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Effects of routine oral iron supplementation with or without folic acid for women during pregnancy

  1. Juan Pablo Peña-Rosas2,*,
  2. Fernando E Viteri3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 19 JUL 2006

Assessed as up-to-date: 17 APR 2006

DOI: 10.1002/14651858.CD004736.pub2


How to Cite

Peña-Rosas JP, Viteri FE. Effects of routine oral iron supplementation with or without folic acid for women during pregnancy. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004736. DOI: 10.1002/14651858.CD004736.pub2.

Author Information

  1. 2

    U.S. Centers for Disease Control and Prevention (CDC), International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt), Atlanta, GA, USA

  2. 3

    Children's Hospital and Oakland Research Institute, Oakland, CA, USA

*Juan Pablo Peña-Rosas, Reduction of Micronutrient Malnutrition Unit, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva 27, 1211, Switzerland. penarosasj@who.int.

Publication History

  1. Publication Status: Edited
  2. Published Online: 19 JUL 2006

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Iron-deficiency anaemia, the late manifestation of chronic iron deficiency, is thought to be the most common nutrient deficiency among pregnant women (WHO 1992) although in pregnancy iron status is often difficult to measure. 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, particularly hookworm, or other blood losses (Crompton 2002; INACG 2002a).

Although haemoglobin and haematocrit are commonly used to screen for iron deficiency, their low values are not specific to iron deficiency. While iron deficiency is the most common cause of anaemia, other causes such as acute and chronic infections that cause inflammation; deficiencies of folate, vitamin C, vitamin B12 and vitamin A; and genetically inherited traits such as thalassaemia and drepanocytosis may be independent or superimposed causal factors (WHO 2001). 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, according to recommended U.S. Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) cut-off points. Readers should be aware of the limitations of cut-off points to define anaemia or haemoconcentration rather than defining these conditions by distributions analysis and the effect of haemoglobin on functional outcomes during pregnancy. Iron-deficiency anaemia is defined as anaemia accompanied by depleted iron stores and signs of a compromised supply of iron to the tissues (WHO 2001).

Iron deficiency in non-pregnant populations can be measured quite precisely using laboratory tests such as serum ferritin, serum iron, transferrin, transferrin saturation and transferrin receptors. However, these tests are often not readily available and have limitations in their interpretation in some settings and conditions, particularly where different infections are present (malaria, HIV/AIDS, vaginosis, and others) and during pregnancy. Each test does not correlate closely with one another because each reflects a different aspect of iron metabolism. Serum ferritin concentration is an indicator of iron reserves. In pregnancy, however, serum ferritin levels as well as bone marrow iron fall even in women ingesting daily supplements with high amounts of iron, which casts doubts about their true significance in pregnancy and suggests the need to review cut-off values (Puolakka 1980; Romslo 1983; Svanberg 1975). In spite of this, a serum ferritin concentration of less than 12 µg/litre in adults is accepted to indicate depleted iron stores, even during pregnancy. Interestingly, the nadir of maternal serum ferritin occurs by week 28, before higher iron demands are believed to occur and the fall is only partially explained by the normal plasma volume expansion (Taylor 1982). Other indicators of iron status are also distorted during pregnancy even among women who are administered supplements containing 200 mg of iron daily (Puolakka 1980). Recently it has been suggested that the ratio of serum transferrin receptors to serum ferritin, a seemingly good estimator of iron nutrition in non-pregnant adults, could be used also in pregnancy to estimate iron nutritional status. However, this ratio does not seem to differentiate clearly between an iron-deficient and an iron-sufficient population of pregnant women (Cook 2003). An important consistent finding in all the above mentioned studies is the preventive effect that iron supplementation on the indicators of iron nutritional status during pregnancy, when compared with unsupplemented women (Hb, iron and ferritin declined less, and lower serum transferrin and erythrocyte protoporphyrins increased less).

Recently, a WHO and CDC Technical Consultation on the Assessment of Iron Status at the Population Level concluded that Hb and ferritin were the most efficient combination of indicators for monitoring change of iron status as a consequence of intake of iron supplements in populations (WHO/CDC 2005). Unfortunately, only two very differing studies on pregnant women were included and only one of them demonstrated changes with iron supplementation. The use of multiple indicators (Hb, ferritin and serum transferrin receptors) is useful for population-based assessments of iron-deficiency anaemia, when this is feasible. There seems to be a need to evaluate the evidence to better understand the observed changes in iron nutrition and its indicators occurring during pregnancy under different circumstances. These studies should also assess the functional significance of iron nutritional status in terms of maternal health and pregnancy outcomes (i.e. birthweight, premature delivery, new born vitality, etc.) in different populations.

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 (less than 70 g/L) anaemia, are associated with maternal and child mortality and infectious diseases (INACG 2002b). The lowest incidence of low birthweight and prematurity appears to occur when Hb levels are between 95 g/L and 105 g/L during the second trimester of gestation (Steer 2000) and between 95 and 125 g of Hb/L at term (Hytten 1964; Hytten 1971; Murphy 1986). However, several studies suggest that near-term Hb levels below 95 g/L or even below 110 g/L may be associated with low birthweight, heavier placentas and increased frequency of prematurity (Garn 1981; Godfrey 1991; Kim 1992; Klebanoff 1989; Klebanoff 1991; Murphy 1986). There is little doubt that unfavourable effects in terms of low birthweight and premature delivery occur when haemoglobin falls below 95 g/L before or during the second trimester of gestation. Favourable pregnancy outcomes occur 30% to 45% less often in anaemic mothers, and probably their infants have less than one half of normal iron reserves (Bothwell 1981). Unfortunately, the time between birth and umbilical cord clamping has not been considered in the estimates of impact of maternal iron status and anaemia on the infant's iron reserves. Delayed cord clamping can provide significant iron reserves to the infant (Mercer 2001; van Rheenen 2004). 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; Steer 2000).

Large epidemiologic retrospective studies (Murphy 1986; Steer 2000; Xiong 2000) and one prospective study in China (Zhou 1998) have shown that both low and high antenatal haemoglobin concentrations are associated with increased risk of premature delivery and low birthweight. In fact, the incidence of these negative consequences increases dramatically when haemoglobin levels, at sea level, are below 95 to 105 or above 130 to 135 g/L at any time in pregnancy. A prospective study in Mexico has shown associations between prenatal daily iron supplement intake at recommended doses, high haemoglobin concentrations and the risk of both low birthweight and premature delivery (Casanueva 2003a). Observational studies have shown that among iron supplemented pregnant women, a failure of ferritin levels to decline during the 2nd and 3rd trimesters and overall high ferritin levels during pregnancy, not due to infection, are also thought to be deleterious for pregnancy outcomes, particularly for women who are anaemic early in pregnancy. However, when some confounding factors are controlled for, the association between high serum ferritin concentrations and the risk of premature delivery remains high but is no longer significant (Scholl 1998; Scholl 2000; Scholl 2005).

The association between iron deficiency without anaemia and adverse perinatal outcomes is less clear. Some studies have shown an association between iron deficiency and inadequate pregnancy weight gain, decreased defense against infections, preterm delivery and low birthweight (Garn 1981; Kandoi 1991; Prema 1982; Scholl 1992).

Interventions to control iron deficiency and iron-deficiency anaemia include iron supplementation and iron fortification, health and nutrition education, control of parasitic infections and improvement of sanitation (INACG 1977). Delayed clamping of the umbilical cord also is an effective preventive measure for iron deficiency in infancy and young children (Mercer 2001; van Rheenen 2004).

Some authors suggest that the amount of iron that can be absorbed from diet alone is insufficient to cover the increased iron requirements during pregnancy except when women can draw enough iron from pre-pregnancy iron reserves. The Institute of Medicine recommends a dietary allowance of 27 mg/day of iron for women during pregnancy (IOM 2001). 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 prevent and correct 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 2000; Mahomed 1997; Villar 2003). However, the overall 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. The effectiveness of this intervention has been evaluated mostly in terms of improvement in haemoglobin concentration, rather than maternal or infant health (Beaton 2000). This narrow scope may have been an important omission in most studies addressing the efficacy, effectiveness and safety of antenatal iron and iron with folic acid supplementation during pregnancy.

International organizations have been advocating routine iron and folic acid supplementation for every pregnant woman in areas of high anaemia prevalence (Beard 2000; Villar 1997). While iron supplementation with or without folic acid has been used in a variety of doses and regimens, current international recommendations for populations 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, if iron deficiency prevalence in women of a given country is high, and if pregnant women are anaemic (INACG 1998). This supplement should include 400 µg of folic acid or lower doses if this amount is not available. Gastrointestinal side-effects have been selected as the critical adverse effect on which to base the tolerable upper intake level for iron, as gastrointestinal distress is observed commonly in women consuming high levels of supplemental iron on an empty stomach. High-dose iron supplements are commonly associated with constipation and other gastrointestinal effects including nausea, vomiting and diarrhea, with frequency and severity varying according to the amount of elemental iron released in the stomach. The Institute of Medicine has established the tolerable upper limit for iron during pregnancy based on gastrointestinal side-effects as 45 mg/day of iron (IOM 2001). This is the level likely to pose no risk of adverse effects for almost all individuals in the general population (IOM 2001). In most industrialized countries the decision to prescribe or recommend antenatal iron with folic acid supplementation to women during pregnancy is left to the health care personnel and is based in the individual maternal condition. In the United States iron supplementation as a primary prevention intervention involves smaller daily iron doses (i.e. 30 mg/day) (CDC 1998).

Less frequent regimens of supplementation, such as weekly or twice weekly with iron alone or in conjunction with folic acid, have been evaluated in the last decade as a promising innovative regimen. The weekly iron administration is based on two lines of evidence: (1) daily iron supplementation, by maintaining an iron-rich environment in the gut lumen and in the intestinal mucosal cells, produces oxidative stress, reduces the long-term iron-absorption efficacy and is prone to increasing the severity and frequency of undesirable side-effects (Srigirihar 1998; Srigiridhar 2001; Viteri 1997; Viteri 1999a); (2) the concept that exposing intestinal cells to supplemental iron less frequently, every week based on the rate of mucosal turnover that occurs every five to six days in the human, may improve absorption capacity. Additionally, compliance could increase due to fewer side-effects and the costs of supplementation may be favourable if provided outside of the medical context (Viteri 1995; Viteri 1999b). 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 (i.e. lower birthweight and premature delivery) 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 late during the second trimester and early into the third trimester but not at term (Casanueva 2003b).

