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Web Appendix 8

Review of iron supplementation in pregnancy and childhood

H.P.S. Sachdev and Siddhartha Gogia

Division of Pediatrics and Clinical Epidemiology, Sitaram Bhartia Institute of Science and Research, B-16 Qutab Institutional Area, New Delhi 110 016, India.

From a public health perspective, iron deficiency is believed to be the most important

causal factor for anemia. Consequently, in public health terminology, the terms ‘anemia’,

‘iron deficiency anemia’, and ‘iron deficiency’ are often used interchangeably. With this

background, iron deficiency is believed to be the most common nutritional disorder

globally. Over 30% of the world’s population (~2 billion) is anemic, mainly due to iron

deficiency [1-3]. In developing countries about 50% pregnant women and about 40% of

preschool children are estimated to be anemic [1-3]. On the basis of animal data, and

cross-sectional and longitudinal observational studies in infants, children, adolescents,

and adults several biological consequences have been attributed to iron deficiency. These

include poor pregnancy outcome, impaired physical and cognitive development, and

increased risk of morbidity in children and reduced work productivity in adults. However,

evidence from iron intervention trials has not consistently supported all these inferences.

The primary objective of this review is to update comprehension about the specific role

of iron supplementation in improving maternal and child health, especially in the context

of less developed countries. The ensuing discussion therefore primarily focuses on

evidence obtained from iron intervention trials in relation to biological advantages or

adverse consequences.

Methodology

Literature search was conducted using the search words “iron” and limited to “clinical

trial”, “review”, “meta-analysis”, “systematic review”, “randomized controlled trial” and

“humans”. This search was conducted on several databases including PubMed, Extended

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Medline, Cochrane Controlled Trial Register, OVID, DARE, CINAHL, HEALTHSTAR

and EMBASE. The references mentioned in the above studies and reviews were also

searched for identifying relevant trials and reviews. An effort was also made to obtain

unpublished studies pertaining to the topic by searching relevant databases and contacting

researchers working in the field, and donor and funding agencies. Using the above-

mentioned strategy, approximately 3000 studies were identified and their abstracts

obtained. These abstracts were studied to scrutinize the relevant trials. Wherever

necessary, the full text of the trial was obtained to clarify whether the study could be

included in the final analysis or not. The full text of the trials hence identified was

obtained and all randomized placebo-controlled trials or trials with a factorial design

where the only difference between the experimental group and the control group was iron

were included. The trials were grouped according to the outcome variables, namely,

anemia, infection, physical growth, motor and mental development, physical

performance, morbidity and mortality. In addition, trials comparing daily and intermittent

iron supplementation were also evaluated. The data from the relevant trials was collected

using a pre-tested data abstraction form. If there were no randomized controlled trials

available for certain outcomes, weaker quality of evidence was reported.

Recent high-quality systematic reviews, several of them conducted by our group, were

available for most of the outcome measures. We therefore are presenting our results as an

overview of this evidence, which has been supplemented with other relevant trials that

may have become available after these systematic reviews

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Efficient Indicators of Population Response to Iron Interventions

Governments and donor agencies have implemented pilot and large-scale iron

supplementation and fortification programs globally. However, there has been no

consensus on the best choice of indicators to monitor population response to these

interventions. A pooled analysis [4] was conducted on data from nine randomized iron

intervention trials in seven countries (sample sizes: controls – 909 and intervention –

991) to determine which of the following indicator(s) of iron status showed the largest

response in a population: hemoglobin (Hb), ferritin, transferrin receptor (TfR), zinc

protoporphyrin (ZPP), mean cell volume (MCV), transferrin saturation (TS), and total

body-iron store. Three of the studies were conducted among non-pregnant women, 2

among pregnant women, 2 among preschool-aged children, and 2 among school-aged

children. The interventions lasted between 4 and 18 months, and the intensity of

interventions ranged between low-level fortifications doses to high-level therapeutic

doses. For the purpose of measuring the population response to an iron intervention, the

best indicator of iron deficiency was considered to be one that showed the largest and

most consistent change in response to an increase in bio-available iron intake. For

comparability within the studies and the various indicators, the authors expressed the

change in each indicator in response to the iron intervention in SD units (SDU). Ferritin

increased by > 0.2 SDU in all trials and was significant in 7. Hb changed by > 0.2 SDU

in 6 and was significant in 5. TfR increased by > 0.2 SDU in 5 of 8 interventions in

which it was measured and was significant in 4. ZPP increased by > 0.2 SDU and was

significant in 3 of 6 interventions. Excluding Hb, the indicator with the largest change in

SDU was ferritin in 4 trials, TS in 2 trials, body-iron store in 2 trials, and TfR in 1. In the

2 cases in which body-iron stores showed the largest change, the change in ferritin was

nearly as large. Thus ferritin showed larger and more consistent response to iron

interventions than ZPP or TfR, and a confident inference could not be made about MCV

or TS, which were included in only 4 and 2 trials, respectively. In no case would a

significant change in iron status due to the intervention have gone undetected if Hb and

ferritin had been the only two indicators measured. It is possible that the optimal

indicator(s) may have varied with age, sex, and pregnancy. However, there were too few

trials in each age and sex group to explore this possibility. Thus, hemoglobin and ferritin

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are currently the most efficient combination of indicators for monitoring population

response to iron interventions, and these may have economic and logistic benefits in less

developed countries.

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Biological Consequences of Iron Deficiency in Infants, Children and Adolescents Assessed by Iron Interventions

Hemoglobin and Anemia

A recent systematic review [5] evaluated change in hemoglobin levels with randomized

controlled trials that included oral or parenteral iron supplementation, or iron fortified

formula milk or cereals. Fifty-five trials (56 cohorts) had relevant information; pooled

data was available on 12179 children, 6579 of whom received iron while 5600

constituted the placebo group. Publication bias was evident (p<0.001). The pooled

estimate (random effects model) for change in hemoglobin with iron supplementation

(weighted mean difference) was 0.74 g/dL (95% confidence interval 0.61–0.87, p<0.001;

p<0.001 for heterogeneity). Lower baseline hemoglobin level, oral medicinal iron

supplementation, and malarial non-hyperendemic region were significant predictors of

greater hemoglobin response, and heterogeneity. Projections suggested that on average

between 38% and 62% of baseline anemia (hemoglobin < 11g/dL) is responsive to iron

supplementation among children under six years old; the corresponding range for

malarial hyperendemic regions is 6% – 32%. Thus, iron supplementation increases

hemoglobin levels in children significantly, but modestly. The rise is greater with

baseline anemia, and lower in malarial hyperendemic areas and in those consuming iron

fortified food. The projected reductions in prevalence of anemia with iron

supplementation alone (38% to 62% in non-malarial regions, and 6% to 32% in malarial

hyper-endemic areas) highlight the need for additional area-specific interventions,

particularly in malarial regions.

