Iron deficiency anaemia, the late manifestation of chronic iron deficiency, is the most common nutrient deficiency among pregnant women (WHO 1992). Iron deficiency is caused by an insufficient supply of iron to the cells following depletion of the body's reserves (Viteri 1998). The main causes of iron deficiency are a diet poor in absorbable iron, an increased requirement for iron (e.g. pregnancy) or a loss of iron due to parasitic infections (Crompton 2002; INACG 2002b).
Although haemoglobin and haematocrit are commonly used to screen for iron deficiency, their low values are not specific to iron deficiency. Anaemia in pregnancy is diagnosed if haemoglobin (Hb) concentration is lower than 110 g/L during the first and third trimesters or lower than 105 g/L during the second trimester. Iron deficiency anaemia is defined as anaemia accompanied with depleted iron stores and signs of a compromised supply of iron to the tissues (WHO 2001). Iron deficiency can be identified using laboratory tests such as serum ferritin, serum iron, transferrin and transferrin receptors. However, these tests are often not readily available and have limitations in their interpretation in some settings and conditions. Each test does not correlate closely with one another because each reflects a different aspect of iron metabolism. The use of multiple indicators is useful for population-based assessments of iron deficiency anaemia, when this is feasible.
The consequences of iron deficiency anaemia are serious and can include diminished intellectual and productive capacity (Hunt 2002) and possibly increased susceptibility to infections (Oppenheimer 2001). During pregnancy, low Hb levels, indicative of moderate (between 70 and 90 g/L) or severe anaemia (less than 70 g/L), are associated with maternal and child mortality and infectious diseases (INACG 2002a). Also, low Hb levels may be associated with low birthweight, heavier placentas and increased frequency of prematurity. Favourable pregnancy outcomes occur 30% to 45% less often in anaemic mothers, and their infants have less than one half of normal iron reserves. Iron deficiency affects adversely the cognitive performance and development and physical growth of these infants (WHO 2001). High haemoglobin levels (greater than 130 g/L) have also been associated with negative pregnancy outcomes (Hytten 1964; Hytten 1971; Murphy 1986; Scholl 1997).
The association between iron deficiency without anaemia and adverse perinatal outcomes is less clear. Some studies have shown an association between iron deficiency and preterm delivery and subsequent low birthweight, inadequate pregnancy weight gain, and decreased defences against infections (Garn 1981; Prema 1982; Kandoi 1991; Scholl 1992).
Interventions to control iron deficiency and iron deficiency anaemia include education, control of parasitic infections, improvement of sanitation, iron supplementation and iron fortification (INACG 1977). The amount of iron that can be absorbed from diet alone is insufficient to cover the increased iron requirements during pregnancy. Most women would need additional iron as well as sufficient iron stores to prevent iron deficiency (Bothwell 2000). Thus, direct iron supplementation has been extensively used in most low- and middle-income countries as an intervention to combat iron deficiency and anaemia during pregnancy. It has been recommended that iron supplements also contain folic acid, an essential B-vitamin. The rationale for this combination lies in the need of folic acid to cover the increased requirements of pregnancy, due to the rapidly dividing cells in the fetus and elevated urinary losses.
There is evidence to show that iron supplementation with or without folic acid during pregnancy results in a substantial reduction of women with haemoglobin levels less than 100 g/L in late pregnancy, at delivery and six weeks postpartum (Mahomed 2003a; Mahomed 2003b; Villar 2003). However, the impact of iron supplementation interventions under field conditions has been limited and its effectiveness questioned (Beaton 1999). The failure has been attributed to inadequate infrastructure and poor compliance (Mora 2002) although few studies have evaluated this issue adequately. It has been suggested that the problem may reside in the sole expectation of this intervention to improve haemoglobin concentration, rather than maternal or infant health (Beaton 2000).
International organizations have been advocating routine iron and folate supplementation for every pregnant woman in areas of high anaemia prevalence (Villar 1997; Beard 2000). While iron supplementation with or without folic acid has been used in a variety of doses and regimens, current recommendations include the provision of a daily dose of 60 mg of iron for pregnant, non-anaemic women if supplementation for more than six months is possible and an increased dose of 120 mg of iron daily if the duration of supplementation is shorter or the women are anaemic (INACG 1998). This supplement should include 400 µg of folic acid or lower doses if this amount is not available.