This review combines and updates the two currently published Cochrane Reviews on iron and iron and folic acid supplementation (Mahomed 2000; Mahomed 1998) that have clearly shown improvements on biochemical and haematological parameters and evaluates the issues related to alternative doses, periodicity as well as the potential benefits and hazards of these interventions.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

To assess the efficacy, effectiveness and safety of daily or intermittent routine 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 2002) are covered in other Cochrane Reviews. The effectiveness of vitamin C is covered in another Cochrane Review (Rumbold 2005). The effects of supplementation with folic acid alone (Mahomed 1998) or its effectiveness on the prevalence of neural tube defects periconceptionally is also evaluated elsewhere (Lumley 2003). The effects of a combination of iron and folic acid with multiple vitamin and mineral supplementation are also being reviewed elsewhere (Bhutta 2004). Studies examining the 'additional effect' of iron rather than iron versus a placebo provided with other micronutrients were excluded in this review and are expected to be analyzed in the multiple vitamin and mineral supplementation during pregnancy review (Bhutta 2004). It is possible that interactions between iron and other nutrients would increase or decrease the effects of iron.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised and quasi-randomised trials comparing any form of routine oral iron with or without folic acid supplements with no treatment/placebo or intermittent supplementation regimens. Studies reporting combinations with other vitamins and minerals and studies dealing with this intervention for anaemic women as a medical treatment were excluded.

 

Types of participants

Pregnant women of any gestational age, parity and number of fetuses.

 

Types of interventions

Daily routine oral supplementation with iron or iron-folic acid compared to no supplementation/placebo.
Daily routine oral supplementation with iron or iron-folic acid compared to routine intermittent (weekly and twice weekly) regimens.
Intermittent oral iron or iron-folic acid supplementation compared to no supplementation/placebo.

 

Types of outcome measures

The outcomes of this review were maternal and perinatal and infant postpartum clinical and laboratory outcomes. The following outcomes were sought for this review.

 

Primary outcomes

 
Infant

Low birthweight (less than 2500 g)
Birthweight (g)

 
Maternal

Premature delivery (less than 37 weeks' gestation)
Haemoglobin concentration at term in g/L
Anaemia at term (Hb less than 110 g/L) (not prespecified)
Haemoconcentration at term (defined as Hb greater than 130 g/L)
Haemoconcentration at any time during 2nd or 3rd trimesters (defined as Hb greater than 130 g/L)
Iron deficiency at term (based on two or more laboratory indicators)
Iron-deficiency anaemia at term (Hb less than 110 g/L and at least one additional laboratory indicator)
Side-effects (any)

 

Secondary outcomes

 
Infant

Very low birthweight (less than 1500 g)
Perinatal mortality
Hb concentration at one month in g/L
Ferritin concentration at one month
Hb concentration at three months in g/L
Ferritin concentration at three months
Hb concentration at six months in g/L
Ferritin concentration at six months
Long-term infant developmental (as defined by trial authors)
Admission to special care unit

 
Maternal

Very premature delivery (less than 34 weeks' gestation)
Severe anaemia at term (Hb less than 70 g/L)
Moderate anaemia at term (Hb greater than 70 g/L and less than 110 g/L)
Severe anaemia at any time during 2nd or 3rd trimesters (Hb less than 70 g/L)
Moderate anaemia at any time during 2nd or 3rd trimesters (Hb greater than 70 g/L and less than 110 g/L)
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)
Haemoglobin concentration within one month postpartum
Severe anaemia postpartum (Hb less than 80 g/L)
Moderate anaemia at postpartum (Hb greater than 80 g/L and less than 100 g/L)
Diarrhoea
Constipation
Nausea
Heartburn
Vomiting
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)

Other outcomes reported by trial authors were recorded and labelled as 'not prespecified'.

 

Search methods for identification of studies

 

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group Trials Register by contacting the Trials Search Co-ordinator (June 2005).

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 hand searched 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.

 

Searching other resources

Additionally, we contacted 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.

 

Data collection and analysis

We assessed trials for methodological quality using the criteria in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005) for adequacy of allocation concealment: adequate (A), unclear (B), inadequate (C) or that allocation concealment was not used (D). We also collected information on blinding of outcome assessment and loss to follow up and incorporated them 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 was considered A - adequate when more than 80% of participants were included in the analysis, B - if unclear, and C - if less than 80% of those initially randomised were included in the analysis.

Two independent authors assessed the eligibility of identified studies. The contact authors extracted data from the reports. We assessed the number of losses to follow up and postrandomisation exclusions systematically for each trial. We included quasi-randomised studies and conducted a sensitivity analysis. We also included cluster-randomised studies and adjusted their samples sizes (Higgins 2005) if sufficient information was available to allow for this. The intracluster correlation coefficients were estimated from original data provided by the authors when available and was estimated for each outcome. Authors of the original reports were contacted for additional data as required for the subgroup analysis.

We designed a form to facilitate the process of data extraction and to request additional (unpublished) information from the authors of the original reports. We entered data onto the Review Manager computer software (RevMan 2003). Any discrepancies between the authors in either the decision to include or exclude studies or in data extraction were resolved by discussion and we requested clarification from the authors of the original reports when necessary. For dichotomous data we used relative risk and for continuous data we used weighted mean difference, unless the trials reported the outcomes on different scales that could not be converted to a common scale. In this case, we used the standard mean difference.

We tested for heterogeneity between the trials using the I-square statistic test available in RevMan 2003. Given the high heterogeneity among trials, the results were pooled using a random-effects model. Because of the high heterogeneity we were cautious in the interpretation of the pooled results.

 

Sensitivity analysis

In the presence of significant heterogeneity, a sensitivity analysis was conducted based on the quality of the studies. A study was considered of high quality if it was graded as adequate or A in the randomisation and allocation concealment and at least adequate (one additional grade A) in either the blinding or the loss to follow-up study characteristics. We conducted an available case analysis and avoidable exclusions were reinstated when possible.

Supplementation regimens were defined as follows: daily, when the person is advised to take every day the dose of iron or iron-folic acid provided either as a single or repeated dose; intermittent, any dose of iron or iron-folic acid ingested less frequently than daily (alternate days, twice a week or weekly).

We aimed to conduct a total of eight comparisons: (1) any iron alone compared to no intervention/placebo; (2) daily iron alone compared to no intervention/placebo; (3) intermittent iron alone compared to no intervention/placebo; (4) intermittent iron alone compared to daily iron alone; (5) any iron-folic acid compared to no intervention/placebo; (6) daily iron-folic acid compared to no intervention/placebo; (7) intermittent iron-folic acid compared to no intervention/placebo; (8) intermittent iron-folic acid compared to daily iron-folic acid. However, to avoid repetitive data and due to the fact that there were no studies in many of the comparisons, we were able to conduct the following four comparisons:

  1. daily iron alone compared to no intervention/placebo;
  2. intermittent iron alone compared to daily iron alone;
  3. daily iron-folic acid compared to no intervention/placebo;
  4. intermittent iron-folic acid compared to daily iron-folic acid.

We conducted analysis with all studies and then a subgroup analysis on the primary outcomes based on the following criteria:

  1. early gestational age (supplementation started before 20 weeks' gestation or prepregnancy);
  2. late gestational age (supplementation started at 20 weeks or more of gestation);
  3. unspecified/mixed gestational ages at the start of supplementation;
  4. anaemic (Hb below 110 g/L during first and third trimesters or below 105 g/L in second trimester) at start of supplementation;
  5. 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;
  6. unspecified/mixed anaemic status at start of supplementation;
  7. daily low dose (60 mg elemental iron or less);
  8. daily higher dose (more than 60 mg elemental iron).

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Our search strategy identified 151 references corresponding to 122 trials. Of these, 40 trials were included, 69 trials were excluded, 12 trials are awaiting assessment and one trial is still ongoing. The trial in Guatemala included two sub-studies and thus was included as two separate trials: one with supervised intake (Chew 1996a) and one with unsupervised intake (Chew 1996b). One study was carried out collaboratively in two different sites and thus was cited as two different trials (Wallenburg 1983) conducted in Rotterdam and (Buytaert 1983) conducted in Antwerp. One trial in China included three comparison groups: one with weekly doses of iron, another with daily doses and a control group. However since the allocation of the control group was not randomised this study was included only in the comparisons for intermittent versus daily iron supplementation in this review (Liu 1996).

Twenty nine trials evaluated supplementation with iron alone compared to no treatment or placebo (Batu 1976; Butler 1968; Buytaert 1983; Chanarin 1971; Charoenlarp 1988; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Hankin 1963; Holly 1955; Hood 1960; Kerr 1958; Makrides 2003; Menendez 1994; Milman 1991; Ortega-Soler 1998; Paintin 1966; Pita Martin 1999; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Tura 1989; Van Eijk 1978; Wallenburg 1983; Willoughby 1967; Wills 1947). Of these, only seven trials were of high quality according to our pre-established criteria (Buytaert 1983; Cogswell 2003; Eskeland 1997; Makrides 2003; Preziosi 1997; Tura 1989; Wallenburg 1983).

Two studies evaluated intermittent supplementation with iron alone compared to daily supplementation with iron alone (Pita Martin 1999; Yu 1998) and no study evaluated intermittent supplementation with iron alone compared to no treatment or placebo. None of these met the pre- established criteria for high quality.

Eight trials evaluated daily iron supplementation with folic acid compared to no treatment (Barton 1994; Batu 1976; Butler 1968; Charoenlarp 1988; Chisholm 1966; Liu 1996; Taylor 1982; Willoughby 1967). These same trials also evaluated daily iron and folic acid compared to no treatment. Only one of them (Barton 1994) met the criteria for high quality.

Seven trials evaluated intermittent supplementation with iron and folic acid compared to daily supplementation with iron and folic acid (Chew 1996a; Chew 1996b; Ekstrom 2002; Liu 1996; Ridwan 1996; Robinson 1998; Winichagoon 2003). One trial met the pre-established criteria of high quality (Chew 1996a).

See table of 'Characteristics of included studies' for a detailed description of the studies. All included studies met the prestated criteria for inclusion in this review.

 

Risk of bias in included studies

Sixteen trials adequately randomised the participants to the treatment groups (Barton 1994; Butler 1968; Buytaert 1983; Charoenlarp 1988; Chew 1996a; Chew 1996b; Cogswell 2003; Ekstrom 2002; Eskeland 1997; Kerr 1958; Makrides 2003; Preziosi 1997; Ridwan 1996; Tura 1989; Wallenburg 1983; Young 2000). Eighteen trials did not report or did not state clearly the randomisation method used (Batu 1976; Chisholm 1966; De Benaze 1989; Holly 1955; Hood 1960; Liu 1996; Menendez 1994; Milman 1991; Ortega-Soler 1998; Paintin 1966; Pritchard 1958; Puolakka 1980; Romslo 1983; Svanberg 1975; Taylor 1982; Van Eijk 1978; Willoughby 1967; Winichagoon 2003) and six trials were quasi-randomised using alternate or sequence allocation (Chanarin 1971; Hankin 1963; Pita Martin 1999; Robinson 1998; Wills 1947; Yu 1998). Three trials used cluster randomisation (Ekstrom 2002; Ridwan 1996; Winichagoon 2003).