Mental and Motor Development

A systematic review determined the effects of iron therapy on psychomotor development

and cognitive function in iron deficient children less than 3 years of age [6]. Studies were

included if children less than 3 years of age with evidence of iron deficiency anemia were

randomly allocated to iron or iron and vitamin C versus a placebo or vitamin C alone and

assessment of developmental status or cognitive function was carried out using

standardized tests by observers blind to treatment allocation. Five trials, including 180

children with iron deficiency anemia, examined the effects of iron therapy on measures of

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psychomotor development between 5 and 11 days of commencement of therapy. Data

from four trials could be pooled. The pooled difference in pre to post treatment change in

Bayley Scale psychomotor development index between iron treated and placebo groups

was -3.2 (95% CI -7.24, 0.85) and in Bayley Scale mental development index, 0.55 (95%

CI -2.84, 1.75). Two studies, including 160 randomized children with iron deficiency

anemia, examined the effects of iron therapy on measures of psychomotor development

more than 30 days after commencement of therapy. One trial reported the mean number

of skills gained after two months of iron therapy, using the Denver test. The intervention

group gained 0.8 (95% CI -0.18, 1.78) more skills on average than the control group.

Another study showed that the difference in pre to post treatment change in Bayley Scale

psychomotor development index between iron treated and placebo groups after 4 months

was 18.40 (95%CI 10.16, 26.64) and in Bayley Scale mental development index, 18.80

(95% CI 10.19, 27.41).

Another systematic review evaluated the effect of iron supplementation on mental and

motor development in children through randomized controlled trials employing

interventions that included oral or parenteral iron supplementation, fortified formula

milk, or cereals [7]. The outcomes studied were mental and motor development scores,

and various individual development tests employed, including Bayley mental and

psychomotor development indices, and intelligence quotient. A comprehensive mental

development score was created, which refers to a logical combination of different tests

that assess the same aspect of mental development, namely, Bayley Mental Development

Index (MDI), Stanford Binet Test, Peabody Picture Vocabulary Tests, intelligence

quotient, and cognition scores. Fifteen studies conducted on 2827 children, 1412 of

which received iron and 1415 placebo, were included in this analysis. The pooled

estimate (random effects model) of mental development score standardized mean

difference (SMD) was 0.30 (95% confidence interval 0.15 to 0.46, p<0.001; p<0.001 for

heterogeneity). Initial anemia and iron deficiency anemia were significant explanatory

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variables for heterogeneity. The pooled estimate of Bayley Mental Development Index

(weighted mean difference) in younger children (8 studies on children <27 months old)

was 0.95 (95% CI -0.56 to 2.46, p=0.22; p=0.016 for heterogeneity). For intelligence

quotient scores (4 trials on subjects >8 years age), the pooled SMD was 0.41 (95% CI

0.20 to 0.62, p<0.001; p=0.07 for heterogeneity). Amongst the ten trials evaluating motor

development, eight used Bayley psychomotor development index, one assessed

psychomotor development through DDST, and one used a physical activity score (data on

1246 children; 630 received iron and 616 placebo). There was no effect of iron

supplementation on motor development score (SMD 0.09, 95% CI -0.08 to 0.26, p=0.28;

p=0.028 for heterogeneity). Thus, iron supplementation improves mental development

score modestly (SMD of 0.3, equivalent to 1.5 to 2 points on a scale of 100). This effect

is particularly apparent for intelligence tests above seven years of age, and in initially

anemic or iron deficient anemic subjects. There is no convincing evidence that iron

treatment has an effect on mental development in children below 27 months of age, or on

motor development. However, (i) confidence intervals suggest that these results could be

compatible with moderate positive or adverse effects of iron therapy, (ii) the possibility

of irreversible structural brain changes, particularly in younger children cannot be

excluded due to paucity of relevant preventive trials, and (iii) the effect of longer term

treatment is unclear.

After publication of the above systematic review [7], other relevant trials have appeared

in the literature. In a longitudinal study [8] designed to evaluate the long lasting effect of

iron deficiency on the functioning of auditory and visual systems, healthy Chilean

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children were compared with peers who had received therapy for iron deficiency anemia.

Absolute latencies for all auditory brainstem response waves and inter-peak latencies

(except I–III interval) were significantly longer in formerly anemic children. Longer

latency was also observed for the P100 wave on visual evoked potential. These findings

suggest that untreated iron deficiency in children may have long lasting consequences.

A pertinent review of the additional relevant randomized controlled trials published after

the systematic review [7], is summarized in Table I [9-14]. A trial from Zanzibar [15]

was excluded, as the intervention comprised both iron and folic acid. Amalgamation of

these findings from the additional trials does not alter the broad conclusions of the earlier

systematic review [7]. However, there is a suggestion of an improvement in subtle

developmental measures like oddity learning test and orientation engagement, which are

not encompassed by the traditional tests.

Physical Growth In meta-analyses of randomized controlled intervention trials conducted to assess the

effects of vitamin A, iron, and multi-micronutrient interventions on the growth of

children <18 years old, 21 iron intervention studies that met the design criteria were

identified [16]. Iron interventions had no significant effect on child growth. Overall effect

sizes were 0.09 (95% CI: -0.07, 0.24) for height and 0.13 (95% CI: -0.05, 0.30) for

weight. The results were similar across categories of age, duration of intervention, mode

and dosage of intervention, and baseline anthropometric status. Iron interventions did

result in a significant increase in hemoglobin (Hb) concentrations with an effect size of

1.49 (95% CI: 0.46, 2.51).

