Iron, folic acid and malaria
iron, folic acid and malaria Fabienne Vautier 07.04.98
Re: iron, folic acid and malaria Fernando E. Viteri 14.04.98
Re: iron, folic acid and malaria Saskia van der Kam 14.04.98
Re: iron, folic acid and malaria Michael Golden 15.04.98
Re: iron, folic acid and malaria Remi Sogunro 14.04.98
iron administration in malarious areas Stephen Oppenheimer 14.04.98
Re: iron, folic acid and malaria Michael Golden 15.04.98
outpatient treatment (or referral) of malaria, anaemia and severe malnutition Bob Pond 15.04.98
iron, folate and malaria Bob Pond 15.04.98
anaemia and malnutrition Rachel Pinniger 21.04.98

Date: Tue, 7 Apr 1998 12:23:23 +0100

From: (Fabienne VAUTIER)

Subject: iron, folic acid and malaria



I have questions about the iron and folic acid treatment for the

malnourished children during an outbreak of malaria.


In Eastern Kenya, there is now a serious outbreak of malaria +

displacement of population due to flooding. The restrospective

mortality survey covering 1 month period showed a mortality rate of

9/10 000/d. The mortality is mainly related to malaria. The nutrional

survey showed a prevalence of global MPE 25.3% (<-2 Zscores) and a

severe malnutrion rate of 3.7% (<-3 Z-score).These figures are high

but not uncommon in this area. The area is known for Vit C

deficiency, cases of scorbut are regularly reported, specially in

lactating and elderly people.

The outbreak of malaria is due to Plasmodium faciparum and resistance

to Chloroquine traitement is known is the area. The first line

treatment is Fansidar.



1.For severe and moderate malnourished children. Does it necessary to

give Folic acid in same time of Fansidar. Does acid folic decrease the

action of Fansidar?. Does acid folic a determinant element in anemia

related to malaria? Would it be better to wait a week before to give

acid folic in this particular situation.

2.TFP. Ferrous ttt in case of anemia due to malaria is controversial.

In this case what could be the recommendations.

3. SFP:Weekly supplementation in iron seems to be effective in

pre-school children and pregnant women. Does it effective in moderatly

malnourished children ?

Thank you for your comments and advices

Sincerely Yours

Date: Tue, 14 Apr 1998 17:07:25 +0100 (BST)

From: (Fernando E. Viteri)

Subject: Re: iron, folic acid and malaria


> Subject iron therapy and acid folic therapy in malaria outbreak

> Author:

> Questions

> 1.For severe and moderate malnourished children. Does it necessary to

> give Folic acid in same time of Fansidar. Does acid folic decrease the

> action of Fansidar?. Does acid folic a determinant element in anemia

> related to malaria? Would it be better to wait a week before to give

> acid folic in this particular situation.




> 2.TFP. Ferrous ttt in case of anemia due to malaria is controversial.

> In this case what could be the recommendations.




> 3. SFP:Weekly supplementation in iron seems to be effective in

> pre-school children and pregnant women. Does it effective in moderatly

> malnourished children ?




Fernando E. Viteri, Professor

Department of Nutritional Sciences, University of California,

Berkeley, CA., 04720 - 3104

Phone: (510) 642 - 6900, FAX: (510) 642 0535

Date: Tue, 14 Apr 1998 12:56:15 +0100

From: (Saskia VD KAM)

Subject: Re: Ngonut: iron, folic acid and malaria


Dear Fabienne,

The idea that folic acid interferes with Fansidar originates form the

study of Hensbroek et al. 1995. They reported that malaria treatment

failure with Fansidar was significantly higher in children

supplemented with folate. This study however, used high doses of folic

acid, between 5 and 10 mg/d.

Recently Fitsum Assefa, (University Aberdeen) conducted a study to the

effect of lower levels of folic acid supplementation on the efficacy

of Fansidar. (in co-operation with Wellcome Trust Unit, Kilifi, Kenya)

The idea behind this study is that it is very likely that Fansidar

works with normal folic acid levels. Otherwise it will not be

effective at all in any healthy subject.

The study is not finished yet, but preliminary results suggests that

folic acid supplementation at lower levels that used in the Hensbroek

study, don't interfere with the efficacy of Fansidar.

