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Multiple MicronutrientSupplementation DuringPregnancy (MMSDP):Efficacy Trials

by UNICEF / UNU / WHO Study Team

Report of a meeting held on March 4-8, 2002at the Centre for International Child Health,Institute of Child Health, UCL, London, UK.

Copyright © 2002 Institute of Child Health, UCL

Published by University College London,Institute of Child Health, Centre for International Child Health

Centre for International Child Health,Institute of Child Health,30 Guilford Street,London WC1N 1EH

Telephone: +44 (0)20 7905 2122Fascimile: +44 (0)20 7404 2062

www.cich.ich.ucl.ac.uk

ISBN 0-9532265-2-2

ContentsExecutive summary 4

Introduction 6

Policy context 7

Programme context 8

Scientific context 9

Description of studies 9

Discussion of outcome measures 11

Discussion of main interventions 13

Adherence 13

Enhancing adherence 13

Internal and external validity 13

Formulation of supplement 13

Group Discussion of the scientific 16and study implementation issues

Group discussion of the process of 17policy change and programmatic implications

Conclusions and recommendations 19

References 20

• 3 •

TablesTable 1: Composition of multiple micronutrient 6supplement for pregnant and lactating womenrecommended for trial purposes by UNICEF / UNU / WHO

Table 2: Outcomes being measured in the 12five studies

Table 3: Planned interventions 14

Table 4: List of required and recommended 16confounders and effect-modifiers to be recorded

Executive SummaryThe high prevalence of low birth weight in infants indeveloping countries is a major health anddevelopment problem. Malnourished mothers aremore likely to have low birth weight babies. Poorwomen tend to have diets that are micronutrient-poor, and many consume diets that inhibitmicronutrient absorption, such that many women ofreproductive age from developing countries sufferfrom multiple micronutrient deficiencies. The multiplemicronutrient supplement agreed for use in trials at aUNICEF, WHO and UNU meeting in 1999, is nowbeing used by research groups in trials funded by avariety of funding agencies. The research questionbeing is whether multiple micronutrient supplementssignificantly improve pregnancy outcome, more sothan iron-folate supplements. An interest wasexpressed to increase collaboration among theongoing efficacy trials, and to that end a meetingwas held at the Centre for International Child Health,Institute of Child Health, London, from March 4-8,2002, funded by the Micronutrient Initiative. It wasattended by leading researchers and principalinvestigators of multiple micronutreus trials, andpolicy-makers from several international agenciesincluding DFID, UNICEF, UNU, WHO, the WorldBank, CIDA, USAID, the Micronutrient Initiative andthe Wellcome Trust. The principal investigators andrepresentatives from UNICEF, WHO, UNU, andUSAID spent the first four days of the meetingdiscussing the details of the trials. On the last daypolicy-makers from the World Bank, CIDA, theWellcome Trust, and the Micronutrient Initiativejoined in the discussion. The primary objectives ofthis meeting were:

• To maximise on the research outcomes from thevarious multiple micronutrient supplementationtrials

• To ensure as far as possible improvedcomparability across various trials

• To maximise possibilities of pooling data acrosssites for a possible meta-analysis

• To discuss mechanisms by which researchfindings could be fast-tracked to policy-makersand programmes.

The efficacy trials under consideration included:

1. a study in Nepal looking at birth weight beingconducted by CICH with funds from theWellcome Trust;

2. a study in Guinea-Bissau looking at birth weightbeing conducted by the Royal Veterinary andAgricultural University with funds from DANIDA;

3. a study in Bangladesh looking at birth weightbeing conducted by ICDDRB with funds fromUNICEF;

4. a study in Pakistan looking at birth weight beingconducted by the Aga Khan University with fundsfrom UNICEF;

5. a study in Indonesia looking at maternal mortalityand birth weight being conducted by Helen KellerInternational with funds from UNICEF and USAID.

In addition, the group discussed three otherprotocols: a study in Bangladesh looking at vitaminA supplementation during pregnancy and maternalmortality being conducted by the Johns Hopkins’University group with funds from USAID and TheGates Foundation; a study in Tanzania looking at adifferent multiple micronutrient supplement duringpregnancy and birth weight in non-HIV infectedmothers being conducted by the Harvard School ofPublic Health group with funds from NIH and

• 4 • MMSDP: Efficacy Trials

UNICEF; a completed study from Nepal looking at adifferent multiple micronutrient supplement duringpregnancy and birth weight and early child moralityconducted by the Johns Hopkins University groupwith funds from UNICEF and USAID. After havingjointly reviewed these protocols, the meeting splitinto two smaller working groups. The first group,consisting of the investigators, discussed further thedesign and ethical issues of efficacy trials and futurecollaboration. A second group considered theprogramme implications of the ongoing research.

A recommended list of minimum requirements forstudy design, outcomes to be measured, andconfounders or effect-modifiers to be included wasagreed, which will enhance the possibility of aneventual pooled analysis. It was agreed that whilstthe use of birth weight as an outcome is important, itdoes not fully capture the potential benefits ofimproved maternal nutritional status on birthoutcomes. All trials should seek to captureinformation on perinatal mortality. Other maternalmortality trials should also be considered.Collaboration across sites in the sharing ofexperience in developing standardized tools, such asverbal autopsy (abortion/miscarriage,stillbirth/neonatal death), and night blindness wasinitiated. All agreed on the desirability of developinglocal data safety and monitoring boards to managethe ongoing ethical aspects of such trials. Indonesiais most advanced in this and others would like tolearn from them. Pathways to facilitate the processof policy change and enabling activities that couldsupport the eventual distribution of multiplemicronutrient supplements should they prove to beefficacious, within safer motherhood initiatives werealso discussed, including the need for effectivenesstrials to be run in parallel with the efficacy trials.

MMSDP: Efficacy Trials • 5 •

The group as a whole felt that the meeting had beenvery constructive and useful, and that continuedefforts were called for to promote furthercollaboration across trial sites. Increased liaison wasdesirable for information sharing, keeping everybodyupdated, and even troubleshooting if necessary. Amailing list was suggested that should be expandedto include all constituents working on multiplemicronutrient supplements, both efficacy andeffectiveness studies, especially from developingcountries. A further meeting was called for, whichpreferably should meet in South Asia within a year,to report on progress and involve an expanded setof research objectives and researchers and bring thenecessary extra expertise onboard.