More recently, the effect of iron supplementation on physical growth in children was

evaluated through a systematic review of randomized controlled trials employing

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interventions that included oral or parenteral iron supplementation, fortified formula

milk, or cereals [17]. Twenty-five trials (26 cohorts) had relevant information. There was

no evidence of publication bias. The pooled estimates (random effects model) did not

document a statistically significant (P>0.05) positive effect of iron supplementation on

any anthropometric variable: weight for age (4327 children, 2329 of whom received iron

while 1998 constituted the placebo group; standardized mean difference (SMD) 0.11,

95% CI -0.01, 0.23, p=0.061, p<0.001 for heterogeneity), weight for height (1246

children, 626 of whom received iron while 620 constituted the placebo group; SMD 0.21,

95% CI -0.09, 0.52, p=0.170, p<0.001 for heterogeneity), height for age (3935 children,

2132 of whom received iron while 1803 constituted the placebo group; SMD 0.01, 95%

CI = -0.10, 0.12, p=0.795, p<0.001 for heterogeneity), mid upper arm circumference

(1163 children, 538 of whom received iron while 525 constituted the placebo group;

SMD 0.0, 95% CI -0.20, 0.20, p=0.991), skinfold thickness, and head circumference.

Significant heterogeneity was evident, and it’s predictors included greater weight for age

in supplemented children in malarious regions, greater weight for height for children

above 5 years of age, but a negative effect on linear growth in developed countries and

with supplementation for 6 months or longer. In the minority of studies showing benefit,

this was primarily in the children with iron deficiency at baseline. A study suggested that

iron supplementation in young children without iron deficiency may jeopardize optimal

height and weight gains during this period. Thus, there is no convincing evidence of a

positive effect of iron supplementation on the physical growth of children. The identified

predictors of heterogeneity should be considered as exploratory requiring confirmation

and not conclusive.

Physical Performance

The effect of iron supplementation on physical performance in children was evaluated

through a systematic review of randomized controlled trials employing interventions that

included oral or parenteral iron supplementation, fortified formula milk, or cereals [18].

Only three studies could be included, and in all of them oral medicinal iron was used. In

the three studies, heart rates measured after exercise at three different running speeds

were combined. At 5, 6 and 7 miles per hour running speeds, the pooled weighted mean

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(95% CI) difference (WMD) in the heart rates (per minute) between the iron and the

placebo, following exercise were –7.3 (-19.6, 4.9; P= 0.241), -6.6 (-19.9, 6.6; P=0.327),

and –8.0 (-19.7, 3.7; P=0.182). After excluding the study with non-anemic subjects, the

corresponding figures were -13.1(-23.2, -3.1; P=0.01), -14.2 (-22.3, -6.1; P= 0.001) and -

12.7 (-23.5, -1.9; P= 0.021), respectively. Oxygen consumption, estimated in two studies,

showed no significant difference between the treatment groups. Blood lactate levels were

estimated in one study only at two different doses of iron, and were significantly lower

(P<0.05) in iron supplemented group in comparison to placebo both before (7.71 and

7.55 mg/dl versus 8.43 mg/dl) and after (14.36 and 14.35 mg/dl versus 16.48 mg/dl)

exercise. Treadmill endurance time was significantly better in iron supplemented group

when compared with placebo in one study. Thus, iron supplementation may have a

positive effect on the physical performance of children, as evaluated through the post

exercise heart rate in anemic subjects, blood lactate levels and treadmill endurance time.

In view of the limited data availability, this finding cannot be considered conclusive.

Morbidity and Mortality

Relevant information is not available on all the aspects (incidence, duration, or severity)

on which iron supplementation may potentially influence infections. A review included

trials in all age groups of parenteral and oral iron supplements or fortified foods in which

groups differed only in the provision of iron [19]. Oral iron was associated with increased

rates of clinical malaria (5 of 9 studies) and increased morbidity from other infectious

disease (4 of 8 studies). In most instances, therapeutic doses of oral iron were used. No

studies in malarial regions showed benefits while no studies of oral iron supplementation

clearly showed deleterious effects in non-malarious areas. Milk fortification reduced

morbidity due to respiratory disease in two very early studies in non-malarious regions,

but this was not confirmed in three later fortification studies, and better morbidity rates

could be achieved by breast-feeding alone. One study in a non-malarious area of

Indonesia showed reduced infectious outcome after oral iron supplementation of anemic

schoolchildren. No systematic studies reported on oral iron supplementation and

infectious morbidity in breast-fed infants in non-malarious regions.

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Subsequently, a systematic review was conducted, which focused on children only [20].

Evaluated outcome measures included the incidence of all recorded infectious

morbidities. Individual morbidities were also studied, including respiratory tract

infection, diarrhea, malaria, other infections (septicemia, cutaneous infections, worm

infestations, tuberculosis, etc.) and prevalence of smear positivity for malaria. Twenty-

eight studies were evaluated. The pooled estimates (random effects model) of the

incidence rate ratio (IRR) and incidence rate difference (IRD) for all the recorded

morbidities were 1.02 (95% CI 0.96 to 1.08; p=0.54; p for heterogeneity < 0.0001) and

0.06 episodes/ child-year (95% CI -0.06 to 0.18; p=0.34; p for heterogeneity < 0.0001),

respectively. However, there was an increase in the risk of developing diarrhea (IRR=

1.11; 95% CI 1.01 to 1.23; p=0.04), which did not translate into a significant public

health impact (IRD = 0.05 episodes/child-year; 95% CI –0.03 to 0.01; p=0.21). The

occurrence of other morbidities and malarial smear positivity (adjusted for baseline smear

positivity) was not significantly affected by iron administration. On meta-regression, the

statistical heterogeneity could not be explained by a variety of study characteristics.

There was a near absence of any adverse effects, particularly diarrhea, in children

receiving fortified foods (compared with medicinal iron), which raises the possibility of a

dose related effect. The authors concluded that iron supplementation has no apparent

harmful effect on the overall incidence of infectious illnesses in children, though it

slightly increases the risk of developing diarrhea.

An unpublished meta-analysis [21] of 9 published and 4 unpublished randomized

controlled trials using prophylactic oral or parenteral iron supplementation with at least

one P. falciparum related outcome, found a pooled estimate of excess risk from iron

supplementation for incidence of clinical malaria RR 1.09 (95% CI 0.92, 1.3), prevalence

of malaria infection RR 1.17 (95% CI 1.08, 1.25), and absolute change in prevalence of

parasitemia RR 5.7% (95% CI 1.2, 8.5).

Pertinent details of subsequent relevant trials are summarized in Table II. This additional

evidence does not alter the inferences of the earlier reviews. However, the risks and

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benefits of iron supplementation in HIV infection, tuberculosis, and hepatitis C virus

infection have not been extensively studied to make any firm conclusions.

