Cleweset al.(2013)containsthesameinformationasthispublishedarticle.
e Serum
ferritin<12 µg/L;insummarizingtheresultsinthischapter,thishealthoutcomewasclassifiedasirondeficiency.
f Whilethefortificationstatusofhouseholdwheatflourw
asmeasured(41.6%
offlourw
asfortified),theresearchersd
idnotcom
pareirondepletion,folatedeficiency
oranemiaprevalencebetweenhouseholdswithfortifiedflourandthosewithnon-fortifiedflour.
g Thi
s res
ult i
s the
opp
osite
of w
hat i
s exp
ecte
d.
Wheat flour fortification and human health40
Published by Burleigh Dodds Science Publishing Limited, 2021.
6.4 Other relevant evidence from individual countries
6.4.1 Result from cost-effectiveness studies in individual countries
Economistscomparethecostsofoperatingprograms,suchasfortification,withthe effectiveness of such programs. They do this at two time points: before a programhasstartedusinghypothesizedcostsandoutcomes(e.g.Dalzielet al.2009), and after a program has operated using actual costs and outcomes. The latter studies are described here.
Afterfortificationinitiation,threecountriescomparedthecostsofaddingfolicacidtoflour,thecostsoftreatingpeoplewithspinabifida,atypeofneuraltube defect, and the effectiveness of fortification in reducing neural tubedefects(Table9).Eachstudyshowedsignificantannualnetsavingsinhealthcareexpenseswhenspinabifidaispreventedthroughfortification:2.0–2.6millioninternationaldollars inChile (Llanoset al. 2007), 40.6millionRand inSouthAfrica(Sayedet al.2008)and88–603millionUSdollarsintheUSA(Grosseet al.2005,2016).Sincetheseareannualfigures,everyyearoffortificationleadstothese net savings.
6.4.2 Results from cross-sectional studies in individual countries that assessed health outcomes only in the post- fortification period
Asnotedearlier,someresearcherspublishonlypost-fortificationresults.Thesearerarelyinformativewithoutacomparisontopre-fortificationvalues.Table10lists studies highlighting an outcome for which there are no pre- and post-fortificationresults:folatedeficiencyforCanadaandfolate-deficiencyanemiafortheUSA.Inbothcases,thepost-fortificationprevalenceoftheseoutcomesis<1%suggestingthatfortificationwithfoliciscontributingtokeepingthesevalues low.
6.4.3 Results from modeling the health impact of wheat flour fortification in individual countries
With information from singles countries, it is possible to statistically model the healthimpactthatfortificationishaving(Table11).Ticeet al.(2001)modeledtheimpactofmandatoryfortificationofwheatflour,maizeflourandricewithfolic acid on myocardial infarctions (heart attacks) and death from coronary heartdisease(CHD)intheUSA.Usingconservativeassumptionsofhowmuchfortificationwouldreducehomocysteinelevels(i.e.by5µmol/L)andwhatthosereductions would be due to the risk of coronary heart disease (i.e. decrease by 9%),theyestimatedthatupto1%ofheartattacksanddeathsfromCHDcould
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 41
Table 9 Resultsfromcost-effectivenessstudiesinindividualcountriesthatassessedcostsandhealthoutcomesinthepost-fortificationperioda
Country Study NutrientbHealth outcomec
Individuals studied Results
Chile Llanoset al.2007
Folic acid Spinabifidad Livebirthsand fetal deathse weighing 500 g or more
Annual net savings in healthcare expenses whenspinabifidaisprevented through fortification:2.0–2.6million international dollars
South Africaa
Sayed et al.2008
Folic acid Spinabifidad Livebirthsand still births
Annual net savings in healthcare expenses when spina bifidaispreventedthroughfortification:40.6 millionRand
USAa Grosse et al.2005,2016
Folic acid Spinabifidad Livebirths Annual net savings in healthcare expenses when spina bifidaispreventedthroughfortification:88–145 millionUSdollars(Grosseet al.2005) and 299–603 millionUSdollars(Grosseet al.2016)
USAa Bentleyet al.2009
Folic acid Neuraltubedefects(NTDs);myocardial infarctions (MIs);coloncancer incidence;vitaminB12masking
Adults 15 years or older
Annual net savings throughfortificationat current levels (140 µg/100 g)whenNTDs,MIsandcoloncancer are averted and when masking ofB12deficiencyoccurs:780.5 millionUSdollars
aWheatflourwastheonlygrainfortifiedwithfolicacidinChile.WheatandmaizeflourwerefortifiedwithfolicacidinSouthAfricaandtheUSA(inadditiontorice);theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbediscernedwiththisstudy.bNutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.c Some of the health outcomes measure the concentration of nutrients or other constituents in the blood or breastmilk and some refer to the prevalence (i.e. percentage of people who have the condition), the incidence (i.e. number of people newly diagnosed with the condition), or deaths (i.e. number of people who die due to the condition). dSpinabifidaisatypeofneuraltubedefect.e ‘Fetal death refers to the spontaneous intrauterine death of a fetus at any time during pregnancy. Fetal deaths later in pregnancy (at 20 weeks of gestation or more, or 28 weeks or more, for example) arealsosometimesreferredtoasstillbirths’(CDC2020).
Wheat flour fortification and human health42
Published by Burleigh Dodds Science Publishing Limited, 2021.
be prevented over a 10-year period. Using less-conservative assumptions(i.e. homocysteine levels reducedby11µmol/L andCHD reducedby29%),theyestimatedthatupto13%ofheartattacksanddeathsfromCHDcouldbeprevented over a 10-year period.
Table 10 Results from cross-sectional studies in individual countries that assessed healthoutcomesinthepost-fortificationperiodonlya
Country Study NutrientaHealth outcomeb
Individuals studied Results
Canada Colapinto et al.2011
Folic acid
Folate deficiency
Females and males 6–79 years
Prevalenceoffolatedeficiencyinthepost-fortificationperiodwas<1%
USAa Odewole et al. 2013
Folic acid
Folate deficiency,folate-deficiencyanemia
Adults 50 years and older
Prevalenceoffolatedeficiencyinthepost-fortificationperiodwas0.1%,prevalenceoffolate-deficiencyanemiainthepost-fortificationperiodwas0.1%
aWheatflourwastheonlygrainfortifiedwithfolicacidinCanada.WheatandmaizeflourandricewerefortifiedwithfolicacidintheUSA;theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomes cannot be discerned with this study. bNutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.c Some of the health outcomes measure the concentration of nutrients or other constituents in the blood or breastmilk and some refer to the prevalence (i.e. percentage of people who have the condition), the incidence (i.e. number of people newly diagnosed with the condition), or deaths (i.e. number of people who die due to the condition).
Table 11 Results frommodeling thehealth impactofwheatflour fortification for individualcountriesa
Study Country Nutrientb Health outcomecIndividuals studied Results
Tice et al.2001
USAa Folic acid Myocardial infarction incidence(MIs);coronary heart disease(CHD)deaths
Adults Cereal grain fortificationcould reduce MI incidenceandCHDdeathsby1–13%over a 10-year period
a In theUnitedStates,cerealgrains thatmustbefortifiedwith folicacid includewheatflour,maizeflourandrice(GlobalFortificationDataExchange2020d).Theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbediscernedwiththisstudy.bNutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.c Some of the health outcomes measure the concentration of nutrients or other constituents in the blood or breastmilk and some refer to the prevalence (i.e. percentage of people who have the condition), the incidence (i.e. number of people newly diagnosed with the condition), or deaths (i.e. number of people who die due to the condition).
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 43
6.5 Results from systematic reviews of multiple studies from multiple countries
Systematic reviews of the literature compare and contrast the health outcomes reported from multiple studies which can come from the same country but also often have information from different countries. Systematic reviews focused on wheatflourfortificationorthatincludewheatflourfortificationaresummarizedin Table 12.
Onesystematicreviewassessedtheimpactofflourfortificationwithfolicacid on neural tube defects (Castillo-Lancellotti et al. 2013). Twenty sevenstudieswereobtainedfromninecountries,ofwhichmostonlyfortifiedwheatflourwithfolicacid(Chile,Argentina,Canada,Iran,Jordan)andsomefortifiedmultiplefoodswithfolicacid(BrazilandSouthAfrica–wheatandmaizeflour;CostaRica–wheatandmaizeflour,rice,milk;USA–wheatflour,maizeflour,rice).Theauthorsconcludedthat‘Fortificationofflourwithfolicacidhashada major impact on [neural tube defects] in all countries where this has been reported.’
ThereviewbyvanGoolet al.(2018)wasdifficulttointerpret.Thedocumentreviewedevidencelinkingfolicacid(fromanysource,includingfortifiedfood)to positive outcomes such as decreasing neural tube defects and to negative outcomes such as masking vitamin B12 deficiency. There was no succinctsummary of each of the outcomes. Instead the authors concluded ‘the risks carriedbyahighdailyintakeoffolateequivalentsdonotoutweighthebenefitsof folic acid fortificationof staple foods, as longas concentrationsof serumun-metabolizedfolicacid,RBCfolate,andserumvitaminB12canbemonitoredperiodically’.
6.6 Results from meta-analyses of multiple studies from multiple countries
Meta-analyses go one step further from systematic reviews and take numeric results from multiple studies and re-analyze them, to come up with a new estimate of what the relationship is between fortification and the healthoutcome. As with systematic reviews, meta-analyses are completed with data from multiple studies and they can be from the same country, or, more often than not, from different countries (Table 13).
Keats et al. (2019) published ameta-analysis of 17 studies of which 16evaluatedanationalfortificationprogram.Inallcases,wheatandmaizeflourwerefortifiedwithfolicacidandthefortificationtookplacefor1–11years instudy countries. Several health outcomes were analyzed: serum folate, folate deficiencyandneuraltubedefects.Ineightstudieswith6765women,serumfolateincreasedby11.94nmol/Lfromthepre-tothepost-fortificationperiod.In
Wheat flour fortification and human health44
Published by Burleigh Dodds Science Publishing Limited, 2021.