Thirteen trials reported using sealed envelopes or opaque bottles when doing the allocation of the women to treatment groups (Barton 1994; Butler 1968; Buytaert 1983; Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Liu 1996; Makrides 2003; Paintin 1966; Preziosi 1997; Tura 1989; Wallenburg 1983). The remaining studies were unclear in their method of concealment of allocation (Batu 1976; Charoenlarp 1988; Holly 1955; Hood 1960; Kerr 1958; Milman 1991; Pritchard 1958; Puolakka 1980; Robinson 1998; Romslo 1983; Svanberg 1975; Taylor 1982; Willoughby 1967; Young 2000). Some trials used an inadequate method or did not use any allocation concealment at all (Chanarin 1971; Chew 1996a; Chew 1996b; Ekstrom 2002; Hankin 1963; Menendez 1994; Ortega-Soler 1998; Pita Martin 1999; Ridwan 1996; Van Eijk 1978; Wills 1947; Winichagoon 2003; Yu 1998). However it is clear that the studies evaluating intermittent compared to daily supplementation regimens would pose an extreme effort to keep the participants blinded as to what treatment they were receiving. Adherence would be obscured if daily placebo for six days and iron plus folic acid once a week were assigned.

See table of 'Methodological quality assessment of included trials' ( Table 1) for a summary of the trials quality.

 

Effects of interventions

Forty trials involving 12706 women were included in the review. The summary results are organized by comparisons and by primary and secondary outcomes. Most of the studies focused on haematological indices and few reported other outcomes prespecified in the protocol. Overall, the results showed significant heterogeneity across all the prespecified outcomes. Heterogeneity could not be explained by standard sensitivity analyses including quality assessment, therefore, all results were analysed by random-effects.

See 'Graphs and tables' for detailed results on primary and secondary outcomes.

 

(1) Daily iron alone compared to no intervention/placebo

 

Infant outcomes

Evidence of significant differences was found in the following outcomes.

Infant ferritin concentration at three months in ug/L: weighted mean difference (WMD) 19.0; 95% confidence interval (CI) 2.75 to 35.25 (one trial involving 197 women) (Figure 01:25) and at six months in ug/L: WMD 11.0; 95% CI 4.37 to 17.63 (one trial involving 197 women) (Figure 01:27).

Infant Hb concentration at six months in g/L: WMD -5.0; 95% CI -9.11 to -0.89 (one trial involving 197 women). This result goes in the opposite direction than was expected (Figure 01:26).

There was no evidence of significant difference found in:
low birthweight (less than 2500 g) (Figure 01:01), birthweight (Figure 01:03), very low birthweight (less than 1500 g) (Figure 01:20), or infant Hb concentration at three months in g/L (Figure 01:24). The data from three trials with 1147 women (Cogswell 2003; Makrides 2003; Menendez 1994) suggest that women who take daily iron supplementation during pregnancy are as likely as women not receiving iron supplements to have a baby with birthweight below 2500 grams (4% versus 6.6%; relative risk (RR) 0.59; 95% CI 0.23 to 1.49). However, the heterogeneity between the treatment effects is substantial (I-square greater than 50%) (Figure 01:01). When selecting only high-quality studies (Cogswell 2003; Makrides 2003) the effect remains not significant. Similarly, the data from five trials (Cogswell 2003; Eskeland 1997; Makrides 2003; Preziosi 1997; Puolakka 1980) with 925 women suggest that there is not any effect in birthweight of newborns born to women who had taken daily supplementation with iron alone during pregnancy as compared to those taking placebo or not taking any supplements at all (WMD 22.49; 95% CI -99.35 to 144.34) (Figure 01:03). Heterogeneity between the treatment effects is substantial (I square greater than 50%) and the results have to be interpreted cautiously.

No trials reported on the remaining outcomes.

 

Maternal outcomes

Evidence of significant differences was found in the following outcomes.

 
Haemoglobin concentration at term in g/L

The data from 15 trials involving 1516 women (Batu 1976; Butler 1968; Buytaert 1983; Chanarin 1971; Cogswell 2003; De Benaze 1989; Eskeland 1997; Makrides 2003; Milman 1991; Ortega-Soler 1998; Puolakka 1980; Romslo 1983; Tura 1989; Van Eijk 1978; Wallenburg 1983) suggest that women who take daily supplementation with iron during pregnancy reach term with 7.53 g/L higher concentration of haemoglobin than women taking placebo or not taking any iron supplements at all (WMD 7.53; 95% CI 4.40 to 10.66) (Figure 01:07). However, the heterogeneity between the treatment effects is substantial (I-square greater than 50%) and the results have to be interpreted with caution. The difference was slightly higher among those receiving a higher dose of iron and those starting supplementation after 20 weeks of gestation (Figure 01:08). The effect of daily iron supplementation did not change significantly after including only high-quality trials (Buytaert 1983; Cogswell 2003; Eskeland 1997; Makrides 2003; Tura 1989) (WMD 4.72; 95% CI 0.95 to 8.49) and heterogeneity remained high.

 
Anaemia at term (Hb less than 110 g/L) (not prespecified)

Data from 13 trials including 1696 women (Batu 1976; Chanarin 1971;Chisholm 1966; Cogswell 2003; De Benaze 1989; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Preziosi 1997; Pritchard 1958; Puolakka 1980; Romslo 1983) suggest that women who receive routine daily supplementation with iron during pregnancy are less likely to have anaemia at term than those taking placebo or not taking any iron supplements at all, as indicated by a Hb less than 110 g/L (10.9% versus 32.6%; RR 0.26; CI 0.16 to 0.43 (Figure 01:09)). However, the heterogeneity between the treatment effects is substantial (I-square greater than 50%) and the results have to be interpreted with caution. The sensitivity analysis when selecting only the four high-quality studies involving a total of 787 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Preziosi 1997) shows that women who take daily iron supplementation during pregnancy are less likely to have anaemia at term (16.2% versus 31.3%; RR 0.56; 95% CI 0.40 to 0.78). The heterogeneity I-square was reduced to 24.1% (not shown).

 
Haemoconcentration at term (defined as Hb greater than 130 g/L)

Data from eight trials involving 1222 women (Butler 1968; Chisholm 1966; Cogswell 2003; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958) suggest that women who routinely take daily iron supplementation during pregnancy are almost three times more likely to have haemoconcentration at term than those taking placebo or not taking any iron supplements at all (defined as an Hb higher than 130 g/l) (32.7% versus 10.4%; RR 3.01; 95% CI 1.46 to 6.19) (Figure 01:10). The heterogeneity between the treatment effects is substantial (I-square greater than 75.8%) and the results have to be interpreted with caution (Figure 01:10). This effect was similar for any gestational age at start of supplementation and lower or higher doses of iron provided. The effect was no longer significant when a sensitivity analysis was conducted with three high-quality trials involving a total of 590 women (Cogswell 2003; Eskeland 1997; Makrides 2003) (28.6% versus 14.8%; RR 1.15; 95% CI 0.05 to 24.75) and the heterogeneity increased (I-square = 85.4%) (not shown).

 
Haemoconcentration at any time during 2nd or 3rd trimesters (defined as Hb greater than 130 g/L)

The effects of oral routine supplementation with iron alone and haemoconcentration at any time during the second or third trimesters was evaluated in six trials including 1133 women (Cogswell 2003; Eskeland 1997; Holly 1955; Makrides 2003; Milman 1991; Pritchard 1958). The data from these trials suggest that women who routinely receive daily iron supplementation during pregnancy are more likely to present haemoconcentration at any time during the second or third trimesters than those taking placebo or not taking any iron supplements at all, according to the definition used here. (30.9% versus 15.4%; RR 1.90; 95% CI 1.07 to 3.35) (Figure 01:12). However, the heterogeneity between the treatment effects is substantial (I-square = 79.6%) and the results have to be interpreted with caution (Figure 01:12). When only three trials of high quality were included (Cogswell 2003; Eskeland 1997; Makrides 2003) the effect was no longer significant (RR 1.60; 95% CI 0.85 to 2.99) and the heterogeneity remained high (77%).

 
Iron deficiency at term (based on two or more laboratory indicators)

Data from six trials involving 1108 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Milman 1991; Preziosi 1997; Tura 1989) suggest that women who routinely receive daily oral supplementation with iron are less likely to have iron deficiency at term than women taking placebo or not taking any iron supplements at all (30.7% versus 54.8%; RR 0.44; 95% CI 0.27 to 0.70) (Figure 01:14). The heterogeneity between the treatment effects is substantial (I-square greater than 50%) and the results have to be interpreted with caution (Figure 01:14). Five of the trials were of high quality.

 
Iron-deficiency anaemia at term (Hb below 110 g/L and at least one additional laboratory indicator)

Data from five trials involving 940 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Milman 1991; Tura 1989) suggest that women who routinely receive daily iron supplementation are less likely to have iron-deficiency anaemia at term than women taking placebo or not taking any iron supplements at all (4.9% versus 15.5%; RR 0.33; 95% CI 0.16 to 0.69) (Figure 01:16). The heterogeneity between the treatment effects was small (I-square less than 50%) (Figure 01:16). These results were similar for the different subgroups including those who start supplementation early in the gestation and those who are non-anaemic at start, and in any iron dose. The effect was similar (5.6% versus 15.2%); when only four trials of high quality involving 820 women (Cogswell 2003; Eskeland 1997; Makrides 2003; Tura 1989) were compared: RR 0.39; 95% CI 0.20 to 0.74 and a test of heterogeneity (I-square = 40.4%) (not shown).

 
Side-effects (any)

Data from six trials involving 1099 women (Charoenlarp 1988; Cogswell 2003; De Benaze 1989; Eskeland 1997; Hood 1960; Kerr 1958) suggest that women who receive daily oral iron supplementation are more likely to report side-effects of any kind than women taking placebo or not taking any iron supplements at all (26.4% versus 11.9%); (RR 1.90; 95% CI 1.09 to 3.33)) (Figure 01:18). However, the heterogeneity between the treatment effects is substantial (I-square greater than 50%) and the results have to be interpreted with caution (Figure 01:18). When only the two high-quality trials involving 520 women were included (Cogswell 2003; Eskeland 1997), the effect is no longer significant (28.7% versus 21.9%); RR 1.31; 95% CI 0.94 to 1.82 (data not shown) with no heterogeneity (I-square = 0%).

 
Maternal haemoglobin concentration within one month postpartum in g/L

The data from four trials involving 833 women (Hankin 1963; Menendez 1994; Milman 1991; Wills 1947) suggest that women that routinely receive daily iron supplementation have a higher concentration of haemoglobin after one month postpartum than those taking placebo or not taking any iron supplements at all (WMD 6.10 g/L; 95% CI 3.70 to 8.49 g/L). The I-square statistic show that heterogeneity of the results is less than 50% (Figure 01:40). None of the trials met the criteria for high quality.