These findings and recommendations werepresented to an expanded group of participants onthe final day, which included representatives ofCanadian CIDA, The Wellcome Trust Foundation,The World Bank, The Division of Reproductive Healthof WHO, USAID, Helen Keller International and theMicronutrient Initiative. After discussion with thisexpanded group, it was largely agreed that thevarious organisations present could and should helpsupport and carry forward the recommendations ofthe meeting.

IntroductionWhilst WHO recommends universal distribution ofiron/folate supplements to anaemic mothers indeveloping countries, it is increasingly recognisedthat many such women suffer from multiplemicronutrient deficiencies, not just iron deficiency. Inrecognition of this UNICEF, WHO and UNU haveagreed upon the formulation of a multiplemicronutrient supplement for use in trials with theview to eventually replacing the iron/folatesupplement(1,2). This supplement, the composition ofwhich is described in Table 1, is being used by avariety of research groups in trials funded by avariety of funding agencies. The research question iswhether multiple micronutrient supplementssignificantly improve pregnancy outcomes ascompared to iron-folate supplements. An interestwas expressed by both researchers and agenciesinvolved to increase collaboration among theongoing efficacy trials, and to that end a meetingwas held at the Centre for International Child Health,Institute of Child Health, London, from March 4-8,2002, funded by the Micronutrient Initiative.

The objectives of the meeting were directed towardsboth increasing the efficiency of the research effortand speeding the translation of scientific results intopolicy and programmes. Whilst the main aim of themeeting was to explore ways of increasing thecollaboration across these research groups, greatpains were taken to try to ensure that thediscussions were firmly grounded in the needs andreality of intervention programmes. The meeting wasattended by leading researchers and principalinvestigators of micronutrient trials, and policy-makers from several international agencies includingUNICEF, UNU, WHO, HKI, the World Bank, CIDA,USAID, the Micronutrient Initiative and the WellcomeTrust. The first objective was to explore how tomaximize the research outcomes that would beobtained from the various multiple micronutrientsupplementation trials. The second objective was toseek ways of ensuring as far as possible improvedcomparability across the various trials, and ifappropriate to maximize possibilities of pooling dataacross sites in the future. The third objective was todiscuss mechanisms by which research findingswould be fast-tracked to policy-makers andprogrammes as soon as results became available.

The meeting was organized in two parts, the firstfocused on research and the second on policy andprogrammes. The first four days mainly involved theprincipal investigators involved in micronutrientsupplementation efficacy trials together withrepresentatives from UNICEF, WHO, UNU, HKI andUSAID discussing the details of the trials. Afterhaving jointly reviewed the various researchprotocols from the respective trials, the meeting splitinto two smaller working groups. Whilst one groupmade up of the principal investigators discussedfurther the design and ethical issues of efficacy trialsand the possibilities for future collaboration, asecond group considered the programmeimplications of the ongoing research. On the finalday, the meeting discussed the results of theconsultation with a wider audience of policy andprogramme oriented participants from the WorldBank, CIDA, the Wellcome Trust and theMicronutrient Initiative.


Table 1. Composition of multiplemicronutrient supplement for pregnant andlactating women recommended for trialpurposes by UNICEF / UNU / WHO.

Nutrient Amount

Vitamin A 800 mcg

Vitamin D 200 IU

Vitamin E 10 mg

Vitamin C 70 mg

Vitamin B1 1.4 mg

Vitamin B2 1.4 mg

Niacin 18 mg

Vitamin B6 1.9 mg

Vitamin B12 2.6 mg

Folic Acid 400 mcg

Iron 30 mg

Zinc 15 mg

Copper 2 mg

Selenium 65 mcg

Iodine 150 mcg

Policy contextPolicy development for micronutrients has largelybeen limited to iron, iodine and vitamin A for severaldecades. If a multiple micronutrient supplement wereadopted instead of iron/folate supplements it wouldbe a significant change, and the new product wouldgive a new dimension to programmes aimed atwomen during pregnancy and lactation. In order tounderstand the process of moving down the scienceto policy to programme track, it is instructive to lookat how this has worked for these othermicronutrients, especially for iron and vitamin A,which are primarily provided as supplements.Understanding what the evidence base was that wasused to decide on the adoption of these policies,and how such evidence was accumulated, mighthelp speed the process of adoption of a multiplemicronutrient supplement should it be provenefficacious.

The evolution of policy and programmes forimproving vitamin A status stretches back over thirtyyears. The first policy recommendations for vitaminA largely concerned the use of vitamin Asupplements for the prevention of blindness(3). Thediscovery that the widespread use of capsules notonly led to the elimination of blindness but also tothe reduction of young child mortality led to the largescale use of vitamin A supplements in differentcountries to further test for these effects(4). Thisprocess was initially developed through thecommittee on international nutrition programmes ofthe Food and Nutrition Board in the US thatproduced a common protocol for conducting furthertrials to investigate the effects of vitamin Asupplements in the field(5). As such research gatheredpace, a further meeting of this sort was held at WHOin Geneva in 1991, when the principal investigatorsof ten vitamin A supplementation trials met andagreed how they might collaborate as theirrespective trials were being conducted(6). Theexistence of these common protocols and researchdesigns facilitated the work of the group that carriedout the meta-analysis of vitamin A supplementationtrials under the umbrella of the ACC/SCN. The reportby Beaton et al (1993) found that improving vitaminA status, whether through high or low dosesupplements or a fortified condiment, reduced childmortality by 23%(7). With this came the internationalrecognition that further randomised studies ofvitamin A and child mortality with placebo controls

would be unethical and that there was now a needto increase investments in vitamin Asupplementation programmes. Despite thisrecognition, by the mid decade there was still nolarge-scale move to introduce massive dosecapsules into programmes. It was only after atechnical consensus meeting was held in UNICEF in1997 and the joint action of both bilateral andmultilateral agency consortium called the Vitamin AGlobal Initiative, that progress was seen in the latterpart of the decade(8). Recent trends for large-scalevitamin A supplementation programmes suggest thatmore capsules are being distributed and high levelsof coverage are being achieved in many countries(9).One study has reported a change in maternalmortality if preconceptual, periconceptual andpostconceptual vitamin A/beta-carotenesupplementation is provided(10). Another is currentlyunderway in Ghana where malaria is common. Thereis a need to define how much research knowledge isneeded before policy can be formulated with regardto vitamin A supplementation of mothers forexample. When is enough enough and who decides,be it at the country or international level?