There are no randomized controlled intervention trials evaluating the effect of iron

supplementation alone on mortality. However, two recent recently published and

adequately powered, randomized controlled trials in children below three years of age

have provided information on the effect of routine iron and folate supplementation on

serious morbidity and mortality from Pemba, Zanzibar [26] and southern Nepal [27]. The

African trial was conducted in an area (Pemba) with high malarial transmission (average

of 400 infective bites per year) whereas the Nepal trial was in an area not exposed to any

significant malaria risk.

In the Pemba trial, children aged 1-35 months were assigned to daily oral

supplementation with: iron (12·5 mg) and folic acid (50 micro-grams; n=7950), iron, folic

acid, and zinc (n=8120), or placebo (n=8006); children aged 1–11 months received half

the dose. The primary endpoints were all-cause mortality and admission to hospital. The

iron and folic acid-containing groups of the trial were stopped early on the

recommendation of the data and safety monitoring board. Till that date, 24076 children

contributed a follow-up of 25524 child-years. Those who received iron and folic acid

with or without zinc were 12% (95% CI 2–23, p=0·02) more likely to die or need

treatment in hospital for an adverse event and 11% (1–23%, p=0·03) more likely to be

admitted to hospital; there were also 15% (-7 to 41, p=0·19) more deaths in these groups.

A sub-study was also done with the original objectives of assessing the effects of

supplementation on hematological and zinc status, malaria prevalence, and infectious

disease morbidity. In this sub-study, the overall effect of supplementation with iron and

folic acid was a non-significant reduction in adverse events. The results suggested that

only children with anemia associated with iron deficiency benefited from

supplementation with iron and folic acid with respect to hospital admissions and death.

Those with iron deficiency without anemia were not adversely affected by

supplementation with iron and folic acid, whereas children without iron deficiency had

adverse effects, even in the presence of enhanced detection and management of malaria

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and other infections. Before extrapolating this results widely, it must be realized that the

data pertain to supplementation by iron and folic acid rather than iron alone; the adverse

effects could arise from iron alone, folic acid alone or a combination of both. There are

experimental, laboratory, and field observations that point the finger of suspicion at iron

[29]. However, the supplement was iron and folic acid in a setting in Pemba where the

first line antimalarial treatment was with an antifolate combination of sulfadoxine and

pyrimethamine. The addition of folate to iron plus sulfadoxine and pyrimethamine for the

treatment of malaria results in a biologically and statistically significant delay in parasite

clearance and parasitological (but not clinical) cure [30]. While the dose of folic acid was

an order of magnitude higher in this treatment trial, it is possible that, in an area where

sulfadoxine and pyrimethamine efficacy was declining rapidly, as was likely in Pemba at

the time of the study, folic acid supplementation contributed to the malaria-related

adverse health outcomes of those receiving iron plus folic acid. However, the authors

could not find any association of recovery from sulfadoxine/pyrimethamine treated

malaria episodes or subsequent recrudescence with iron and folic acid versus placebo. In

the absence of a direct comparison of iron with placebo, for the purist, the effect of iron

supplementation alone would remain conjectural.

In the Nepal trial, 1 to 36 months old children were randomly assigned to daily oral

supplementation with: iron (12·5 mg) and folic acid (50 micro-grams; n=8337), zinc

alone (10 mg), iron, folic acid, and zinc (n=9230), or placebo (n=8683); children aged 1–

11 months received half the dose. The primary outcome measure was all-cause mortality,

and secondary outcome measures included cause-specific mortality and incidence and

severity of diarrhea, dysentery, and acute respiratory illness. A total of 25490 children

had participated till the time that the trial was stopped early and analyses are based on

29097·3 person-years of follow-up. There was no difference in mortality between the

groups who took iron and folic acid without or with zinc when compared with placebo

(HR 1·03, 95% CI 0·78–1·37, and 1·00, 0·74–1·34, respectively). There were no

significant differences in the attack rates for diarrhea, dysentery, or respiratory infections

between groups, although all the relative risks except one indicated modest, non-

significant protective effects. The authors concluded that daily supplementation of young

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children in southern Nepal with iron and folic acid with or without zinc have no effect on

their risk of death, but might protect against diarrhea, dysentery, and acute respiratory

illness.

An expert WHO meeting convened specifically to examine these two trials [31],

concluded that in regions with a high prevalence of malaria and other infections, iron and

folic acid supplementation for young children be targeted to those who are iron deficient.

Every effort should also be made to combine iron supplementation with effective

treatment and control of malaria and other severe infectious and parasitic disease. It was

also emphasized that these findings should be regarded as specific to iron and folic acid

supplementation of young children in regions of the world where malaria transmission is

intense and severe infectious disease prevalence is high. The conclusions should not be

extrapolated to fortification or food-based approaches for delivering iron. Thus, iron

administration slightly increases the risk of developing diarrhea (IRR 1.11). In non-

malarious regions iron supplementation has no apparent beneficial or harmful effects on

the overall incidence of infectious illnesses in children. In malarious regions, particularly

those with high transmission rates, iron supplementation may result in increased risk of

malarial infection. In populations with high rates of malaria, routine supplementation

with iron and folic acid in preschool children can result in an increased risk of severe

illness and death. However, in the presence of an active program to detect and treat

malaria and other infections, iron deficient and anemic children can benefit from iron and

folic acid supplementation. In areas where iron deficiency is common and malaria absent,

daily supplementation of young children with iron and folic acid has no effect on their

risk of death, but might protect against diarrhea, dysentery, and acute respiratory illness.