There was no evidence of significant difference between women receiving daily iron supplementation and women receiving placebo or not taking any iron supplements at all, in the following outcomes.
Premature delivery (less than 37 weeks' gestation) (Figure 01:05), very premature delivery (less than 34 weeks' gestation) (Figure 01:30), placental abruption (Figure 01:50), pre-eclampsia (Figure 01:52), severe anaemia at term (Figure 01:31), at any time during 2nd or 3rd trimesters (Figure 01:33) or postpartum (Figure 01:41), moderate anaemia at term (Figure 01:32), at any time during 2nd or 3rd trimesters (Figure 01:34) and in the postpartum (Figure 01:42), puerperal infection (Figure 01:36), antepartum haemorrhage (Figure 01:37) and postpartum haemorrhage (Figure 01:38), transfusion given (Figure 01:39), diarrhoea (Figure 01:43), constipation (Figure 01:41), nausea (Figure 01:45), heartburn (Figure 01:46), vomiting (Figure 01:47), maternal death (Figure 01:48), pre-eclampsia (Figure 01:52) or maternal wellbeing/satisfaction (Figure 01:49).

No trials reported on the remaining outcomes.

 

(2) Intermittent iron alone compared to daily iron alone

 

Infant outcomes

No evidence of significant differences was found between these groups of infants in birthweight (Figure 02:03). Only one study (Pita Martin 1999) with 41 women provided data for this outcome.

No trials reported on the remaining outcomes.

 

Maternal outcomes

No evidence of significant differences was found between these groups of women in the following outcomes.
Premature delivery (less than 37 weeks' gestation) (Figure 02:05), haemoconcentration at any time during 2nd or 3rd trimesters (defined as Hb greater than 130 g/L) (Figure 02:12), or moderate anaemia at any time during 2nd or 3rd trimesters (Figure 02:34). The effect of the intervention on severe anaemia at any time during second or third trimesters could not be estimated (Figure 02:33).

No trials reported on the remaining outcomes.

 

(3) Daily iron-folic acid compared to no intervention/placebo

 

Infant outcomes

No evidence of significant differences was found between infants from these groups of women receiving daily iron an folic acid supplementation and those taking placebo or not taking any supplements at all in the following outcomes.
Low birthweight (less than 2500 g) (Figure 03:01), birthweight (g) (Figure 03:03), very low birthweight (less than 1500 g) (Figure 03:20), perinatal mortality (Figure 03:21) or admission to special care unit (Figure 03:29).

No trials reported on the remaining outcomes.

 

Maternal outcomes

Evidence of significant differences was found in the following outcomes.

 
Haemoglobin concentration at term in g/L

The data from four trials including 179 women (Barton 1994; Batu 1976; Butler 1968; Taylor 1982) suggest that women who routinely receive daily iron and folic acid supplementation reach term with higher Hb concentration than women taking placebo or not taking any iron and folic acid supplement at all (WMD 12.00 g/L; 95% CI 2.93 to 21.07). However, the heterogeneity between the treatment effects is substantial (I-square greater than 50%) and the results have to be interpreted with caution (Figure 03:07). The effect of iron-folic acid supplementation did not change significantly after including only the one high-quality trial (WMD 17.10; 95% CI 8.44 to 25.76 ) (data not shown). The subgroup analysis provided similar results (Figure 03:08).

 
Anaemia at term (Hb less than 110 g/L) (not prespecified)

The data from two trials including 346 women (Batu 1976; Chisholm 1966) suggest that women who routinely receive daily iron and folic acid supplementation during pregnancy are less likely to have anaemia at term than those not taking any supplements at all (defined as Hb less than 110 g/L) (8.2% versus 35.5%; RR 0.27; 95% CI 0.12 to 0.56) (Figure 03:09). However, the heterogeneity between the treatment effects is substantial (I-square greater than 50%) and the results have to be interpreted with caution. No studies met the prespecified criteria for high quality.

 
Side-effects (any)

One trial including 456 women (Charoenlarp 1988) suggest that women routinely receiving iron and folic acid supplementation are more likely to report any side-effects in comparison to none from those receiving no supplementation (RR 44.32; 95% CI 2.77 to 709.09) (Figure 03:18). The scarcity of data makes it difficult to draw any conclusion.

 
Haemoglobin concentration within one month postpartum in g/L

One study (Taylor 1982) involving 45 women reported this outcome. The data from this trial suggest that women receiving daily iron and folic acid supplementation achieve a higher concentration of haemoglobin at one month postpartum than women not taking any supplements at all (WMD 10.40; 95% CI 4.03 to 16.77) (Figure 3:40) but no firm conclusions can be made given the scarcity of the data.

No evidence of significant differences was found in the following outcomes.
Premature delivery (less than 37 weeks' gestation) (Figure 03:05), very premature delivery (Figure 03:30), antepartum haemorrhage(Figure 03:37), postpartum haemorrhage (Figure 03:38), placental abruption (Figure 03:50), pre-eclampsia (Figure 03:52), haemoconcentration at term (defined as Hb greater than 130 g/L) (Figure 03:08), severe anaemia at any time during 2nd or 3rd trimesters (Figure 03:33) or severe anaemia at term (Figure 03:31), moderate anaemia at any time during 2nd or 3rd trimesters (Figure 03:34) or at term (Figure 03:32), infection during pregnancy (Figure 03:35), or puerperal infection (Figure 03:36).

No trials reported on the remaining outcomes.

 

(4) Intermittent iron-folic acid compared to daily iron-folic acid

 

Infant outcomes

Evidence of significant differences was found in the following outcome.
Infant ferritin concentration at six months in ug/L
One study (Winichagoon 2003) including involving 88 women reported this outcome (Figure 04:27). The data from this trial suggest that the infants from women receiving intermittent iron and folic acid supplementation achieve a higher concentration of serum ferritin at six months (WMD 0.09; 95% CI 0.05 to 0.13) (Figure 4:27) but no firm conclusions can be made given the scarcity of the data.

No evidence of significant differences was found in the following outcomes.
Low birthweight (less than 2500 g) (Figure 04:01), birthweight (Figure 04:03) and very low birthweight (less than 1500 g) was not estimable (Figure 04:20).
The data from three trials (Chew 1996a; Chew 1996b; Winichagoon 2003) involving 650 women suggest that women who take intermittent iron and folic acid supplementation during pregnancy are as likely to have a baby with birthweight below 2500 grams (4.8% versus 5.4%; RR 0.99; 95% CI 0.50 to 1.97) (Figure 04:01) and that there is no significant effect in birthweight of newborns born from women who had taken daily supplementation with iron and folic acid during pregnancy or from those being supplemented intermittently (WMD -8.36; 95% CI -73.56 to 56.85) (Figure 04:03).

No trials reported on the remaining outcomes.

 

Maternal outcomes

Evidence of significant differences was found in the following outcomes.

 
Haemoconcentration at any time during 2nd or 3rd trimesters (defined as Hb greater than 130 g/L)

Five trials recorded this outcome (Ekstrom 2002; Liu 1996; Ridwan 1996; Robinson 1998; Winichagoon 2003) but only four trials including 1031 women reported cases. The data from these four trials suggest that women who routinely receive intermittent iron and folic acid supplementation during pregnancy are less likely to have haemoconcentration at any time during the second or third trimesters as those receiving the daily regimen (7.75% versus 19.31%; RR 0.41; 95% CI 0.21 to 0.80) (Figure 04:12). None of the trials met the criteria for high quality.

 
Vomiting

The data from four trials including 774 women (Chew 1996a; Chew 1996b; Ekstrom 2002; Robinson 1998) suggest that women who routinely receive intermittent iron and folic acid supplementation during pregnancy are more likely to report vomiting during pregnancy as a side-effect as compared to those receiving the daily regimen (15.7% versus 8.94%; RR 1.69; 95% CI 1.15 to 2.47 (four trials including 774 women) (Figure 04:47).

There was no evidence of significant difference in the following outcomes
Haemoglobin concentration at term in g/L (Figure 04:07), anaemia at term (Hb less than 110 g/L) (Figure 04:09), haemoconcentration at term (Figure 04:11), iron-deficiency anaemia at term (Hb below 110 g/L and at least one additional laboratory indicator) (Figure 04:16), severe anaemia at any time during 2nd or 3rd trimesters (Figure 04:33), severe anaemia at term (Figure 04:31) or postpartum (Figure 04:41), moderate anaemia at term (Figure 04:32), at any time during 2nd or 3rd trimesters (Figure 04:34) and postpartum (Figure 04:42), side-effects (any) (Figure 04:18), diarrhoea (Figure 04:43), constipation (Figure 04:44), nausea (Figure 04:45), or heartburn (Figure 04:46).

No trials reported on the remaining outcomes.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

This review addresses only supplementation with iron or a combination of iron and folic acid. Exclusion of the additional effects of other micronutrients in antenatal supplements allowed us to focus on the effects of iron and folic acid. Possible synergistic effects of additional supplements are being addressed by other systematic Cochrane Reviews (Bhutta 2004).

The number of women in each study and even when all studies were combined did not allow firm conclusions about events that are infrequent but important. Also, the great majority of studies with daily iron supplementation were carried out in industrialized/high-income countries, with minor representation from African, Asian and Latin American countries. On the other hand, intermittent iron and folic acid antenatal supplementation trials came from developing countries.

Unfortunately, there is very limited information relating to clinical outcomes in the included studies. Most studies chose to focus mostly on haematological indices after a certain period of supplementation. Outcome data at term or postpartum are very scanty, except for maternal haematology.

The interpretation of the data in the presence of significant heterogeneity remains a challenge. Pooling the results may also not be a good way to understand the effects. For example in the United States study (Cogswell 2003) non iron deficient non-anaemic women were enrolled before 20 week of gestation and were randomly assigned to receive 30 mg of iron or placebo only until 28 week of gestation. From 28 to 38 week of gestation, the women received different interventions according to the Institute of Medicine guidelines for iron supplementation during pregnancy, regardless of initial assignment. Most women received some iron supplementation throughout pregnancy. The Australia study (Makrides 2003) evaluated the effects of supplementing pregnant women with a low dosage (20 mg/d) of iron from 20 week until delivery. Therefore these two studies provided low doses of iron supplementation during different periods of pregnancy.

Women receiving iron alone or iron with folic acid had higher haemoglobin concentration at term than women who had no supplements. This was the case whether supplementation started early or at any time in pregnancy, whether women were anaemic or non-anaemic at the start of supplementation. In most cases available, iron dosage was high. There were no data for supplementation with low-dose iron in combination with folic acid.

The data available do not allow us to differentiate between iron dosage and the women's haematological condition at the start of supplementation because non-anaemic women received low doses of iron while women with no predetermined haematological condition received high doses of iron.

There are no studies that compare intermittent iron alone with non-supplemented women because all the studies with intermittent supplementation have been carried out in developing countries whose legislature requires mandatory antenatal supplementation with iron. Also, there are only very few cases that allow a comparison between the effects of intermittent iron alone with daily iron alone because common supplementation practice in those regions of the world include iron with folic acid tablets.

