WORLD HEALTH ORGANIZATION DEPARTMENT OF NUTRITION FOR HEALTH AND DEVELOPMENT

EVIDENCE AND PROGRAMME GUIDANCE UNIT

Intermittent iron and folic acid supplementation

for prevention of anaemia in menstruating women and adolescent girls

This submission was prepared by Dr Juan Pablo Pena-Rosas with technical input from Dr Luz

Maria De-Regil, Dr Lisa Rogers, and Harinder Chahal.

EML Section 10.1 - Antianaemia Medicines

Page 1 of 23

Table of Contents Acronyms and abbreviations .......................................................................................................2

Executive summary .....................................................................................................................3

I. Background and rationale for the application........................................................................5

II. Background on iron-deficiency anaemia ...........................................................................5

1. Public health relevance .....................................................................................................5

2. Current public health interventions ...................................................................................6

3. Proposed public health intervention ..................................................................................6

III. Methods ...........................................................................................................................7

1. Methods for assessment of dosing, efficacy and safety......................................................7

2. Methods for the assessment of costs .................................................................................7

3. Methods for the assessment of current availability amongst Member States ......................7

4. Assessment of the evidence ..............................................................................................7

IV. Regulatory information on iron supplements ....................................................................7

V. Analysis of costs...............................................................................................................8

VII. Current NEML availability evaluation ..............................................................................9

VIII. Evidence on dosing, efficacy and safety of intermittent iron and folic acid

supplementation ........................................................................................................................ 11

1. Quality of the evidence ................................................................................................... 12

2. Summary of the evidence ............................................................................................... 12

IX. WHO guidelines on intermittent iron and folic acid supplementation .............................. 13

X. Summary and recommendations ..................................................................................... 15

XI. References ...................................................................................................................... 16

Page 2 of 23

Acronyms and abbreviations CI 95% Confidence interval

BNF British National Formulary

EC Expert committee

EML Essential Medicines List (for adults)

EMLc Essential Medicines List (for children)

FDA Food and Drug Administration

GRADE Grading of Recommendations Assessment, Development and Evaluation

LMICs Low and middle-income countries

MD Mean difference

MSH Management Sciences for Health

MHRA Medicines and Healthcare Products Regulatory Agency

RR Relative risk

SRA Stringent Regulatory Authority

TGA Therapeutic Goods Administration

UK United Kingdom

UNICEF United Nations’ Children Fund

USD United States dollar

WHO World Health Organization

Page 3 of 23

Executive summary This application presents a comprehensive review of the evidence for the effective use of

intermittent supplementation (that is one, two or three times a week on non-consecutive days)

with 60 mg elemental iron plus 2.8 mg of folic acid in menstruating women and adolescent girls

as a public health intervention in areas where anaemia prevalence is 20% or higher and there are

no interventions to control anaemia in place..

Evidence summarized in a Cochrane review shows that intermittent supplementation with iron

(either alone or in combination with other nutrients) is significantly more effective in reducing

anaemia among menstruating women compared to receiving no supplementation or placebo

(average relative risk (RR) 0.73, 95% confidence interval (CI) 0.56 to 0.95). Evidence from 13

studies (2599 participants) showed a significant increase in haemoglobin concentration (mean

difference (MD) 4.58 g/l, 95% CI 2.56 to 6.59) with supplementation. Additionally, 6 studies

(980 participants) showed that supplementation significantly increases ferritin concentrations

(MD 8.32 μg/l, 95% CI 4.97 to 11.66) compared to receiving no intervention or placebo.

Benefits were observed with intermittent supplementation with iron when given either alone or

in combination with folic acid or other micronutrients. However, compared to women receiving

daily iron supplements, women receiving iron supplements intermittently were more likely to

have anaemia (RR 1.26, 95% CI 1.04 to 1.51) and have lower serum/plasma ferritin

concentrations (MD -11.32 μg/l, 95% CI -22.61 to -0.02, although they had similar haemoglobin

concentrations (MD -0.15 g/l, 95% CI -2.20 to 1.91).

The review found evidence that intermittent supplementation with iron (with or without folic

acid) in menstruating women is effective in decreasing the risk of anaemia, and increasing

haemoglobin and ferritin concentrations. Positive effects of intermittent supplementation were

seen in patients receiving iron once or twice per week. Furthermore, the haematological

responses were evaluated with supplements containing more or less than 60 mg of elemental iron

per week for a duration of 3 months or less or more than 3 months.