The World Health Organization first formulated apolicy that recommended that pregnant women besupplemented with iron supplements in 1968(1). Theprimary objective in formulating this policy was toreduce the high prevalence of iron-deficiencyanaemia observed in women during lactation andpregnancy across the globe(1). No thought was givenat that time of the need to show or improvebeneficial effects of iron supplementation beyond thereduction of anaemia. Since that time however, littlemore scientific evidence has accrued to support theuse of iron supplements for other benefits beyondthat of anaemia reduction, and there is a growingconcern in some quarters that high haemoglobinlevels during pregnancy are not always beneficial(11,12).The systematic reviews of both iron and folatesupplementation conclude that whilst there isevidence that anaemia is improved, there is noevidence of improvement in other birth outcomessuch as low birth weight and maternal mortality(13,14).These systematic reviews have agreed however thatthere is a lack of studies in resource poor settingsamongst women that are likely to be most deficient.In addition to this, there are ethical issues that makeit difficult to test the efficacy against a placebo


control since the policy in most countries is to giveiron supplements to women during pregnancy.Governments have increasingly adopted this policyas a means to tackle iron-deficiency anaemia andhave implemented large-scale supplementationprogrammes(9). Yet the prevalence of iron-deficiencystill remains high in most countries(15). This has oftenbeen attributed to poor compliance and distributionof supplements, but also the para-professional’s lackof knowledge about the supplements(9). A consensusmeeting was held to try to establish the technicalconsensus to move forward with iron programmes inUNICEF in 1998(16). But there has not been any largemove at the programme level, such that levels ofsupplements and programmes aimed at trying toreduce iron deficiency anaemia are not movingforward(9). There is also a growing concern with therisks iron supplementation may bring for somemothers, especially those that don’t showhaemodilution and the consequent lowerhemoglobin levels in the latter part of pregnancy(11,17).

This is the policy environment that forms thebackdrop for policy development for multiplemicronutrient supplements. The UNU/WHO/UNICEFsupplements are similar in formulation to thosereadily available on the open market in manydeveloping countries, and that are taken by thoseable to purchase them. The ethical dilemma thatsurrounds these micronutrient trials concerns the actof withholding them from poor women when it isknown that their dietary intakes are belowrecommended levels for these nutrients. At the sametime having evidence that providing the nutrientsresulted in measurable improvements in birthoutcomes would help convince health economistsand senior officials in Ministries of Health that thereare strong cost benefits for adopting suchsupplements. The potential advantage of a multiplemicronutrient supplement in pregnancy is simply thatiron folate is already being distributed, if it wereswitched to a multiple micronutrient supplement,then a single supplement could have multiple andimportant effects on maternal and infant well being.How best to investigate these possible benefits andhow to deal with the ethical issues around knowingwhen to stop the experiment are the issues thatneed to be dealt with. The group was asked toreflect on these dilemmas and to come up withsuggestions during their deliberations.

Programme contextThe multiple micronutrient supplements that arebeing tested in the different country settings arebeing provided through a variety of differentprogrammatic settings. These interventions are beingpursued because the evidence that they are likely tobe beneficial is already considerable. In all theUNICEF supported studies, the supplements arebeing tested as part of a new initiative to prevent lowbirth weight. At a programmatic level, interventionsdesigned to tackle childhood malnutrition have oftenhad only limited success because of their inability toaddress the larger problem of low-birth weight(18).Although a balanced protein energy supplement hasbeen shown to have an effect on low birth weight,few programmes have been proven to prevent low-birth weight, and it is admittedly a difficult outcometo impact upon(19,20,21). Improvements in birth weighthave been shown to be independently associated tomaternal weight gain during pregnancy and maternalpre-pregnant weight(19). The Institute of Medicine inthe US introduced recommendations on desirableweight gain during pregnancy that were considerablyhigher to those recommended prior to 1990(22). Theserecommendations have been widely implemented inthe US through the Women, Infants and Children(WIC) programmes of the Government, and evidenceso far is that these are proving both feasible andbeneficial in the US context(23). However, fewprogrammatic interventions that aim to improvematernal nutritional status and thus pregnancyoutcome have been tested in developing countrysettings. There are no programmaticrecommendations from WHO for example, on how toproceed in this area. Increasingly, it is becomingclear that packages of interventions will need to beimplemented to improve pregnancy outcome andprevent low-birth weight and that micronutrientinterventions should be part of this(19,24,25).

In most programmatic settings, the introduction ofthe multiple micronutrient supplements will not be astand-alone activity(26). It will almost always be part ofa package of interventions aimed at improving thehealth and the nutrition status of the pregnant andlactating mother. To date, interventions that havebeen implemented to improve maternal nutrition andto prevent low birth weight range from communitybased food supplementation programmes, such asthe BINP programme in Bangladesh, to safemotherhood programmes, be they clinic based as in


the Philippines or community based as in Indonesia.Where malaria is a problem, the use of insecticidetreated bed nets is likely to be a programmaticcomponent together with chemoprophylaxis, as isthe case in Tanzania where deworming is also part ofthe antenatal care package. Together, these variousinterventions provide an opportunity where pregnantwomen can be given multiple micronutrientsupplements; in many cases, the infrastructure is inplace, though it may be imperfect. The participantswere asked to reflect on these aspects ofprogramme design and context of the multiplemicronutrient supplements and makerecommendations as to how to best deal with theseissues in the extrapolation of the research result toprogrammes in the future.