Tabl
e 12 Resultsfrom
system
aticreviewsofm
ultiplestudiesfrommultiplecountriesthatevaluatedthehealthim
pactofwheatflourfortification
Stud
yCo
untri
es (n
)Nutrient
aH
ealth
out
com
eb In
divi
dual
s stu
died
Resu
lts
Assu
nção
and
San
tos 2
007
6Iro
nAn
emia
Chi
ldre
nPr
eval
ence
of a
nem
ia lo
wer
in p
ost-
fortificationthanpre-fortificationperiod
Castillo-Lancellottiet al.2013
9Fo
lic a
cid
Neuraltubedefects
(NTDs)
Differeddepending
on a
rticl
e re
view
edPrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
Pach
eco
Sant
os a
nd Z
anon
Pe
reira
200
7 5
Folic
aci
dNeuraltubedefectsLivebirths
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
Pachónet al.2015
13M
ultip
leIrondeficiency,
anem
iaC
hild
ren
and
wom
enPr
eval
ence
of l
ow fe
rriti
n lo
wer
in p
ost-
fortificationthanpre-fortificationperiod
forw
omen;
no d
iffer
ence
in th
e pr
eval
ence
of l
ow
ferritininpost-fortificationandpre-
fortificationperiodinchildren;
no d
iffer
ence
in th
e pr
eval
ence
of a
nem
ia
inpost-fortificationandpre-fortification
perio
d in
wom
en a
nd c
hild
ren
Rosenthalet al.2014
15Fo
lic a
cid
NeuraltubedefectsLivebirths
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
vanGoolet al.2018
Notspecified
Folic
aci
dM
ultip
leM
ultip
leNotclear
vanGoolet al.2020
Notspecified
Folic
aci
dCo
gniti
ve fu
nctio
nNotspecified
‘The
hyp
othe
sis th
at c
ogni
tive
impa
irmen
t in“subclinical”cyanocobalamindeficiency
is fo
late
-med
iate
d is
unte
nabl
e.’
a Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
b So
me
of t
he h
ealth
out
com
es m
easu
re t
he c
once
ntra
tion
of n
utrie
nts
or o
ther
con
stitu
ents
in t
he b
lood
or
brea
stm
ilk a
nd s
ome
refe
r to
the
pre
vale
nce
(i.e.
pe
rcen
tage
of p
eopl
e w
ho h
ave
the
cond
ition
), th
e in
cide
nce
(i.e.
num
ber o
f peo
ple
new
ly d
iagn
osed
with
the
cond
ition
), or
dea
ths (
i.e. n
umbe
r of p
eopl
e w
ho d
ie
due
to th
e co
nditi
on).
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 45
fourstudieswith4645women,theprevalenceofwomenwithfolatedeficiencydecreasedby80% from thepre- to thepost-fortificationperiod. Fromeightstudies with 19 million data points, the odds of a baby being born with neural tube defects declined by 41% between the pre- and the post-fortificationperiod.
The National Toxicology Program (2015) reviewed research assessingadverse health outcomes after consuming high levels of folate (whether from food sources, supplements containing folic acid or foods fortifiedwith folicacid). Four health outcomes were considered high priority (cancer, cognition, hypersensitivity, and thyroid- and diabetes-related disorders) and thus meta-analyseswereconducted.Insummary,96%of27milliondatapointsshowednorelationship between high folate and cancer, and for cognition, hypersensitivity (such as asthma) and thyroid- and diabetes-related disorders, results were ‘not supportive’ or ‘inconclusive’ of a relationship between these outcomes andhighfolate(Table13).Theeffectofwheatflourfortificationwithfolicacidcannot be isolated from these studies; however, these results suggest thathigh folate levels (independent of the source) are not associated with negative health outcomes.
Forotherhealthoutcomes,thatweredeemedlowerprioritybytheNationalToxicology Program, research results were briefly summarized in their 2015report. From these summaries, it is not clear what the folate source(s) were. Nevertheless, they consistently found no relationship between folate intakefrom any source and adverse health outcomes, as follows:
• Cardiovascular outcomes. ‘None of the 39 identified meta-analysesreported any adverse effects associated with folic acid intake.’
• Twinning and multiple births. ‘While it may be biologically plausible that periconceptional vitamin use plays a role in the incidence of multiple births, the available evidence has been well explored – the most recent human studyidentifiedwaspublishedin2006–sothiswasnotdeterminedtobea high priority topic for this review.’
• Autism. ‘Due toweaknesses in thedesignof studies reporting adverseeffects, the currently available literature did not support consideration of autism as a high priority outcome for this review.’
• Otherneurologicaloutcomes. ‘Noneof the10 identifiedmeta-analysesreported adverse effects of folic acid.’
• Other immunological outcomes. ‘The majority of other immunological outcomes which were not considered hypersensitive-related, such as autoimmune diseases, did not suggest any adverse effects of folic acid and were not considered a high priority category.’
• Other endocrine andmetabolic diseaseoutcomes. ‘Bodyweight, bodycomposition, and BMI constituted the largest group of studies (~50),
Wheat flour fortification and human health46
Published by Burleigh Dodds Science Publishing Limited, 2021.
Tabl
e 13 Resultsfrom
meta-analysesofm
ultiplebeforeandafterstudiesfrom
multiplecountriesthatevaluatedthehealthim
pactofwheatflourfortification
Stud
yCo
untri
es o
r st
udie
s (n)
Nutrient
aH
ealth
out
com
eb In
divi
dual
s stu
died
Resu
lts
Attaet al.2016
52 c
ount
ries
Folic
aci
dSpinabifidac
Livebirths;livebirths
andstillbirths;live
birth
s, st
ill b
irths
and
te
rmin
atio
ns
Prevalenceofspinabifidalowerin
countrieswithmandatoryfortificationthan
voluntaryfortification
Blencoweet al.
2010
6 co
untri
esFo
lic a
cid
Neuraltubedefects
Notspecified
PrevalenceofN
TDslow
erinpost-
fortificationthanpre-fortificationperiod
Daset al.2013
10 c
ount
ries
Folic
aci
dSerumfolate;neuraltube
defe
cts
Wom
en o
f re
prod
uctiv
e ag
eNodifferenceinserumfolatelevels
betweenpre-andpost-fortification
periods;prevalenceofNTDslow
erinpost-
fortificationthanpre-fortificationperiod
Keatset al.2019
12d c
ount
ries
Folic
aci
dSerumfolate;folate
deficiency;neuraltube
defe
cts
Livebirths;stillbirths
Hig
her s
erum
fola
te le
vels
in th
e po
st-
fortificationthanpre-fortificationperiod;
prevalenceoffolatedeficiencyandNTDs
lowerinpost-fortificationthanpre-
fortificationperiod
Millacuraet al.
2017
9 co
untri
esFo
lic a
cid
Oro
faci
al c
lefts
Tota
l birt
hsPr
eval
ence
of n
on-s
yndr
omic
cle
ft lip
with
or
with
out c
left
pala
te is
low
er in
pos
t-fortificationthanpre-fortificationperiod;
no d
iffer
ence
in to
tal o
rofa
cial
cle
fts, c
left
lip w
ith o
r with
out c
left
pala
te, c
left
pala
te,
non-
synd
rom
ic o
rofa
cial
cle
fts, a
nd n
on-
synd
rom
ic c
left
pala
te b
etw
een
pre-
and
post-fortificationperiods
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 47
National
Toxi
colo
gy
Prog
ram
201
5
43 p
oole
d an
d m
eta-
anal
ysis
stud
ies
Fola
tee
Canc
erNotspecified
From
27milliondatapoints,96%show
ed
no re
latio
nshi
p or
a p
rote
ctiv
e re
latio
nshi
p be
twee
n hi
gh fo
late
(int
ake
or b
lood
levels)andcancerand4%show
eda
harm
ful r
elat
ions
hip
betw
een
high
fola
te
(inta
ke o
r blo
od le
vels)
and
can
cer
National
Toxi
colo
gy
Prog
ram
201
5
28 st
udie
s and
2
met
a-an
alys
esf
Fola
tee
‘Cog
nitio
n in
con
junc
tion
withvitaminB12deficiency’
Adul
tsRe
sults
‘not
supp
ortiv
e’ o
f a re
latio
nshi
p be
twee
n hi
gh fo
late
and
cog
nitiv
e impairm
entinthepresenceofvitaminB12
deficiency
National
Toxi
colo
gy
Prog
ram
201
5
42 st
udie
s and
1
met
a-an
alys
isfFo
late
eH
yper
sens
itivi
ty (e
.g.
asth
ma,
ecz
ema)
All a
ge g
roup
sRe
sults
‘not
supp
ortiv
e’ o
r ‘in
conc
lusiv
e’
of a
rela
tions
hip
betw
een
high
fola
te a
nd
hype
rsen
sitiv
ityNational
Toxi
colo
gy
Prog
ram
201
5
72 st
udie
s and
1
met
a-an
alys
isfFo
late
eTh
yroi
d- a
nd d
iabe
tes-
rela
ted
diso
rder
s (e.
g.
insu
lin re
sista
nce,
m
etab
olic
synd
rom
e)
Resu
lts “n
ot su
ppor
tive”
of a
rela
tions
hip
betw
een
high
fola
te a
nd th
yroi
d or
di
abet
es-re
late
d di
sord
ers
a Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
b So
me
of t
he h
ealth
out
com
es m
easu
re t
he c
once
ntra
tion
of n
utrie
nts
or o
ther
con
stitu
ents
in t
he b
lood
or
brea
stm
ilk a
nd s
ome
refe
r to
the
pre
vale
nce
(i.e.
pe
rcen
tage
of p
eopl
e w
ho h
ave
the
cond
ition
), th
e in
cide
nce
(i.e.
num
ber o
f peo
ple
new
ly d
iagn
osed
with
the
cond
ition
), or
dea
ths (
i.e. n
umbe
r of p
eopl
e w
ho d
ie
due
to th
e co
nditi
on).
c Spinabifidaisatypeofneuraltubedefect.
d Studiesfrom
these12countriesdidnotallreportonthethreeoutcom
es:serum
folate,folatedeficiencyandneuraltubedefects.
e Researchersassessedhighlevelsoffolatefrom
anysource:non-fortifiedfood,supplem
entscontainingfolicacidorfoodsfortifiedwithfolicacid;theeffectofwheat
flourfortificationwithfolicacidcannotbeisolatedfromthisstudy(NationalToxicologyProgram2015).
f Unabletodow
nloadthemeta-analysisresultsfrom
thestudywebsite(https://hawcproject.org/assessment/67/downloads/;https://hawcproject.org/assessment/48
/dow
nloads/)(NationalToxicologyProgram2015).
Wheat flour fortification and human health48
Published by Burleigh Dodds Science Publishing Limited, 2021.
withonly2studiesreportinganysignificantrelationshipbetweenhigherfolate intake or level and increased body weight. No studies of folateand polycystic ovary syndrome or pancreatitis reported any adverse associations.’