The most common side-effects of iron supplementation include nausea, constipation, dark stools,

and metallic taste. The current evidence suggests there is no significant difference in adverse

side-effects between once weekly intermittent iron supplementation versus no intervention or

placebo (RR 1.98, 95% CI 0.31 to 12.72) and between once weekly intermittent iron

supplementation versus daily iron supplementation (RR 0.36, 95% CI 0.10 to 1.31).

The recommendations for changes to the EML Section 10.1 - Antianaemia Medicines, are as

follow:

1. Add 60 mg elemental iron in a ferrous form plus folic acid 2.8 mg tablet/capsule

formulation for the prevention of anaemia in menstruating women and adolescent

girls. The frequency and duration of the intermittent supplementation is as follow:

a. One tablet per week

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b. Three months of supplementation followed by 3 months of no

supplementation after which the provision of supplements should restart.

i. If feasible, intermittent supplements could be given throughout the school

or calendar year

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I. Background and rationale for the application Daily supplementation with iron and folic acid for a period of 3 months has been the

standard approach for the prevention and treatment of iron deficiency anaemia among

women of reproductive age. Despite its proven efficacy, there has been limited success

with the daily regimen public health programmes, which is thought to be primarily due

to low coverage rates, insufficient tablet distribution and, low adherence because of the

side-effects (e.g. constipation, dark stools or metallic taste). Intermittent use of oral iron

supplements (i.e. once, twice or three times a week on non-consecutive days) has been

used as an effective alternative to daily iron supplementation to prevent anaemia among

menstruating women.

The 18th

EC requested a review of evidence to determine the appropriate dosing of iron

and folic acid combination in menstruating women to prevent anaemia (1). A Cochrane

review was commissioned to gather evidence in 2011, followed by the development of

WHO guidelines on Intermittent iron and folic acid supplementation in menstruating

women. (2, 3). This EML application presents evidence summarized in the Cochrane

review and proposes recommendations for the EMLc.

II. Background on iron-deficiency anaemia Iron-deficiency anaemia occurs as a result of decreased haemoglobin concentration in the

blood and decreased iron concentrations, leading to iron deficiency (4). The causes of

anaemia are several, including parasitic infections, inflammatory disorders, disorders of

haemoglobin structure, or vitamin and mineral deficiencies, including iron and folate (4).

It is estimated that at least half the burden of anaemia is due to iron deficiency and can be

induced by sustained negative iron balance due to inadequate dietary intake, absorption

or utilization of iron or chronic loss of iron due to bleeding (4). Women, during

reproductive age, are at higher risk of developing iron deficiency due to menstruation.

With prolonged iron deficiency, the haemoglobin concentration starts to decrease,

resulting in iron deficiency anaemia (3). Haemoglobin is responsible for carrying oxygen

from the lungs to the tissue; therefore, during anaemia, the blood has a decreased capacity

to carry oxygen through the blood leading to a deficit of oxygen in the body of the

affected individual, leading to a series of functional problems (3). Iron deficiency

anaemia is diagnosed by measuring haemoglobin concentration, along with serum ferritin

and transferrin concentrations (5-7). A decrease in these values by predefined laboratory

measures that differ by age and sex indicate iron-deficiency anaemia.

1. Public health relevance The world-wide prevalence of anaemia in non-pregnant women is estimated at 30.2%.

Anaemia impairs resistance to infection and reduces physical capacity and work

performance among all age groups (4). In addition, women with anaemia who become

pregnant are at higher risk of negative maternal and neonatal outcomes (4).

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2. Current public health interventions The standard approach used for prevention of anaemia in menstruating women where

prevalence of anaemia is higher than 40%is daily supplementation with iron and folic

acid for a period of 3 months (8). Although this method of supplementation is effective,

the success with daily supplementation has been limited (8). This limited success is

attributed to low coverage rates, insufficient supplement distribution, and low adherence

due to the side-effects of iron supplements, such nausea, constipation, dark stools and

metallic taste (4). In 2009 a temporary statement on Weekly iron and folic acid

supplementation was released by WHO and updated in 2011 according to the procedures

stipulated in the WHO handbook for guideline development.