 

Adverse effects

Side-effects are a clear drawback to most current iron compounds used as supplements either alone or with folic acid. The results of this review confirm that daily iron doses are associated with a higher risk for side-effects, as has been recognized for many years.

The search for highly bioavailable iron compounds that produce less side-effects and that can be administered at low doses or intermittently (please see below) is evident. The intermittent supplemented group showed a significantly higher risk for vomiting because the dose administered weekly was twice or three times higher than the daily dose, although it was given only once weekly. Most iron and iron and folic acid supplementation regimens have involved doses that surpass the upper tolerable level of 45 mg/day.

Similar to the debate on the best indicators for iron deficiency and anaemia during pregnancy, there is a debate on the benefits of routine daily iron supplementation during pregnancy at the currently high-levels recommended by various agencies. It appears that small daily doses as recommended by the US Food and Nutrition Board, the U.S. Centers for Disease Control and Prevention and the Institute of Medicine (Anderson 1991; CDC 1998; IOM 1993) as well as weekly dosing are essentially as efficacious as daily iron at current doses in preventing significant anaemia at term, defined as that having health and functional consequences. The risk for haemoconcentration in the 2nd and/or 3rd trimester is lower with intermittent supplementation, either low daily iron supplements or weekly iron supplementation appear safer. Unfortunately, the studies exploring the risk for haemoconcentration as well as those exploring iron deficiency and iron-deficiency anaemia at term with daily iron supplementation are confounded by the fact that low iron doses were administered to non-anaemic women and high iron doses were administered to women with undefined anaemia at the start of supplementation.

This review suggests that haemoconcentration at term as well as in/or during the 2nd and 3rd trimester of pregnancy is associated with daily iron supplementation, particularly when doses are high and started early in pregnancy . Haemoconcentration secondary to excessive erythropoiesis during pregnancy in association with iron supplementation has been previously suggested by researchers in Newcastle and others (Hytten 1971; Hytten 1985; Lund 1961; Letsky 1991; Mahomed 1989). Low haemoglobin levels but also high haemoglobin levels have been associated with low birthweight (Garn 1981; Huisman 1986; Koller 1979; Murphy 1986; Scanlon 2000; Steer 1995; Zhou 1998). Further associations were reported between preterm birth and low haemoglobin during the first and second trimesters, and low birthweight due to intrauterine growth retardation and high haemoglobin concentrations also during the first two trimesters (Scanlon 2000). Haemoglobin levels during the 3rd trimester had erratic consequences regarding birthweight. Importantly, the odds ratios for small-for-gestational-age babies were lower when haemoglobin concentrations were low-normal or low (Z scores < -1 and > -2, and < -2 and > -3 for haemoglobin, respectively) during the 2nd and 3rd trimesters.

It would appear that the normal haemodilution reaching a nadir during the second and early third trimester of pregnancy favours the uneventful course of pregnancy and fetal growth and wellbeing, resulting in normal newborns. In many instances antenatal iron supplementation at doses currently recommended for developing nations (60 mg to 300 mg of iron/day) and commonly prescribed by obstetricians in industrial societies may annul the normal haemodilution and even produce abnormally elevated haemoglobin levels in pregnancy (Scanlon 2000). Whether high doses of iron during pregnancy increase the risk of low birthweight and premature delivery is not yet clear. It is not only important to explore that possible association but also to refute other possible adverse consequences of high iron supplementation doses besides haemoconcentration and possible poor placental perfusion such as oxidative stress, as suggested by different studies (Casanueva 2003b). This issue merits research because the literature abounds in data suggesting that haemoconcentration increases the risk of low birthweight.

Presently, most researchers associate high haemoglobin levels during pregnancy with plasma volume depletion, pre-eclampsia, eclampsia, pregnancy complications and low birthweight (Gallery 1979; Goodlin 1981; Koller 1979; Silver 1998). Reduced plasma volume appears to precede late pregnancy hypertension and low birthweight (Gallery 1979; Huisman 1986). The most recent trial that studied both plasma and red blood cell volumes simultaneously showed that both plasma and red cell volumes were reduced, plasma volume reduction averaging 16% was present only in pre-eclampsia (hypertension with albuminuria) but not in non-albuminuric gestational hypertension and was associated with a greater risk of small-for-gestational-age babies (Silver 1998). Other studies involving low birthweight babies where maternal plasma volume was measured failed to demonstrate a level of haemoconcentration that resulted in haemoglobin levels greater than or equal to 135 g/L (Gallery 1979; Hytten 1971; Hytten 1985; Koller 1979; Letsky 1991; Poulsen 1990). These results may suggest that, in otherwise normal pregnant women, haemoconcentration defined as haemoglobin greater than 135 g/l cannot be wholly explained by reduction in maternal plasma volume.

Can haemoconcentration of the levels reported in the studies included in this review result in hyperviscosity, poor placental perfusion and placento/fetal hypoxia? This seems possible based on the data presented by some authors (Erslev 2001; LeVeen 1980). On the one hand, blood viscosity increases essentially in a linear form by about 45% (from 3.2 to 4.3 units relative to H2O) between a haematocrit of 30% and 47% (corresponding to haemoglobin concentrations of 89 and 140 g/L) but oxygen transport declines only by about 4% between the optimum at haematocrit of 30 % to that of 45% (corresponding to haemoglobin concentration of 134 g/L) (LeVeen 1980).

The direct evidence that daily iron supplementation increases the risk of low birthweight and premature delivery is still lacking. Further studies are needed to explore the mechanisms involved.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

Implications for practice

Antenatal supplementation with iron or with iron and folic acid results in a substantial reduction in the prevalence of haemoglobin levels below 10 or 10.5 g/L at term or near term. There are not enough data to determine that routine supplementation with iron alone or in combination with folic acid had any substantial benefits or adverse effects on maternal and fetal health and pregnancy outcomes (premature delivery and low birthweight) among populations where anaemia is common. Weekly supplementation appears to be as effective as daily in preventing low haemoglobin levels. Routine daily or weekly antenatal iron or iron plus folic acid supplementation may be of benefit, especially where pre-gestational iron deficiency and anaemia are prevalent. There is not enough evidence to suggest a change in current recommended iron and folic acid doses with either modality of supplementation.

 
Implications for research

This review has identified the following recommendations for research.

  1. It is important to establish a solid basis for defining desirable ranges of iron nutrition and haematological conditions in pregnancy leading to safe and desirable outcomes of clinical relevance.
  2. Understand the mechanisms involved in haemoconcentration and its functional consequences.
  3. Establish effective and safe doses (healthwise and functionwise) of supplemental iron with folic acid and possibly other nutrients using daily and intermittent preventive supplementation, considering early nutritional and haematological status of the mothers, in industrial settings as well as in the developing world.
  4. Find effective, safe and affordable iron compounds that have reduced or no side-effects for use in public health antenatal supplementation programs that have been proven safe.
  5. Lastly, there is a clear need to carry out much larger multicenter studies to define effective and safe antenatal supplementation strategies and modalities. This research should focus in populations where gestational anaemia and iron deficiency are highly prevalent by current standards and where routine antenatal supplementation with iron and folic acid is the norm, independent of iron status and anaemia at the start of supplementation. Supplementation strategies with different iron doses and starting supplementation before gestational week 20 or at this or later pregnancy stages as well as daily or weekly modality of administration should be explored. In this case the intermittent schedule should be compared to the daily regimen. The influence of altitude should be included in these studies.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

We would like to thank the trial authors who have contributed additional data for this review. In addition, we would 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 review and, in particular, Professor Zarko Alfirevic for his guidance. We would also like to thank Deborah Galuska, Abe Parvanta, Dr Mary E Cogswell and Dr Laurence Grummer-Strawn from the Centers for Disease Control and Prevention for their thoughtful comments and reviews of this publication.

As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team), one or more members of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Daily iron alone versus no intervention/placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Low birthweight (less than 2500 g) (ALL)41147Risk Ratio (M-H, Random, 95% CI)0.59 [0.23, 1.49]

 2 Low birthweight (less than 2500 g) (BY SUBGROUPS)4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
2643Risk Ratio (M-H, Random, 95% CI)0.59 [0.12, 2.96]

    2.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2504Risk Ratio (M-H, Random, 95% CI)0.55 [0.22, 1.38]

    2.4 Non-anaemic at start of supplementation
3697Risk Ratio (M-H, Random, 95% CI)0.59 [0.12, 2.96]

    2.6 Unspecified/mixed anaemic status at start of supplementation
1450Risk Ratio (M-H, Random, 95% CI)0.55 [0.22, 1.38]

    2.8 Daily lower dose (60 mg elemental iron or less)
41147Risk Ratio (M-H, Random, 95% CI)0.59 [0.23, 1.49]

 3 Birthweight (g) (ALL)5925Mean Difference (IV, Random, 95% CI)22.49 [-99.35, 144.34]

 4 Birthweight (g) (BY SUBGROUPS)6Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4791Mean Difference (IV, Random, 95% CI)-7.14 [-158.36, 144.09]

    4.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2251Mean Difference (IV, Random, 95% CI)39.72 [-67.69, 147.12]

    4.4 Non-anaemic at start of supplementation
4728Mean Difference (IV, Random, 95% CI)12.15 [-164.99, 189.29]

    4.6 Unspecified/mixed anaemic status at start of supplementation
2314Mean Difference (IV, Random, 95% CI)6.99 [-83.27, 97.25]

    4.7 Daily low dose (60 mg elemental iron or less)
4814Mean Difference (IV, Random, 95% CI)43.36 [-74.70, 161.43]

    4.8 Daily higher dose (more than 60 mg elemental iron)
3341Mean Difference (IV, Random, 95% CI)-47.09 [-189.44, 95.27]

 5 Premature delivery (less than 37 weeks of gestation) (ALL)3690Risk Ratio (M-H, Random, 95% CI)0.76 [0.47, 1.24]

 6 Premature delivery (less 37 weeks of gestation) (BY SUBGROUPS)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    6.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
2643Risk Ratio (M-H, Random, 95% CI)0.78 [0.45, 1.32]

    6.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
147Risk Ratio (M-H, Random, 95% CI)0.32 [0.01, 7.48]

    6.4 Non-anaemic at start of supplementation
3690Risk Ratio (M-H, Random, 95% CI)0.76 [0.47, 1.24]

    6.7 Daily lower dose (60 mg elemental iron or less)
3690Risk Ratio (M-H, Random, 95% CI)0.76 [0.47, 1.24]

 7 Maternal Hb concentration at term (g/L) (ALL)151516Mean Difference (IV, Random, 95% CI)7.53 [4.40, 10.66]

 8 Maternal Hb concentration at term (g/L) (BY SUBGROUPS)15Mean Difference (IV, Random, 95% CI)Subtotals only

    8.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
111345Mean Difference (IV, Random, 95% CI)8.05 [4.85, 11.25]