• Otherreproductiveoutcomes.‘Noneofthe9meta-analysesreportedanadverse effect of folic acid, so reproductive effects were not considered a high priority category.’
• Mortality. ‘18 meta-analyses have been conducted for several mortality outcomes with a sufficient number of available studies (e.g. all-cause,cardiovascular, cancer, perinatal) and none report any statistically significantadversemeta-estimates.’
6.7 Results from modeling the health impact of wheat flour fortification for multiple countries
Withinformationfrommultiplecountries,itispossibletomodelfortification’shealth impact (Table 14). For example, researchers estimated how much of the neural tube defects that can be prevented with folic acid is being prevented through fortification of wheat and/ormaize flour with folic acid (Kancherlaet al. 2018). The investigatorsmodeled the impact of fortification on threegroups of countries: those with high prevention potential, because they have fortificationprograms inplace; thosewithnopreventionpotentialbecausethey have no fortification programs; and those with modest preventionpotentialbecausetheirfortificationprogramsdonothavehighcoverageorhigh-enough levels of folic acid to prevent neural tube defects. They estimated 50270birthdefectswerepreventedin2017whereflourwasfortifiedwithfolicacid.
6.8 Studies from multiple countries that did not assess the independent contribution of mandatorily fortified wheat flour
Additional systematic reviews and meta-analyses were completed that analyzed thehealth impactofmany fortified foodssimultaneously, includingwheat flour.However, theywerenot included in this chapter foroneof tworeasons(Table15).One,thewheatflourwasnotfortifiedaspartofthecountry’smandatory fortification program, but rather for the explicit purposes ofconducting the research project. Two, the results were presented combined, for allfoodstogether,anditwasnotpossibletoisolatethecontributionoffortifiedwheatflour.
For example, Best and colleagues (2011) reviewed the impact of foodsfortified with multiple micronutrients on many health outcomes including
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 49
Tabl
e 14 Resultsfrom
modelingthehealthim
pactofwheatflourfortification,aloneorincombinationwithmaizeflour,form
ultiplecountries
Stud
yCo
untri
es (n
)Nutrient
aH
ealth
out
com
eb In
divi
dual
s stu
died
Resu
lts
Youngbloodet al.2013
65Fo
lic a
cid
Neuraltubedefects
Livebirths
In2012,flourfortificationwithfolicacid
prevented25%ofneuraltubedefectsc
Arthet al.2016
58Fo
lic a
cid
Neuraltubedefects
Livebirths
In2015,flourfortificationwithfolicacid
prevented13.2%ofneuraltubedefectsc
Kancherlaet al.2018
59Fo
lic a
cid
Neuraltubedefects
Livebirths
In2017,flourfortificationwithfolicacid
prevented18%ofneuraltubedefectsc
a Nutrientaddedtowheatflourthroughfortificationwhichispurportedtoaffectthehealthoutcome.
b So
me
of t
he h
ealth
out
com
es m
easu
re t
he c
once
ntra
tion
of n
utrie
nts
or o
ther
con
stitu
ents
in t
he b
lood
or
brea
stm
ilk a
nd s
ome
refe
r to
the
pre
vale
nce
(i.e.
pe
rcen
tage
of p
eopl
e w
ho h
ave
the
cond
ition
), th
e in
cide
nce
(i.e.
num
ber o
f peo
ple
new
ly d
iagn
osed
with
the
cond
ition
), or
dea
ths (
i.e. n
umbe
r of p
eopl
e w
ho d
ie
due
to th
e co
nditi
on).
c The
se a
re th
e ne
ural
tube
def
ects
that
can
be p
reve
nted
by w
omen
hav
ing
optim
um b
lood
fola
te le
vels
arou
nd th
e tim
e of
conc
eptio
n, kn
own
as fo
lic a
cid
prev
enta
ble
spinabifidaandanencephaly.
Wheat flour fortification and human health50
Published by Burleigh Dodds Science Publishing Limited, 2021.
Table 15 Systematicreviewsormeta-analysesthatevaluatedwheatflourintheassessmentoffortification’shealthimpactandreasonforexclusionfromthischapter
Study Nutrienta Health outcomeb Reason for exclusionc
Athe et al. 2014 Iron Hemoglobin Effectofwheatflourcould not be isolated
Bestet al.2011 Multiple Multiple Flournotfortifiedpermandatoryfortificationprogram
Blacket al.2012 VitaminD VitaminDstatus Flournotfortifiedpermandatoryfortificationprogram
Castillo-Lancellottiet al.2012
Folic acid Breastcancerrisk Effectofwheatflourcould not be isolated
Chenet al.2014 Folic acid Breastcancerrisk Effectofwheatflourcould not be isolated
CentenoTablanteet al.2019
Folic acid Multiple Formoststudies,flournotfortifiedpermandatoryfortificationprogram
Eichleret al.2019 Multiple Multiple Formoststudies,flournotfortifiedpermandatoryfortificationprogram
Geraet al.2012 Iron Multiple Effectofwheatflourcould not be isolated
Ghanchiet al.2019 Iron Diarrhea Flournotfortifiedpermandatoryfortificationprogram
Hesset al.2016 Multiple Multiple Flournotfortifiedpermandatoryfortificationprogram
Hombaliet al.2019 VitaminA Multiple Effectofwheatflourcould not be isolated
Kennedyet al.2011 Folic acid Colorectal cancer Effectofwheatflourcould not be isolated
Menduet al.2019 VitaminA VitaminAstatus Effectofwheatflourcould not be isolated
O’Donnellet al.2008 VitaminD VitaminDstatus Effectofwheatflourcould not be isolated
Petryet al.2016 Iron, Zinc Multiple Effectofwheatflourcould not be isolated
Salamet al.2019 Multiple Multiple Effectofwheatflourcould not be isolated
Shahet al.2016 Zinc Multiple Flournotfortifiedpermandatoryfortificationprogram
Tamet al.2020 Multiple Multiple Effectofwheatflourcould not be isolated
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 51
nutritional status, growth and cognitive development. Of 12 studies included in theirreview,twoassessedtheimpactoffortifiedbiscuits.Bothofthesestudiesusedflourthatwasfortifiedtomeettheresearchers’scientificinterests;theflourwasnotfortifiedaccordingtothecountry’smandatoryfortificationprogram(orthe country did not have such a national program at that time).
7 Summary • The health impact of wheat flour fortification after large-scale
implementation in countries has been studied employing different study designs and in a diversity of health outcomes that span all age groups and many systems of the human body.
• Folicacidwas themost studiednutrient.Toa lesserextent, fortificationwithiron,vitaminB12andzincwasalsoexamined.
• The most studied outcomes were neural tube defects, cancer, folate status,folatedeficiency,anemia,irondeficiency,ironstatus,hemoglobinandiron-deficiencyanemia.
• Foralloftheseoutcomesexceptiron-deficiencyanemia,themajorityofstudies showed improvements after fortification. That is, these studiessuggest that fortification reduces neural tube defects, cancer, folatedeficiency, anemia, and iron deficiency, and that fortification improvesfolate status, iron status, and hemoglobin levels.
• For some of the outcomes (cancer, anemia, hemoglobin, folate deficiency),therewerestudiesthatindicatedhealthoutcomesworsenedafterfortification.Theseanalysessuggestthatcancer,anemiaandfolatedeficiencyincreasedandhemoglobinlevelsdecreasedafterfortification.
• Discrepantvaluesforcancermaybeduetothedifferenceinyearssincefortificationwas initiated (e.g. increased incidenceofcoloncancerafterfortificationissuggestedbystudiespublishedinthe2000s;theopposite
Study Nutrienta Health outcomeb Reason for exclusionc
Tioet al.2014 Folic acid Breastcancerrisk Effectofwheatflourcould not be isolated
Yanget al.2016 Folic acid Multiple Effectofwheatflourcould not be isolated
aNutrientaddedtofoodsthroughfortificationwhichispurportedtoaffectthehealthoutcome.b Some of the health outcomes measure the concentration of nutrients or other constituents in the blood or breastmilk and some refer to the prevalence (i.e. percentage of people who have the condition), the incidence (i.e. number of people newly diagnosed with the condition), or deaths (i.e. number of people who die due to the condition). cReasonwhytheresearchwasexcludedfromthischapter:(1)thewheatflourwasnotfortifiedunderthe rubric of the country’smandatory fortification program and/or (2) the results were presentedcombinedforallfortifiedfoodsandtheindependentcontributionoffortifiedwheatflourcouldnotbe isolated.
Wheat flour fortification and human health52
Published by Burleigh Dodds Science Publishing Limited, 2021.
is observed in studies published in the 2010s) or by the sample size in studies (e.g. increased breast cancer incidence after fortification isobserved in studieswith sample sizes<2000; studies thatobservednodifferenceoradecreasedincidenceafter fortificationhavesamplesizes>2000 and going into the millions).
• Discrepant values for anemia and hemoglobin may be due to the (1)existence of non-nutritional causes of anemia which cannot be addressed by fortification, (2) nutritional causes of anemia not addressed byfortificationbecausea limitednumberofnutrientswereaddedthroughfortificationand(3)levelsofnutrientsorfortificationcompoundsusedinfortificationdonotfollowinternationalguidelines.
• Many more outcomes were studied which only have results for four or fewer analyses: folate-deficiency anemia, homocysteine status,high homocysteine, vitamin B12 deficiencymasking, congenital heartdisease, coronary heart disease, stroke, myocardial infarction, cognitive function, hypersensitivity, thyroid- and diabetes-related disorders, orofacial clefts, vitamin B12 status, vitamin B12 deficiency, zinc statusandzincdeficiency.
• Homocysteine status, high homocysteine, stroke death, myocardial infarction,orofacialclefts,vitaminB12status,vitaminB12deficiency,zincstatusandzincdeficiencytrendtowardimprovementafterfortification.
• Vitamin B12 deficiency masking and cognitive function trend towardshowingnodifferencebeforeandafterfortification.
• Noneoftheoutcomeswithtwo,threeorfouranalysesshowsaworseningofhealthafterfortification.
• While none of the study designs employed can be used to confirma causal relationship between fortification and health outcomes, thepreponderance of the evidence suggests that wheat flour fortificationimproves many health outcomes.
• Because fortification may also be associated with negative healthoutcomes such as cancer, health monitoring should continue to assess theseoutcomesincountrieswithfortification.