3. Proposed public health intervention In order to minimize side-effects associated with iron supplementation and increase

adherence, intermittent use of oral iron and folic acid supplements is recommended as an

effective to prevent anaemia among menstruating women and adolescent girls in areas

where no other interventions are in place or where daily iron supplementation has proven

not to be effective. The rationale for this intervention is that intestinal cells turn over

every 5–6 days and have limited iron absorptive capacity (3). Thus intermittent provision

of iron would expose only the new epithelial cells to this nutrient, which may improve the

efficiency of absorption (3). Intermittent supplementation may also reduce oxidative

stress and the frequency of other side-effects associated with daily iron supplementation

such as nausea and constipation as well as minimize blockage of absorption of other

minerals due to the high iron levels in the gut lumen and in the intestinal epithelium (3).

Furthermore, experience has shown that intermittent regimens may also be more

acceptable to women and increase compliance with supplementation (9).

Additionally, the use of this regimen can result in the improvement in women’s folate

status prior to pregnancy, which may help prevent some congenital anomalies,

specifically neural tube defects (3). Child growth, development and risk of chronic

disease later in life depend, in part, on maternal iron nutrition during pregnancy. The

prevention of both anaemia and iron deficiency in menstruating women and girls prior to

pregnancy and the assurance of desirable iron reserves prior to pregnancy is an important

public health goal that requires multi-pronged, integrated and flexible approaches (9).

Iron and folate deficiency may occur concurrently in menstruating women and girls,

particularly during or after pregnancy. Because of the essential role for folate in

erythropoiesis, combined iron and folic acid supplementation may be required to ensure

an optimal haematological response in menstruating women and girls. Because of the role

of folate in preventing neural tube defects (10), women should have a folate level that is

likely to protect against congenital anomalies before entering pregnancy, especially

where pregnancies are not planned. The neural tube closes by day 28 of pregnancy, a

period when pregnancy may not have been detected. Folic acid supplementation after the

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first month of pregnancy will not prevent neural tube defects, but will contribute to other

aspects of maternal and fetal health.

III. Methods

1. Methods for assessment of dosing, efficacy and safety

A Cochrane review was commissioned to determine if any evidence existed on

intermittent iron and folic acid supplementation in menstruating women, and if so, what

are the safe and effective doses of the interventions (2). The reviewers assessed

randomized and quasi-randomized trials with either individual or cluster randomization in

which the participants were non-pregnant women beyond menarche and prior to

menopause (2). The intervention assessed was intermittent iron supplementation (with or

without folic acid and other micronutrients) compared with a placebo, no intervention or

daily supplementation (2). More than 10 international databases were searched and an

equal number of international agencies were contacted for unpublished reports.

2. Methods for the assessment of costs For tablets containing 60 mg elemental iron and 2.8 mg folic acid, the 2011 edition of the

International Drug Price Indicator Guide and the UNICEF Supply Catalogue website

were searched ((16,17).

3. Methods for the assessment of current availability amongst Member

States A survey of National Lists of Essential Medicine (NEMLs) of 20 low and middle income

countries was undertaken to determine availability of iron supplement formulations and

folic acid supplements (18).

4. Assessment of the evidence Strength and quality of evidence was assessed using the Grading of Recommendations

Assessment, Development and Evaluation (GRADE) methodology (19).

IV. Regulatory information on iron supplements Both iron and folic acid supplements are currently on the EML for adults; furthermore,

iron supplements are not reviewed for safety or efficacy and are not approved for sale as

medications by the Stringent Regulatory Authorities (SRAs) in United States (Food and

Drug Administration, FDA), Australia (Therapeutic Goods Administration, TGA) and the

United Kingdom (Medicines and Healthcare products Regulatory Agency, MHRA) (20-

22). Rather supplements are registered as food supplements and are held to good

manufacturing practices for purities only (22). Therefore, no additional specific analysis

of regulatory status of iron or folic acid supplements was warranted. However,

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manufacturers of supplements must be registered entities and certified to adhere to good

manufacturing practices (23).

V. Analysis of costs VI. Currently there are no available iron and folic acid supplements in the market for this

intervention with the recommended composition. No Fe 60+FA 2.8 mg manufacturer

found. WPRO has been actively searching for a qualified manufacturer, however, the

company making the product does not have all certificates yet.

The most recent International Drug Price Indicator Guide (16) and the UNICEF Supply

Catalogue (17) were used to compile the cost of iron and folic acid supplements. A

combination formulation of ferrous salt 60 mg elemental iron plus 2.8 mg folic acid was

not found. Single nutrient formulations and the combination of only 60 mg elemental

iron plus 0.4 mg folic acid tablets were found.