    8.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3130Mean Difference (IV, Random, 95% CI)10.24 [2.45, 18.04]

    8.3 Unspecified/mixed gestational age at start of supplementation
141Mean Difference (IV, Random, 95% CI)-11.0 [-18.65, -3.35]

    8.4 Non-anaemic at start of supplementation
81014Mean Difference (IV, Random, 95% CI)6.73 [2.89, 10.57]

    8.6 Unspecified/mixed anaemic status at start of supplementation
7502Mean Difference (IV, Random, 95% CI)8.40 [3.16, 13.64]

    8.7 Daily low dose (60 mg elemental iron or less)
6995Mean Difference (IV, Random, 95% CI)6.42 [2.63, 10.21]

    8.8 Daily higher dose (more than 60 mg elemental iron)
9521Mean Difference (IV, Random, 95% CI)8.38 [3.10, 13.66]

 9 Anaemia at term (Hb less than 110 g/L) (not pre-specified)131696Risk Ratio (M-H, Random, 95% CI)0.26 [0.16, 0.43]

 10 Haemoconcentration at term (Hb more than 130 g/L) (ALL)81222Risk Ratio (M-H, Random, 95% CI)3.01 [1.46, 6.19]

 11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS)8Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
3752Risk Ratio (M-H, Random, 95% CI)1.60 [0.22, 11.41]

    11.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3198Risk Ratio (M-H, Random, 95% CI)3.94 [0.31, 50.47]

    11.3 Unspecified/mixed gestational age at start of supplementation
2272Risk Ratio (M-H, Random, 95% CI)4.67 [2.53, 8.60]

    11.4 Non-anaemic at start of supplementation
3590Risk Ratio (M-H, Random, 95% CI)1.15 [0.05, 24.75]

    11.6 Unspecified/mixed anaemic status at start of supplementation
5632Risk Ratio (M-H, Random, 95% CI)4.03 [1.39, 11.72]

    11.7 Daily low dose (60 mg elemental iron or less)
3590Risk Ratio (M-H, Random, 95% CI)1.15 [0.05, 24.75]

    11.8 Daily higher dose (more than 60 mg elemental iron)
5632Risk Ratio (M-H, Random, 95% CI)4.03 [1.39, 11.72]

 12 Haemoconcentration during second or third trimester (ALL)61133Risk Ratio (M-H, Random, 95% CI)1.90 [1.07, 3.35]

 13 Haemoconcentration during second or third trimester (BY SUBGROUPS)6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
3814Risk Ratio (M-H, Random, 95% CI)2.18 [0.97, 4.89]

    13.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
147Risk Ratio (M-H, Random, 95% CI)1.44 [0.72, 2.86]

    13.3 Unspecified/mixed gestational age at start of supplementation
2272Risk Ratio (M-H, Random, 95% CI)1.94 [0.30, 12.29]

    13.4 Non-anaemic at start of supplementation
3654Risk Ratio (M-H, Random, 95% CI)1.60 [0.85, 2.99]

    13.6 Unspecified/mixed anaemic status at start of supplementation
3479Risk Ratio (M-H, Random, 95% CI)2.61 [0.64, 10.65]

    13.7 Daily low dose (60 mg elemental iron or less)
3654Risk Ratio (M-H, Random, 95% CI)1.60 [0.85, 2.99]

    13.8 Daily higher dose (more than 60 mg elemental iron)
3479Risk Ratio (M-H, Random, 95% CI)2.61 [0.64, 10.65]

 14 Iron deficiency at term (as defined by two or more indicators) (ALL)61108Risk Ratio (M-H, Random, 95% CI)0.44 [0.27, 0.70]

 15 Iron deficiency at term (as defined by two or more indicators) (BY SUBGROUPS)6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    15.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4867Risk Ratio (M-H, Random, 95% CI)0.56 [0.35, 0.90]

    15.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2241Risk Ratio (M-H, Random, 95% CI)0.28 [0.17, 0.44]

    15.4 Non-anaemic at start of supplementation
4944Risk Ratio (M-H, Random, 95% CI)0.60 [0.41, 0.90]

    15.6 Unspecified/mixed anaemic status at start of supplementation
2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]

    15.7 Daily low dose (60 mg elemental iron or less)
4944Risk Ratio (M-H, Random, 95% CI)0.60 [0.41, 0.90]

    15.8 Daily higher dose (more than 60 mg elemental iron)
2164Risk Ratio (M-H, Random, 95% CI)0.14 [0.07, 0.29]

 16 Iron deficiency anaemia at term (ALL)5940Risk Ratio (M-H, Random, 95% CI)0.33 [0.16, 0.69]

 17 Iron deficiency anaemia at term (BY SUBGROUPS)5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    17.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
4895Risk Ratio (M-H, Random, 95% CI)0.37 [0.18, 0.76]

    17.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
145Risk Ratio (M-H, Random, 95% CI)0.07 [0.00, 1.13]

    17.4 Non-anaemic at start of supplementation
4820Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]

    17.6 Unspecified/mixed anaemic status at start of supplementation
1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

    17.7 Daily low dose (60 mg elemental iron or less)
4820Risk Ratio (M-H, Random, 95% CI)0.39 [0.20, 0.74]

    17.8 Daily higher dose (more than 60 mg elemental iron)
1120Risk Ratio (M-H, Random, 95% CI)0.04 [0.00, 0.72]

 18 Side-effects (Any) (ALL)61099Risk Ratio (M-H, Random, 95% CI)1.90 [1.09, 3.33]

 19 Side-effects (Any) (BY SUBGROUPS)6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    19.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
2466Risk Ratio (M-H, Random, 95% CI)1.42 [0.89, 2.26]

    19.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
3428Risk Ratio (M-H, Random, 95% CI)1.75 [0.99, 3.08]

    19.3 Unspecified/mixed gestational age at start of supplementation
1205Risk Ratio (M-H, Random, 95% CI)62.79 [3.89, 1013.31]

    19.4 Non-anaemic at start of supplementation
2329Risk Ratio (M-H, Random, 95% CI)1.31 [0.94, 1.82]

    19.6 Unspecified/mixed anaemic status at start of supplementation
4770Risk Ratio (M-H, Random, 95% CI)3.94 [1.09, 14.28]

    19.7 Daily low dose (60 mg elemental iron or less)
4566Risk Ratio (M-H, Random, 95% CI)1.36 [0.99, 1.87]

    19.8 Daily higher dose (more than 60 mg elemental iron)
3580Risk Ratio (M-H, Random, 95% CI)10.64 [0.67, 170.03]

 20 Very low birthweight (less than 1500 g) (ALL)3697Risk Ratio (M-H, Random, 95% CI)0.55 [0.03, 9.07]

 24 Infant Hb concentration at 3 months (g/L) (ALL)1197Mean Difference (IV, Random, 95% CI)Not estimable

 25 Infant serum ferritin concentration at 3 months (ug/L) (ALL)1197Mean Difference (IV, Random, 95% CI)19.0 [2.75, 35.25]

 26 Infant Hb concentration at 6 months (g/L) (ALL)1197Mean Difference (IV, Random, 95% CI)-5.0 [-9.11, -0.89]

 27 Infant serum ferritin concentration at 6 months (ug/L) (ALL)1197Mean Difference (IV, Random, 95% CI)11.0 [4.37, 17.63]

 30 Very premature delivery (less than 34 weeks' gestation) (ALL)3690Risk Ratio (M-H, Random, 95% CI)0.32 [0.10, 1.09]

 31 Severe anaemia at term (Hb less than 70 g/L) (ALL)71024Risk Ratio (M-H, Random, 95% CI)4.83 [0.23, 99.88]

 32 Moderate anaemia at term (Hb more than 70 g/L and less than 90 g/L) (ALL)81141Risk Ratio (M-H, Random, 95% CI)0.94 [0.55, 1.62]

 33 Severe anaemia at any time during second and third trimester (ALL)61075Risk Ratio (M-H, Random, 95% CI)4.98 [0.24, 103.01]

 34 Moderate anaemia at any time during second or third trimester (ALL)71252Risk Ratio (M-H, Random, 95% CI)0.59 [0.35, 1.01]

 36 Puerperal infection (ALL)11442Risk Ratio (M-H, Random, 95% CI)0.58 [0.14, 2.40]

 37 Antepartum haemorraghe (ALL)1430Risk Ratio (M-H, Random, 95% CI)2.97 [0.12, 72.56]

 38 Postpartum haemorraghe (ALL)3583Risk Ratio (M-H, Random, 95% CI)0.77 [0.47, 1.27]

 39 Transfusion provided (ALL)132Risk Ratio (M-H, Random, 95% CI)0.33 [0.01, 7.62]

 40 Haemoglobin concentration within one month postpartum (ALL)4833Mean Difference (IV, Random, 95% CI)6.10 [3.70, 8.49]

 41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)6778Risk Ratio (M-H, Random, 95% CI)Not estimable

 42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL)3478Risk Ratio (M-H, Random, 95% CI)2.81 [0.12, 68.54]

 43 Diarrhoea (ALL)1173Risk Ratio (M-H, Random, 95% CI)0.98 [0.09, 10.61]

 44 Constipation (ALL)2580Risk Ratio (M-H, Random, 95% CI)0.88 [0.18, 4.40]

 45 Nausea (ALL)3650Risk Ratio (M-H, Random, 95% CI)2.38 [0.49, 11.52]

 46 Heartburn (ALL)1408Risk Ratio (M-H, Random, 95% CI)1.0 [0.82, 1.22]

 47 Vomiting (ALL)2477Risk Ratio (M-H, Random, 95% CI)0.88 [0.38, 2.07]

 48 Maternal death (death while pregnant or within 42 days of termination of pregnancy) (ALL)147Risk Ratio (M-H, Random, 95% CI)Not estimable

 49 Maternal wellbeing/satisfaction (ALL)149Risk Ratio (M-H, Random, 95% CI)0.91 [0.77, 1.08]

 50 Placental abruption (ALL)11442Risk Ratio (M-H, Random, 95% CI)2.88 [0.12, 70.53]

 52 Pre-eclampsia (ALL)147Risk Ratio (M-H, Random, 95% CI)0.96 [0.06, 14.43]

 93 Cesarean delivery (not prespecified)3508Risk Ratio (M-H, Random, 95% CI)1.06 [0.75, 1.50]

 94 Birth length in cm (not prespecified)4877Mean Difference (IV, Random, 95% CI)0.24 [-0.17, 0.65]

 95 Forceps or vacuum delivery (not prespecified)2477Odds Ratio (M-H, Random, 95% CI)1.59 [0.93, 2.74]

 96 Breastfeeding at least 4 months (not prespecified)148Risk Ratio (M-H, Random, 95% CI)1.00 [0.89, 1.13]

 97 Haemoglobin concentration at 4-8 weeks' postpartum (g/L) (not prespecified)7586Mean Difference (IV, Random, 95% CI)2.28 [0.40, 4.16]