8 Future trends in researchProgram decision makers are urged to consider several actions that can facilitatethehealthimpactevaluationoftheirflourfortificationprograms:
• Plan for health impact evaluations while planning for the implementation offortification.
• Useexistingdataordata-collectionsystemstoevaluatethehealthimpactoffortificationatlowercostthanplanningastand-alonefortificationevaluation.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 53
• Regularly reviewall kindsof informationon the fortificationprogram todetermine if it is likely to be having health impact, such as intake, coverage and compliance. And, review this information before proceeding with an impact evaluation.
• Craft program impact pathways to document the plausibility that fortificationcontributedtothehealthoutcomeobserved.
• Makefortificationinformationpubliclyavailableforscrutinybyinterestedparties.
• Ensure that multiple programs (such as fortification, supplementation,micronutrient powders, biofortification) are not providing an excessof nutrients to the population. If they are, review and adjust programs accordingly.
• Continuetoassessforpotentialnegativehealthoutcomesoffortification.This is especially important for outcomes that may take years or decades to manifest, such as cancer.
9 Where to look for further information9.1 World Health Organization guidelines
The World Health Organization (WHO) offers several guidelines related to food fortificationgenerallyandwheatflourfortificationspecifically.
WHO’swebsiteonwheatflourfortification.
WHO. e-Library of Evidence for NutritionActions (eLENA): fortification ofwheatflour.https://www.who.int/elena/titles/wheat-flour-fortification/en/.
WHOandFAO’sbookwithbasicprinciplesoffoodfortification.
WHO and FAO. (2006). Guidelines on food fortification with micronutrients.https :/ /ww w .who .int/ nutri tion/ publi catio ns /mi cronu trien ts /92 41594 012 /e n/.
WHO’srecommendationsforwheatandmaizeflourfortification.
WorldHealthOrganization,FoodandAgricultureOrganizationoftheUnitedNations, the United Nations Children’s Fund, Global Alliance for FoodFortification,Micronutrient Initiative,and theFoodFortification Initiative.(2009).Recommendationsonwheatandmaizeflourfortification.Meetingreport: interim consensus statement. https :/ /ww w .who .int/ nutri tion/ publi cations/micronutrients/wheat_maize_fortification/en/.
Special issue of the Food and Nutrition Bulletin journal that summarizesthe evidence that generated WHO’s 2009 recommendations.
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(2010).Theopportunityofflourfortification:buildingontheevidencetomove forward. https :/ /jo urnal s .sag epub. com /t oc /fn ba /3 1 /1 _su ppl1.
9.2 Flour Millers toolkit
TheFoodFortificationInitiativeprovidesbasicspecificationsforfortifyingflourat the wheat mill.FoodFortificationInitiative.FlourMillersToolkitforimplementingwheatandmaize flour fortification. http://www.ffinetwork.org/tools_training/flour_mil lers_ toolk it .ht ml.
9.3 Best practices for foundational fortification documents
Areviewofbestpracticesforfortificationlegislationandstandarddocumentsand monitoring protocols and an assessment of how closely countries with mandatory fortificationofwheatflour,maizeflourand rice follow thesebestpractices. Marks,K.J.et al. (2018),Reviewofgrainfortification legislation,standards,
and monitoring documents. https :/ /ww w .ghs pjour nal .o rg /co ntent /6 /2/ 356.
9.4 Government monitoring of fortification
Monitoring by governments is essential to ensure flour is adequately andconsistently fortified. This document provides guidance on the minimumelements that should be included in a country’s monitoring plan. GlobalAllianceforImprovedNutritionandProjectHealthyChildren.(2018).
Regulatorymonitoring of national food fortification programs:A policyguidancedocument.https://fortificationdata.org/resources/.
9.5 Country statistics on wheat flour fortification
These can be found at two websites:
GlobalFortificationDataExchange.https://fortificationdata.org.FoodFortificationInitiative.http://www.ffinetwork.org.
9.6 Book on food fortification
Arecentlypublishedbookonfortificationoffersover40chaptersondifferentaspectsoffoodfortification,includinghealthimpactevaluations.
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Mannar,M.G.V.andHurrell,R.F. (2018),Food fortification inaglobalizedworld. https://www.elsevier.com/books/food-fortification-in-a-globalized-worl d /man nar /9 78 -0- 12 -80 2861- 2.
10 ReferencesAbdollahi,Z.,Elmadfa,I.,Djazayery,A.,Golalipour,M.J.,Sadighi,J.,Salehi,F.andSharif,
S.S.(2011).Efficacyofflourfortificationwithfolicacidinwomenofchildbearingagein Iran, Ann. Nutr. Metab. 58(3), 188–96.
Alasfoor,D.,Elsayed,M.K.andMohammed,A.J.(2010).SpinabifidaandbirthoutcomebeforeandafterfortificationofflourwithironandfolicacidinOman,East. Mediterr. Health J. 16(5), 533–8.
Allen,L.H.,Miller,J.W.,deGroot,L.,Rosenberg,I.H.,Smith,A.D.,Refsum,H.andRaiten,D.J.(2018).BiomarkersofNutritionforDevelopment(BOND):vitaminB-12review,J. Nutr. 148(suppl_4), 1995S–2027S.
Amarin,Z.O.andObeidat,A.Z.(2010).Effectoffolicacidfortificationontheincidenceofneural tube defects, Paediatr. Perinat. Epidemiol. 24(4),349–51.
Arth,A.,Kancherla,V.,Pachón,H.,Zimmerman,S.,Johnson,Q.andOakley,G.P.Jr.(2016).A2015globalupdateonfolicacid-preventablespinabifidaandanencephaly,Birth Defects Res. A 106(7), 520–9.
Assunção, M. C. F. and Santos, I. S. (2007). Effect of food fortification with iron onchildhoodanemia:a reviewstudy [Efeitoda fortificaçãodealimentoscom ferrosobre anemia em crianças: um estudo de revisão], Cad. Saúde Pública 23(2), 269–81.
Assunção,M.C.,Santos,I.S.,Barros,A.J.,Gigante,D.P.andVictora,C.G.(2007).Effectof ironfortificationofflouronanemiainpreschoolchildreninPelotas,Brazil,Rev. Saude Publ. 41(4), 539–48.
Assunção, M. C., Santos, I. S., Barros, A. J., Gigante, D. P. and Victora, C. G. (2012).Flour fortificationwith ironhasno impactonanaemia inurbanBrazilianchildren,Public Health Nutr. 15(10), 1796–801. Erratum in: Public Health Nutr. (2013) 16(1), 188.
Athe,R.,Rao,M.V.andNair,K.M.(2014).Impactofiron-fortifiedfoodsonHbconcentrationin children (<10 years): a systematic review and meta-analysis of randomized controlled trials, Public Health Nutr. 17(3), 579–86.
Atta, C.A., Fiest, K.M., Frolkis,A. D., Jette, N., Pringsheim,T., StGermaine-Smith, C.,Rajapakse, T., Kaplan, G. G. and Metcalfe, A. (2016). Global birth prevalence of spina bifidabyfolicacidfortificationstatus:asystematicreviewandmeta-analysis,Am. J. Public Health 106(1), e24–34.
Avagliano, L., Massa, V., George, T. M., Qureshy, S., Bulfamante, G. P. and Finnell,R. H. (2018). Overview on neural tube defects: from development to physical characteristics, Birth Defects Res. 111(19), 1455–67.
BarbozaArgüello,M. P. andUmañaSolís, L.M. (2011). ‘Impactode la fortificacióndealimentos con ácido fólico en los defectos del tubo neural en Costa Rica’, Rev. Panam. Salud Publica.., 30(1), 1–6.
Barboza Argüello, M. L., Umaña-Solís, L. M., Azofeifa, A., Valencia, D., Flores, A. L.,Rodríguez-Aguilar,S.,Alfaro-Calvo,T.andMulinare,J.(2015).Neuraltubedefects
Wheat flour fortification and human health56
Published by Burleigh Dodds Science Publishing Limited, 2021.
in Costa Rica, 1987–2012: origins and development of birth defect surveillance and folicacidfortification,Matern. Child Health J. 19(3), 583–90.
Bauernfeind,J.C.andDeRitter,E.(1991).Foodsconsideredfornutrientaddition:cerealgrainproducts.In:Bauernfeind,J.C.andLachance,P.A.(Eds)Nutrient Additions to Food: Nutritional, Technological and Regulatory Aspects.Food&NutritionPress,Inc,Trumbull, pp. 143–209.
Beckett,E.L.,Martin,C.,Boyd,L.,Porter,T.,King,K.,Niblett,S.,Yates,Z.,Veysey,M.andLucock, M. (2017). Reduced plasma homocysteine levels in elderly Australiansfollowing mandatory folic acid fortification—a comparison of two cross-sectionalcohorts, J. Nutr. Intermed. Metab. 8, 14–20.
Bentley,T.G.,Weinstein,M.C.,Willett,W.C.andKuntz,K.M.(2009).Acost-effectivenessanalysisoffolicacidfortificationpolicyintheUnitedStates,Public Health Nutr. 12(4), 455–67.
Berry, R. J. (2019). Lack of historical evidence to support folic acid exacerbation ofthe neuropathy caused by vitamin B12 deficiency, Am. J. Clin. Nutr. 110(3), 554–61.
Best,C.,Neufingerl,N.,DelRosso,J.M.,Transler,C.,vandenBriel,T.andOsendarp,S.(2011).Canmulti-micronutrientfood fortification improvethemicronutrientstatus,growth, health, and cognition of schoolchildren? a systematic review,Nutr. Rev. 69(4), 186–204.
Bidondo,M.P.,Liascovich,R.,Barbero,P.andGroisman,B.(2015).PrevalenciadedefectosdeltuboneuralyestimacióndecasosevitadosposfortificaciónenArgentina,Arch. Argent. Pediatr. 113(6), 498–501.
Black,L.J.,Seamans,K.M.,Cashman,K.D.andKiely,M.(2012).Anupdatedsystematicreview and meta-analysis of the efficacy of vitamin D food fortification, J. Nutr. 142(6), 1102–8.
Blencowe,H., Cousens,S., Modell,B.and Lawn,J.(2010).Folicacidtoreduceneonatalmortality from neural tube disorders, Int. J. Epidemiol. 39 (Suppl. 1), i110–21.
Blencowe,H.,Kancherla,V.,Moorthie,S.,Darlison,M.W.andModell,B.(2018).Estimatesof global and regional prevalence of neural tube defects for 2015: a systematic analysis, Ann. N.Y. Acad. Sci. 1414(1), 31–46.