Table 1 - Cost of tablets containing 60 mg elemental iron plus 2.8 mg folic acid

Source Compound Form Cost per tablet or

mL (USD)*

MSH 2011 Ferrous Salt 60-65 mg tab/cap 0.0024 (median)

UNICEF Ferrous salt 60 mg tab 0.00311

MSH 2011 Folic Acid 5mg tab 0.0023 (median)

UNICEF Folic acid 5 mg tabs 0.00429

MSH 2011 Folic Acid 1 mg tab 0.0277 (median)

MSH 2011 Ferrous salt + folic acid 60 mg elemental iron

plus 0.4 mg folic acid

(tab)

0.0029 (median)

UNICEF

Ferrous fumarate +

folic acid

60 mg elemental iron

plus 0.4 mg folic acid

(tab)

0.00507

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VII. Current NEML availability evaluation While there are several projects in countries targeting women and adolescent girls

through weekly iron and folic acid supplementation, and it is now a policy for

implementation in India, there are not suppliers with the formulation recommended.

NEMLs of 20 LMICs were reviewed to determine current availability of iron and folic

acid supplements containing 60 mg elemental iron plus 2.8 mg folic acid combined, 60

mg of elemental iron tablets (either alone or in combination with folic acid), and folic

acid supplements containing 1 mg or 5 mg per tablet/capsule (16).

The table below shows that the majority of countries’ NEMLs contain iron and folic acid

supplements. However, most NEMLs did not specify the elemental iron content of the

formulations.

None of the NEMLs surveyed contained a combination of 60 mg elemental iron with 2.8

mg folic acid. This is as expected since this formulation is not currently on the EML or

EMLc, and most LMICs use the model WHO EML/EMLc to build their respective

national formularies (18).

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# country 60 mg

elemental

iron

folic acid

1 mg

folic acid 5

mg

60 mg elemental iron

plus folic acid 2.8 mg

Notes (…)

1 Angola … No Yes No Ferrous sulfate 200 mg found, unknown elemental iron content

2 Bangladesh … … … No Ferrous salt liquid and tablet found, unknown elemental iron content. Folic Acid

tablet found, unknown strength.

3 Bhutan Yes No Yes No Ferrous sulfate 60 mg tablet in combination with 0.4 mg folic acid

4 Central

African

Republic

… … … No Ferrous salt liquid and tablet found, unknown elemental iron content. Folic Acid

tablet found, unknown strength.

5 China … … … No Ferrous salt tablet found, unknown elemental iron content. Folic Acid tablet

found, unknown strength

6 Democratic

Republic of

Congo

… No Yes No Ferrous sulfate liquid and 200 mg + 5 mg folic acid tablet found, unknown

elemental iron content

7 Ecuador … … … No Ferrous salt liquid and tablet found, unknown elemental iron content. Folic acid –

the NEML list tablet strength range 0.5 – 5 mg.

8 Fiji … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.

9 Ghana Yes No Yes No Ferrous salt liquid found, unknown elemental iron content.

10 India No No No No Ferrous salt liquid and tablet (20mg elemental iron) in combination with 100mcg

folic acid found.

11 Honduras … Yes Yes No Ferrous salt tablet (65 mg elemental iron) found

12 Lesotho … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.

13 Malaysia … No Yes No Ferrous salt tablet found, unknown elemental iron content.

14 Namibia … No Yes No Ferrous salt tablet (65 mg elemental iron) found; Ferrous salt liquid found,

unknown elemental iron content.

15 Oman … Yes Yes No Ferrous salt tablet (45 – 70 mg elemental iron) found; Ferrous salt liquid (15

mg/0.6 mL elemental iron) found.

16 Pakistan Yes Yes Yes No

17 Rwanda Yes Yes Yes No

18 Senegal … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.

19 Thailand … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.

20 Vanuatu … No Yes No Ferrous salt liquid and tablet found, unknown elemental iron content.

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VIII. Evidence on dosing, efficacy and safety of intermittent iron and

folic acid supplementation Based on the Cochrane review, pertinent outcomes of efficacy are presented here.

Summary of Findings (GRADE) tables are presented in Appendix A to provide details on

the evidence from which the recommendations were made (2).

The review included 21 trials with 10,258 participants from 15 countries in Latin

America, Africa and Asia from 1997 to 2010. In 11 of the 21 trials, the duration of

supplementation was less than 3 months and in the others the maximum duration was 6

months (2).