The recommendation given by the researcher for folic acid

supplemetation for severely malnourished is:

5 mg initial Folic acid dose on admission in TFC and 100 ug/100 kcal

in the diet.

If F100 milk is used only the initial dose of 5 mg folic acid on

admission should be given.


The second question about Ferrous ttt in malaria in a TFC should be

put in a larger context.

Administration of ferrous ttt for severely malnourished children

before the initial adjustment of the metabolism is dangerous.

Nevertheless we encounter huge number of severely malnourished

children with severe anaemia.

The cause of the anaemia is multi factorial. Indeed in areas with

high incidence of malaria, folic acid deficiency is important.

Looking at the circumstances iron deficiency is as important as folic

acid deficiency.

The instruction to avoid the use of iron the first 2 weeks makes our

health personnel in the field desperate. What are the options? Blood

transfusion is often not possible, and if there is a facility, there

are numerous problems, with risks involved and lack of donor blood.

On top of that blood transfusion for severely malnourished is not very

easy (I am told).

The health personnel has great difficulties to leave the children in

this state, the feeling is that those children will die because of

anaemia, if nothing is done.

I think it is an awful situation, that we are not able to come up with

a satisfactory ( to a certain extent) solution.

I invite my dear colleagues to discuss this problem.

Saskia van der Kam

MSF-Holland Amsterdam

E-mail: Saskia_vd_

Date: Wed, 15 Apr 1998 11:13:45 +0100

From: Michael Golden <>

Subject: Re: Ngonut: iron, folic acid and malaria


The questions that you raise about iron and folate, Fabienne, are very important and frequently asked.


> 1.For severe and moderate malnourished children. Is it necessary to

> give Folic acid in same time of Fansidar. Does acid folic decrease the

> action of Fansidar?. Does acid folic a determinant element in anemia

> related to malaria? Would it be better to wait a week before to give

> acid folic in this particular situation.


It would seem from the paper published in Transaction R.Soc Trop Med Hygiene (see Saskia's mail) that at high daily doses folate may lead to a higher failure rate to eliminate malarial parasites. Because of this paper Saskia and myself sent a student (Fitsum) to Kevin Marshe's Unit in Kenya last year precisely to answer this question. The full results are not analysed, as Saskia says, however several things are clear: From the first 70 cases there is no significant difference in the failure rate between giving 5mg stat and then 400 or 800 ug/d (depending upon weight) and giving placebo. Even in those children who technically fail to eradicate parasites there is a reduction in the parasitaemia from thousands to tens of parasites and there is symptomatic relief irrespective of whether folate is given or not. Given the urgency of treating both malaria and folate deficiency in the severely malnourished child these are gratifying results.

About 20% of the malnourished children are folate deficient (this has been shown to be the case in most places in the world). Folate deficiency can itself be fatal - (associated with sudden "unexpected" death). It would be wrong not to treat all severely malnourished children with folic acid with one statum dose followed by about 100 micrograms per 100 kcal of diet (which is perfectly adequate to correct folate deficiency).

In an emergency situation folate deficiency is likely to be much more prevalent than under "normal conditions", certainly in situations where lack of fresh food or deficiency of folate's "dietary fellow travellers" - vitamin C etc - are seem, folate deficiency will become very prevalent and will contribute significantly to the anaemia. Even after hurricane Gilbert in Jamaica, where there was no overt malnutrition because of the rapid and full response, the simple loss of fresh produce led to a mini-epidemic of neural tube defects and to a marked reduction in the population mean folate level of cohorts of children that were being studied longitudinally by the Sickle-Cell unit. Folate status seems to be very sensitive to loss of fresh produce. In emergency situations (such as you describe) folate surveys have not been conducted.

So for all severely malnourished children the strong advice is to continue to give folic acid irrespective of the malarial status or the administration of Fansidar. And do not delay!


> 2.TFP. Ferrous ttt in case of anemia due to malaria is controversial.

> In this case what could be the recommendations.


In a Therapeutic Feeding Programs (TFP)

1. For severely malnourished children with oedema there is no longer controversy. Iron should not be given until they regain their appetite no matter what the haemoglobin level. This particular group of children have very low levels of transferrin, a high iron saturation, stainable iron in their marrow and liver and they have high levels of iron excretion after desferrioxamine. Such data have been described from Jamaica, South Africa, Nigeria and India. In Jamaica and South Africa transferrin has been shown to be more than 100% saturated in kwashiorkor and for there to be free iron circulating. In one study hospital in Nigeria the mortality rate for severe malnutrition FELL when the pharmacy ran out of iron!

