Effect+of+Iron+Supplementation+on+the+Incidence+of+Infections+in+..

7/30/2019 Effect+of+Iron+Supplementation+on+the+Incidence+of+Infections+in+..

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Effect of Iron Supplementation on InfectiousMorbidity and Mortality in Children

Prof. H.P.S. SachdevSenior ConsultantPediatrics and Clinical Epidemiology,

Sitaram Bhartia Institute of Science & Research, New Delhi

Adjunct Professor, St. Johns Research Institute, St. JohnsNational Academy of Health Sciences, Bangalore

E-mail: [email protected]


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Rationale

Iron deficiency major public health problem

Adverse effects on :

psychomotor development

work performance

o Prompted early intervention recommendation

o Safety to be unequivocally established


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Iron and Infections

Iron deficiency a

defense mechanism

NutritionalImmunity

Iron deficiency

impaired CMI

Free radical injury dueto supplementation


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Inclusion Criteria

(i) randomised placebo controlled trials except forparenteral route

(ii) iron supplementation through the oral or theparenteral route or in the form of iron fortifiedformulas or cereals in the intervention group

(iii) one or more infectious morbidity as an evaluated

outcome measure.Where other micronutrients/drugs administered-

included if the only difference was iron only


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Data Collection

MEDLINE, COCHRANE controlled trials

register, EMBASE, IBIDS and Healthstar

database

Reference lists of the identified articles, hand

searches of reviews, bibliographies of books and

abstracts and proceedings of international

conferences or meetings Donor agencies, experts and authors of recent

iron supplementation trials


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Methodologic Quality

Allocation Concealment

(A) adequate

(B) unclear

(C) inadequate

(D) not used


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Completeness of follow-up

(A)


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Blinding

(A) Double blinding

(B) Single blinding

(C) No blinding

(D) unclear


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Data Abstraction

Preformed questionnaires

Derived from the published manuscript

Morbidities and the outcomes included were

as defined by the authors

Wherever possible, the authors contacted

for clarifications


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Statistical Analysis

StatsDirect Statistical Software

Graphical test (funnel plot) for bias

Incidence rate ratio and incidence rate differencepooled estimates calculated

Both fixed effects and random effects model used

Actual vs. computed

Metaregression done for prevalence of slideconfirmed malaria parasitemia


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Statistical Analysis

Stratified analysis done for

(i) methodologic quality

(ii) case detection (active or passive)(iii) case definition specificity

(iv) route of iron administration

(v) duration of supplementation

(vi) type of morbidity

(vii) baseline haemoglobin of the supplementedgroup


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Results

Medline Cochrane Embase

285 trials 233 trials 112 trials146 RCTs

28 trials (22 published)

IBIDS, Healthstar References, Handsearch

Personal communications- experts, authors, donor

agencies


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Baseline Characteristics- Age

Below one year of age - 13 trials

Preschool children (upto 5 years of age) -

10 trials

> 5 years - 5 trials


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Baseline Characteristics

Place of study

Africa11

Asia8

Americas5

Europe2 Australia-New Zealand - 2


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BaselineCharacteristics

Route of Supplementation

Oral iron20

Fortified feeds/ cereals - 5

Parenteral iron3

Surveillance Methodology Passive/ Facility based - 15

Active - 13


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Bias Detection Plot

-4 -2 0 2 4 0

1

2

3

Incidence rate difference

1/Weight


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Pooled Estimates

Data on 7892 subjects followed up for

5650.8 child years

4027 children and 2802.1 child years- ironsupplemented group

3865 children and 2848.7 child years in the

placebo group.


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Total Morbidity

Incidence rate ratio

IRR (iron versus

placebo) for all therecorded morbidities =

1.02 (95% CI 0.96,

1.08; p=0.54)

Incidence Rate

Difference

IRD (iron minusplacebo) for all the

recorded morbidities =

0.06 episodes/child-

year (95% CI0.06,0.18; p=0.34)


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Cochrane incidence rate ratio plot (random eff ects)

0.1 0.2 0.5 1 2 5 10

CANTWELL ET AL

ATUKORALA ET AL 2

ATUKORALA ET AL 1

GABRESELLASIE ET AL

ADAM ET AL

SMITH ET AL

IDJRADIN ATA ET AL

RICE ET AL

NAGPAL ET AL

AGARWAL ET AL

HEMM INKI ET AL

MITRA ET AL

SINGHAL ET AL

OPPENHEIMER ET AL

IRIGOYEN ET AL

LAWLESS ET AL

BERGER ET AL

JAVAID ET AL

ROSADO ET AL 2

ROSADO ET AL 1

PALUPI ET AL

POWER ET AL

ANGELES ET AL

HOMBERGH ET AL

MENENDEZ ET AL 2

MENENDEZ ET AL 1

FUERTH ET AL

BRUNSER ET AL

JAMES ET AL

DL pooled incidence rate ratio = 1.017547 (95% CI = 0.96297 to 1.075217)