Iron alone was provided in nine trials, while eight trials assessed efficacy of iron plus

folic acid supplementation and two studies used iron plus multiple micronutrient

supplements (2). All except two trials used iron sulfate as the iron salt for

supplementation (2).

The Cochrane group undertook 6 comparisons of evidence:

1. Comparison 1: Intermittent iron supplementation versus placebo or no

intervention

2. Comparison 2: Intermittent iron supplementation versus daily iron

supplementation

For each comparison listed, a summary of information on three outcomes (anaemia,

haemoglobin and ferritin) is provided in Appendix B. For each outcome, the following

factors were considered: 1) the overall effect size of the intervention, 2) effect size with

supplementation of 60 mg (or less) of elemental iron per week, 3) effect size with iron

supplementation alone, and 4) effect size with supplementation of a combination of iron

and folic acid. There are other several studies on folic acid absorption and retention in

the body since 1975 and while there is plenty of evidence that 80%-100% of a folic acid

dose may be absorbed, it seems clear that much less is retained and contributes to

improved status. The fraction of a dose that is retained within the tissues seems to depend

on the dose and ultimately on renal handling and the threshold where excess folic acid

spills into the urine. The evidence points out that 2.8 mg of folic acid weekly in New

Zealand is efficacious in elevating erythrocyte folate concentrations above 905 µmol/L

and in reducing homocysteine levels (11). Similar results have been observed with a 5 mg

weekly dose in Mexico (12,13). In intervention trials where supplements containing up

to 5 mg of folic acid/ day were administered during pregnancy, there was no evidence of

toxicity or additional side-effects when compared to women receiving a placebo (14).

Page 12 of 23

1. Quality of the evidence The overall quality of evidence comparing intermittent iron supplementation to placebo

or no intervention was low for outcomes of anaemia, haemoglobin, iron deficiency and

ferritin (2).

The overall quality of evidence comparing intermittent iron supplementation to daily

supplementation was moderate for the outcome of anaemia; however, for the outcomes of

haemoglobin and ferritin, the quality of evidence was low, and for iron deficiency it was

very low (2).

2. Summary of the evidence The results from the systematic review (2) show (Appendix A) that intermittent

supplementation with iron (either alone or in combination with other nutrients) is

effective in reducing anaemia among menstruating women compared to no

supplementation or placebo (RR 0.73, 95% CI 0.56 to 0.95) (2). Evidence from 13

studies (2599 participants) shows that there is a significant increase in haemoglobin

concentration (MD 4.58 g/l, 95% CI 2.56 to 6.59) with supplementation (2). Additionally,

six studies (980 participants) showed that supplementation significantly increases ferritin

concentrations (MD 8.32 μg/l, 95% CI 4.97 to 11.66), compared to no intervention or

placebo (2). Furthermore, the evidence shows that the benefits are seen with intermittent

iron supplementation, either alone or in combination with folic acid or other

micronutrients (2). The greatest benefits of intermittent supplementation are observed in

settings of moderate to high prevalence of anaemia (2).

The evidence also shows that the effect on haemoglobin concentration is similar in

patients who receive intermittent supplementation versus patients who receive daily iron

supplementation (MD -0.15 g/l, 95% CI -2.20 to 1.91) (2). However, the mean difference

in ferritin concentration was lower with intermittent supplementation compared to daily

supplementation (MD -11.32 μg/l, 95% CI-22.61 to -0.02) and the risk of anaemia was

higher in women receiving intermittent supplementation as compared to women receiving

daily iron supplements (RR 1.26, 95% CI 1.04 to 1.51) (2).

The review found evidence that intermittent supplementation with iron (with or without

folic acid) in menstruating women is effective in decreasing risk of anaemia and

increasing hemoglobin and ferritin concentrations (2). The positive effect of the

intermittent supplement was seen in patients receiving iron once or twice a week (2).

Furthermore, the haematological response was seen with supplementation containing

more or less than 60 mg of elemental iron for a duration of more or less than 3 months

(2).

Although adherence has been claimed as one of the advantages of this intervention, its

reporting is still inadequate. Results of three studies (556 participants) comparing

Page 13 of 23

adherence to intermittent iron supplementation versus no supplementation or placebo

were not statistically significant (RR 0.99, 95% CI 0.96 to 1.01) (2). Four studies with

507 participants comparing intermittent supplementation to daily supplementation also

found no difference in adherence (RR 1.04, 95% CI 0.99 to 1.09) (2).

