Effect of Iron Supplementation on Infectious Morbidity and Mortality in Children

Prof. H.P.S. Sachdev

Senior Consultant Pediatrics and Clinical Epidemiology, Sitaram Bhartia Institute of Science & Research, New Delhi Adjunct Professor, St. Johns Research Institute, St. Johns National Academy of Health Sciences, Bangalore
E-mail: hpssachdev@gmail.com

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

Iron and Infections

Iron deficiency a defense mechanism Nutritional Immunity

Iron deficiency impaired CMI Free radical injury due to supplementation

Inclusion Criteria
randomised placebo controlled trials except for parenteral route (ii) iron supplementation through the oral or the parenteral route or in the form of iron fortified formulas or cereals in the intervention group (iii) one or more infectious morbidity as an evaluated outcome measure. Where other micronutrients/drugs administeredincluded if the only difference was iron only
(i)

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

Methodologic Quality

Allocation Concealment (A) adequate (B) unclear (C) inadequate

(D) not used

Methodologic Quality

Completeness of follow-up (A) <3% of participants excluded (B) 3% to 9.9% of participants excluded (C) 10% to 19.9% of participants excluded (D) 20% or more of participants excluded

Methodologic Quality

Blinding (A) Double blinding (B) Single blinding (C) No blinding (D) unclear

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

Statistical Analysis

StatsDirect Statistical Software Graphical test (funnel plot) for bias Incidence rate ratio and incidence rate difference pooled estimates calculated Both fixed effects and random effects model used Actual vs. computed Metaregression done for prevalence of slide confirmed malaria parasitemia

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 supplemented group

Results
Medline
285 trials 146 RCTs

Cochrane
233 trials

Embase
112 trials

28 trials (22 published) IBIDS, Healthstar References, Handsearch

Personal communications- experts, authors, donor agencies

Baseline Characteristics- Age

Below one year of age - 13 trials Preschool children (upto 5 years of age) 10 trials > 5 years - 5 trials

Baseline Characteristics
Place

of study Africa 11 Asia 8 Americas 5 Europe 2 Australia-New Zealand - 2

Baseline Characteristics
Route

of Supplementation Oral iron 20 Fortified feeds/ cereals - 5 Parenteral iron 3 Surveillance Methodology Passive/ Facility based - 15 Active - 13

Bias Detection Plot

1/Weight 3

0 -4 -2 0 2 4 Incidence rate difference

Pooled Estimates

Data on 7892 subjects followed up for 5650.8 child years 4027 children and 2802.1 child years- iron supplemented group 3865 children and 2848.7 child years in the placebo group.

Total Morbidity

Incidence rate ratio IRR (iron versus placebo) for all the recorded morbidities = 1.02 (95% CI 0.96, 1.08; p=0.54)

Incidence Rate Difference IRD (iron minus placebo) for all the recorded morbidities = 0.06 episodes/childyear (95% CI 0.06, 0.18; p=0.34)

Cochrane incidence rate ratio plot (random eff ects)

JAMES ET AL BRUNSER ET AL FUERTH ET AL MENENDEZ ET AL 1 MENENDEZ ET AL 2 HOMBERGH ET AL ANGELES ET AL POW ER ET AL PALUPI ET AL ROSADO ET AL 1 ROSADO ET AL 2 JAVAID ET AL BERGER ET AL LAW LESS ET AL IRIGOYEN ET AL OPPENHEIMER ET AL SINGHAL ET AL MITRA ET AL HEM MINKI ET AL AGARW AL ET AL NAGPAL ET AL RICE ET AL IDJRADINATA ET AL SMITH ET AL ADAM ET AL GABRESELLASIE ET AL ATUKORALA ET AL 1 ATUKORALA ET AL 2 CANTW ELL ET AL

0.1

0.2

0.5

10

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

Cochrane incidence rate dif ference plot (random eff ects)

