wheat flour fortification and human health

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

http://dx.doi.org/10.19103/AS.2021.0087.23

Wheat flour fortification and human health2

Published by Burleigh Dodds Science Publishing Limited, 2021.

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.


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.

http://(FortificationData.org)



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.



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



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.



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).



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).



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.



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).



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



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.



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



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



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).



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.



• 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.



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.



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



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



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)



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



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


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



(Con

tinue

d)



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


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



Cost

a Ri

caa

Tacs

an C

hen

and

Asce

ncio

Rivera2004;Barboza

ArgüelloandUmañaSolís

2011;BarbozaArgüello

et al.2015

Folic

aci

dNeuraltube

defe

cts


stillbirthsweighing500 g

or m

ore

(Tac

san

Che

n an

d AscencioRivera2004;

BarbozaArgüelloand

UmañaSolís2011;Barboza

Argüelloet al.2015)

PrevalenceofN

TDslow


thanpre-fortificationperiode

Iran

Abdo

llahi

et a

l. 20

11Fo

lic a

cid

Neuraltube

defe

cts


weighing500 gormore

with

a g

esta

tiona

l age

of

20 w

eeks

or m

ore

PrevalenceofN

TDslow



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



Peru

Rickset al.2012;Sanabria

Rojaset al.2013;Tarqui-

Mam

aniet al.2016

Folic

aci

dNeuraltube

defe

cts


(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


PrevalenceofN

TDslow



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



NTDs,neuraltubedefects

a Wheatflourwastheonlygrainfortifiedwithfolicacidinmostcountries.WheatandmaizeflourwerefortifiedwithfolicacidinBrazil,CostaRica(inadditiontoriceand

milk),SouthAfricaandtheUSA(inadditiontorice);theindependenteffectofanyoneofthesefortifiedfoodsonhealthoutcomescannotbediscernedwiththisstudy.


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).



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



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)



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


h no

diffe

renc

e in

pre

vale

nce

of lo

w p

lasm

a ferritinandiron-deficiencyanem

iabetweenpost-fortificationandpre-


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


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


heatflour

fortificationa

(Con

tinue

d)



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)



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-


inurbanandruralareas:prevalenceoffolatedeficiencylowerinthe


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


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


heatflour

fortificationa

(Con

tinue

d)



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-


j

prev

alen

ce o

f low

seru

m fo

late

and

hig

h pl

asm

a ho

moc

yste

ine

low

er in


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-


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-


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)



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.


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


heatflour

fortificationa

(Con

tinue

d)



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).



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.



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-


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-


Om

anAlasfooret al.2010

Folic

aci

dSpinabifidae;non-spina

bifidaneuraltubedefects

fLivebirths

Prevalenceofspinabifidalowerinpost-


no d

iffer

ence

in th

e pr

eval

ence

of o

ther

, non-spina-bifidaNTDsbetweenpost-and

pre-fortificationperiods

(Con

tinue

d)



Saud

i Ara

biaSafdaret al.2007

Folic

aci

dNeuraltubedefects

Livebirths

PrevalenceofN

TDslow

erinpost-


Tanz

ania

aNooret al.2017

Folic

aci

dPlasmafolate;

folatedeficiency

Wom

enH

ighe

r pla

sma

fola

te le

vels

in th

e po

st-


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)



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-


(Mathewset al.2002;W

illiamset al.

2002);forHispanicandnon-Hispanic

whites:prevalenceofNTDslow

erinpost-


(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.


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).



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



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.



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



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).



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).



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



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-


Castillo-Lancellottiet al.2013

9Fo

lic a

cid

Neuraltubedefects

(NTDs)

Differeddepending

on a

rticl

e re

view

edPrevalenceofN

TDslow

erinpost-


Pach

eco

Sant

os a

nd Z

anon

Pe

reira

200

7 5

Folic

aci

dNeuraltubedefectsLivebirths

PrevalenceofN

TDslow

erinpost-


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-


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-


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.’


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).



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),



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-


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-


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-


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



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


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).

https://hawcproject.org/assessment/67/downloads/;

https://hawcproject.org/assessment/48/downloads/)

https://hawcproject.org/assessment/48/downloads/)



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



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


prevented13.2%ofneuraltubedefectsc

Kancherlaet al.2018

59Fo

lic a

cid

Neuraltubedefects

Livebirths


prevented18%ofneuraltubedefectsc


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.



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



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.



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.



• 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.

https://www.who.int/elena/titles/wheat-flour-fortification/en/

https://www.who.int/nutrition/publications/micronutrients/9241594012/en/

https://www.who.int/nutrition/publications/micronutrients/wheat_maize_fortification/en/

https://www.who.int/nutrition/publications/micronutrients/wheat_maize_fortification/en/



(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.

https://journals.sagepub.com/toc/fnba/31/1_suppl1

http://www.ffinetwork.org/tools_training/flour_millers_toolkit.html

http://www.ffinetwork.org/tools_training/flour_millers_toolkit.html

https://www.ghspjournal.org/content/6/2/356

https://www.ghspjournal.org/content/6/2/356

https://fortificationdata.org/resources/

https://fortificationdata.org

http://www.ffinetwork.org



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.

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