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Cochrane incidence rate difference plot (random effects)

-10 -6 -2 2 6

CANTWELL ET AL

ATUKORALA ET AL 2

ATUKORALA ET AL 1

GABRESELLASIE ET AL

ADAM ET AL

SMITH ET AL

IDJRADIN ATA ET AL

RICE ET AL

NAGPAL ET AL

AGARWAL ET AL

HEMM INKI ET AL

MITRA ET AL

SINGHAL ET AL

OPPENHEIMER ET AL

IRIGOYEN ET AL

LAWLESS ET AL

BERGER ET AL

JAVAID ET AL

ROSADO ET AL 2

ROSADO ET AL 1

PALUPI ET AL

POWER ET AL

ANGELES ET AL

HOMBERGH ET AL

MENENDEZ ET AL 2

MENENDEZ ET AL 1

FUERTH ET AL

BRUNSER ET AL

JAMES ET AL

0

DL pooled incidence rate difference = 0.059256 ( 95% CI = -0.062465 to 0.180977)


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Stratified Analysis- Actual vs

ComputedStratifi

cation

feature

No. of

Trials

IRR

(95%

CI)

p IRD

(95%

CI)

p

Actual 7 1.00

(0.85,

1.16)

0.96 -0.01 (-

0.16,

0.14)

0.93

Compu

ted

19 1.02

(0.96,

1.02)

0.50 0.07 (-

0.12,

0.27)

0.45


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Stratified Analysis

No Difference With:

Methodologic quality

Surveillance Methodology

Geographic location

Duration of supplementation


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Route of Supplementation

Stratifi

cation

feature

No. of

Trials

IRR

(95%

CI)

p IRD

(95%

CI)

p

Oral 17 1.03(0.96,

1.09)

0.40 0.09 (-0.08,

0.26)

0.29

Fortified 6 0.99

(0.89,1.11)

0.89 -0.07 (-

0.48,0.35)

0.76

Parenter

al

3 0.94

(0.67,

1.31)

0.70 0.19 (-

0.26,

0.63)

0.42


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Basal Hemoglobin


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Individual Morbidities -

Diarrhea and DysenteryStratific

ation

feature

No.

Trial

IRR

(95%

CI)

p IRD

(95%

CI)

p

Diarrhea 17 1.11(1.

01,

1.23)

0.04 0.05 (-

0.03,

0.13)

0.21

Dysentery 2 1.00

(0.87,

1.15)

0.99 0.00 (-

0.05,

0.06)

0.90


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Diarrhea - IRRCochrane incidence rate ratio plot (random effects)

0.001 0.01 0.1 0.2 0.5 1 2 5 10 100

CANTW ELL ET AL

ATUKORALA ET AL 2

ATUKORALA ET AL 1

ADAM ET AL

NAGPAL ET AL

RICE ET AL

MITRA ET AL

SINGHAL ET AL

OPPENHEIMER ET AL

IRIGOYEN ET AL

LAWLESS ET AL

BERGER ET AL

JAVAID ET AL

ROSADO ET AL 2

ROSADO ET AL 1

POWER ET AL

ANGELES ET AL

BRUNSER ET AL

JAMES ET AL



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Diarrhea and Oral ironCochrane incidence rate ratio plot (random effects)

0.01 0.1 0.2 0.5 1 2 5 10 100

ATUKORALA ET AL 2

ATUKORALA ET AL 1

ADAM ET AL

NAGPAL ET AL

RICE ET AL

MITRA ET AL

LAWLESS ET AL

BERGER ET AL

ROSADO ET AL 2

ROSADO ET AL 1

ANGELES ET AL



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RTI and LRTI

Stratifi

cation

feature

No. of

Trials

IRR

(95%

CI)

p IRD

(95%

CI)

p

RTI 17 0.98

(0.90,

1.06)

0.54 0.02

(-0.13,

0.18)

0.79

LRTI 8 0.97

(0.83,

1.23)

0.93 0.01

(-0.11,

0.13)

0.84


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RTI and Fortified IronIRR=0.92; 95% CI 0.86, 0.98 (p=0.02)

Cochrane incidence rate ratio plot (random effects)

0.5 1 2

HEMMINKI ET AL

SINGHAL ET AL

JAVAID ET AL

POWER ET AL



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RTI and fortified ironIRD=0.19 episodes/ child-year (95% CI 0.54, 0.16; p=0.28)

Cochrane incidence rate difference plot (random eff ects)

-2 -1 1

HEMMINKI ET AL

SINGHAL ET AL

JAVAID ET AL

POWER ET AL

0

DL pooled incidence rate difference = -0.191868 (95% CI = -0.541553 to 0.157818)


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Malaria and Other Infections

Stratifi

cation

feature

No. of

Trials

IRR

(95%

CI)

p IRD

(95%

CI)

p

Malaria 5 1.07

(0.94,

1.24)