Scientific contextSeveral studies have now shown that poor women indeveloping country settings consume diets that aremicronutrient poor, and in some cases may havediets that inhibit micronutrient absorption (e.g. thehigh phytate diets based on maize for example).Such diets are more qualitatively than quantitativelydeficient, such that even if energy needs are metmicronutrient needs are not(27,28). A recent review byRamakrishnan et al (1999) on micronutrients andpregnancy outcome found that there was strongevidence from well-designed randomised controlledtrials that zinc, calcium and magnesium improvepregnancy outcomes, mainly affecting pre-maturity,birth weight, and pregnancy-induced hypertension(29).The authors found the effect of other singlemicronutrients on pregnancy outcome to beinconclusive, mainly due to weak study designs andsmall sample sizes. They recommended that furtherresearch be undertaken particularly for iodine, iron,folic acid, and for multiple micronutrientsupplements, specifically in relation to pregnancyoutcomes (e.g., birth weight and perinatal mortality).Recent research on vitamin A and pregnancyoutcome by West et al (1999) found thatsupplementing women of reproductive age with aweekly low dose of vitamin A in Nepal significantlyreduced maternal mortality in those mothers thatbecame pregnant by 44%(10). Importantly, recentresearch in Tanzania shows that multiplemicronutrient supplements significantly improvedpregnancy outcome in HIV-positive women, reducingLBW by 44%, pre-term delivery (<34 weeks) by39%, and IUGR by 43%(30). In view of the

considerable variations in infection load betweencommunities (e.g. malaria and HIV), there needs tobe clarification on what ‘scenarios’ need to bedefined for vitamin A studies to be performed.Defining how to assess micronutrient status inpregnancy and lactation in the presence of infection,especially becomes an important research issue.

All of these findings indicate that it is reasonable anduseful to further test a multiple micronutrientsupplement to determine the size of the effect onpregnancy outcomes. The research trials to testmicronutrient supplements that are planned orcurrently on-going provide an opportunity tomaximise on these research findings. A meta-analysis of these studies would allow a moreconsolidated analysis of their findings and helpcreate the cast iron scientific arguments needed toconvince Ministries of Health to invest in suchinterventions should that prove warranted. Althoughthere is concern that when combined, some of themicronutrients may interact with one another andthus inhibit absorption, there is some evidencesuggesting that absorption of certain nutrients suchas iron may actually be enhanced(27). Every effortshould also be given to ensure that such trials havethe capacity to detect any adverse consequences atan early stage, even though this may be consideredto be very remotely possible. The group was askedto reflect on these issues during their deliberationsand to make recommendations on how to deal withthem.

Description of studiesThe principal investigators from eight planned oron-going efficacy trials of nutrient supplementationduring pregnancy were invited to attend thismeeting. The studies included for joint examinationare either planned, underway or completed, inPakistan, Bangladesh (two studies), Nepal (twostudies), Guinea-Bissau, Indonesia, Tanzania, andNiger. All are randomised controlled trials, and withthe exception of the Johns Hopkins’ Bangladeshstudy, all are multiple micronutrientsupplementation efficacy trials. Each one intends tosupplement pregnant women with a multiplemicronutrient supplement. The supplements usedin the different trials are largely similar. With theexception of the Johns Hopkins’ Bangladesh study


and the Harvard Tanzania study and the JohnsHopkins’ Nepal study, all others will be or are usingsupplements based on the UNICEF/WHO/UNUformulation, as described in Table 1. These studiesvary in design and duration of supplementation, butthe outcome variables measured in each of thestudies are similar for most studies. The studydesign details are given in Annex 1.

The Aga Kahn study in Pakistan aims to determinewhich of four interventions during pregnancy willimprove maternal nutritional status and infant birthweight, and reduces the prevalence of low birthweight in the sample. It is designed as a clusterrandomised control trial with a 2x2 factorial design.Thirty clusters will be divided into four cells with atotal sample size of 1600 pregnant women. Each cellwill be randomly allocated to receive one of fourinterventions including either a multiple micronutrientsupplement or an iron-folate supplement with orwithout nutrition education. The main outcomesmeasured will be birth weight and maternalnutritional status

In Nepal, the primary aim of the CICH study is toevaluate the effect of antenatal multiplemicronutrient supplements on birth weight,gestation, and perinatal infections in mothers andinfants. This is a double-blind randomised controltrial where 1200 pregnant women will be randomisedat the individual level to receive either an iron-folatesupplement or a multiple micronutrient supplement.The main outcomes being measured will includebirth weight, perinatal mortality, maternal nutritionalstatus, and maternal immunological status (on asub-sample).

The Royal Veterinary and Agricultural Universitystudy in Guinea-Bissau aims to determine the effectsof antenatal multiple micronutrient supplements onpregnancy outcome, and peri- and neonatalmortality. It is designed as a double blindrandomised controlled intervention study where2250 pregnant women will be randomised at theindividual level to receive one of three treatments.One arm will receive iron-folate supplements, thesecond will receive a multiple micronutrientsupplement equivalent to one RDA, and the thirdarm will receive twice the RDA. The main outcomesmeasured will be maternal nutritional status, birthweight, peri- and neonatal mortality, infant mortality,and early infant growth.

The primary research aim for the Johns Hopkins’study in Bangladesh is to determine whethersupplementing women of reproductive age with asingle RDA of vitamin A can reduce all-causepregnancy related mortality by 35% or more. Thestudy is designed as a cluster randomised doubleblind placebo controlled trial. Women of reproductiveage will receive a weekly supplement of a placebo, avitamin A capsule of 7000 retinol equivalents. Theplanned sample size is 54000 pregnancies. The mainstudy outcomes are maternal mortality, foetal loss,and infant mortality.

The HKI study in Indonesia aims to assess therelative impact of multiple micronutrient supplementscompared to iron/folate supplements on maternalmortality, infant mortality and low-birth weight. Thisis a community-based cluster randomised doubleblind intervention trial. Pregnant women will besupplemented with either the multiple micronutrientsupplement or an iron-folate supplement. Theintended sample size is 126000 pregnancies. Themain study outcomes are maternal mortality, infantmortality, low birth weight, and maternalbiochemistry.

The study aims of the ICDDR,B study in Matlab,Bangladesh are to determine whether supplementingpregnant women with a multiple micronutrientsupplement will significantly improve maternalhaematological status or birth weight. It will also lookat the interaction between supplements and early orlate food supplementation. This is a double blindrandomised controlled study where pregnant womenwill be randomised at the individual level. It follows a2x3 factorial design (6 cells) and intends to recruit3000 pregnant women. Three cells will be started onfood supplementation early in pregnancy and theremaining three will begin food supplementation laterin pregnancy. A third of the women will receive amultiple micronutrient supplement, a second groupwill receive a low-dose iron-folate supplement, andthe third group will receive a high dose iron-folatesupplement. The main outcomes measured willinclude birth weight, maternal haematological status,pre-term delivery, weight gain during pregnancy,gestational age, and maternal micronutrient status.