Botto, L.D., Lisi,A.,Bower,C.,Canfield,M.A.,Dattani,N.,DeVigan,C.,DeWalle,H.,Erickson,D. J., Halliday, J., Irgens, L.M., Lowry, R. B.,McDonnell, R.,Metneki, J.,Poetzsch, S., Ritvanen, A., Robert-Gnansia, E., Siffel, C., Stoll, C. and Mastroiacovo, P. (2006). Trends of selected malformations in relation to folic acid recommendations and fortification: an international assessment, Birth Defects Res. A 76(10), 693–705.
Britto,J.C.,Cançado,R.andGuerra-Shinohara,E.M. (2014).Concentrationsofbloodfolate in Brazilian studies prior to and after fortification of wheat and cornmeal(maizeflour)withfolicacid:areview,Rev. Bras. Hematol. Hemoter. 36(4), 275–86.
Brown,R.D.,Langshaw,M.R.,Uhr,E.J.,Gibson,J.N.andJoshua,D.E.(2011).Theimpactofmandatory fortificationof flourwith folic acidon theblood folate levelsof anAustralian population, Med. J. Aust. 194(2), 65–7.
Castilla,E.E.,Orioli,I.M.,Lopez-Camelo,J.S.,daGracaDutra,M.andNazer-Herrera,J.andfortheECLAMC:LatinAmericanCollaborativeStudyofCongenitalMalformations.(2003). Preliminary data on changes in neural tube defect prevalence rates after folic acidfortificationinSouthAmerica,Am. J. Med. Genet. A 123A(2), 123–8.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 57
Castillo-Lancellotti,C.,Tur,J.A.andUauy,R.(2012).Folatosyriesgodecáncerdemama:revisiónsistemática[Folateandbreastcancerrisk:asystematicreview],Rev. Med. Chil. 140(2), 251–60.
Castillo-Lancellotti,C.,Tur,J.A.andUauy,R. (2013). Impactof folicacidfortificationofflouronneuraltubedefects:asystematicreview,Public Health Nutr. 16(5), 901–11. Erratum in: Public Health Nutr. (2013) 16(8), 1527.
Centeno Tablante, E., Pachón, H., Guetterman, H. M. and Finkelstein, J. L. (2019).Fortificationofwheatandmaizeflourwithfolicacidforpopulationhealthoutcomes,Cochrane Database Syst. Rev.7(7),CD012150.
CentersforDiseaseControlandPrevention.(2003).Folatestatusinwomenofchildbearingage,byrace/ethnicity-Unitedstates,1999–2000,M.M.W.R. Morb. Mortal. Wkly. Rep. 51, 808–10.
CentersforDiseaseControlandPrevention.(2004).Spinabifidaandanencephalybeforeandafterfolicacidmandate-UnitedStates,1995–1996and1999–2000,M.M.W.R. Morb. Mortal. Wkly. Rep. 53(17), 362–5.
CentersforDiseaseControlandPrevention.(2020).Fetaldeaths.Availableat:https://www.cdc.gov/nchs/nvss/fetal_death.htm;Accessed10May2020.
Chaparro, C. M. and Suchdev, P. S. (2019). Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries, Ann. N.Y. Acad. Sci. 1450(1), 15–31.
Chen, P., Li, C., Li, X., Li, J., Chu, R. andWang,H. (2014).Higher dietary folate intakereduces the breast cancer risk: a systematic review and meta-analysis, Br. J. Cancer 110(9), 2327–38.
Colapinto,C.K.,O’Conner,D.L.andTremblay,M.S.(2011).Folatestatusofthepopulationin the Canadian Health Measures Survey, C.M.A.J. 183(2), E100–6.
Corral,S.E.,Moreno,S.R.,Pérez,G.G.,Ojeda,B.M.E,Valenzuela,G.H.,Reascos,M.M.andSepúlvedaL.W.(2006).Defectoscongénitoscráneo-encefálicos:variedadesyrespuestaalafortificacióndelaharinaconácidofólico,Rev. Méd. Chile 134(9), 1129–34.https://scielo.conicyt.cl/scielo.php?script=sci_arttext&pid=S0034-98872006000 900007
Cortés,F.,Mellado,C.,Pardo,R.A.,Villarroel,L.A.andHertrampf,E.(2012).Wheatflourfortificationwithfolicacid:changesinneuraltubedefectsratesinChile,Am. J. Med. Genet. A 158A(8), 1885–90.
Costa,C.A.,Machado,E.H.,Colli,C.,Latorre,W.C.andSzarfarc,S.C.(2009).[Anemiain pre-school children attending day care centers of São Paulo: perspectives of the wheatandmaizeflourfortification],Nutrire 34(1), 59–74.
Czeizel, A. E. and Dudás, I. (1992). Prevention of the first occurrence of neural-tubedefects by periconceptional vitamin supplementation, N. Engl. J. Med. 327(26), 1832–5.
Dalziel,K.,Segal,L.andKatz,R.(2009).Cost-effectivenessofmandatoryfolatefortificationv. other options for the prevention of neural tube defects: results from Australia and NewZealand,Public Health Nutr. 13(4), 566–78.
Das,J.K.,Salam,R.A.,Kumar,R.andBhutta,Z.A. (2013).Micronutrient fortificationof food and its impact on woman and child health: a systematic review, Syst. Rev. 2, 67.
DeWals,P.,Rusen,I.D.,Lee,N.S.,Morin,P.andNiyonsenga,T.(2003).TrendinprevalenceofneuraltubedefectsinQuebec,Birth Defects Res. A 67(11), 919–23.
Wheat flour fortification and human health58
Published by Burleigh Dodds Science Publishing Limited, 2021.
DeWals,P.,Tairou,F.,VanAllen,M.I.,Uh,S.H.,Lowry,R.B.,Sibbald,B.,Evans,J.A.,VandenHof,M.C.,Zimmer,P.,Crowley,M.,Fernandez,B.,Lee,N.S.andNiyonsenga,T.(2007).Reductioninneural-tubedefectsafterfolicacidfortificationinCanada,N. Engl. J. Med. 357(2), 135–42.
Dietrich, M., Brown, C. J. P. and Block, G. (2005). The effect of folate fortification ofcereal-grain products on blood folate status, dietary folate intake, and dietary folate sourcesamongadultnon-supplementusersintheUnitedStates,J. Am. Coll. Nutr. 24(4), 266–74.
DonosoD,A.,Villarroeldel,P.L.andPinedo,M.G.(2006).AumentodelamortalidadporcáncerdecolonenChile,1990–2003,Rev. Méd. Chile 134(2), 152–8.
Eichler, K., Hess, S., Twerenbold, C., Sabatier, M., Meier, F. and Wieser, S. (2019). Health effects ofmicronutrient fortifieddairy products and cereal food for children andadolescents: a systematic review, PLoS ONE 14(1), e0210899.
Engle-Stone,R.,Nankap,M.,Ndjebayi,A.O.,Allen,L.H.,Shahab-Ferdows,S.,Hampel,D.,Killilea,D.W.,Gimou,M.M.,Houghton,L.A.,Friedman,A.,Tarini,A.,Stamm,R.A.andBrown,K.H.(2017),Iron,zinc,folate,andvitaminB-12statusincreasedamongwomenandchildren inYaoundéandDouala,Cameroon,1yearafter introducingfortifiedwheatflour,J. Nutr. 147, 1–11.
Enquobahrie,D.A.,Feldman,H.A.,Hoelscher,D.H.,Steffen,L.M.,Webber,L.S.,Zive,M.M.,Rimm,E.B.,Stampfer,M.J.andOsganian,S.K.(2012),. ‘SerumhomocysteineandfolateconcentrationsamongaUScohortofadolescentsbeforeandafterfolicacidfortification’,Public Health Nutr., 15(10), 1818-–26.
Food Fortification Initiative. (2020). 2019 Annual Report. Food Fortification Initiative,Atlanta.
Fothergill, A., Fonseca Centeno, Z. Y., Ocampo Téllez, P. R. and Pachón, H. (2019).Consumptionoffortifiedwheatflourandassociationswithanemiaandlowserumferritin in Colombia, Perspect. Nutr. Hum. 21(2), 159–71.
French,A.E.,Grant,R.,Weitzman,S.,Ray,J.G.,Vermeulen,M.J.,Sung,L.,Greenberg,M.andKoren,G.(2003).Folicacidfoodfortificationisassociatedwithadeclineinneuroblastoma, Clin. Pharmacol. Ther. 74(3), 288–94.
Fujimori,E.,Sato,A.P.,Szarfarc,S.C.,Veiga,G.V.,Oliveira,V.A.,ColliC,Moreira-Araújo,R.S.,Arruda,I.K.,Uchimura,T.T.,Brunken,G.S.,Yuyama,L.K.,Muniz,P.T.,Priore,S.E., Tsunechiro, M. A., Frazão, A. d., Passoni, C. R. and Araújo, C. R. (2011). Anemia in Brazilianpregnantwomenbeforeandafterflourfortificationwithiron,Rev. Saude Publ. 45(6), 1027–35.
Gera,T.,Sachdev,H.S.andBoy,E.(2012).Effectofiron-fortifiedfoodsonhematologicand biological outcomes: systematic review of randomized controlled trials, Am. J. Clin. Nutr. 96(2), 309–24.
Ghanchi, A., James, P. T. and Cerami, C. (2019). Guts, germs, and iron: a systematic review on iron supplementation, iron fortification, and diarrhea in children aged 4–59months, Curr. Dev. Nutr. 3(3), nzz005.
Gibson, R. S. (1990). Principles of Nutritional Assessment.OxfordUniversityPress,NewYork.
Gibson, T. M., Weinstein, S. J., Pfeiffer, R. M., Hollenbeck, A. R., Subar, A. F., Schatzkin, A., Mayne,S.T.andStolzenberg-Solomon,R.(2011).Pre-andpostfortificationintakeoffolateandriskofcolorectalcancerinalargeprospectivecohortstudyintheUnitedStates, Am. J. Clin. Nutr. 94(4), 1053–62.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 59
Global Fortification Data Exchange. (2020a). Interactive map: fortification legislation.Available at: https://fortificationdata.org/interactive-map-fortification-legislation/#;Accessed 10 February 2020.
Global Fortification Data Exchange. (2020b). Interactive map: nutrient levels infortification standards (mid-range or average). Available at: https://fortificationdata.org/map-nutrient-levels-in-fortification-standards/; Accessed 10 February2020.