I know that many of these children have severe anaemia and that many of these children die within the first 2 weeks of treatment - but in this particular situation iron will kill additional children and the anaemia in the others will not respond to iron as it is not related to iron deficiency.

The anaemia of Kwashiorkor has been related to many different problems including - infection, malaria, folate def, riboflavin def, vitamin E def, etc. About 15% are megaloblastic another 15% have schistocytosis (broken cells) about 2% have burr-cells (phospholipid def). A good diet with ALL the essential nutrients EXCEPT iron, blind treatment of infections with antibiotics and treatment of malaria/hookworm etc remain the cornerstone of treatment at this stage - Iron should be started when the children start to grow rapidly, have resynthesised their transferrin and have reversed the oxidised intracellular environment - recent longitudinal results where we measured GSH and NADPH longitudinally show that this takes about 14 days.

So my current advice is that oedematous children should not get iron for 14 days after admission.

Life threatening anaemia (3g/100ml or so) has to be treated by transfusion- being very careful not to precipitate (and to watch for) cardiac failure.

Would you treat a massive haemorrhage with iron tablets? Where transfusion is simply not available it is very frustrating - but iron is not the right way for those looking after these patients to ease their minds by "doing something".

2. For severely marasmic children the position is not so clear as some of this group do have genuine iron deficiency. However, where they are very severely anaemic the response to iron is to slow for there to be a significant change in Hb in the few days from admission to their regain of appetite and rapid growth when iron is added to the diet, and where it is life-threatening they also need transfusion. In regions where oedematous malnutrition occurs as well as marasmus I would not give iron as a single diet is needed for both sets of patients to simplify the management and avoid any mistakes.

3. For moderately malnourished children these considerations do not apply and they should be given iron with their malaria treatment.


> 3. SFP:Weekly supplementation in iron seems to be effective in

> pre-school children and pregnant women. Does it effective in moderatly

> malnourished children ?


Yes, there are about 20 studies that now show that weekly iron is as effective as daily iron, the compliance is better and there are fewer side effects. Furthermore, this lends itself to programs where iron can be directly administered in schools, clinics and supplemental feeding programs. One of the most common forms of poisoning in young children is iron poisoning where a child has taken more than 10 tablets given to the mother - with weekly iron there are far fewer tablets and this should have the additional advantage of reducing the prevalence of iron poisoning.

Prof. Michael H.N.Golden

From: Remi Sogunro

Date: Tue, 14 Apr 1998 16:58:02 +0100 (BST)


I agree with Prof. Golden's suggestion. Will the Nutrition community recommend 2 levels of RDA, one for those living in the West (including developing country persons who are residing in the West), and another one for those leaving in developing countries (including Westerners who reside in developing countries). Who can spearhead a research to determine by what factor we multiply existing RDA to make such recommendations.


Dr. Remi Sogunro, Chief Of Party

BASICS project, Zambia

From: Stephen Oppenheimer

Date: Tue, 14 Apr 1998 16:24:28 +0100 (BST)


As author of several of the earlier papers showing deleterious effects of iron administration (in my study - parenteral) in malarious areas, I feel jointly guilty that so many questions of dose, route, age-group, risk group, timing etc. are still apparently up in the air, thus preventing appropriate intervention, when there is so much real iron deficiency in malarious areas.

Without offering any immediate answers to Fabienne's question, I would like to mention that an international consultative committee is meeting later this year (under the auspices of the INACG) in the ILSI Human Nutrition Institute Wash. DC. The remit is to review all literature on the specific question of iron supplementation in malarious areas in different age groups, with the aim of producing a consensus recommendation.


Stephen Oppenheimer

Date: Wed, 15 Apr 1998 14:42:28 +0100

From: Michael Golden <>

Subject: Ngonut: injectable iron in nomadic populations


I wonder if anyone (and in particular Fernando Viteri and Stephen Oppenheimer) would care to comment!