JAMES ET AL BRUNSER ET AL FUERTH ET AL MENENDEZ ET AL 1 MENENDEZ ET AL 2 HOMBERGH ET AL ANGELES ET AL POW ER ET AL PALUPI ET AL ROSADO ET AL 1 ROSADO ET AL 2 JAVAID ET AL BERGER ET AL LAW LESS ET AL IRIGOYEN ET AL OPPENHEIMER ET AL SINGHAL ET AL MITRA ET AL HEM MINKI ET AL AGARW AL ET AL NAGPAL ET AL RICE ET AL IDJRADINATA ET AL SMITH ET AL ADAM ET AL GABRESELLASIE ET AL ATUKORALA ET AL 1 ATUKORALA ET AL 2 CANTW ELL ET AL

-10

-6

-2

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

Stratified Analysis- Actual vs Computed

Stratifi No. of cation Trials feature Actual 7 IRR (95% CI) 1.00 (0.85, 1.16) 1.02 (0.96, 1.02) p IRD (95% CI) -0.01 (0.16, 0.14) 0.07 (0.12, 0.27) p

0.96

0.93

Compu ted

19

0.50

0.45

Stratified Analysis
No Difference With: Methodologic quality Surveillance Methodology Geographic location Duration of supplementation

Route of Supplementation
Stratifi No. of cation Trials feature
Oral 17

IRR (95% CI)

1.03 (0.96, 1.09) 0.99 (0.89, 1.11) 0.94 (0.67, 1.31)

IRD (95% CI)

0.40

Fortified 6

0.89

Parenter 3 al

0.70

0.09 (- 0.29 0.08, 0.26) -0.07 (- 0.76 0.48, 0.35) 0.19 (0.42 0.26, 0.63)

Basal Hemoglobin<10g/dl
IRR=1.11(1.00, 1.23; p=0.06); n=6
Cochrane incidence rate ratio plot (random eff ects)

HOMBERGH ET AL

BERGER ET AL

RICE ET AL

SMITH ET AL

ADAM ET AL

GABRESELLASIE ET AL

0.5

DL pooled incidence rate ratio = 1.109332 (95% CI = 0.997512 to 1.233687)

Individual Morbidities Diarrhea and Dysentery

Stratific No. IRR p ation Trial (95% feature CI) Diarrhea 17 1.11(1. 0.04 01, 1.23) Dysentery 2 1.00 0.99 (0.87, 1.15) IRD p (95% CI) 0.05 (- 0.21 0.03, 0.13) 0.00 (- 0.90 0.05, 0.06)

Diarrhea - IRR
Cochrane incidence rate ratio plot (random eff ects)
JAMES ET AL BRUNSER ET AL ANGELES ET AL POW ER ET AL ROSADO ET AL 1 ROSADO ET AL 2 JAVAID ET AL BERGER ET AL LAW LESS ET AL IRIGOYEN ET AL OPPENHEIMER ET AL SINGHAL ET AL MITRA ET AL RICE ET AL NAGPAL ET AL ADAM ET AL ATUKORALA ET AL 1 ATUKORALA ET AL 2 CANTW ELL ET AL

0.001

0.01

0.1 0.2

0.5

10

100

DL pooled incidence rate ratio = 1.110208 (95% CI = 1.005139 to 1.226259)

Diarrhea and Oral iron

Cochrane incidence rate ratio plot (random eff ects)
ANGELES ET AL ROSADO ET AL 1 ROSADO ET AL 2 BERGER ET AL LAW LESS ET AL MITRA ET AL RICE ET AL NAGPAL ET AL ADAM ET AL ATUKORALA ET AL 1 ATUKORALA ET AL 2

0.01

0.1

0.2

0.5

10

100

DL pooled incidence rate ratio = 1.154616 (95% CI = 1.007919 to 1.322665)

RTI and LRTI

Stratifi No. of IRR p cation Trials (95% feature CI) RTI 17 0.98 0.54 (0.90, 1.06) LRTI 8 0.97 0.93 (0.83, 1.23) IRD p (95% CI) 0.02 0.79 (-0.13, 0.18) 0.01 0.84 (-0.11, 0.13)

RTI and Fortified Iron

IRR=0.92; 95% CI 0.86, 0.98 (p=0.02)
Cochrane incidence rate ratio plot (random eff ects)