The primary research aim for the Harvard study inTanzania is to determine whether supplementing HIVnegative pregnant women with a daily multiplemicronutrient supplement will reduce the risk offoetal loss, low-birth weight, and pre-term delivery


compared to women who receive an iron-folatesupplement. The study is a clinic-to-communitydouble blind randomised controlled interventionstudy where women will be randomised at theindividual level. Pregnant women will be randomlyallocated to receive either a multiple micronutrientsupplement or an iron-folate supplement. Themicronutrient supplement has several nutrients inmultiple RDA doses, and as such is more apharmacological than physiological level ofsupplementation. The intended sample size is 6000HIV negative pregnant women. The main outcomesmeasured will include foetal loss, low birth weight,and pre-term birth.

After having discussed all these protocols it wasdecided to focus further discussions only on the fivestudies that will be using the UNICEF/UNU/WHOsupplement. The Tanzania study will besupplementing women with a multiple micronutrientsupplement containing pharmacological doses ofmicronutrients, which differs from the aforesaidformulation. The Johns Hopkins’ Bangladesh studyis looking at the effects of vitamin A, and has nomultiple micronutrient supplements included as yet,and the finished study of Johns Hopkins in Nepal didnot use the UNICEF/WHO/UNU supplementformulation. The study design for the HKI study inNiger is still being formulated, and was therefore notdiscussed. The group felt that of these eight studies,only five should be discussed more thoroughly.Because of these fundamental differences, it was feltthat any eventual pooled analysis would only includethese five studies. It was made clear though thatother trials not discussed at this meeting could beincluded in an eventual pooled analysis as long asthe trials were consistent with the basic guidelinesand recommendations defined at this meeting.

Discussion ofoutcome measuresThe unifying feature among all the studies is thatthey intend to measure birth weight as thedependent outcome variable. They also assessmaternal nutritional status, mainly maternal weightand height. Some of these studies will alsoundertake more thorough assessments ofbiochemical status. Four studies will assess infantgrowth in the first year of life. The Indonesian studywill look at maternal mortality. Details about the

outcome measures for each study are given inTable 2.

Several issues were discussed with regard to theoutcomes measured in these studies. The discussioncentred on three major issues namely obtainingaccurate birth weights, measuring thestillbirth/neonatal mortality rate and headcircumference. It was agreed that every effort shouldbe made to get birth weight within 24 hours of birth.A locally constructed normogramme could be usedto validate the use of weights taken beyond 24hours. The disadvantage of using such anormogramme is that it artificially restricts thevariability attributed to those birth weights. Althoughthe UNISCALE only weighs to the nearest 100g it isstill an accurate scale. In reality weighing to lessthan 100g gives a false idea of accuracy sinceweighing procedures cannot ensure that the baby isweighed with an empty stomach and an emptybladder, and these two alone can producedifferences in weight of 100g or more. The effect ofonly weighing to 100g as compared to using abalance that weighs to the nearest 10g does notseem to affect the variance of the measure, but thismerits further investigation. The sample sizecalculations for birth weight are all calculated basedon estimates of variance associated with the use of“normal” balances that weigh to 100g and not themore precise scales that weigh to 10g. Whilst 10gprecision was called for in metabolic work with newborn babies, for population based studies suchprecision is of dubious value. The UNISCALE isbeing used to construct the new growth curve beingprepared by WHO, and the investigator group fromthat study has checked the precision and accuracyof the scale for this purpose. The various documentsavailable on precision, accuracy and ease of use ofthe UNISCALE should be shared with the principalinvestigators. All trials should routinely check forprecision and accuracy of scales on a three monthlybasis.

It was felt that the use of birth weight alone tomeasure the efficacy of multiple micronutrientsupplements is not advised. The spectrum ofabortion, miscarriage, stillbirth, and neonatalmortality is an important one to investigate. Moststudies will also measure perinatal mortality. Thosethat do not are seeking extra funds to be able toinclude these outcomes. The investigation of theseevents requires the construction of verbal autopsymethods. Standardized tools exist that can be


adapted to the local cultural context. Pakistan andIndonesia have already developed tools which coverthese aspects and have agreed to share it withothers as appropriate.

It was suggested that measuring head circumferencewould be important for advocacy purposes to helpallay the myth that bigger birth weight will meanmore difficult births. All trials agreed that they wouldmeasure head circumference. Researchers felt thatto measure haemoglobin, venous blood is preferredover capillary blood. However, assessinghaemoglobin by using a haemocue was thought tobe acceptable as long as care is taken with the use

of haemocue cuvettes. It was felt that these trialsshould include instruments to investigate maternalnight blindness and treatment protocols for womenwith night blindness in their sample. Several trialsare attempting to capture maternal morbidity. Someare using a periodic recall. Others recognizing thedifficulty of getting reliable data from recall methodsare using biochemical markers of infection. Thedesirability of developing local data safety andmonitoring boards to manage the ongoing ethicalaspects of such trials was agreed by all. Indonesia ismost advanced in this and others would like to learnfrom them.


Table 2: Outcomes being measured in the five studies

Outcome Pakistan Nepal Guinea Bissau Bangladesh Indonesia

Birth weight Yes Yes Yes Yes Yes

Head circumference Yes Yes Yes Yes Yes

Infant development Yes No No Yes No

Infant growth Yes No Yes Yes Yes

Infant morbidity Yes Yes (neonatal) Yes Yes Yes

Perinatal and neonatal mortality Yes No Yes Yes Yes

Gestational age Yes Yes Yes Yes Yes

Maternal night blindness Yes No No Yes Yes

Maternal anaemia Yes Yes Yes Yes Yes

Maternal Yes (iron, Yes (retinol, Yes (folate, Yes (iron, Yes (B-vitamins,micronutrient status zinc, retinol, Vit C, Vit E, retinol, Vit E, retinol, retinol,

and carotene) carotenoids) iron, carotene) carotenoids, carotenoids,tocopherol, Vit E, Fe, selenium, Zn, Cu, Se)arsenic)

Maternal anthropometrics Yes Yes Yes Yes(weight gain) (height, weight) (height, (weight

weight, gain,MUAC) weight,

height,skin folds, MUAC)

Maternal morbidity No Yes (lab) No Yes Yes

Maternal mortality No No No No Yes

The outcomes denoted in bold are the dependent variables in the hypothesis being tested and for whichsample size calculations were developed. The other outcomes are being measured for use in the analysis asindependent variables, and may be effect modifiers. Some of these outcomes may also show a treatmenteffect. They may also be used to check for confounding variables.