Less frequent regimens of supplementation, such as weekly or fortnightly with iron alone or in conjunction with folic acid, have been evaluated in the last decade as a promising innovative regimen. The rationale is that taking iron less frequently increases compliance due to fewer side-effects, particularly gastrointestinal effects (heartburn, nausea, vomiting, diarrhoea, or constipation). However, some authors have questioned this belief indicating that the main reason for the poor compliance with the programs is the unavailability of iron supplements for the targeted women (Galloway 1994). Recently, other potentially detrimental effects have been associated with excess iron intake (i.e. cell damage from the production of reactive oxygen species) and with higher levels of haemoglobin concentrations (Casanueva 2003).
This review will combine the two currently published Cochrane Reviews on iron and iron and folate supplementation that have clearly shown improvements on biochemical and haematological parameters, and evaluate the issues related to alternative doses and periodicity as well as the potential hazards of these interventions (Mahomed 2003a; Mahomed 2003c).
To assess the efficacy, effectiveness and safety of daily or intermittent supplementation of pregnant women with iron alone or in conjunction with folic acid.
The effectiveness of different treatments for iron deficiency anaemia in pregnancy (Cuervo 2003) and the effects of supplementation with iron and vitamin A (Van den Broek 2003) are covered in other Cochrane Reviews. The effectiveness of vitamin C will be covered in another Cochrane Review currently in preparation (Rumbold 2003). The effects of supplementation with folic acid alone (Mahomed 2003c) or its effectiveness on the prevalence of neural tube defects periconceptionally is also evaluated elsewhere (Lumley 2003).
Criteria for considering studies for this review
Types of studies
Randomised and quasi-randomised trials comparing any form of oral iron/folic acid supplements with no treatment/placebo or alternative supplementation regimens. Studies reporting combinations with other micronutrients will be excluded.
Types of participants
Pregnant women of any gestational age, parity and number of fetuses.
Types of intervention
Daily oral supplementation with iron or iron-folic acid versus no supplementation/placebo.
Daily oral supplementation with iron or iron-folic acid versus intermittent (weekly, twice weekly or thrice weekly) regimens.
Types of outcome measures
The outcomes of this review will be maternal and perinatal and infant postpartum clinical and laboratory outcomes. The following outcomes will be sought for this review.
Premature delivery (< 37 weeks' gestation)
Very premature delivery (< 34 weeks' gestation)
Severe anaemia at term (defined as Hb < 70 g/L)
Severe anaemia at any time during second or third trimester (defined as Hb < 70 g/L)
Severe anaemia at postpartum (defined as Hb < 80 g/L)
Moderate anaemia at term (defined as Hb > 70 g/L and < 90 g/L)
Moderate anaemia at any time during second or third trimester (defined as Hb > 70/L and < 90 g/L)
Moderate anaemia at postpartum (defined as Hb > 80 g/L and < 100 g/L)
Moderate-severe haemoconcentration at term (defined as Hb > 130 g/L)
Moderate-severe haemoconcentration during second or third trimester (defined as Hb > 130 g/L)
Mean Corpuscular Volume at term (mean values and standard deviation)
Mean Corpuscular Haemoglobin at term (mean values and standard deviation)
Haemoglobin concentration at term (mean values and standard deviation, adjusted by altitude)
Haemoglobin concentration within one month postpartum (mean values and standard deviation, adjusted by altitude)
Ferritin concentration at term (mean values and standard deviation)
Ferritin concentration one month postpartum (mean values and standard deviation)
Transferrin receptors at term (mean values and standard deviation)
Iron deficiency at term (as defined by two or more indicators)
Iron deficiency anaemia at term (as defined by trial authors based on two or more indicators)
Infection during pregnancy (including urinary tract infections and others as specified by trial authors)
Puerperal infection (as defined by trial authors)
Antepartum haemorrhage (as defined by trial authors)
Postpartum haemorrhage (intrapartum and postnatal, as defined by trial authors)
Transfusion given (as defined by trial authors)
Non-compliance with allocated intervention
Rejection of allocated intervention
Maternal death (any known)
Maternal wellbeing/satisfaction (as defined by trial authors)
Placental abruption (as defined by trial authors)
Premature rupture of membranes (as defined by trial authors)
Pre-eclampsia (as defined by trial authors)
Low birthweight (< 2500 g among singleton births)
Very low birthweight (< 1500 g among singleton births)
Birthweight (mean values and standard deviation)
Infant Hb concentrations at one month
Infant ferritin concentration at one month
Infant Hb concentrations at three months
Infant ferritin concentration at three months
Infant Hb concentrations at six months
Infant ferritin concentration at six months
Long-term infant developmental (as defined by trial authors)
Admission to special care unit
Other outcomes reported by trial authors will be recorded and labelled as 'not pre-specified'.