 98 Apgar score < 7 at 5 minutes (not prespecified)2475Risk Ratio (M-H, Random, 95% CI)0.74 [0.17, 3.28]

 99 Apgar Score at 5 min (not prespecified)2228Mean Difference (IV, Random, 95% CI)0.27 [-0.07, 0.62]

 
Comparison 2. Intermittent iron alone versus daily iron alone

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 3 Birthweight (ALL)141Mean Difference (IV, Random, 95% CI)-68.0 [-398.33, 262.33]

 5 Premature delivery (less than 37 weeks of gestation) (ALL)141Risk Ratio (M-H, Random, 95% CI)0.46 [0.02, 8.96]

 12 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (ALL)264Risk Ratio (M-H, Random, 95% CI)0.54 [0.18, 1.58]

 33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)264Risk Ratio (M-H, Random, 95% CI)Not estimable

 34 Moderate anaemia at any time during second or third trimester (ALL)264Risk Ratio (M-H, Random, 95% CI)2.42 [0.16, 35.56]

 
Comparison 3. Daily iron-folic acid versus no intervention/placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Low birthweight (less than 2500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 3 Birthweight (ALL)145Mean Difference (IV, Random, 95% CI)-32.0 [-213.62, 149.62]

 5 Premature delivery (less than 37 weeks of gestation) (ALL)148Risk Ratio (M-H, Random, 95% CI)7.00 [0.38, 128.61]

 7 Haemoglobin concentration at term (ALL)4179Mean Difference (IV, Random, 95% CI)12.00 [2.93, 21.07]

 8 Haemoglobin concentration at term (BY SUBGROUPS)4Mean Difference (IV, Random, 95% CI)Subtotals only

    8.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
293Mean Difference (IV, Random, 95% CI)15.65 [11.84, 19.46]

    8.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
286Mean Difference (IV, Random, 95% CI)7.92 [-11.68, 27.52]

    8.4 Non-anaemic at start of supplementation
148Mean Difference (IV, Random, 95% CI)17.10 [8.44, 25.76]

    8.6 Unspecified/mixed anaemic status at start of supplementation
3131Mean Difference (IV, Random, 95% CI)10.47 [-1.07, 22.00]

    8.8 Daily higher dose (more than 60 mg elemental iron)
4179Mean Difference (IV, Random, 95% CI)12.00 [2.93, 21.07]

 9 Anaemia at term (Hb less than 110 g/L) (not pre-specified)3346Risk Ratio (M-H, Random, 95% CI)0.27 [0.12, 0.56]

 10 Haemoconcentration at term (Hb more than 130 g/L) (ALL)2222Risk Ratio (M-H, Random, 95% CI)1.28 [0.24, 6.78]

 11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS)2Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
2222Risk Ratio (M-H, Random, 95% CI)1.28 [0.24, 6.78]

    11.8 Daily higher dose (more than 60 mg elemental iron)
2222Risk Ratio (M-H, Random, 95% CI)1.28 [0.24, 6.78]

 18 Side-effects (Any) (ALL)1456Risk Ratio (M-H, Random, 95% CI)44.32 [2.77, 709.09]

 20 Very low birthweight (less than 1500 g) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 21 Perinatal death (ALL)2145Risk Ratio (M-H, Random, 95% CI)2.5 [0.10, 59.88]

 29 Admission to special care unit (ALL)148Risk Ratio (M-H, Random, 95% CI)Not estimable

 30 Very premature delivery (less than 34 weeks' gestation) (ALL)148Risk Ratio (M-H, Random, 95% CI)5.0 [0.25, 98.96]

 31 Severe anaemia at term (Hb less than 70 g/L) (ALL)2136Risk Ratio (M-H, Random, 95% CI)Not estimable

 32 Moderate anaemia at term (Hb more than 70g/L and less than 90 g/L) (ALL)2136Risk Ratio (M-H, Random, 95% CI)Not estimable

 33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)2164Risk Ratio (M-H, Random, 95% CI)Not estimable

 34 Moderate anaemia at any time during second or third trimester (ALL)2164Risk Ratio (M-H, Random, 95% CI)Not estimable

 35 Infection during pregnancy (including urinary tract infections) (ALL)148Risk Ratio (M-H, Random, 95% CI)1.0 [0.15, 6.53]

 36 Puerperal infection (ALL)12863Risk Ratio (M-H, Random, 95% CI)0.55 [0.13, 2.28]

 37 Antepartum haemorraghe (ALL)2145Risk Ratio (M-H, Random, 95% CI)1.25 [0.22, 7.12]

 38 Postpartum haemorraghe (ALL)168Risk Ratio (M-H, Random, 95% CI)0.12 [0.00, 2.71]

 40 Haemoglobin concentration within one month postpartum (ALL)145Mean Difference (IV, Random, 95% CI)10.40 [4.03, 16.77]

 41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)167Risk Ratio (M-H, Random, 95% CI)Not estimable

 42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL)167Risk Ratio (M-H, Random, 95% CI)Not estimable

 50 Placental abruption (ALL)12863Risk Ratio (M-H, Random, 95% CI)8.19 [0.49, 138.16]

 52 Pre-eclampsia (ALL)148Risk Ratio (M-H, Random, 95% CI)3.00 [0.13, 70.16]

 92 Oedema during pregnancy (not prespecified)167Risk Ratio (M-H, Random, 95% CI)2.82 [0.99, 8.09]

 93 Cesarean delivery (not prespecified)197Risk Ratio (M-H, Random, 95% CI)0.83 [0.22, 3.13]

 97 Haemoglobin concentration at 4-8 weeks postpartum (not prespecified)2112Mean Difference (IV, Random, 95% CI)2.01 [-0.68, 4.70]

 
Comparison 4. Intermittent iron-folic acid versus daily iron-folic acid

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Low birthweight (less than 2500 g) (ALL)3650Risk Ratio (M-H, Random, 95% CI)0.99 [0.50, 1.97]

 2 Low birthweight (less than 2500 g) (BY SUBGROUPS)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    2.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
1375Risk Ratio (M-H, Random, 95% CI)1.33 [0.42, 4.22]

    2.3 Unspecified/mixed gestational age at start of supplementation
2275Risk Ratio (M-H, Random, 95% CI)0.85 [0.36, 1.99]

    2.7 Daily low dose (60 mg elemental iron or less)
3650Risk Ratio (M-H, Random, 95% CI)0.99 [0.50, 1.97]

 3 Birthweight (ALL)3650Mean Difference (IV, Random, 95% CI)-8.36 [-73.56, 56.85]

 4 Birthweight (BY SUBGROUPS)3Mean Difference (IV, Random, 95% CI)Subtotals only

    4.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
1375Mean Difference (IV, Random, 95% CI)1.51 [-79.35, 82.37]

    4.3 Unspecified/mixed gestational age at start of supplementation
2275Mean Difference (IV, Random, 95% CI)-26.71 [-137.00, 83.58]

    4.7 Daily low dose (60 mg elemental iron or less)
3650Mean Difference (IV, Random, 95% CI)-8.36 [-73.56, 56.85]

 7 Haemoglobin concentration at term (ALL)3475Mean Difference (IV, Random, 95% CI)-0.83 [-4.74, 3.08]

 8 Haemoglobin concentration at term (BY SUBGROUPS)3Mean Difference (IV, Random, 95% CI)Subtotals only

    8.7 Daily low dose (60 mg elemental iron or less)
3422Mean Difference (IV, Random, 95% CI)-0.10 [-5.15, 4.95]

    8.8 Daily higher dose (more than 60 mg elemental iron)
1109Mean Difference (IV, Random, 95% CI)-0.82 [-4.99, 3.35]

 9 Anaemia at term (Hb < 110 g/L) (not prespecified)3475Risk Ratio (M-H, Random, 95% CI)1.20 [0.78, 1.83]

 10 Haemoconcentration at term (Hb more than 130 g/L) (ALL)3475Risk Ratio (M-H, Random, 95% CI)0.93 [0.47, 1.82]

 11 Haemoconcentration at term (Hb more than 130 g/L) (BY SUBGROUPS)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

    11.7 Daily low dose (60 mg elemental iron or less)
3422Risk Ratio (M-H, Random, 95% CI)1.24 [0.42, 3.66]

    11.8 Daily higher dose (more than 60 mg elemental iron)
1109Risk Ratio (M-H, Random, 95% CI)0.63 [0.19, 2.11]

 12 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (ALL)51031Risk Ratio (M-H, Random, 95% CI)0.41 [0.21, 0.80]

 13 Haemoconcentration during second or third trimester (Hb more than 130 g/L) (BY SUBGROUPS)5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    13.1 Early gestational age (less than 20 weeks of gestation or pre-pregnancy) at start of supplementation
1170Risk Ratio (M-H, Random, 95% CI)0.49 [0.23, 1.07]

    13.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
1166Risk Ratio (M-H, Random, 95% CI)0.24 [0.10, 0.55]

    13.3 Unspecified/mixed gestational age at start of supplementation
3695Risk Ratio (M-H, Random, 95% CI)0.46 [0.13, 1.65]

    13.4 Anaemic at start of supplementation (Hb <110 g/L if in first or <105 g/L if in second trimester)
147Risk Ratio (M-H, Random, 95% CI)Not estimable

    13.6 Unspecified/mixed anaemic status at start of supplementation
4966Risk Ratio (M-H, Random, 95% CI)0.41 [0.21, 0.80]

    13.7 Daily low dose (60 mg elemental iron or less)
5953Risk Ratio (M-H, Random, 95% CI)0.41 [0.20, 0.82]

    13.8 Daily higher dose (more than 60 mg elemental iron)
1167Risk Ratio (M-H, Random, 95% CI)0.77 [0.41, 1.44]

 16 Iron deficiency anaemia at term (based on two or more indicators) (ALL)1156Risk Ratio (M-H, Random, 95% CI)0.71 [0.08, 6.63]

 18 Side-effects (any) (ALL)61227Risk Ratio (M-H, Random, 95% CI)0.80 [0.54, 1.17]

 19 Side-effects (any) (BY SUBGROUPS)6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    19.2 Late gestational age (20 weeks or more of gestation) at start of supplementation
1172Risk Ratio (M-H, Random, 95% CI)1.0 [0.79, 1.27]

    19.3 Unspecified/mixed gestational age at start of supplementation
51055Risk Ratio (M-H, Random, 95% CI)0.72 [0.42, 1.26]