GlobalFortificationDataExchange.(2020c).Brazilfortificationdashboard.Availableat:https://fortificationdata.org/country-fortification-dashboard/?alpha3_code=BRA&lang=en;Accessed12April2020.
Global Fortification Data Exchange. (2020d). United States of America fortificationdashboard.Availableat:https://fortificationdata.org/country-fortification-dashboard/?alpha3_code=USA&lang=en;Accessed12April2020.
Grimm,K.A.,Sullivan,K.M.,Alasfoor,D.,Parvanta,I.,MohammadSuleiman,A.J.,Kaur,M.,Al-Hatmi,F.O.andRuth,L.J.(2012).Iron-fortifiedwheatflourandirondeficiencyamong women, Food Nutr. Bull. 33(3), 180–5.
Grosse,S.D.,Berry,R.J.,Tilford,J.M.,Kucik,J.E.andWaitzman,N.J.(2016).Retrospectiveassessmentofcostsavingsfromprevention:folicacidandspinabifidaintheU.S,Am. J. Prev. Med. 50 (Suppl. 1), S74–80.
Grosse,S.D.,Waitzman,N.J.,Romano,P.S.andMulinare,J. (2005).Reevaluating thebenefitsoffolicacidfortificationintheUnitedStates:economicanalysis,regulation,and public health, Am. J. Public Health 95(11), 1917–22.
Grupp,S.G., Greenberg,M.L., Ray,J.G., Busto,U., Lanctôt,K.L., Nulman,I.andKoren,G.(2011).PediatriccancerratesafteruniversalfolicacidflourfortificationinOntario,J. Clin. Pharmacol. 51(1), 60–5.
Hertrampf, E.,Cortés, F., Erickson, J.D.,Cayazzo,M., Freire,W., Bailey, L. B.,Howson,C.,Kauwell,G.P.andPfeiffer,C. (2003).Consumptionof folicacid-fortifiedbreadimproves folate status in women of reproductive age in Chile, J. Nutr. 133(10), 3166–9.
Hess,S.,Tecklenburg,L.andEichler,K. (2016).Micronutrient fortifiedcondimentsandnoodles to reduce anemia in children and adults--a literature review and meta-analysis, Nutrients 8(2), 88.
Hilder, L. (2016). Neural tube defects in Australia, 2007–2011: before and afterimplementationofthemandatoryfolicacidfortificationstandard.TechnicalReport11488,NationalPerinatalEpidemiologyandStatisticsUnit,UniversityofNewSouthWales, Wales.
Hirsch,S.,de laMaza,P.,Barrera,G.,Gattás,V., Petermann,M.andBunout,D. (2002).TheChileanflourfolicacidfortificationprogramreducesserumhomocysteinelevelsandmasksvitaminB-12deficiencyinelderlypeople,J. Nutr. 132(2), 289–91.
Hirsch, S., Sanchez,H.,Albala,C., de laMaza,M. P., Barrera,G., Leiva, L. andBunout,D.(2009).ColoncancerinChilebeforeandafterthestartoftheflourfortificationprogram with folic acid, Eur. J. Gastroenterol. Hepatol. 21(4), 436–9.
Hombali, A. S., Solon, J. A., Venkatesh, B. T., Nair, N. S. and Peña-Rosas, J. P. (2019).Fortification of staple foods with vitamin A for vitamin A deficiency, Cochrane Database Syst. Rev.5(5),CD010068.
Honein,M.A.,Paulozzi,L.J.,Mathews,T.J.,Erickson,J.D.andWong,L.Y.(2001).Impactof folicacid fortificationof theUS foodsupplyon theoccurrenceofneural tubedefects, J.A.M.A. 285(23), 2981–6.
Wheat flour fortification and human health60
Published by Burleigh Dodds Science Publishing Limited, 2021.
Houghton,S.C.,Eliassen,A.H.,Zhang,S.M.,Selhub,J.,Rosner,B.A.,Willett,W.C.andHankinson, S. E. (2019a). Plasma B-vitamin and one-carbonmetabolites and riskofbreastcancerbeforeandafterfolicacidfortificationintheUnitedStates, Int. J. Cancer 144(8), 1929–40.
Houghton, S. C., Eliassen, A. H., Zhang, S.M., Selhub, J., Rosner, B. A.,Willett,W. C.and Hankinson, S. E. (2019b). Plasma B-vitamins and one-carbon metabolitesand the risk of breast cancer in younger women, Breast Cancer Res. Treat. 176(1), 191–203.
Hund, L., Northrop-Clewes, C. A., Nazario, R., Suleymanova, D., Mirzoyan, L., Irisova,M.,Pagano,M.andValadez,J.J. (2013).Anovelapproach toevaluating the ironandfolatestatusofwomenofreproductiveageinUzbekistanafter3yearsofflourfortificationwithmicronutrients,PLoS ONE 8(11), e79726.
Hurrell, R. F., Ranum, P., de Pee, S., Biebinger, R., Hulthen, L., Johnson,Q. and Lynch,S. (2010). Revised recommendations for iron fortification of wheat flour and anevaluation of the expected impact of current national wheat flour fortificationprograms, Food Nutr. Bull. 31(1), S7–21.
Institute ofMedicine (US) StandingCommittee on the Scientific Evaluation ofDietaryReference Intakesand itsPanelonFolate,OtherBVitamins,andCholine. (1998).Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate,VitaminB12,PantothenicAcid,Biotin,andCholine.NationalAcademiesPress(US),Washington,DC.
Ionescu-Ittu, R.,Marelli,A. J.,Mackie,A. S. and Pilote, L. (2009). Prevalence of severecongenitalheartdiseaseafter folicacid fortificationofgrainproducts: time trendanalysisinQuebec,Canada,B.M.J. 338, b1673.
Kancherla,V.,Wagh,K.,Johnson,Q.andOakley,G.P.Jr.(2018).A2017globalupdateonfolicacid-preventablespinabifidaandanencephaly,Birth Defects Res. 110(14), 1139–47.
Kassebaum,N.J.,Jasrasaria,R.,Naghavi,M.,Wulf,S.K.,Johns,N.,Lozano,R.,Regan,M.,Weatherall,D.,Chou,D.P.,Eisele,T.P.,Flaxman,S.R.,Pullan,R.L.,Brooker,S.J.andMurray, C. J. (2014). A systematic analysis of global anemia burden from 1990 to 2010, Blood 123(5), 615–24.
Keats, E. C., Neufeld, L. M., Garrett, G. S., Mbuya, M. N. N. and Bhutta, Z. A. (2019).Improved micronutrient status and health outcomes in low- and middle-income countriesfollowinglarge-scalefortification:evidencefromasystematicreviewandmeta-analysis, Am. J. Clin. Nutr. 109(6), 1696–708.
Kennedy,D.A., Stern, S. J.,Moretti,M.,Matok, I., Sarkar,M.,Nickel, C. andKoren,G.(2011). Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis, Cancer Epidemiol. 35(1), 2–10.
Keum,N.andGiovannucci,E.L.(2014).Folicacidfortificationandcolorectalcancerrisk,Am. J. Prev. Med. 46(3) (Suppl. 1), S65–72.
Kraemer,K. andZimmermann,M.B. (2007).Nutritional Anaemia. Sight andLifePress,Basel,Switzerland.
Layrisse,M.,Chaves,J.F.,Mendez-Castellano,H.,Bosch,V.,Tropper,E.,Bastardo,B.andGonzález,E.(1996).Earlyresponsetotheeffectofiron fortification intheVenezuelanpopulation, Am. J. Clin. Nutr.64(6),903–7.
Layrisse,M.,García-Casal,M.N.,Méndez-Castellano,H.,Jiménez,M.,Henry,O.,Chávez,J. E. andGonzález, E. (2002). Impact of fortification of flourswith iron to reduce
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 61
the prevalence of anemia and iron deficiency among schoolchildren in Caracas,Venezuela:afollow-up,Food Nutr. Bull. 23(4), 384–9.
Lin,J.,Lee,I.M.,Cook,N.R.,Selhub,J.,Manson,J.E.,Buring,J.E.andZhang,S.M.(2008).Plasmafolate,vitaminB-6,vitaminB-12,andriskofbreastcancerinwomen,Am. J. Clin. Nutr. 87(3), 734–43.
Liu,S.,West,R.,Randell,E.,Longerich,L.,SteelO’Connor,K.S.,Scott,H.,Crowley,M.,Lam,A., Prabhakaran,V. andMcCourt,C. (2004).A comprehensive evaluation offoodfortificationwithfolicacidfortheprimarypreventionofneuraltubedefects,BMC Preg. Childbirth 4(1), 20.
Llanos,A.,Hertrampf,E.,Cortes,F., Pardo,A.,Grosse,S.D. andUauy,R. (2007).Cost-effectiveness of a folic acid fortification program in Chile,Health Policy 83(2–3), 295–303.
López-Camelo,J.S.,Castilla,E.E.,Orioli,I.M.,INAGEMP(InstitutoNacionaldeGenéticaMédica Populacional) and ECLAMC (Estudio Colaborativo Latino Americano deMalformaciones Congénitas). (2010). Folic acid flour fortification: impact on thefrequencies of 52 congenital anomaly types in three South American countries, Am. J. Med. Genet. A 152A(10), 2444–58.
López-Camelo,J.S.,Orioli,I.M.,daGraçaDutra,M.,Nazer-Herrera,J.,Rivera,N.,Ojeda,M. E., Canessa, A., Wettig, E., Fontannaz, A. M., Mellado, C. and Castilla, E. E. (2005). Reductionofbirthprevalenceratesofneuraltubedefectsafterfolicacidfortificationin Chile, Am. J. Med. Genet. A 135(2), 120–5.
Marks,K.J.,Luthringer,C.L.,Ruth,L.J.,Rowe,L.A.,Khan,N.A.,De-Regil,L.M.,López,X. and Pachón,H. (2018). Reviewof grain fortification legislation, standards, andmonitoring documents, Glob. Health Sci. Pract. 6(2), 356–71.
Martinez,H.,Weakland,A.P.,Bailey,L.B.,Botto,L.D.,De-Regil,L.M.andBrown,K.H.(2018).Improving maternal folate status to prevent infant neural tube defects: working group conclusions and a framework for action, Ann. N.Y. Acad. Sci. 1414(1), 5–19.