>Date: 15 Apr 98 14:04:44 +0100

>From: Bruce Laurence <>

>Subject: RE>Re: Ngonut: iron, folic acid and malaria ttt


>I have another iron related question pertinent to the same discussion, on possible use of IM iron administration. MERLIN is also working in Wajir, running mobile clinics, and seeing large numbers of patients with malaria and anaemia (certainly at least in part iron-deficient) amongst nomadic populations. Any regular access to these people is very difficult, and it is impossible to ensure that there will be reliable follow up to monitor and treat anaemia, so we give out iron and folate and hope that it will be of some use. Obviously poor follow up among many communities is a major issue. The group that is maybe of greatest worry is pregnant women with severe anaemia.

>What I would like to know is whether in hard to access groups of pregnant women, and maybe others as well, there is any use for IM injectable iron.

>This route of supplementation seems to have practically fallen off the menu, probably for good reasons, yet in some of the most difficult situations maybe it has a place if it can act as a sort of depot treatment.

>Also, because here the malaria situation and hopefully that of food security might improve in the near future, even a time-limited improvement might be valuable (and of course an individual pregnancy is also time limited).

>I would be interested to hear any comments and experiences relating to this... or suggestions of what to do for the best when access is so difficult.


>Bruce Laurence, MERLIN, UK

Date: Wed, 15 Apr 1998 14:27:57 -0400

From: "Bob Pond" <>

Subject: Ngonut: outpatient treatment (or referral) of malaria, anaemia and severe malnutition


Having read all of these comments I am left with the impression that the conclusions of Hensbroek et al still hold for outpatient management unless:

1) a front-line health worker has access to 5 mg tablets of folate (how commonly available are these?); or

2) the child with malaria also has severe malnutrition.


The IMCI guidelines make it clear enough that any child with severe malnutrition needs urgent referral and should not be given iron (or folate for that matter) as a pre-referral treatment. According to the IMCI guidelines, the decision about treatment of the severe malnutrition and adminstration of iron, folate and several other drugs should be made at the referral level facility.

Date: Wed, 15 Apr 1998 12:46:51 -0400

From: "Bob Pond" <>

Subject: Ngonut: iron, folate and malaria


Dear Fabienne Vautier,

Here is what the WHO/CHD/Geneva IMCI guidelines have to say in response to your questions:

The Traiter l'Enfant module (I can't find my English version module at the moment) says on page 11: "Si un enfant presentant une paleur palmaire recoit l'antipaludeen sulfadoxine-pyrimethamine (Fansidar), ne pas lui donner de comprimes de fer/folate avant la visite de suivi programmee 2 semaines plus tard. L'action du fer/folate peut s'opposer a l'action du sulfadoxine-pyrimethamine qui contient un medicament antifolate."

The administration of iron to children with malaria should not be controversial. One good research study on this topic was published in the Transactions of the Royal Sociaety of Tropical Medicine and Hygiene (1995) 89, pages 1 to 5. The article was entitled very relevantly, "Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria." The study, carried out on 600 Gambian children with falciparum malaria found that one month after therapy children who had recieved iron plus fansidar had a haemoglobin that was 0.7 g/dl higher than children who had received fansidar alone. Moreover, the study found that iron supplementation was not associated with increased prevalence of malaria.

Supplementation with folic acid in this population, in contrast, did not improve the hemotogical response but, among children who received fansidar, the treatment failure rate was significantly higher among those given folic acid than among those given placebo. The authors conclude that "Thus, supplementation with iron, but not folic acid, improves haemotological recovery without increasing susceptibility to malaria."

This should resolve issues regarding iron, folate and malaria (which should be handled by primary care outpatient facilites) but not the separate set of issues regarding iron, folate and severe malnutrition (which often involves referral facilities).


Bob Pond, BASICS Project


<note added by M.golden - this is the same paper that both Saskia and myself were referring to - the study by Fitsum was precisely to address the point about folic acid because the Gambian authors had used very high doses>

Date: Tue, 21 Apr 1998 19:25:58 +0100


Subject: anaemia and malnutrition and malaria


Re Bob Ponds call for referral: While I agree with the principle of referral of severely ill kids it is sometimes impossible - take the case of many here (Nepal) who live days walk away from a hospital, which if they reached it would probably be unstaffed. There has to be some alternative guidelines for the far-flung health worker with no support. We are trying to come up with some at the moment and I am always happy for suggestions to consider.

Rachel Pinniger, Dept of Community Medicine, Institute of Medicine, Tribhuvan University, Kathmandu,