Search methods for identification of studies
See: Cochrane Pregnancy and Childbirth Group methods used in reviews.
We will search the Cochrane Pregnancy and Childbirth Group trials register. The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:
1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major conferences;
4. weekly current awareness search of a further 37 journals.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the "Search strategies for identification of studies" section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co-ordinator searches the register for each review using these codes rather than keywords.
Additionally, we will contact the Iron Deficiency Project Advisory Service (IDPAS), Micronutrient Initiative (MI), International Anaemia Consultative Group (INACG), WHO Maternal and Reproductive Health and WHO Nutrition Division for the identification of ongoing and unpublished studies.
Methods of the review
We will assess trials for methodological quality using the criteria in the Cochrane Reviewers' Handbook (Clarke 2003) for adequacy of allocation concealment: adequate (A), unclear (B), inadequate (C) or that allocation concealment was not used (D). We will also collect information on blinding of outcome assessment and loss to follow up and incorporate in the additional table of methodological quality. Blinding is A when both the participant and care provider/assessor are blind to the treatment, B when either the participant or care provider/assessor is blind to the treatment and C when it is unclear or is open. Follow up will be considered adequate when more than 80% of subjects were included in the analysis, B if unclear, and C if less than 80% of those randomised into the trial were included in the analysis.
Two independent reviewers will assess the eligibility of identified studies. The contact reviewer will extract data from the reports. We will assess the number of losses to follow up and postrandomisation exclusions systematically for each trial. We will include quasi-randomised studies and conduct a sensitivity analysis. We will also include cluster randomised studies and will adjust their samples sizes (Clarke 2003) if sufficient information is available to allow for this.
We will design a form to facilitate the process of data extraction and to request additional (unpublished) information from the authors of the original reports. We will enter data onto the RevMan computer software (RevMan 2003). Any discrepancies between the reviewers in either the decision to include/exclude studies or in data extraction will be resolved by discussion and we will request clarification from the authors of the original reports if necessary. For dichotomous data we will use relative risk and for continuous data we will use weighted mean difference, unless the trials report the outcomes on different scales that cannot be converted to a common scale. In this case, we will use the standard mean difference. We will test for heterogeneity between the trials using the I
Supplementation regimens will be defined as follows: daily, when the person is advised to take the dose of iron or iron-folate provided every day either as a single or repeated doses; intermittent, any dose of iron or iron-folate ingested less frequently than daily (alternate days, twice a week or weekly).
We will conduct a total of 14 comparisons:
1. any iron alone versus no intervention/placebo;
2. daily iron alone versus no intervention/placebo;
3. intermittent iron alone versus no intervention/placebo;
4. daily iron alone versus intermittent iron alone;
5. any iron-folate versus no intervention/placebo;
6. daily iron-folate versus no intervention/placebo;
7. intermittent iron-folate versus no intervention/placebo;
8. daily iron-folate versus intermittent iron-folate.
We will conduct subgroup analysis based on the following criteria:
1. early gestational age (less than 20 weeks pregnancy and pre-pregnancy);
2. late gestational age (more than 20 weeks pregnancy);
3. anaemic (Hb below 110 g/L during first and third trimesters or below 105 g/L in second trimester);
4. non-anaemic (Hb 110 g/L or above during first and third trimesters or Hb 105 g/L or above if in second trimester) at start of supplementation;
5. low compliance with treatment (less than 50% intended);
6. high compliance (50% or more);
7. daily low dose (60 mg elemental iron or less);
8. daily higher dose (more than 60 mg elemental iron).
Potential conflict of interest
This protocol was developed during the Fellowship Programme organized by the Cochrane Infectious Diseases Group in July 2003. The Department for International Development (UK) supports this programme through the Effective Health Care Alliance Programme at the Liverpool School of Tropical Medicine.
We would also like to thank the staff at the editorial office of the Cochrane Pregnancy and Childbirth Group in Liverpool for their support in the preparation of this protocol and, in particular, Professor Zarko Alfirevic for his guidance in the preparation of this protocol.
Sources of support
External sources of support
- No sources of support supplied
Internal sources of support
- Children's Hospital and Oakland Research Institute (CHORI) USA