Martorell,R.,Ascencio,M.,Tacsan,L.,Alfaro,T.,Young,M.F.,Addo,O.Y.,Dary,O.andFlores-Ayala, R. (2015). Effectiveness evaluation of the food fortification programof Costa Rica: impact on anemia prevalence and hemoglobin concentrations in women and children, Am. J. Clin. Nutr. 101(1), 210–7.
Mason,J.B.,Dickstein,A.,Jacques,P.F.,Haggarty,P.,Selhub,J.,Dallal,G.andRosenberg,I.H.(2007).Atemporalassociationbetweenfolicacidfortificationandanincreasein colorectal cancer rates may be illuminating important biological principles: a hypothesis, Cancer Epidemiol. Biomarkers Prev. 16(7), 1325–9.
Mathews,T.J.,Honein,M.A.andErickson,J.D. (2002).Spinabifidaandanencephalyprevalence—UnitedStates,1991–2001,M.M.W.R. Recomm. Rep. 51(RR-13), 9–11.
Mendu,V.V.R.,Nair,K.P.M.andAthe,R. (2019).Systematic reviewandmeta-analysisapproachonvitaminAfortifiedfoodsanditseffectonretinolconcentrationinunder10 year children, Clin. Nutr. E.S.P.E.N. 30, 126–30.
Millacura,N.,Pardo,R.,Cifuentes,L.andSuazo,J.(2017).Effectsoffolicacidfortificationon orofacial clefts prevalence: a meta-analysis, Public Health Nutr. 20(12), 2260–8.
Mills,J.L.,VonKohorn,I.,Conley,M.R.,Zeller,J.A.,Cox,C.,Williamson,R.E.andDufour,D.R.(2003).LowvitaminB-12concentrationsinpatientswithoutanemia:theeffectoffolicacidfortificationofgrain,Am. J. Clin. Nutr. 77(6), 1474–7.
Modjadji,S.E.P.,Alberts,M.andMamabolo,R.L.(2007).FolateandironstatusofSouthAfricannon-pregnantruralwomenofchildbearingage,beforeandafterfortificationoffoods,S.A.J.C.N.20(3),89–93.
Wheat flour fortification and human health62
Published by Burleigh Dodds Science Publishing Limited, 2021.
MRCVitaminStudyResearchGroup.(1991).Preventionofneuraltubedefects:resultsoftheMedicalResearchCouncilVitaminStudy.Lancet, 338(8760), 131–7.
Muthayya,S.,Thankachan,P.,Hirve,S.,Amalrajan,V.,Thomas,T.,Lubree,H.,Agarwal,D.,Srinivasan,K.,Hurrell,R.F.,Yajnik,C.S.andKurpad,A.V.(2012).Ironfortificationofwholewheatflourreducesirondeficiencyandirondeficiencyanemiaandincreasesbody iron stores in Indian school-aged children, J. Nutr. 142(11), 1997–2003.
NationalFoodandNutritionCentre.(2012).Impact of Iron Fortified Flour in Child Bearing Age (CBA) Women in Fiji, 2010 Report.NationalFoodandNutritionCentre,Suva.
NationalInstituteofStatistics,DirectorateGeneralforHealthandICFInternational.(2015).Cambodia Demographic and Health Survey 2014. National Institute of Statistics,DirectorateGeneralforHealth,andICFInternational,PhnomPenh,CambodiaandRockville,MD.
NationalToxicology Program (2015).NTP Monograph: Identifying Research Needs for Assessing Safe Use of High Intakes of Folic Acid.UnitedStatesDepartmentofHealthandHumanServices,WashingtonDC.
Nazer, H. J. and Cifuentes, O. L. (2013). Effects of wheat flour fortification with folicacid on the prevalence of neural tube defects in Chile, Rev. Med. Chile 141(6), 751–7.
Nazer,H.J.,Cifuentes,O.L.,Aguila,R.A.,Juárez,H.M.E.,Cid,R.M.P.,Godoy,V.M.L.,García,A.K.andMelibosky,R.F.(2007).Effectsoffolicacidfortificationintheratesof malformations at birth in Chile, Rev. Méd. Chile 135(2), 198–204.
Noor,R.A.,Abioye,A.I.,Ulenga,N.,Msham,S.,Kaishozi,G.,Gunaratna,N.S.,Mwiru,R.,Smith, E.,Dhillon,C.N., Spiegelman,D. and Fawzi,W. (2017). Large-scalewheatflourfolicacidfortificationprogramincreasesplasmafolatelevelsamongwomenofreproductive age in urban Tanzania, PLoS ONE 12(8), e0182099.
Northrop-Clewes,C.,Hund,L.,Valadez,J.,Mirzoyan,L.andIrisova,M.(2013).LC-LQASsurveyreport.GlobalAllianceforImprovedNutrition,Geneva.
Oakley,G.P.Jr. (2009).Thescientificbasis foreliminating folicacid-preventablespinabifida:amodernmiraclefromepidemiology,Ann. Epidemiol. 19(4), 226–30.
Odewole, O. A., Williamson, R. S., Zakai, N. A., Berry, R. J., Judd, S. E., Qi, Y. P.,Adedinsewo,D.A. andOakley,G. P. (2013).Near-eliminationof folate-deficiencyanemia by mandatory folic acid fortification in older US adults: reasons forgeographic and racial differences in stroke study 2003–2007, Am. J. Clin. Nutr. 98(4), 1042–7.
O'Donnell,S.,Cranney,A.,Horsley,T.,Weiler,H.A.,Atkinson,S.A.,Hanley,D.A.,Ooi,D.S.,Ward,L.,Barrowman,N.,Fang,M.,Sampson,M.,Tsertsvadze,A.andYazdi,F.(2008).Efficacyoffoodfortificationonserum25-hydroxyvitaminDconcentrations:systematic review, Am. J. Clin. Nutr.88(6),1528–34.
Pacheco Santos, L.M., Reyes Lecca, R. C., Cortez-Escalante, J. J., Sanchez,M. N. andRodrigues,H.G.(2016).Preventionofneuraltubedefectsbythefortificationofflourwithfolicacid:apopulation-basedretrospectivestudyinBrazil,Bull. World Health Organ., 94(1), 22–9.
Pacheco, S. S., Braga,C., Souza,A. I. and Figueiroa, J.N. (2009). Effects of folic acidfortification on the prevalence of neural tube defects, Rev. Saúde Publ. 43(4), 565–71.
PachecoSantos,L.M.andZanonPereira,M.(2007).Efeitodafortificaçãocomácidofóliconareduçãodosdefeitosdotuboneural[Theeffectoffolicacidfortificationonthereduction of neural tube defects], Cad. Saúde Publ. 23(1), 17–24.
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 63
Pachón, H., Spohrer, R., Mei, Z. and Serdula, M. K. (2015). Evidence of the effectiveness offlourfortificationprogramsonironstatusandanemia:asystematicreview,Nutr. Rev. 73(11), 780–95.
Persad,V.L.,VandenHof,M.C.,Dubé,J.M.andZimmer,P.(2002).IncidenceofopenneuraltubedefectsinNovaScotiaafterfolicacidfortification,C.M.A.J. 167(3), 241–5.
Petry,N.,Olofin,I.,Boy,E.,DonahueAngel,M.andRohner,F.(2016).Theeffectoflowdose iron and zinc intake on child micronutrient status and development during thefirst1000daysof life:a systematic reviewandmeta-analysis,Nutrients 8(12), pii: E773.
Pfeiffer,C.M.,Hughes,J.P.,Lacher,D.A.,Bailey,R.L.,Berry,R.J.,Zhang,M.,Yetley,E.A.,Rader,J.I.,Sempos,C.T.andJohnson,C.L.(2012).Estimationoftrendsinserumand RBC folate in the U.S. population from pre- to postfortification using assay-adjusteddatafromtheNHANES1988–2010,J. Nutr. 142(5), 886–93.
Pfeiffer, C. M., Sternberg, M. R., Zhang, M., Fazili, Z., Storandt, R. J., Crider, K. S., Yamini, S.,Gahche,J.J.,Juan,W.,Wang,C.Y.,Potischman,N.,Williams,J.andLaVoie,D.J.(2019).FolatestatusintheUSpopulation20yaftertheintroductionoffolicacidfortification,Am. J. Clin. Nutr. 110(5), 1088–97.
Qi,Y.P.,Do,A.N.,Hamner,H.C.,Pfeiffer,C.M.andBerry,R.J.(2014).TheprevalenceoflowserumvitaminB-12statusintheabsenceofanemiaormacrocytosisdidnotincrease among older U.S. adults aftermandatory folic acid fortification, J. Nutr. 144(2), 170–6.
Ray, J. G., Meier, C., Vermeulen, M. J., Boss, S., Wyatt, P. R. and Cole, D. E. (2002).AssociationofneuraltubedefectsandfolicacidfoodfortificationinCanada,Lancet 360(9350), 2047–8.
Ray,J.G.,Vermeulen,M.J.,Langman,L.J.,Boss,S.C.andCole,D.E.(2003).PersistenceofvitaminB12insufficiencyamongelderlywomenafterfolicacidfoodfortification,Clin. Biochem. 36(5), 387–91.
Ricks,D.J.,Rees,C.A.,Osborn,K.A.,Crookston,B.T.,Leaver,K.,Merrill,S.B.,Velásquez,C.andRicks,J.H.(2012).Peru’snationalfolicacidfortificationprogramanditseffectonneuraltubedefectsinLima,Rev. Panam. Salud Publ. 32(6), 391–8.
Rosenthal,J.,Casas,J.,Taren,D.,Alverson,C.J.,Flores,A.andFrias,J.(2014).Neuraltubedefects inLatinAmericaand the impactof fortification:a literature review,Public Health Nutr. 17(3), 537–50.
Sadighi, J., Mohammad, K., Sheikholeslam, R., Amirkhani, M. A., Torabi, P., Salehi, F. and Abdolahi,Z.(2009).Anaemiacontrol:lessonsfromtheflourfortificationprogramme,Public Health 123(12), 794–9.
Sadighi, J., Sheikholeslam, R., Mohammad, K., Pouraram, H., Abdollahi, Z., Samadpour, K.,Kolahdooz,F. andNaghavi,M. (2008). Flour fortificationwith iron:amid-termevaluation, Public Health 122(3), 313–21.
Safdar,O.Y.,Al-Dabbagh,A.A.,Abuelieneen,W.A.andKari,J.A.(2007).Declineintheincidenceofneuraltubedefectsafterthenationalfortificationofflour(1997–2005),Saudi Med. J. 28(8), 1227–9.