0.35 0.04 (-

0.04,

0.11)

0.32

Other

Infectio

ns

13 1.04

(0.98,

1.11)

0.20 0.05 (-

0.02,

0.12)

0.15


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Prevalence of Smear Positive

Malarial Parasitemia Pooled log OR of acquiring malaria with

iron supplementation = 1.13 (95% CI 0.91,

1.40; p=0.28) Significantly (p=0.004) related to the

baseline log OR of malaria smear positivity


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Conclusions

No significant increase in the risk ofinfection with iron supplementation

Slight (11%; 95% CI 1-23%) increasein the risk of developing diarrhea,more so in the group supplemented

orally; public health significance ??


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Conclusions

Possibilities Requiring Further Research

Protective effect for respiratory tract

infections with fortified feeds Mildly increased risk of infections with

mean baseline hemoglobin below 10g/dl


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The story thereafter..

Study, Country Morbidities TreatmentGroups

Conclusions

Baqui et al,

2003

(Bangladesh)

Diarrhea and

ARI

Iron vs control;

Iron and Zn vs

Zn

a) No effect on overall risk

for diarrhea; Fe-Zn had

lower severe diarrheal

episodes

b) No effect on ALRI

Richard et al,

2006

(Peru)

Malaria,

Diarrhea, ALRI

Iron vs control;

Iron and Zn vs

Zn

a) Fe alone higher incidence

of Vivax malaria versus

placebo

b) Increased diarrheal

morbidity in child>9 yrsLe Huong T, et

al, 2007

(Vietnam)

Worm

Infestation

Iron vs Placebo;

Iron and Meb vs

Meb

a) No significant effect on

hookworm and ascaris

b) Lower prevalence of

Trichuris infestation with

Fe


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Lancet 2006; 367: 133-43.

Lancet 2006; 367: 144-52.


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Four Treatment Groups

Iron (12.5 mg) AND Folic Acid (50mcg)

and Zinc (10mg)

Iron (12.5 mg) AND Folic Acid (50mcg)

Zinc (10 mg)

Placebo


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Sub-study of Pemba RCT

Random sample of clusters with more extensiveand diagnostic practices

2413 children included

Adverse events lower in supplemented group (notsignificant)

Deaths RR 0.73 (0.31-1.71)

Hospitalization RR 0.76 (0.54-1.06)

Children with moderate anemia had significantprotection from adverse events


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Comment


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Caveats

1. Nepal - well functioning primary

health-care system, a factor that the

Pemba sub-study results suggest maychange the balance of risk and benefit

with iron and folic acid.

2. Major malaria related adverse effects(45%) misclassification possible


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Caveats (contd)


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Caveats (contd)

4. Finger of suspicioniron; IFA given in a

setting where first line antimalarial is

Sulphadoxine-pyrimethamine (SP), an anti-folate. It is also likely that folic acid

supplementation contributed to the malaria-

related adverse health outcomes of thosereceiving iron plus folic acid.


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Dihydrofolate Reductase

DHFR is a small enzymethat plays an essential rolein DNA synthesis

Catalyzes the conversion of

dihydrofolate totetrahydrofolate, a cofactorrequired for the biosynthesisof thymidylate, pyrimidinenucleotides, methionine, andglycine

DHFR-TS


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Folic Acid Pathway


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Sulphadoxine-pyrimethamine

Introduced in 1967 as a synergistic anti-malarialdrug, with reports of resistance occurring within afew years

Used as a second-line drug in areas wherechloroquine is still used

In areas that are chloroquine resistant, it hasbecome the first-line antimalarial

There are many hyperendemic and holoendemicareas that are now SP resistant


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Drug-resistance worldwide


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Folate and Malaria

Mulenga et al, 2006(Zambia)

a) SP group: Higher parasitemia with folic acid at days 3, 7,and 14 ; the difference at day 3 was statistically significant

(P = 0.013).

Mbaye et al, 2006

(Gambia)

Pregnancy

No interference with effect of SP

Carter et al, 2005

(Kenya)

Reduction in the efficacy of SP with folic acid using the

survival curve for parasitologic failure (P < 0.0001), but no

difference for clinical failure (P = 0.7008)

Ven Hansbroek et al,

1995(Gambia)

Higher treatment failure in SP group in those receiving Folate

Ouma et al, 2006

(Kenya)

Pregnancy

Concomitant use of 5 mg FA supplementation compromises the

efficacy of SP for the treatment of uncomplicated malaria in

pregnant women.


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Caution should be exercised in altering policy on

the basis of a single set of observations

Caution should be exercised in settings where the

prevalence of malaria and other infectious diseases

is high - targeted to those who are anaemic and at

risk of iron deficiency with concurrent protectionfrom malaria and other infectious diseases

Should not be extrapolated to fortification or

food-based approaches for delivering iron


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