The most common side-effects of iron supplementation include nausea, constipation, dark

stools and metallic taste (2). As shown in Appendix C, the current evidence suggests

there is no significant difference is adverse side-effects between once weekly,

intermittent iron supplementation versus no intervention or placebo (RR 1.98, 95% CI

0.31 to 12.72) and between once weekly intermittent iron supplementation versus daily

iron supplementation (RR 0.36, 95% CI 0.10 to 1.31) (2).

IX. WHO guidelines on intermittent iron and folic acid

supplementation The WHO Department of Nutrition for Health and Development released an interim

statement in 2009 on weekly iron and folic acid supplementation (15), which was further

informed by a Cochrane systematic review. These updated guidelines on intermittent iron

and folic supplementation for menstruating women were published in 2011 (3). Even

though the overall quality of evidence for outcomes of iron supplementation, intermittent

or daily, with or without folic acid, ranges from low to moderate, the strength of the

recommendation is strong (3).

The guideline development group felt that the evidence suggests that once weekly,

intermittent supplementation with iron in menstruating women is effective in increasing

haemoglobin and ferritin levels and in reducing the prevalence of anaemia and this is one

of the few public health interventions widely supported by program experience (3).

Intermittent supplementation with iron and folic acid in women, delivered by variety of

channels ,has been a successful intervention in several countries (Cambodia, Egypt, Laos,

the Philippines and Viet Nam), reaching over a half a million women. In general, the

compliance has been high, with a decrease in the prevalence of anaemia between 9.3%

and 56.8% (9).

Furthermore, citing experimental evidence, the guidelines provide a strong

recommendation for using 2.8 mg folic acid alongside 60 mg elemental iron to reduce

risk of neural tube defects in a fetus should the woman or adolescent girl become

pregnant (2, 5). Therefore, WHO guidelines recommend the following schedule of iron

and folic acid supplementation as a public health intervention to reduce the risk of

anaemia in menstruating women and neural tube defects in newborn children for

menstruating women and adolescent girls living in settings where anaemia is 20% or

higher (5).

Page 14 of 23

Table 2 - Suggested scheme for intermittent iron and folic acid supplementation in menstruating women

Target Group All menstruating adolescent girls and adult women

Supplement

composition

Iron: 60 mg of elemental iron*

Folic acid: 2800 μg (2.8 mg)

Supplement form Tablets/capsules

Frequency One supplement per week

Duration and time

interval between periods

of supplementation

3 months of supplementation followed by 3 months of no

supplementation after which the provision of

supplements should restart.

If feasible, intermittent supplements could be given

throughout the school or calendar year

Settings

Populations where the prevalence of anaemia among non-

pregnant women of reproductive age is 20% or higher

*60 mg of elemental iron equals 300 mg of ferrous sulfate heptahydrate, 180 mg of ferrous

fumarate or 500 mg of ferrous gluconate.

Page 15 of 23

X. Summary and recommendations There is sufficient evidence to show that intermittent supplementation with iron and folic acid is

a feasible and effective public health policy to decrease the risk of anaemia in menstruating

women and adolescent girls. The addition of folic acid can help prevent neural tube defect-

affected pregnancies should a woman become pregnant.

The recommendations for changes to the EML Section 10.1 - Antianaemia Medicines, are as

follows:

1. Add 60 mg elemental iron in a ferrous form plus 2.8 mg folic acid tablet/capsule formulation

for the prevention of anaemia in menstruating women.

a. Dose

i. 60 mg of elemental iron equals 300 mg of ferrous sulfate heptahydrate, 180 mg of

ferrous fumarate or 500 mg of ferrous gluconate.

b. Frequency and duration of intermittent supplementation

i. Once weekly for menstruating women for three months followed by 3 months of

no supplementation, after which the provision of supplements should restart.

ii. If feasible, intermittent supplements could be given throughout the school or

calendar year.

Page 16 of 23

XI. References

1. Report of the 18th WHO Expert Committee: The Selection and Use of Essential Medicines.

Geneva: World Health Organization, 2011.

2. Fernandez-Gaxiola AC, De-Regil LM. Intermittent iron supplementation for reducing anaemia

and its associated impairments in menstruating women. Cochrane Database of systematic

Reviews. 2011(12):CD009218. Epub 2011/12/14.

3. Guideline: Intermittent iron and folic acid supplementation in menstruating women. Geneva,

Switzerland: World Health Organization, 2011.