Salam,R.A.,Das,J.K.,Ahmed,W.,Irfan,O.,Sheikh,S.S.andBhutta,Z.A.(2019).Effectsof preventive nutrition interventions among adolescents on health and nutritional status in low- and middle-income countries: a systematic review and meta-analysis, Nutrients 12(1), pii: E49.
Samet,J.M.,Wipfli,H.,Platz,E.A.andBhavsar,N.(2008).In:Porta,M.(Eds).A Dictionary of Epidemiology(5thedn.).OxfordUniversityPress,NewYork.
Wheat flour fortification and human health64
Published by Burleigh Dodds Science Publishing Limited, 2021.
Sanabria Rojas, H.A., Tarqui-Mamani, C. B.,Arias Pachas, J. and Lam Figueroa,N.M.(2013). Impacto de la fortificación de la harina de trigo con ácido fólico en losdefectosdeltuboneural,enLima,Perú,An. Fac. Med. 74(3), 175–80.
Sargiotto,C.,Bidondo,M.P.,Liascovich,R.,Barbero,P.andGroisman,B.(2015).Descriptivestudy on neural tube defects in Argentina, Birth Defects Res. A 103(6), 509–16.
Sayed,A.-R., Bourne, D., Pattinson, R., Nixon, J. andHenderson, B. (2008). Decline intheprevalenceofneuraltubedefectsfollowingfolicacidfortificationanditscost-benefitinSouthAfrica,Birth Defects Res. A 82(4), 211–6.
Shah,D.,Sachdev,H.S.,Gera,T.,De-Regil,L.M.andPeña-Rosas,J.P.(2016).Fortificationof staple foods with zinc for improving zinc status and other health outcomes in the general population, Cochrane Database Syst. Rev.6(6),CD010697.
Siegel,R.L.,Miller,K.D.andJemal,A.(2019).Cancerstatistics,2019,C.A. Cancer J. Clin. 69(1), 7–34.
Smarter Futures. (n.d.). FORTIMAS: An Approach for Tracking the Population Coverage and Impact of a Flour Fortification Program.InternationalFederationforSpinaBifidaandHydrocephalus,Brussels.
Smith,A.D.,Kim,Y.I.andRefsum,H.(2008).Isfolicacidgoodforeveryone?,Am. J. Clin. Nutr. 87(3), 517–33.
Solomons,N.W.andAllen,L.H.(1983).Thefunctionalassessmentofnutritionalstatus:principles, practice and potential, Nutr. Rev. 41(2), 33–50.
Stevens,G.A.,Finucane,M.M.,De-Regil,L.M.,Paciorek,C.J.,Flaxman,S.R.,Branca,F.,Peña-Rosas,J.P.,Bhutta,Z.A.andEzzati,M.(2013).Global,regional,andnationaltrends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995–2011: a systematic analysis of population-representative data, Lancet Glob. Health 1(1), e16–25.
Stevens,V.L.,McCullough,M.L.,Sun,J.andGapstur,S.M. (2010).Folateandotherone-carbon metabolism-related nutrients and risk of postmenopausal breast cancer in the cancer prevention study II nutrition cohort, Am. J. Clin. Nutr. 91(6), 1708–15.
Stolzenberg-Solomon,R.Z.,Chang,S.C.,Leitzmann,M.F.,Johnson,K.A.,Johnson,C.,Buys,S.S.,Hoover,R.N.andZiegler,R.G. (2006).Folate intake,alcoholuse,andpostmenopausalbreastcancer risk in theProstate,Lung,Colorectal,andOvarianCancer Screening Trial, Am. J. Clin. Nutr. 83(4), 895–904.
TacsanChen,L.andAscencioRivera,M.(2004).TheCostaRicanexperience:reductionofneural tubedefects followingfoodfortificationprograms,Nutr. Rev. 62(6 Pt 2), S40–3.
Tam, E., Keats, E. C., Rind, F., Das, J. K. and Bhutta, A. Z. A. (2020). Micronutrientsupplementation and fortification interventions on health and developmentoutcomes among children under-five in low- and middle-income countries: asystematic review and meta-analysis, Nutrients 12(2), pii: E289.
Tarqui-Mamani,C. B. (2013). Sobreel estudiodeevaluaciónde losdefectosde tuboneuralenLima,Rev. Panam. Salud Publ. 34(3), 210–.
Tarqui-Mamani, C. B., Sanabria-Rojas, H., Rossi de Chiarella, G., Arana-Panduro, M.,Altamirano,H.,et al.(2016).Impactofwheatflourfolicacidfortificationonneuraltube defects in three cities in Peru, J. Glob. Health. https :/ /pu bmed. ncbi. nlm .n ih .go v /242 3 3115 /.
Tice, J. A., Ross, E., Coxson, P. G., Rosenberg, I., Weinstein, M. C., Hunink, M. G. M., Goldman,P.A.,Williams,L.andGoldman,L. (2001).Cost-effectivenessofvitamin
Published by Burleigh Dodds Science Publishing Limited, 2021.
Wheat flour fortification and human health 65
therapy to lower plasma homocysteine levels for the prevention of coronary heart disease:effectofgrainfortificationandbeyond,J.A.M.A. 286(8), 936–43.
Tio,M.,Andrici,J.andEslick,G.D.(2014).Folateintakeandtheriskofbreastcancer:asystematic review and meta-analysis, Breast Cancer Res. Treat. 145(2), 513–24.
UNICEFandtheFoodFortificationInitiative.(2004).Monitoringofflourfortification:thecaseofSouthAfrica.Availableat:http://www.ffinetwork.org/monitor/Documents/SouthAfricaCS.pdf;Accessed9March2020.
UnitedNationsStatisticsDivision.(2020).Standardcountryorareacodesforstatisticaluse(vol.M49).Availableat:https://unstats.un.org/unsd/methodology/m49/;Accessed9 March 2020.
UnitedStatesDepartmentofAgriculture. (2020).FoodDataCentral:wheatflour,white,all-purpose,unenriched.Availableat:https://fdc.nal.usda.gov/fdc-app.html#/food-details/169761/nutrients;Accessed10February2020.
vanGool,J.D.,Hirche,H.,Laz,H.andDeSchaepdrijver,L.(2018).Folicacidandprimaryprevention of neural tube defects: a review, Reprod. Toxicol. 80, 73–84.
vanGool,J.D.,Hirche,H.,Lax,H.andSchaepdrijver,L.(2020).FallaciesofclinicalstudiesonfolicacidhazardsinsubjectswithalowvitaminB12status,Crit. Rev. Toxicol. 31, 1–11.
Victora,C.G.,Habicht,J.P.andBryce,J.(2004).Evidence-basedpublichealth:movingbeyond randomized trials, Am. J. Public Health 94(3), 400–5.
Vollset,S.E.,Clarke,R.,Lewington,S.,Ebbing,M.,Halsey,J.,Lonn,E.,Armitage,J.,Manson,J.E.,Hankey,G.J.,Spence,J.D.,Galan,P.,Bønaa,K.H.,Jamison,R.,Gaziano,J.M.,Guarino,P.,Baron,J.A.,Logan,R.F.,Giovannucci,E.L.,denHeijer,M.,Ueland,P.M.,Bennett,D.,Collins,R.andPeto,R.(2013).Effectsoffolicacidsupplementationonoverall and site-specific cancer incidenceduring the randomised trials:meta-analyses of data on 50 000 individuals, Lancet 381(9871), 1029–36.
Williams,J.,Mai,C.T.,Mulinare,J.,Isenburg,J.,Flood,T.J.,Ethen,M.,Frohnert,B.,Kirby,R.S.andCentersforDiseaseControlandPrevention(2015).Updatedestimatesofneuraltubedefectspreventedbymandatoryfolicacidfortification—UnitedStates,1995–2011, M.M.W.R. Morb. Mortal. Wkly. Rep. 64(1), 1–5.
Williams,L.J.,Mai,C.T.,Edmonds,L.D.,Shaw,G.M.,Kirby,R.S.,Hobbs,C.A.,Sever,L.E.,Miller,L.A.,Meaney,F.J.andLevitt,M. (2002).PrevalenceofspinabifidaandanencephalyduringthetransitiontomandatoryfolicacidfortificationintheUnitedStates, Teratology 66(1), 33–9.
Williams,L.J.,Rasmussen,S.A.,Flores,A.,Kirby,R.S.andEdmonds,L.D.(2005).Declinein theprevalenceof spinabifida and anencephalyby race/ethnicity: 1995–2002,Pediatrics 116(3), 580–86.
WorldBank.(2020).HowdoestheWorldBankclassifycountries?.Availableat:https://datahel pdesk .worl dbank .org/ knowl edgeb ase /a rticl es /37 8834- how -d oes -t he -wo rld -b ank-classify-countries;Accessed9March2020.
World Health Organization. (2020). Anaemia. Available at: https :/ /ww w .who .int/ healt h -topics/anaemia#tab=tab_1;Accessed27April2020.
World Health Organization and Food and Agriculture Organization of the UnitedNations.(2006).Guidelines on Food Fortification with Micronutrients. World Health Organization, Geneva.
WorldHealthOrganization,FoodandAgricultureOrganizationof theUnitedNations,theUnitedNationsChildren’sFund isaUnitedNations,GlobalAlliance forFoodFortification, Micronutrient Initiative, and the Food Fortification Initiative. (2009).
Wheat flour fortification and human health66
Published by Burleigh Dodds Science Publishing Limited, 2021.
Recommendationsonwheatandmaizeflour fortification.Meetingreport: interimconsensus statement. World Health Organization, Geneva.
Yang,Q.,Botto,L.D.,Erickson,J.D.,Berry,R.J.,Sambell,C.,Johansen,H.andFriedman,J.M.(2006).ImprovementinstrokemortalityinCanadaandtheUnitedStates,1990to 2002, Circulation 113(10), 1335–43.
Yang, X., Chen, H., Du, Y.,Wang, S. andWang, Z. (2016). Periconceptional folic acidfortification for the risk of gestational hypertension and pre-eclampsia: a meta-analysis of prospective studies, Matern. Child Nutr. 12(4), 669–79.
Youngblood,M.E.,Williamson,R.,Bell,K.N.,Johnson,Q.,Kancherla,V.andOakley,G.P.(2013).2012Updateonglobalpreventionoffolicacid-preventablespinabifidaandanencephaly, Birth Defects Res. A 97(10), 658–63.