Discussion of main interventions Broadly, four important issues were discussed withregard to the interventions being implemented ineach trial. These were to ensure and enhancecompliance, to increase internal and external validity,and the formulation of the supplement. Thesuggestions as discussed by the group are givenbelow. Details of the planned interventions for eachstudy are given in Annex 1. Table 3 presents asummary of the sample size and power calculations,the planned analysis, and details of the ethicalapproval obtained for each study.

Adherence The investigators recognized that the effort put intotrying to verify the degree of adherence with theexperimental protocol with regard to taking thesupplements was critical. The difference betweenefficacy and efficiency trials largely revolve aroundwhether the treatment is provided by a third party orself-administered. In large scale trials carried outthrough regular programme infra-structures (as is thecase in the five studies concerned) it is vital to provethat treatments are taken.

The investigators felt that checking adherence(commonly called compliance) by pill countingshould be done more frequently than just monthly.The validity of pill counting could be improved byproviding more supplements than needed that couldthen be replenished periodically (e.g. provide 45 pillsand the fieldworker would return in 28 days toreplenish). A suggestion was made to assess urinaryriboflavin or erythrocyte riboflavin randomly, whichwould be useful to give an indication of complianceat the group level, but not at the individual level.Indonesia has a predictive index of compliance thatis used to identify mothers requiring specialattention; it was felt that this could be shared withothers. Recommendations about how thesupplements were to be taken whether on an emptystomach or after meals need to be clear as theywould differ by context due to variations intraditional diets (e.g. high phytate diets that couldinhibit absorption).

EnhancingadherenceThe investigators agreed that as is amply shown inthe literature, one of the most importantdeterminants of adherence is the subject’s belief inthe good intentions of the health provider. All felt it isimportant to adequately train staff so theyunderstood how to counsel participants on potentialside effects and to enquire about and documentthese side effects. It is important to ensure thatsubjects understand what to expect and what not toexpect from the supplement (i.e. it is not a headachepill or an antibiotic). To enhance adherence,Indonesia and Pakistan have also undertaken/plan toundertake community and social marketingactivities.

Internal and external validitySuggestions to increase internal and external validitywere to take a random sample of supplements fromthe field at various time-points in the study and totest them locally and send them to an independentlab for testing. Tests can include testing fordegradation of folic acid, vitamin E and/or vitamin A.Most sites don’t have the funds or resources for thisand would require external help to make it happen.

Formulation of supplementMultiple doses of RDAs may be necessary inpopulations where disease states are excessively high(e.g. malaria/ HIV) or where dietary inhibitors arepresent in high amounts. Trials may use formulationsother than the UNICEF/UNU/WHO supplement but, ifso, should compare these variant supplements withthe basic supplement. The issue of whether thesupplements are halal or non-halal was largelyresolved. Indonesia has dealt with this by using acapsule with fish oil encapsulation. It was also notedthat a letter had been shared at a WHO/UNICEFmeeting in the Middle Eastern Region, which had beenproduced by prominent members of several Islamicstates stating that the gelatin used to coat tablets hasbeen processed so much that the product used isconsidered acceptable in Islamic communities.



Table 3 Planned interventions

1. Pakistan 1. MMC

2. MMC andnutritioneducation

3. Iron-folate

4. Iron-folateandnutrition ed

• Pills to be taken dailyonce

• Pill counting andreplacement

• Checked every 2weeks

• Maternalusage andacceptabilityofsupplementand energyproteinsupplement

• Communityeducation

Enrolment at16-20 weeksto delivery and3 monthspost-partum

Tablet –UNICEF MMN

Iron/Folate60/400

StandardUNICEF/WHOrecommendedsupplementsand antenatalcare

(withinstudytesting oftabs)

(tabs sentout fortesting)

2. Nepal 1. MMC

2. Iron-folate

• Monthly in-clinic pillcounting

• Fortnightly pillcounting

• Monthly home visit pillcounting

• Self-admin-isteredsup-plements takendaily once

• Change in maternalblood mi-cronutrientstatus

• Fortnightlycounselling

From amaximum ofWeek 20 todelivery

UNICEF MMNTablets andIron/Folate60/400

StandardUNICEF/WHOrecommendedsupplements

6 monthlyanalysisof tabletconstituents bythirdparty lab-oratory

3. Guinea-Bissau

1. MMC (1RDA)*

2. MMC (2RDA)

3. Iron andfolate

*1 will be theUNICEF tabletproduced bythe UNICEFsupplier

• Supplementsdistributed every 2weeks until delivery

• Taken once daily

• Pill count andreplenish every twoweeks

• Women willbeinstructedon theimportanceof regularintake of thetablets forher and herbaby’shealth

Week 16-35 todelivery

UNICEF MMTablets (1RDA, 30mgIron), MMTablets (2RDA, 30mgiron) oriron/folateTablets(60/0.4mg)

Women withsevereanaemia weregiven anadditionaliron/folate

Tablets

All threetablets areidentical

StandardUNICEF/WHOrecommendedsupplements

Site Interventions Methods to checkadherence

Enhancingadherance

SupplementType

Duration ofSupplement-ation

Standard-ization

Tech-niquesInternalvalidity

ExternalValidity

Table 3 Planned interventions (continued)


5. Indonesia 1. MMC

2. Iron-folate

• Pills to be taken dailyonce

• Supplements will bedistributed monthly

• Field workers willcheck adherence byspot-checking andpill-counting

• Biochemical indiceswill be assessed tocheck for erythrocyteenzymatic activity forriboflavin, plasmavitamin A and zinc

• Adherence will bechecked 3x a month

• Fieldworkers willcheck if anyone else istaking the capsule

• Use the predictiveindex of compliance

• Random inspections

Qualitativeassessment ofperceptionsand attitudestowardsprenatalsupplements

Socialmarketing

Enrolment todelivery(enrolled assoon asidentified aspregnant)

UNICEF MMNformulation inlocally producecapsule

Iron-folate30/400

CheckcapsulesinIndonesia

Checktabs inCopenhagen

4. Bangladesh– 2

Individual-levelrandomisedinterventiontrial

I) Earlycaloriesupplementation

1. MMC

2. Iron-folate30/400


II) Usualsupplementation

1. MMC



Pills to be taken dailyonce

Pills to be replenishedmonthly.