POW ER ET AL

JAVAID ET AL

SINGHAL ET AL

HEM MINKI ET AL

0.5

1 DL pooled incidence rate ratio = 0.919562 (95% CI = 0.858902 to 0.984506)

RTI and fortified iron

IRD=0.19 episodes/ child-year (95% CI 0.54, 0.16; p=0.28)
Cochrane incidence rate dif ference plot (random eff ects)

POW ER ET AL

JAVAID ET AL

SINGHAL ET AL

HEM MINKI ET AL

-2

-1

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

Malaria and Other Infections

Stratifi No. of IRR p cation Trials (95% feature CI) Malaria 5 1.07 0.35 (0.94, 1.24) Other 13 1.04 0.20 Infectio (0.98, ns 1.11) IRD p (95% CI) 0.04 (- 0.32 0.04, 0.11) 0.05 (- 0.15 0.02, 0.12)

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

Conclusions
No

significant increase in the risk of infection with iron supplementation Slight (11%; 95% CI 1-23%) increase in the risk of developing diarrhea, more so in the group supplemented orally; public health significance ??

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

The story thereafter..

Study, Country Morbidities Treatment Groups Iron vs control; Iron and Zn vs Zn
a)

Conclusions

Baqui et al, 2003 (Bangladesh)

Diarrhea and ARI

b)

No effect on overall risk for diarrhea; Fe-Zn had lower severe diarrheal episodes No effect on ALRI Fe alone higher incidence of Vivax malaria versus placebo Increased diarrheal morbidity in child>9 yrs

Richard et al, 2006 (Peru)

Malaria, Diarrhea, ALRI

Iron vs control; Iron and Zn vs Zn

a)

b)

Le Huong T, et al, 2007 (Vietnam)

Worm Infestation

Iron vs Placebo; a) Iron and Meb vs Meb b)

No significant effect on hookworm and ascaris Lower prevalence of Trichuris infestation with Fe

Lancet 2006; 367: 133-43.

Lancet 2006; 367: 144-52.

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

Sub-study of Pemba RCT

Random sample of clusters with more extensive and diagnostic practices 2413 children included Adverse events lower in supplemented group (not significant) Deaths RR 0.73 (0.31-1.71) Hospitalization RR 0.76 (0.54-1.06) Children with moderate anemia had significant protection from adverse events

Comment

Caveats
1.

2.

Nepal - well functioning primary health-care system, a factor that the Pemba sub-study results suggest may change the balance of risk and benefit with iron and folic acid. Major malaria related adverse effects (45%) misclassification possible

Caveats (contd)

Caveats (contd)
4. Finger of suspicion iron; IFA given in a setting where first line antimalarial is Sulphadoxine-pyrimethamine (SP), an antifolate. It is also likely that folic acid supplementation contributed to the malariarelated adverse health outcomes of those receiving iron plus folic acid.

Dihydrofolate Reductase

DHFR is a small enzyme that plays an essential role in DNA synthesis Catalyzes the conversion of dihydrofolate to tetrahydrofolate, a cofactor required for the biosynthesis of thymidylate, pyrimidine nucleotides, methionine, and glycine

DHFR-TS

Folic Acid Pathway

Sulphadoxine-pyrimethamine

Introduced in 1967 as a synergistic anti-malarial drug, with reports of resistance occurring within a few years Used as a second-line drug in areas where chloroquine is still used In areas that are chloroquine resistant, it has become the first-line antimalarial There are many hyperendemic and holoendemic areas that are now SP resistant

Drug-resistance worldwide

Folate and Malaria

Mulenga et al, 2006 (Zambia) Mbaye et al, 2006 (Gambia) Pregnancy Carter et al, 2005 (Kenya) 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). No interference with effect of SP

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)

Ouma et al, 2006 (Kenya) Pregnancy

Higher treatment failure in SP group in those receiving Folate

Concomitant use of 5 mg FA supplementation compromises the efficacy of SP for the treatment of uncomplicated malaria in pregnant women.

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 protection from malaria and other infectious diseases Should not be extrapolated to fortification or food-based approaches for delivering iron