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Biological Consequences of Maternal Iron Deficiency as Assessed by Iron Interventions

Work Capacity in Non-Pregnant, Non-Lactating Women

The causal relationship between iron deficiency and physical work capacity has been

evaluated through a systematic review of the research literature, including animal and

human studies [32]. Although the review examined human subjects of various ages and

both genders, the inferences appear to be valid for the sub-set of non-pregnant, non-

lactating women. Iron deficiency was examined along a continuum from severe iron-

deficiency anemia (SIDA) to moderate iron-deficiency anemia (MIDA) to iron deficiency

without anemia (IDNA). Work capacity was assessed by aerobic capacity, endurance,

energetic efficiency, voluntary activity and work productivity. The 29 research reports

examined demonstrated a strong causal effect of SIDA and MIDA on aerobic capacity in

animals and humans. The presumed mechanism for this effect is the reduced oxygen

transport associated with anemia; tissue iron deficiency may also play a role through

reduced cellular oxidative capacity. Endurance capacity was also compromised in SIDA

and MIDA, but the strong mediating effects of poor cellular oxidative capacity observed

in animals have not been demonstrated in humans. Energetic efficiency was affected at

all levels of iron deficiency in humans, in the laboratory and the field. The reduced work

productivity observed in field studies is likely due to anemia and reduced oxygen

transport. The social and economic consequences of iron-deficiency anemia (IDA) and

IDNA have yet to be elucidated. The reviewers concluded that biological mechanisms for

the effect of IDA on work capacity are sufficiently strong to justify interventions to

improve iron status as a means of enhancing human capital. A critical review of this

report also concluded that from both the laboratory and field experiments, the evidence is

strong and suggests that the potential magnitude of the effect of iron-deficiency anemia

on work productivity is substantial [33]. Thus, iron supplementation in non-pregnant,

non-lactating women suffering from severe or moderate iron deficiency anemia improves

work capacity.

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Hemoglobin and Anemia

A systematic review [34] evaluated change in hemoglobin levels with randomized

controlled trial design interventions. Only 23 studies, 15 of which were conducted in

developing countries met the inclusion criteria. The average baseline hemoglobin level of

women in 13 of the 15 randomized controlled trials conducted in developing countries

was below 11 g/dl. Relative to no supplementation, iron supplementation alone increased

hemoglobin change by 1.0 + 0.013 g/dl (P < 0.001, n=1118, df =13). In the three studies

reporting on iron deficiency, iron supplementation alone reduced the percentage of

women with hemoglobin levels of less than 11 g/dl by 38% (the mean effect on

hemoglobin change was 1.2 g/dl). The effect was greater with lower baseline hemoglobin

levels and there was evidence of a dose response relationship (greater effect in studies

providing supplementation for longer duration). Another subsequent systematic review

from Cochrane database [35] found that iron supplementation in pregnancy raised or

maintained the serum ferritin above 10 milligrams per liter, and prevented low

hemoglobin at birth or at six weeks post partum. Observational data and a few relevant

controlled trials, indicate that maternal iron status has a positive impact on the neonatal

iron stores [36-38]. Thus, iron supplementation in pregnancy increases the maternal iron

stores, and prevents low hemoglobin at birth or at six weeks post partum. The effect is

greater with lower baseline hemoglobin levels and with longer duration of

supplementation. Iron administration in pregnancy also has a positive impact on the

neonatal iron stores.

Maternal Mortality and Morbidity

Relevant evidence in this context is only observational in nature. The available data

confirm an associative – not causal – relationship between severe anemia (hemoglobin

concentrations below 7 or 8 g/dl) and the risk of maternal mortality [37]. Nevertheless the

strength of this relationship makes it appropriate to presume that it is causal. However,

routine iron supplementation has not been shown to reverse severe anemia; thus the

potential benefit of iron administration in reducing maternal mortality is questionable.

The evidence of a relationship between maternal death and moderate anemia, however, is

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both scanty and contradictory. Until further data are available, it appears that moderate

concentrations of anemia are probably best considered unrelated to excess maternal

mortality; thus there is no likely benefit of iron supplementation in this context. There is

negligible evidence evaluating the effect of iron administration on prevention or

treatment of maternal morbidity other than anemia [39].

Recent preliminary evidence, primarily from observational studies in developed

countries, has linked maternal iron supplementation and increased iron stores to

gestational diabetes mellitus and increased oxidative stress during pregnancy [40]. The

possibility that prophylactic iron supplementation may increase risk of maternal

morbidity when there is no iron deficiency or iron deficiency anemia, deserves

exploration through relevant intervention trials. Thus, iron administration in pregnancy is

not likely to reduce maternal mortality or morbidity other than anemia. The possibility

that prophylactic iron supplementation may increase risk of gestational diabetes mellitus

when there is no iron deficiency, deserves exploration.

Newborn Size and Gestation, and Perinatal Health Strong evidence exists for an association between maternal hemoglobin concentration

and birth weight as well as between maternal hemoglobin concentration and preterm birth

[41]. From the available data, it is not possible to determine how much of this association

is attributable to iron deficiency anemia in particular. Minimal values for both low birth

weight and preterm birth occurred at maternal hemoglobin concentrations below the

usual cut-off value for anemia during pregnancy (11 g/dl) in a number of studies,

particularly those in which maternal hemoglobin values were not controlled for the

duration of gestation. In randomized controlled trials, iron supplementation of anemic or

non-anemic pregnant women had no detectable effect on either birth weight or the

duration of gestation or perinatal morbidity and mortality [35,42]. However, the

individual information on neonatal and perinatal outcomes is available in only a limited

number of studies, especially from communities where iron deficiency is common.

Further, the available studies need to be interpreted with caution because most are subject

to a bias towards false-negative findings.

18

Observational data on anemia imply that iron supplementation should be started early in

pregnancy, if not before, to improve neonatal and perinatal outcomes [39]. An important

limitation of adequately designing iron intervention studies in pregnancy has been the

exclusion of women with anemia at baseline, and/or lack of a placebo group due to

ethical concerns [36]. Using an innovative approach to limit this problem, an intervention

trial was conducted in Cleveland, Ohio [42] that provided 30 mg iron daily from < 20

weeks to 28 weeks of gestation. A placebo group was included because women found to

have a hemoglobin concentration <10 g/dl or ferritin <20 micrograms/ liter at 28 weeks

or 38 weeks of gestation were supplemented with iron. Iron supplementation from

enrollment through 28 weeks of gestation did not affect the prevalence of anemia but

increased birth weight by 206 g and gestation by 0.6 weeks. The trial documented a

lowered incidence of low birth weight from 17% to 4% while preterm delivery incidence

was not lowered. In Nepal, another cluster-randomized study with early supplementation

arrived at a similar, but not identical result [43]. In comparison to controls, gravidas

receiving folate showed no reduction in the risk of low birth weight, whereas those

receiving iron plus folate increased birth weight by 37 g and showed a reduction of 14%

in risk of low birth weight. Preliminary intervention evidence thus suggests that early

supplementation with iron can increase birth weight and gestational duration with

concomitant reduction in risk of low birth weight or preterm low birth weight but not

preterm delivery.