Special electronicequipment called eDEM‚will be used to monitoradherence. This methodwill be compared withother measures ofcompliance such as pill-counts and recalls of thepregnant women.

Micronutrientsupplementation from week14 to 3 monthspost partum.

UNICEF MMNtablet

Iron-folatetablet (30/400)

Iron-folatetablet (60/400)

All tablets lookalike

StandardUNICEF/WHOrecommendedsupplementsand antenatalcare

Tabletssent outfor testing

Site Interventions Methods to checkadherence

Enhancingadherance

SupplementType

Duration ofSupplement-ation

Standard-ization

Tech-niquesInternalvalidity

ExternalValidity

Group discussionof the scientificand studyimplementationissues The group of principal investigators discussed aseries of issues related to common indicators andvariables, biomarkers, ethics, analysis, and furtherneed for increased coordination. The variouscommon variables that all studies should collect tohelp typify the study population and to demonstratethat randomisation worked include: rural/peri-urban/urban settings; SES indicators, includingownership of house and other assets, andenvironmental sanitation; education;health system indicators including homebirths, birth attended by trainedattendants, anti-malarial and bed net usein malarial areas; age; parity; previouspregnancy outcome; gestational age atenrolment; date and season of enrolment;maternal nutritional status (weight, height,MUAC); substance use including tobacco,alcohol and betel nut; birth weights takenwithin 24hrs, 24-48 hours, 48-72 hours.

The biomarkers recommended for use insuch studies were of two types: the corebiomarker indicators are that all studiesshould include haemoglobin, ferritin andserum retinol. Additional indicators to beconsidered for inclusion included serumzinc, transferrin receptor, serum and redcell folate, urinary and red cell riboflavin,vitamin C, and total carotenoids. Theacute phase reactant proteins (ACT, AGP,and CRP) are also recommended asmarkers for infections.

On ethical issues the group agreed thatwhilst ethics’ committees in bothsponsoring institutions and fundingagencies had cleared most studies as astandard requirement, in few places was alocal capacity created to monitor the trialas it progressed. The use of local datasafety and monitoring boards was


strongly recommended in all studies. The group withthe best experience in this was the HKI study inIndonesia. The possibility of linking up coremembers of data monitoring boards in each site inorder to transfer capacity is one possibility for futureaction, but this would require extra funds.

Any future analysis, be it joint or individual, shouldbe developed with an “intent to treat” approach andfollow the CONSORT guidelines (www.consort-statement.org) for the consolidated standards ofreporting randomised control trials. These analysesshould consider potential confounders and effectmodifiers as discussed below and look at birthweight, gestational age, and mortality (as rates andrelative risks) and survival outcomes.

A discussion about the possible confounders oreffect-modifiers led the group to develop a list ofwhich variables it would be advisable to collect.

Table 4. List of required and recommended confoundersand effect-modifiers to be recorded.

Parameter* Required Recommended

Maternal height at enrolment X

Maternal weight at enrolment X

Parity X

Age at enrolment X

Previous pregnancy outcomes X

Smoking habits X

Alcohol/substance abuse X

Date of last menstrual period X

Other supplements consumed X

Date of enrolment (seasonal issues) X

Date of delivery X Time of birth X

Time of weighing infant X

Completed years of education X

Who was present at delivery X

Bednet use and anti-malarial use X

Maternal work load X

Maternal MUAC X

Number of antenatal care visits X

Dietary habits X

Domestic violence X

Water and sanitation X

Night blindness during pregnancy X

Exposure to domestic smoke X

* order not indicative of importance

Table 4 presents which data would be required andwhich would be recommended. This is the keyinformation that would need to be collected todescribe the study population and facilitatecomparability between studies and enable analysesincluding other factors likely to influence outcomessuch as birth weight, infant mortality, and maternalmortality

The group agreed that some form of continuedliaison after the meeting was very desirable forcontinued information sharing, technical updatesand troubleshooting. The notion was put forward ofcreating a mailing list for a Multiple MicronutrientInterest Group that should include all key players,especially those from developing countries. Thegroup supported the idea that such a capacity becreated at CICH. Another meeting of the group wasrequested within the year and that should be held inSouth Asia, and include the expanded group ofconstituents. It was agreed that such a meetingshould attempt to bring additional expertise onboard including: basic scientists, reproductive healthexperts, randomised control trial experts andbiostatisticians, and public health experts.

Group discussionof the process ofpolicy change andprogrammaticimplicationsThe discussions by the non-investigator group onthe process of policy change and how the provisionof multiple micronutrient supplements could beachieved at a programmatic level focused on severalareas. Firstly, the group recognised that policyimplementation would need to occur at severallevels, at the international, national and/or districtlevels. At each level, the benefits of the interventionbased on consistent and plausible research findingswould need to be clearly presented and defined.International agencies and consultative groups andnational governments would have to be convinced ofthe benefits and that implementation would beaffordable, especially within strategic partnerships.To be convinced of the need for policy change,policy-makers would need to see

changes/improvements in key indicators. The groupfelt that the indicators of greatest interest includedmonitoring the prevalence of low birth weight;maternal mortality and morbidity; infant and youngchild mortality and morbidity; maternal nutrition;breast milk nutrition; anaemia; vitamin A deficiency;and child development. The group also felt that theinfrastructure by which supplements could be madeavailable was already in place. Enabling activitiesthat could support multiple micronutrientsupplementation included malaria, HIV, de-wormingand STD control programmes; pelvic infectiontreatment programmes; birth spacing activities; safermotherhood initiatives; and integrated managementof childhood infection programmes. All of theseprogrammes provide an opportunity forsupplementation and a point of contact.

Sectors through which multiple micronutrientsupplementation could be undertaken includedhealth systems, such as antenatal care andimmunization programmes; community healthprogrammes, such as national immunisation/HIVdays; social development programmes, such ascommunity groups/NGOs. But it was clear that forinclusion of a multiple micronutrient interventionthere was a need to identify the full cost of activitiesand the added value of multiple micronutrientsupplementation to specific sectoral activities. Thekey question is what is the added value ofmicronutrients over and above the various othercomponents of an integrated package ofinterventions aimed at improving birth outcomes. Forthese reasons the planned trials should all attemptto develop cost benefit analyses.