4. Stoltzfus RJ, L Mullany L, Black RE. Iron deficiency anaemia. In: Global and regional

burden of diseases attributable to selected major risk factors. Ezzati, M., Lopez, A.D., Rodgers,

A., Murray, C.J.L (eds). Geneva; World Health Organization 2004. Available at

http://www.who.int/publications/cra/chapters/volume1/0163-0210.pdf

5. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin

and Mineral Nutrition Information System. Geneva, World Health Organization, 2011

(WHO/NMH/NHD/MNM/11.1) (http://www.who.int/vmnis/indicators/haemoglobin.pdf,

accessed 1 November 2012).

6. Serum ferritin concentrations for the assessment of iron status and iron deficiency in

populations. Vitamin and Mineral Nutrition Information System. Geneva, World Health

Organization, 2011 (WHO/NMH/NHD/MNM/11.2).

http://www.who.int/vmnis/indicators/serum_ferritin.pdf , accessed 1 December 2012).

7. WHO/CDC. Assessing the iron status of populations: report of a joint World Health

Organization/ Centers for Disease Control and Prevention technical consultation on the

assessment of iron status at the population level. Geneva, World Health Organization, 2005.

Available at http://whqlibdoc.who.int/publications/2004/9241593156_eng.pdf

Page 17 of 23

8. WHO/UNICEF/UNU. Iron deficiency anaemia: assessment, prevention and control, a guide

for programme managers. Geneva, World Health Organization, 2001. Available at

http://www.who.int/nutrition/publications/micronutrients/anaemia_iron_deficiency/WHO_NHD

_01.3/en/index.html

9. Weekly iron and folic acid supplementation programmes for women of reproductive age: an

analysis of best programme practices. Manila, World Health Organization Regional Office for

the Western Pacific, 2011

10. De-Regil LM, Fernández-Gaxiola AC, Dowswell T, Peña-Rosas JP. Effects and safety of

periconceptional folate supplementation for preventing birth defects. Cochrane Database of

Systematic Reviews 2010, Issue 10. Art. No.: CD007950.

DOI:10.1002/14651858.CD007950.pub2.

11. Norsworthy B, Skeaff CM, Adank C, Green TJ. Effects of once-a-week or daily folic acid

supplementation on red blood cell folate concentrations in women. European Journal of Clinical

Nutrition. 2004 Mar;58(3):548-54

12. Martínez de Villarreal LE, Arredondo P, Hernández R, Villarreal JZ. Weekly administration

of folic acid and epidemiology of neural tube defects. Maternal and Child Health Journal. 2006

Sep;10(5):397-401.

13. Martínez de Villarreal L, Pérez JZ, Vázquez PA, Herrera RH, Campos Mdel R, López RA,

Ramírez JL, Sánchez JM, Villarreal JJ, Garza MT, Limón A, López AG, Bárcenas M, García JR,

Domínguez AS, Nuñez RH, Ayala JL, Martínez JG, González MT, Alvarez CG, Castro RN.

Decline of neural tube defects cases after a folic acid campaign in Nuevo León, México.

Teratology. 2002 Nov;66(5):249-56.

14. Peña-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Daily oral iron supplementation

during pregnancy. Cochrane Database Systematic Reviews. 2012 Dec 12;12:CD004736. doi:

10.1002/14651858.CD004736.pub4.

15. Weekly iron–folic acid supplementation (WIFS) in women of reproductive age: its role in

promoting optimal maternal and child health. Position statement. Geneva, World Health

Organization, 2009

(http://www.who.int/nutrition/publications/micronutrients/weekly_iron_folicacid.pdf, accessed

10 December 2012).

Page 18 of 23

16. MSH. International Drug Price Indicator Guide. Management Sciences for Health, 2011.

17. UNICEF. Supply Catalogue. available at

https://supply.unicef.org/unicef_b2c/app/displayApp/%28layout=7.0-

12_1_66_67_115&carea=%24ROOT%29/.do?rf=y

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[cited 2012 November 1st]; Available from: http://www.mhra.gov.uk/.

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lists: progress and challenges. Lancet. 2003;361(9370):1723-9. Epub 2003/05/28.

