Mortality risk in anaemic children
Mortality risk in anaemic children Bernard Brabin 06.01.2000
Mortality risk in anaemic children: surprising data Stephen Oppenheimer 07.01.2000
Re: Mortality risk in anaemic children: surprising data Fernando E. Viteri 07.01.2000
Subject: Re: Mortality risk in anaemic children: surprising data Stephen Oppenheimer 07.01.2000
Iron supplementation in Papua New Guinea André Briend 07.01.2000
Re: Iron supplementation in Papua New Guinea Stephen Oppenheimer 07.01.2000
Anaemia and risk of mortality Stephen Allen 13.01.2000


From: lesley jean taylor <l.j.tayloratliverpool.ac.uk>

Subject: Mortality risk in anaemic children

Date: Thu, 6 Jan 2000 13:48:32 +0000 (GMT)

 

I am currently searching the literature to address the question:

How does anaemia in children, especially young children, relate to risk of death?

There is some published hospital data, in particular in relation to when to transfuse (eg Lackritz, Lancet 1992; 340: 524-528), but almost no community based data.

A recent Cochrane review addressed the issue of blood transfusion for treating malarial anaemia and there are a few papers on mortality risk in severe malarial anaemia (eg Marsh et al N Eng J Med 1995; 332: 1399-1404; and the study by Steve Allen completed in Papua New Guinea).

What information do we have on children, who are not hospitalised or who are not desperately ill, on survival in relation to their Hb levels. Are there some intervention trials that have investigated anaemia prevention with mortality as a main outcome variable? Should programme planners consider screening infants for anaemia at 6 months, in order to identify those at possible higher risk of death?

A further question is how severity of anaemia in PEM relates to mortality risk during admission in NRUs, or subsequently at follow-up?

Your comments and advice on information sources very welcome.

 

Bernard Brabin

Child Health,Liverpool School of Tropical Medicine

----------------------

Jean Taylor

l.j.tayloratliverpool.ac.uk

Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA


Date: Fri, 07 Jan 2000 11:47:02 +0000

From: Stephen <Stephen.Oppenheimeratpaediatrics.oxford.ac.uk>

Subject: Mortality risk in anaemic children: surprising data

 

Dear Bernard & NGOnuters

Bernard Brabin wrote (see above)

Bernard just sent me a fax with the same queries in relation to a 1 year cohort study of 478 infants I ran in Madang Papua New Guinea - so I thought I would reply here. The results may surprise some. Briefly this was a community sampled, randomised, placebo controlled study of iron intervention. Full haematological/haematinic work-up was made at birth, two months, six months and one year. 97% survivor-ship follow-up was achieved.

There were 12 deaths in the study period: five intervention and seven placebo infants. The primary cause of death was pneumonia in every case - associated with measles or pertussis in nine. In one infant (intervention group) anaemia was recorded as an associated cause. These numbers were inadequate to make valid statistical comparisons of intervention vs placebo let alone haematological predictor variables.

Risk of hospital admission from the cohort could, however, be usefully looked at as an outcome with preceding haematological and nutritional variables at all three survey dates as predictors. Logistic regression was performed with the risk of admission as an outcome using these variables. In this analysis, only certain variables measured at birth and two months contributed significantly to risk of admission during the first year of life. The strongest predictor was birth haemoglobin which correlated negatively with risk of admission.

In other words a lower birth haemoglobin was protective against subsequent admission.

This was the case whether one looked at the trial groups separately (placebo and intervention) or combined. There was also a significant positive interaction between birth haemoglobin and iron intervention which multiplied the subsequent risk of admission. The effect appeared to be linear. Higher birth haemoglobin also incidentally was associated with more random malaria slide positivity at the six month visit in the placebo group.

Whether this low birth haemoglobin protective effect was related to total body iron at birth or alpha thal genotype or both is an interesting question.

Infants with low weight-for-length at 2 months (<33rd centile for cohort) had a significantly higher risk of subsequent admission.This effect was non-linear, independent and with no interactions with haematological variables.

No other measurement haematological or nutritional (micronutrient or anthropometric) at any visit was a useful predictor of risk of subsequent admission in this cohort.

Stephen Oppenheimer

 


Date: Fri, 07 Jan 2000 14:49:18 +0000

From: viteriatnature.berkeley.edu

Subject: Re: Mortality risk in anaemic children: surprising data

 

Dear NGOnuters:

This is an important issue. Just a small clarification on Dr. Oppenheimer's response:

>He indicates in his letter that " The strongest predictor was birth haemoglobin which correlated negatively with risk of admission." but it seems to me he wanted to say "correlated positively", that is, the higher the Hb the higher the risk of hospital admission.