Evidence, primarily from observational studies in developed countries, has linked

increased maternal hemoglobin and/or iron stores and iron supplementation to impaired

fetal growth [37,41]. The possibility that prophylactic iron supplementation may impair

fetal growth when there is no iron deficiency deserves exploration through relevant

intervention trials. Thus, there is no conclusive evidence that routine iron

supplementation in pregnancy will increase newborn size and duration of gestation, and

improve perinatal health. However, this information is available from a limited number of

studies, which are subject to a bias towards false-negative findings. Preliminary

intervention evidence suggesting that early supplementation can increase birth weight and

19

duration of gestation needs urgent validation. The possibility that prophylactic iron

supplementation may impair fetal growth when there is no iron deficiency also deserves

exploration.

20

Relative Efficacy of Intermittent and Daily Iron Supplementation for the Control of Iron Deficiency Anemia in Developing Countries

The relative efficacy of intermittent and daily iron supplementation for the control of iron

deficiency anemia in developing countries has been examined in a meta-analysis of 22

completed trials involving nearly 6000 subjects [44]. The review examined results in the

individual projects, grouped into three categories: pregnant women, school children and

adolescents, and preschool children. Both weekly and daily iron supplementation were

efficacious in reducing anemia. However, weekly iron supplementation was less effective

than daily iron supplementation in reducing anemia; the pooled relative risk of being

anemic at the end of the intervention with weekly dosing was 1.34 (95% confidence

interval 1.20 – 1.49). With both forms of supplementation, compliance was an important

predictor of hemoglobin response. A pertinent review of subsequent iron supplementation

trials comparing daily versus intermittent administration is summarized in Table III [13,

24, 45-62], which reaffirms the main conclusion of the earlier systematic review [44].

Thus, daily iron supplementation is more efficacious than intermittent iron administration

for the control of anemia in developing countries.

Recently, an evaluation has been published of the pilot programs initiated in some States

of India to demonstrate effectiveness and feasibility for scale-up of weekly iron (100mg

ferrous sulphate) and folic acid (500 micrograms) supplementation in adolescent girls

[63]. Impact assessments were conducted in seven of the programs, and were based on

reported compliance with tablet intake and on the analysis of hemoglobin concentration.

Randomly selected (non-paired) samples for hemoglobin measurements were collected

before the start of the programme and 12-14 or 24 months after programme initiation. In

some cases, a large impact was reported, as in Andhra Pradesh, with a decrease in

prevalence of anemia by 70% in two years. In some other states, the impact after one year

was more modest. It was concluded that that weekly supplementation of adolescent girls

with iron and folic acid tablets did lead to a marked decrease in the prevalence of anemia.

Conclusions

A summary of the major conclusions of the review is articulated in Table IV.

21

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28

Table I. Effect of Iron Supplementation on Mental and Motor Development

(Additional RCTs).

Author Year Country Subjects Dose

Follow up

time Outcomes evaluated Conclusions

Friel9 2003 Canada

77 term breast fed neonates, preterm & low birth weight

excluded 7.5 mg/d for

5 months

12-18 months of age

CBC, SF, red cell

superoxide dismutase, catalase,

plasma ferric reducing

antioxidant power, zinc and copper

levels, BSID, visual

acuity

Higher Hb & MCV at 6 months in iron group

(no difference at other times), higher PDI at 13 months of

age, no difference in

other parameters, recruitment

stopped before

sample size adequate due

to lack of funds

Black10 2004 Bangladesh

346 infants, ~6 months,

18% stunted, none wasted, 68% anemic;

severely malnourished

& severely anemic

excluded

Iron (20 mg/d), zinc (20 mg/d), iron and

zinc, micronutrient

mix or placebo.

6 months

BSID II, HOME scale (behaviour)

Iron & zinc in

combination resulted in

better development.

However, given alone each had a significant effect on

orientation engagement

only. No effect on Hb.

Lind11 2004 Indonesia

680 infants, <6 months, Hb<9 g/dl excluded; stunting,

underweight & wasting

<5%.

10 mg iron/d, 10 mg

Zinc/d, both, or placebo

6 months

BRS, BSID, PDI

Higher PDI in iron

group, no effect on MDI and

BRS

Metallinos-Katsaras12 2004 Greece 49, 3-4 year 15 mg/d

2 months

Simple reaction time

test, continuous

performance task, oddity

learning tasks

After iron treatment,

anemic subjects

made fewer errors of

commission, exhibited

higher

29

Author Year Country Subjects Dose

Follow up

time Outcomes evaluated Conclusions

accuracy and were

significantly more

efficient. No effect in iron

replete subjects. No effect on the

oddity learning task

Sungthong13 2004 Thailand

397 primary school

children, severe iron deficiency anemia and

severe malnutrition

excluded, anemia 27%, thalessemia trait 17%

60 mg iron 1d/week, 5d/week, placebo

16 weeks

Hb, SF, IQ, language,

mathematics

Comparable & significant increase in

Hb in weekly and daily

iron groups, SF increment most in daily iron group &

least in placebo

group. IQ increment

least in daily iron group

(weekly iron group and

placebo had similar

increase). No effect on school

performance.

Zhou14 2006 Australia

430 pregnant women (20

wk) 20 mg/d till

delivery 4 year

Stanford-Binet

Intelligence Scale,

Strength and Difficulties

Questionnaire

No effect on intelligence,

increased abnormal

behavior in iron group

BSID: Bayley`s scale of infant development; BRS: Behaviour rating scale; CBC: Complete blood count; IDA: Iron deficiency anemia; Hb: Hemoglobin; IQ: Intelligence quotient; MCV: Mean corpusclar volume; MDI: Mental development index; PDI: Psychomotor development index; SF: Serum ferritin

30

Table II. Effect of Iron Supplementation on Infectious Morbidity in Children (Additional RCTs).

Author Ye

ar Coun

try Subjects Dose

Follow up Outcome

Richard22

2006 Peru

855, 6 mo-15 years

Increased morbidity due to Plasmodium vivax and diarrhea in children >5yr. In children <5 year, iron+zinc provided protection against P. vivax, but iron interfered with diarrhea protection

associated with zinc. No effect on the incidence of respiratory infection.