Page 19 of 23

Appendix A: Summary of Findings (GRADE) tables 1. Intermittent use of iron supplements versus placebo or no intervention

Page 20 of 23

2. Intermittent versus daily use of iron supplements

Page 21 of 23

Appendix B: Dosing and efficacy evidence 1. Comparison 1: Intermittent iron supplementation versus placebo or no intervention

Comparison 1: Intermittent iron supplementation versus placebo or no intervention

# Outcome No of Studies No of Participants Effect size (RR*)

1 Anaemia (for all) 10 2996 0.73 [0.56, 0.95]

2 Anaemia with 60 mg (or less) elemental iron

per week 5 1855

0.68 [0.43, 1.10]

3 Anaemia by intervention (iron alone) 2 292 0.45 [0.09, 2.13]

4 Anaemia by intervention (iron plus folic

acid) 7 1732

0.82 [0.64, 1.04]

RR = average relative risk

Comparison 1: Intermittent iron supplementation versus placebo or no intervention

# Outcome No of Studies No of Participants Effect size (MD*)

1 Haemoglobin (for all) 13 2599

4.58 g/l

[2.56, 6.59]

2 Haemoglobin with 60 mg (or less) elemental

iron per week 6 971

5.21 g/l

[2.06, 8.36]

3 Haemoglobin by intervention (iron alone) 4 606

6.13 g/l

[1.90, 10.36]

4 Haemoglobin by intervention (iron plus folic

acid) 8 1671

3.56 g/l

[1.11, 6.01]

MD = Mean Difference

Comparison 1: Intermittent iron supplementation versus placebo or no intervention

# Outcome No of Studies No of Participants Effect size (MD*)

1 Ferritin (for all) 6 980

8.32 μg/l

[4.97, 11.61]

2 Ferritin with 60 mg (or less) elemental iron

per week 3 269

12.37 μg/l

[7.06, 17.69]

3 Ferritin by intervention (iron alone) 2 204

7.80 μg/l

[1.38, 14.23]

4 Ferritin by intervention (iron plus folic

acid) 3 455

5.87 μg/l [3.23,

8.52]

MD = Mean Difference

Page 22 of 23

2. Comparison 2: Intermittent iron supplementation versus daily iron supplementation

Comparison 2: Intermittent iron supplementation versus daily iron supplementation

# Outcome No of Studies No of Participants Effect size (RR*)

1 Anaemia (for all) 6 1492 1.26 [1.04, 1.51]

2 Anaemia with 60 mg (or less) elemental iron

per week 4 614

1.23 [0.82, 1.85]

3 Anaemia by intervention (iron alone) 3 690 1.39 [0.97, 1.99]

4 Anaemia by intervention (iron plus folic

acid) 2 604

1.23 [0.98, 1.53]

RR = average relative risk

Comparison 2: Intermittent iron supplementation versus daily iron supplementation

# Outcome No of Studies No of Participants Effect size (MD*)

1 Haemoglobin (for all) 8 1676

-0.15 g/l

[-2.20, 1.91]

2 Haemoglobin with 60 mg (or less) elemental

iron per week 6 843

1.14 g/l

[-0.34, 2.62]

3 Haemoglobin by intervention (iron alone) 4 671

0.31 g/l

[-1.15, 1.78]

4 Haemoglobin by intervention (iron plus folic

acid) 3 807

-0.99 g/l

[-6.10, 4.13]

MD = Mean Difference

Comparison 2: Intermittent iron supplementation versus daily iron supplementation

# Outcome No of Studies No of Participants Effect size (MD*)

1 Ferritin (for all) 3 657

-11.32 μg/l

[-22.61, -0..02]

2 Ferritin with 60 mg (or less) elemental iron

per week

… … …

3 Ferritin by intervention (iron alone) … … …

4 Ferritin by intervention (iron plus folic

acid)

… … …

MD = Mean Difference

Page 23 of 23

Appendix C: Safety profile of iron supplementation 1. Intermittent iron supplementation versus placebo or no intervention

Intermittent iron supplementation versus placebo or no intervention

# Outcome No of Studies No of Participants Effect size (RR*)

1 All cause morbidity 1 119 1.12 [0.82, 1.52]

2 Any side effects 3 630 1.98 [0.31, 12.72]

3 Diarrhea 1 209 0.28 [0.05, 1.49]

RR = average relative risk

2. Intermittent iron supplementation versus daily iron supplementation

Intermittent iron supplementation versus daily iron supplementation

# Outcome No of Studies No of Participants Effect size (RR*)

1 Diarrhea 1 198 2.41 [0.12, 49.43]

2 Any side effects 4 823 0.36 [0.10, 1.31]

RR = average relative risk