I wonder if anybody has a reason for it outside of clinical malaria which, if I recall, was not evident in most of these children (I have to go back to read again these papers !). The same with the "There was also a significant positive interaction between birth haemoglobin and iron intervention which multiplied the subsequent risk of admission".

I wonder if iron intervention was excessive, creating a situation we have termed "Early or temporary iron overload condition" as manifested by high serum ferritins and % saturations of transferrin and high levels of biomarkers of lipid peroxidation (breath ethane and plasma malodialdehyde levels). We have seen this recently in animal studies and in adult human clinical supplementation trials.

Our first paper on this is in press in the J. Nutrition. This condition is either not present or is greatly ameliorated with intermittent iron supplementation: every 3 days in rats and weekly in humans. Interestingly enough, iron deficient-anemic rats also have high levels of breath ethane and plasma malodialdehyde. The risks associated with iron deficiency and excess in this respect appear to be U SHAPED.

My message is: Iron supplementation is desirable where iron deficiency is prevalent and food-based strategies are not working BUT it must not be excessive. We are in the process of demonstrating the effectiveness of weekly preventive supplementation for the SAFE control of iron deficiency. We already know it is efficacious.

 

Fernando E. Viteri


Date: Fri, 07 Jan 2000 18:17:41 +0000

From: Stephen <Stephen.Oppenheimeratpaediatrics.oxford.ac.uk>

Subject: Re: Mortality risk in anaemic children: surprising data

 

Dear Prof Viteri wrote:

> This is an important issue. Just a small clarification on Dr. Oppenheimer's response:

> >He indicates in his letter that " The strongest predictor was birth haemoglobin which correlated negatively with risk of admission." but it seems to me he wanted to say "correlated positively", that is, the higher the Hb the higher the risk of hospital admission.

You are correct. Sorry if it was unclear.

> I wonder if anybody has a reason for it outside of clinical malaria which, if I recall, was not evident in most of these children (I have to go back to read again these papers !).

You are right 'clinical malaria' was not evident in most admissions, but their spleen and slide positivity rates were much higher than the same cohort when measured in the field. I suspect the effects of both birth haemoglobin and of the iron intervention on admissions (which were mostly for respiratory disease) were mediated indirectly through their effect on malaria(I said so in the paper). This iceberg effect of malaria on susceptibility to other infections is not new and has also I believe been raised as a possibility by Steve Allen in his PNG study.

> The same with the "There was also a significant positive interaction between birth haemoglobin and iron intervention which multiplied the subsequent risk of admission".

> I wonder if iron intervention was excessive, creating a situation we have termed "Early or temporary iron overload condition" as manifested by high serum ferritins and % saturations of transferrin and high levels of biomarkers of lipid peroxidation

We were well aware of the risks of excessive iron treatment and of treating in the neonatal period. This is dealt with at length in our protocol paper (1) In fact at the time of the study relatively large doses of parenteral iron were recommended in standard national policy to be given to low birth-weight babies routinely during the neonatal period in PNG. We gave iron only at two months of age.

However as measured by subsequent serum ferritins and transferrin saturations in the intervention group the level of intervention was not excessive. I hope this was a result of the following rational precaution: The dose of iron used was calculated in two ways based on the results of two pilot surveys in Madang (2): firstly the deficit in ideal total body iron (TBI) was calculated in newborns; second the deficit in ideal TBI was calculated in one year olds. The two results were not greatly dissimilar and the mean was used in deciding the dose of supplemental iron at 2months age. The dose used was 150mg elemental iron which is a low dose compared with that used in other studies and protocols up to that date (250-350mg)

> My message is: Iron supplementation is desirable where iron deficiency is prevalent

That we were dealing with an iron deficient infant population was evident from pilot studies and in the improved mean haemoglobins of the intervention group.

I hesitate to point out that my last mail was an attempt to answer a very specific question posed by Bernard Brabin on the predictive value of random haemoglobins on subsequent mortality in my study. I did not wish to drop the red rag of iron into the bullring and confuse the issue or to give any opinions. There was a main effect of birth haemoglobin in the placebo group alone. In other words the issue of parenteral iron is a 'red' herring as far as the predictive effects of birth haemoglobin on subsequent risk of admission in this group. There was also a main effect of birth haemoglobin in the intervention group when looked at on its own.

When logistic regression was performed on the whole cohort, there continued to be a main effect of birth haemoglobin while the intervention effect was controlled for.