Lopez de

Romana23

2005 Peru

313, 6-12 mo; preterm, low birth weight;

severely wasted and

severely anemic

excluded

10 mg/d iron, daily multiple

micronutrient, weekly multiple

micronutrient, placebo

6 mont

hs

Hemoglobin increased significantly in all experimental groups (no difference

in weekly & daily iron groups), no significant difference in change in

serum ferritin. Anemia decreased in all experimental groups with greater decrease in the daily iron group

compared to weekly iron group. Iron status better in the daily iron group than

in placebo or weekly iron group. No difference in the monthly prevalence of

diarrhea, acute respiratory infection, and fever

Untoro2

4 2005

Indonesia

284, 6-12 months (58%

anemic)

Multiple

micronutrient supplements daily,

multiple micronutrients

weekly, 10 mg iron daily, placebo

6 mont

hs No difference in respiratory infection,

diarrhea and fever.

Mebrahtu25

2004

Zanzibar

614, 4-71 mo, 94.4% anemic, 48.1% stunted, >80% malaria

positive 10 mg/d

12 mont

hs

No difference in various malariometric indices or any malarial infection

outcome.

Lind10 2004

Indonesia

680 infants, <6 months; Hb<9 g/dl excluded;

stunting, underweight & wasting <5%.

10 mg iron/d, 10 mg Zinc/d, both, or

placebo

6 mont

hs

No significant difference in the incidence of diarrhea and lower

respiratory infection

Baqui26 2003

Bangladesh

799, 6 months; Hb<9 g/dl, MUAC <11 cm excluded

20 mg/wk iron+1 mg riboflavin (rb), zinc+

rb, iron+zinc+rb, iron+zinc+rb+MM,

rb as control 12 mo

Iron & zinc alone had no effect on

morbidity. However, iron + zinc group had a lower rate of severe diarrhea in all infants and a lower rate of severe

lower respiratory infection in malnourished

31

Table III. Trials Comparing the Effect of Daily versus Intermittent Iron Supplementation in

developing Countries (Additional RCTs).

Author Year Country Subjects Dose Follow

up Conclusion

Kianfar45 2000 Iran

260 anemic & 260 non-anemic

school girls

50 mg daily, weekly & twice

weekly 3 months

Significant increase in Hb in all experimental groups (no difference between experimental

groups), significant increase in SF in all experimental groups (daily iron group had more increment than weekly iron groups).

Mumtaz46 2000 Pakistan

191 pregnant women, 17-35 years, Hb<11

g/dl 60 mg daily, twice weekly 12 weeks

Rise of Hb significant only in the daily iron

group.

Zavaleta47 2000 Peru

312 Girls 12-18 years, Hb> 8

g/dl 60 mg 5d/wk, twice weekly 17 weeks

Hb increments higher with increased frequency than intermittent iron, but SF and FEP were similar between the two groups.

Goonewardene48 2001 Sri Lanka

92 pregnant women (12-24

weeks)

100 mg weekly vs thrice weekly

vs daily 12 –20 weeks Daily better

Ekstrom49 2002 Bangladesh

50 antenatal centers, 140

pregnant women 60 mg daily vs 120 mg weekly 3 mo

Daily iron group had higher Hb levels at 12

weeks. No difference in prevalence of anemia.

Ermis50 2002 Turkey 113 infants more

than 5 mo

1 mg/kg/day vs 2 mg/kg/day vs

2 mg/kg alternate day 3 mo

Hematological values (except Hb) higher in 2

mg/kg/day group, ferritin values higher in 2 mg/kg alternate day

group

Nguyen51 2002 Vietnam 270,

5-12 mo 15 mg daily vs 15 mg weekly 6 mo Daily better

Shah52 2002 Nepal

209 adolescent

girls 11-18 years, ~50%

anemic

350 mg

FeSO4/d for 100 days,

weekly for 14 weeks

14 weeks

Rise of Hb, Hct and

prevalence of anemia in post supplementation period comparable in

both groups.

Sungthong53 2002 Thailand 397 primary

school children 300 mg FeSO4 daily vs weekly 16 weeks

Height gain better in weekly group

Haidar54 2003 Ethiopia

207 lactating women from urban slums

60 mg daily vs 5 d/week No difference

2003 Turkey 95, 6-60 months, 6 mg/kg daily 2 months

32

Author Year Country Subjects Dose Follow

up Conclusion Tavil55 Hb <10 g/dl,

TS< 12%, SF< 12 ng/ml

or twice weekly No differences between Hb, Hct, MCV, MCHC,

SI & SF in the 2 experimental groups.

However; RDW, SIBC, TS, transferrin receptor,

and transferrin receptor/log ferritin better in intermittent

group.

Desai56 2004 Kenya

1049,

2-59 months with mild to

moderate anemia (Hb 5-10.9 g/dl); 31%, 7.1% and 23.2% stunted,

wasted & underweight, respectively,

~60% malaria positive

3-6 mg/kg daily vs 6-12 mg/kg twice weekly 6 weeks

No difference in malarial and non-

malarial morbidity. Daily iron resulted in

greater increase in Hb.

de Souza57 2004 Brazil

150 pregnant women, 13-38 years Hb 8-11

g/dl, 16-20 weeks

pregnancy

60 mg daily, weekly, twice

weekly 16 weeks

Both Hb & MCV increased more in the daily iron group. SF

increase was comparable in all three

groups (SF was not comparable at entry into

the trial).

Mukhopadhyay58 2004 India

111 Pregnant women (< 20

weeks) 100 mg/d vs 200 mg/wk

Till 34 wk

gestation

Greater rise of Hb in anemic subjects in daily iron group, higher SF in

daily iron group, no difference in mean birth

weight, period of gestation and mode of

delivery

Pena-Rosas59 2004 Venezuela 16 pregnant

women

60 mg twice weekly vs 120

mg weekly

Till 36-39 wk

gestation

No difference in Hb, SF and Hct. Transferring

saturation more in twice weekly group.

Siddiqui60 2004 Pakistan 60,

5-10 years 200 mg FeSO4 daily vs weekly 2 mo No difference

Sungthong13 2004 Thailand

397 primary school children, severe IDA and

severe malnutrition

excluded, anemia 27%,

thalessemia trait 17%

60 mg Fe 1d/wk, 5d/wk,

placebo 16 weeks

Comparable &

significant increase in Hb in weekly and daily

iron groups, SF increment most in daily

iron group & least in placebo group. IQ

increment least in daily iron group (weekly iron group and placebo had

33

Author Year Country Subjects Dose Follow

up Conclusion similar increase). No

effect on school performance, language & mathematical ability.