Efficacy trials could shed light on other policy andprogramme issues. The group felt that facilitatingfactors might need to be included in “routine”programmes, such as sharing methods of monitoringcompliance. Efficacy trials could provide thenecessary information for IEC programmes, andcould guide cost/benefit analyses. These trials wouldalso provide a clearer definition of what could beclaimed for a multiple micronutrient intervention, andprovide information of unexpected findings andadverse effects.

Assuming that efficacy of the multiple micronutrientsupplements is shown, then effectiveness studiesthat enable the comparison/validation of the multiplemicronutrient intervention when applied in differentcontexts would eventually be needed. The idea that


such effectiveness trials be run in parallel with theefficacy trials could permit greatly cutting the timefor translation of science into programmes. It wasagreed that effectiveness studies could be “risky” ifapplied within dysfunctional health/communityprogrammes. On the other hand such studies shouldseek to identify levels of adequacy and plausibilityconcerning the delivery of the programmeinterventions, in order to be able to understand whatworks and what doesn’t work. Such “operational”research that could identify where the “blocks” arewhen and if a multiple micronutrient interventionwere introduced could be useful. The group felt therewould be a need to examine the supply and demandaspects of a multiple micronutrient intervention andto examine the additional cost of achieving whatever“added value” these supplements might bring.


Conclusions andrecommendationsOn the final day, the findings and recommendationsof the smaller group were presented to an expandedgroup of participants, which included representativesof Canadian CIDA, The Wellcome Trust Foundation,The World Bank, The Division of Reproductive Healthof WHO, USAID, Helen Keller International and theMicronutrient Initiative. After discussion with thisexpanded group, it was largely agreed that thevarious organizations present could and should helpsupport and carry forward the recommendations ofthe meeting.

The meeting was considered to have beensuccessful at discussing design issues in that theresearchers agreed upon which outcomes would beimportant to measure, how compliance could beensured and enhanced, how internal and externalvalidity could be increased, and which confoundersor effect-modifiers would need to be included indata collection. Participants were open to the idea ofincreased comparability between studies and thepossibility of an eventual pooled analysis. Theminimum criteria for study design for other trials tobe included were agreed upon and basic guidelineswere developed. Collaboration across sites in thesharing of experience in developing standardizedtools, such as verbal autopsy (abortion/miscarriage,stillbirth/neonatal death), and night blindness wasinitiated. All agreed the desirability of developinglocal data safety and monitoring boards to managethe ongoing ethical aspects of such trials. Indonesiais most advanced in this and others would like tolearn from them. Pathways to facilitate the processof policy change and enabling activities that couldsupport the eventual distribution of multiplemicronutrient supplements within safe motherhoodinitiatives were also discussed, including the needfor effectiveness trials to be run in parallel with theefficacy trials.

The participants felt strongly that this meeting wasvery constructive and useful and had provided themwith an opportunity to share ideas. It was felt thatfurther on-going collaboration across study siteswould be desirable for information sharing, updates,and troubleshooting. An expanded electronic mailinglist was suggested for all constituents working onmultiple micronutrient supplementation trials, forboth efficacy and effectiveness studies, especiallyfrom developing countries. A further meeting wascalled for, which preferably should meet in SouthAsia within a year, involve an expanded set ofconstituents and bring extra expertise onboard. Asuggestion was made that a literature review of theeffects of micronutrients in the UNICEF/WHO/UNUmultiple micronutrient supplement would be usefulfor programme managers.


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Meeting attended by:Lindsey Allen, World Health Organisation, Switzerland([email protected])France Begin, Micronutrient Initiative, Canada ([email protected])Mohamed Ag Bendech, Helen Keller International, Mali([email protected])Bruno de Benoist, World Health Organisation, Switzerland([email protected])Zulfiqar Bhutta, Aga Khan University, Pakistan([email protected])Parul Christian, Johns Hopkins University, USA([email protected])Catherine Davies, The Wellcome Trust, UK([email protected])Lotte Ekstrom, International Centre for Diarrhoeal DiseaseControl, Bangladesh ([email protected])Wafaie Fawzi, Harvard School of Public Health, USA([email protected])Suzanne Filteau, Institute of Child Health, UK([email protected])Henrik Friis, Royal Agricultural University, Denmark([email protected])Jeya Henry, Oxford Brookes University, UK([email protected])Ian Darnton Hill, World Health Organisation, Switzerland([email protected])Marion Kelly, Department for International Development, UK([email protected])Barbara MacDonald, CIDA, Canada([email protected])Milla McLachlan, World Bank, USA([email protected])Penny Nestel, USAID, USA ([email protected])David Osrin, Institute of Child Health, UK ([email protected])Saskia de Pee, Helen Keller International, Asian Pacific Region([email protected])Laird Ruth, Institute of Child Health, UK ([email protected])Werner Schultink, UNICEF, USA ([email protected])Andrew Seal, Institute of Child Health, UK ([email protected])Kavita Sethuraman, Institute of Child Health, UK([email protected])Anuraj Shankar, Johns Hopkins University, USA([email protected])Roger Shrimpton, Institute of Child Health, UK([email protected])Zeina Sifri, Helen Keller International, USA ([email protected])Andrew Tomkins, Institute of Child Health, UK([email protected])Barbara Underwood, National Academy of Sciences, USA([email protected])Keith West, Johns Hopkins University, USA ([email protected])Jelka Zupan, World Health Organisation, Switzerland([email protected])

High rates of maternal morbidity and mortality are all toooften the tragic outcome of pregnancy in poor countries.Many factors contribute to these, among them is nutritionaldeficiency of a number of micronutrients. As a result of aWHO/UNICEF collaboration a new product – a multiplemicronutrient tablet – has been developed which providesimportant micronutrient supplementation on a daily basisduring pregnancy and early lactation. The impact of this newpreparation is being assessed in a number of countries andthis review summarises the design and data analysis issuesof the various efficacy trials.

A meeting held at the Institute of Child Health in March 2002provided a unique opportunity for investigators to collaboratein study design and data analysis. It also provided anexcellent opportunity to place the results within a policy andprogramme framework at an early stage.

The meeting was generously supported by the MicronutrientInitiative who play a key role in promoting nutritional healthof women and children through improving micronutrientstatus in poor countries.

ISBN 0-9532265-2-2

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