Stephen Oppenheimer

 

1. Oppenheimer, S.J., Hendrickse, R.G., Macfarlane, S.B.J., Moody, J.B., Harrison, C., Alpers, M., Heywood, P. & Vrbova, H. (1984). Iron and infection in infancy. Report of field studies in Papua New Guinea. 2. Protocol and description of study cohort. Ann. Trop. Paed. 4, 145-153.

2. Oppenheimer, S.J., Macfarlane, S.B.J., Moody, J.B., Bunari, O., Williams, T.E., Harrison, C. & Hendrickse, R.G. (1984). Iron and infection in infancy. Report on field studies in Papua New Guinea. 1. Demographic description and pilot surveys. Ann. Trop. Paed. 4, 135-143.


Date: Fri, 07 Jan 2000 16:15:25 +0100

From: "Andre' Briend" <briendaatcnam.fr>

Subject: Iron supplementation in Papua New Guinea

 

 

Dear Ngonut's,

To add on Fernando's comments, I understand that the studies quoted in Stephen's mail refer to a supplementation with parenteral iron. Stephen, is this correct ? In this case, the findings of an unfavourable effect of iron supplementation cannot be extrapolated to oral supplementation and even less to food based programmes.

Regards,

 

André

 

Dr. André Briend

CNAM - ISTNA, 5 rue du Vertbois, 75003 Paris, France

tel : 33-1-53 01 80 36 fax : 33-1-53 01 80 38


Date: Fri, 07 Jan 2000 18:19:48 +0000

From: Stephen <Stephen.Oppenheimeratpaediatrics.oxford.ac.uk>

Subject: Re: Iron supplementation in Papua New Guinea

 

Dear André

Please see the message I just posted in response to Fernando.

However since you have both raised the issue of parenteral iron and oral iron therapy in malarious areas may I point you to my recent review where I have ventured some opinions along with a review of literature:

S.J. Oppenheimer. (1998) "Iron and Infection in the Tropics: paediatric clinical correlates", Annals of Tropical Paediatrics, Vol 18 (supp) S81-S87

and:

to the INACG consensus statement which I was involved in drafting: "Safety of Iron Supplementation Programs in Malaria-Endemic Regions" which has been (or is just about to be) published on-line at: www.ilsi.org


Date: Thu, 13 Jan 2000 21:07:49 +0000

From: "Stephen Allen" <sallenatmrc.gm>

Subject: Anaemia and risk of mortality

 

Dear Bernard,

I have followed the discussion of anaemia and risk of mortality with great interest. I do not have answers to your questions but have talked with colleagues here in The Gambia and hope that the following comments are useful.

Most of the research done here has been hospital based. Andrew Smith1,2 did address the issue of response to oral iron (3-6 mg/kg/day elemental iron) in a placebo-controlled trial of children aged 6 months to 5 years with moderate microcytic anaemia and living in the community. No deaths occurred amongst the 213 children followed-up for 12 weeks. The study was done during the malaria-transmission season and anaemia worsened in the placebo group but improved in the iron group. However, significantly more episodes of fever + high malaria parasitaemia occurred in the iron than the placebo group. He concluded that it might be necessary to give malaria chemoprophylaxis with iron in malaria-endemic areas.

Stephen Oppenheimer reported his observation that a lower birth haemoglobin protected against hospital admission in infants in PNG. He suggested that this may be an effect of alpha-thalassaemia and the studies that we undertook in children in PNG following-on from Stephen's work would support this.3

In a hospital-based, prospective, case-community control study, homozygous alpha-thalassaemia significantly reduced the risk of admission with severe malaria (OR 0.40; 95% CI 0.22-0.74) and also of admission with non-malaria infections (OR 0.36; 95% CI 0.22-0.60). We thought that the latter observation was probably an "indirect" effect of the protection against malaria and would appear to be consistent with the reduced all-cause mortality that occurs with the use of insecticide-impregnated bed nets. In children living in the community, median haemoglobin levels in homozygous alpha-thalassaemia were 0.5g/dl lower than in normals. Therefore, in this population, anaemia may well be observed to decrease morbidity and mortality. Clearly, it would be important to consider haemoglobinopathies in studies that assess the risk of mortality that is associated with anaemia.

 

1. Smith AW et al. Annals of Tropical Peadiatrics 1989; 9: 6-16 2. Smith AW et al. Annals of Tropical Peadiatrics 1989; 9: 17-23 3. Allen SJ et al. Proc. Nat. Acad. Sci. USA 1997; 94: 14736-14741.