Yang61

2004

China

353 Preschool

children

Daily iron or once weekly

iron or placebo

14 weeks

Iron deficiency

reduction and weight gain better in daily iron, No difference in height

gain, Hb

Yurdakok62 2004 Turkey

79, 4mo old, exclusively breast-fed

healthy infants excluding

preterm, low birth weight

infants & infants of mothers who

were iron deficient

1 mg/kg daily vs 7 mg/kg

weekly for 3 months 6 mo No difference

Untoro24 2005 Indonesia

284, 6-12 months (58%

anemic)

Multiple micronutrient daily (DMM),

multiple micronutrient

weekly (WMM), 10 mg iron daily (DI),

placebo 6 months

DMM & DI had higher Hb post-treatment compared with baseline; however, the changes in Hb were not significantly different from placebo. SF increase most with DI & least with WMM (DMM better than WMM).

FEP: Free erythrocyte protoporphyrin; Hb: Hemoglobin; Hct: Hematocrit; IQ: Intelligence quotient; MCHC: Mean corpuscular hemoglobin concentration; MCV: Mean corpuscular volume; RDW: Red cell distribution width; SF: Serum ferritin; SI: Serum iron; SIBC: Serum iron binding capacity; TS: Transferrin saturation.

34

Table IV. Summary of key conclusions of the iron review.

Issues or questions Conclusions Quality of evidence

What are the efficient indicators of population response to iron interventions?

Hemoglobin and ferritin are currently the most efficient combination of indicators for monitoring population response to iron interventions, and these may have economic and logistic benefits in less developed countries.

1+

Iron deficiency is only one of the important causes of anemia. What is the effect, if any, of iron supplementation on hemoglobin response in children, and can effect predictors be identified to aid public health decisions?

Iron supplementation increases hemoglobin levels in children significantly, but modestly. The rise is greater with baseline anemia, and lower in malarial hyperendemic areas and in those consuming iron fortified food. The projected reductions in prevalence of anemia with iron supplementation alone (38% to 62% in non-malarial regions, and 6% to 32% in malarial hyper-endemic areas) highlight the need for additional area-specific interventions, particularly in malarial regions.

1++

What is the effect of iron administration on mental and motor development in children?

Iron supplementation improves mental development score modestly (standardized mean difference of 0.3, equivalent to 1.5 to 2 points on a scale of 100). This effect is particularly apparent for intelligence tests above seven years of age, and in initially anemic or iron deficient anemic subjects. There is no convincing evidence that iron treatment has an effect on mental development in children below 27 months of age, or on motor development. However, (i) there is a suggestion of an improvement in subtle developmental measures like oddity learning test and orientation engagement, which are not encompassed by the traditional tests; (ii) confidence intervals suggest that these results could be compatible with moderate positive or adverse effects of iron therapy; (iii) the possibility of irreversible structural brain changes, particularly in younger children cannot be excluded due to paucity of relevant preventive trials; and (iii) the effect of longer term treatment is unclear.

1++

What is the effect of iron administration on physical growth in children?

There is no convincing evidence of a positive effect of iron supplementation on the physical growth of children.

1++

What is the effect of iron administration on physical performance in children?

Iron supplementation may have a positive effect on the physical performance of children, as evaluated through the post exercise heart rate in anemic subjects, blood lactate levels and treadmill endurance time. In view of the limited data availability, this finding cannot be considered conclusive.

1++

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Issues or questions Conclusions Quality of evidence

What is the effect of iron administration on morbidity and mortality in children?

Iron administration slightly increases the risk of developing diarrhea (11%). In non-malarious regions iron supplementation has no apparent beneficial or harmful effects on the overall incidence of infectious illnesses. In malarious regions, particularly those with high transmission rates, iron supplementation may result in increased risk of malarial infection. In populations with high rates of malaria, routine supplementation with iron and folic acid in preschool children can result in an increased risk of severe illness and death. However, in the presence of an active program to detect and treat malaria and other infections, iron deficient and anemic children can benefit from iron and folic acid supplementation. In areas where iron deficiency is common and malaria absent, daily supplementation of young children with iron and folic acid has no effect on their risk of death, but might protect against diarrhea, dysentery, and acute respiratory illness.

1+ to 1++

What is the effect of iron administration on work capacity in non-pregnant, non-lactating women?

Iron supplementation in non-pregnant, non-lactating women suffering from severe or moderate iron deficiency anemia improves work capacity.

2++

What is the effect, if any, of iron supplementation in pregnancy on maternal and neonatal hemoglobin response and iron stores, and can effect predictors be identified to aid public health decisions?

Iron supplementation in pregnancy increases the maternal iron stores, and prevents low hemoglobin at birth or at six weeks post partum. The effect is greater with lower baseline hemoglobin levels and with longer duration of supplementation. Iron administration in pregnancy also has a positive impact on the neonatal iron stores.

1++

2++

What is the effect, if any, of iron supplementation in pregnancy on maternal mortality and morbidity other than anemia?

Iron administration in pregnancy is not likely to reduce maternal mortality or morbidity other than anemia. The possibility that prophylactic iron supplementation may increase risk of gestational diabetes mellitus when there is no iron deficiency, deserves exploration.

2-

What is the effect, if any, of iron supplementation in pregnancy on newborn size, duration of gestation and perinatal health?

There is no conclusive evidence that routine iron supplementation in pregnancy will increase newborn size and duration of gestation, and improve perinatal health. However, this information is available from a limited number of studies, which are subject to a bias towards false-negative findings. Preliminary intervention evidence suggesting that early supplementation can increase birth weight and duration of gestation needs urgent validation. The possibility that prophylactic iron

1-

2-

36

Issues or questions Conclusions Quality of evidence

supplementation may impair fetal growth when there is no iron deficiency also deserves exploration.

Is intermittent iron supplementation as effective as daily iron administration for the control of anemia in developing countries?

Both daily and intermittent iron supplementation are efficacious in reducing anemia in developing countries. However, daily iron supplementation is more efficacious than intermittent iron administration.

1 ++

Levels of Evidence

1++ High quality meta analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias

1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs with a low risk of bias

1 - Meta analyses, systematic reviews of RCTs, or RCTs with a high risk of bias

2++ High quality systematic reviews of case-control or cohort or studies High quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal

2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal

2 - Case control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal

3 Non-analytic studies, e.g. case reports, case series

4 Expert opinion