    19.7 Daily low dose (60 mg elemental iron or less)
61171Risk Ratio (M-H, Random, 95% CI)0.92 [0.71, 1.19]

    19.8 Daily higher dose (more than 60 mg elemental iron)
1173Risk Ratio (M-H, Random, 95% CI)0.11 [0.05, 0.23]

 20 Very low birthweight (less than 1500 g) (ALL)3Risk Ratio (M-H, Random, 95% CI)Subtotals only

 27 Infant ferritin concentration at 6 months (ug/L) (ALL)188Mean Difference (IV, Random, 95% CI)0.09 [0.05, 0.13]

 31 Severe anaemia at term (Hb less than 70 g/L) (ALL)3475Risk Ratio (M-H, Random, 95% CI)Not estimable

 32 Moderate anaemia at term (Hb more than 70g/L and less than 90 g/L) (ALL)3475Risk Ratio (M-H, Random, 95% CI)1.03 [0.07, 16.23]

 33 Severe anaemia at any time during second and third trimester (Hb less than 70 g/L) (ALL)51160Risk Ratio (M-H, Random, 95% CI)Not estimable

 34 Moderate anaemia at any time during second or third trimester (ALL)51031Risk Ratio (M-H, Random, 95% CI)2.80 [0.39, 19.88]

 41 Severe anaemia at postpartum (Hb less than 80 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)0.43 [0.04, 4.64]

 42 Moderate anaemia at postpartum (Hb more than 80 g/L and less than 100 g/L) (ALL)1169Risk Ratio (M-H, Random, 95% CI)1.14 [0.26, 4.95]

 43 Diarrhea (ALL)3473Risk Ratio (M-H, Random, 95% CI)1.26 [0.56, 2.81]

 44 Constipation (ALL)3473Risk Ratio (M-H, Random, 95% CI)1.08 [0.51, 2.29]

 45 Nausea (ALL)4774Risk Ratio (M-H, Random, 95% CI)0.71 [0.36, 1.40]

 46 Heartburn (ALL)3473Risk Ratio (M-H, Random, 95% CI)0.78 [0.29, 2.06]

 47 Vomiting (ALL)4774Risk Ratio (M-H, Random, 95% CI)1.69 [1.15, 2.47]

 68 Ln (serum ferritin concentration) 4-8 wk postpartum (not prespecified)1160Mean Difference (IV, Random, 95% CI)-0.13 [-0.42, 0.16]

 70 Low serum ferritin concentration at post partum (4-8 wk) (not prespecified)1146Risk Ratio (M-H, Random, 95% CI)1.19 [0.40, 3.57]

 71 High serum transferrin receptors at 6 weeks postpartum (not prespecified)1146Risk Ratio (M-H, Random, 95% CI)0.69 [0.36, 1.33]

 97 Haemoglobin concentration at 4-8 weeks postpartum (not prespecified)1146Mean Difference (IV, Random, 95% CI)2.0 [-3.86, 7.86]

 

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  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 17 April 2006.


DateEventDescription

13 August 2008AmendedConverted to new review format.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 2, 2004
Review first published: Issue 3, 2006

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Juan Pablo Pena-Rosas and Fernando Viteri co-wrote the protocol and the review. Juan Pablo Pena-Rosas abstracted the trial data and carried out the analysis with the technical support and guidance of Fernando Viteri. Both took primary responsibility in producing the final manuscript.

Disclaimer: "The findings and conclusions in this review are those of the authors and do not necessarily represent the Centers for Disease Control and Prevention (CDC)".

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

We certify that we have no affiliations with or involvement in any organisation or entity with a direct financial interest in the subject matter of the review (e.g. employment, consultancy, stock ownership, honoraria, expert testimony).

Fernando Viteri was involved in some included studies with intermittent iron supplementation. Juan Pablo Pena-Rosas was author of an excluded study on iron and folic acid intermittent supplementation.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • Children's Hospital and Oakland Research Institute (CHORI), USA.
  • International Micronutrient Malnutrition Prevention and Control Program (IMMPaCt) - U.S. Centers for Disease Control and Prevention (CDC), USA.

 

External sources

  • Department of Reproductive Health and Research, World Health Organization (WHO), Switzerland.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Barton 1994 {published data only}
  • Barton DPJ, Joy MT, Lappin TRJ, Afrasiabi M, Morel JG, O'Riordan J, et al. Maternal erythropoietin in singleton pregnancies: a randomized trial on the effect of oral hematinic supplementation. American Journal of Obstetrics and Gynecology 1994;170:896-901.
Batu 1976 {published data only}
  • Batu AT, Toe T, Pe H, Nyunt KK. A prophylactic trial of iron and folic acid supplements in pregnant Burmese women. Israel Journal of Medical Sciences 1976;12:1410-7.
Butler 1968 {published data only}
  • Butler EB. The effect of iron and folic acid on red cell and plasma volume in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1968;75:497-510.
Buytaert 1983 {published data only}
  • Buytaert G, Wallenburg HCS, Van Eijk HG, Buytaert P. Iron supplementation during pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 1983;15:11-6.
Chanarin 1971 {published data only}
  • Chanarin I, Rothman D. Further observations on the relation between iron and folate status in pregnancy. BMJ 1971;2:81-4.
Charoenlarp 1988 {published data only}
  • Charoenlarp P, Dhanamitta S, Kaewvichit R, Silprasert A, Suwanaradd C, Na-Nakorn S, et al. A WHO collaborative study on iron supplementation in Burma and in Thailand. American Journal of Clinical Nutrition 1988;47(2):280-97.
Chew 1996a {published and unpublished data}
  • Chew F, Torun B, Viteri FE. Comparison of weekly and daily iron supplementation to pregnant women in Guatemala (supervised and unsupervised). FASEB Journal 1996;10:A4221.
  • Chew F, Torun B, Viteri FE. Individual patient data (as supplied 15 January 2004). Data on file.
  • Chew F, Torún B, Viteri FE. Comparison of daily and weekly iron supplementation in pregnant women with and without direct supervision [Comparación de la suplementación diaria o semanal de hierro en mujeres embarazadas con y sin supervisión directa]. XI Congreso Latino Americano de Nutrición, Libro de Resumenes. Guatemala: SLAN, 1997:94.
Chew 1996b {published and unpublished data}
  • Chew F, Torun B, Viteri FE. Comparison of weekly and daily iron supplementation to pregnant women in Guatemala (supervised and unsupervised). FASEB Journal 1996;10:A4221.
  • Chew F, Torun B, Viteri FE. Individual patient data (as supplied 15 January 2004). Data on file.
  • Chew F, Torún B, Viteri FE. Comparison of daily and weekly iron supplementation in pregnant women with and without direct supervision [Comparación de la suplementación diaria o semanal de hierro en mujeres embarazadas con y sin supervisión directa]. XI Congreso Latino Americano de Nutrición, Libro de Resumenes. Guatemala: SLAN, 1997:94.
Chisholm 1966 {published data only}
  • Chisholm M. A controlled clinical trial of prophylactic folic acid and iron in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1966;73:191-6.
Cogswell 2003 {published and unpublished data}
  • Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham GM. Individual patient data (as supplied 4 February 2004). Data on file.
  • Cogswell ME, Parvanta I, Ickes L, Yip R, Brittenham GM. Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial. American Journal of Clinical Nutrition 2003;78(4):773-81.
  • Cogswell ME, Parvanta I, Yip R, Brittenham GM. Iron supplementation during pregnancy for initially non-anemic, iron replete women - decreased prevalence of low birth weight infants. Report of the 2001 INACG Symposium. Why iron is important and what to do about it: a new perspective. Washington D.C.: ILSI Human Nutrition Institute, 2002; Vol. 1 Abstract 7:42.
  • Cogswell ME, Parvanta I, Yip R, Brittenham GM. Low iron during pregnancy increases the risk of delivering preterm or small infants. Report of the 2001 INACG Symposium. Why iron is important and what to do about it: a new perspective. Washington DC: ILSI Human Nutrition Institute, 2002; Vol. 1 Abstract 8:42.
De Benaze 1989 {published data only}
  • De Benaze C, Galan P, Wainer R, Hercberg S. Prevention of iron deficient anemia during pregnancy by early iron supplementation: a controlled trial. Revue d Epidemiologie et de Sante Publique 1989;37:109-18.
Ekstrom 2002 {published and unpublished data}
  • Ekstrom EC. Personal communication 12 April 2004.
  • Ekstrom EC, Hyder SM, Chowdhury AM, Chowdhury SA, Lonnerdal B, Habicht JP, et al. Efficacy and trial effectiveness of weekly and daily iron supplementation among pregnant women in rural Bangladesh: disentangling the issues. American Journal of Clinical Nutrition 2002;76(6):1392-400.
  • Hyder SM, Persson LA, Chowdhury AM, Ekstrom EC. Do side-effects reduce compliance to iron supplementation? A study of daily- and weekly-dose regimens in pregnancy. Journal of Health, Population and Nutrition 2002;2:175-9.
  • Hyder SM, Persson LA, Chowdhury R, Lonnerdal B, Ekstrom EC. Impact of daily and weekly iron supplementation to women in pregnancy and puerperium on haemoglobin and iron status six weeks postpartum: results from a community-based study in Bangladesh. Scandinavian Journal of Nutrition 2003;47(1):19-25.
Eskeland 1997 {published and unpublished data}
  • Eskeland B. Database provided by authors (as supplied 22 February 2004). Data on file.
  • Eskeland B, Malterud K, Ulvik RJ, Hunskaar S. Iron supplementation in pregnancy: is less enough? A randomized, placebo controlled trial of low dose iron supplementation with and without heme iron. Acta Obstetricia et Gynecologica Scandinavica 1997;76(9):822-8.
Hankin 1963 {published data only}
  • Hankin ME. The value of iron supplementation during pregnancy. Australian and New Zealand Journal of Obstetrics and Gynaecology 1963;3:111-8.
  • Hankin ME, Symonds EM. Body weight, diet and pre-eclamptic toxaemia in pregnancy. Australian and New Zealand Journal of Obstetrics and Gynaecology 1962;4:156-60.
Holly 1955 {published data only}
  • Holly RG. Anemia in pregnancy. Obstetrics & Gynecology 1955;5:562-9.
Hood 1960 {published data only}
  • Hood WE, Bond WL. Iron deficiency prophylaxis during pregnancy. Obstetrics & Gynecology 1960;16:82-4.
Kerr 1958 {published data only}
  • Kerr DNS, Davidson S. The prophylaxis of iron-deficiency anemia in pregnancy. Lancet 1958;2:483-8.
Liu 1996 {published and unpublished data}
  • Liu XN, Liu PY. The effectiveness of weekly iron supplementation regimen in improving the iron status of Chinese children and pregnant women. Biomedical and Environmental Sciences 1996;9:341-7.
  • Liu XN, Liu PY, Viteri FE. Individual patient data (as supplied December 2003). Data on file.
Makrides 2003 {published and unpublished data}
  • Makrides M. Personal communication April 12 2004.
  • Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomised controlled trial. American Journal of Clinical Nutrition 2003;78:145-53.
  • Makrides M, Crowther CA, Gibson RA, Gibson RS, Skeaff CM. Low-dose iron supplements in pregnancy prevent iron deficiency at the end of pregnancy and during the post-partum period: the results of a randomised controlled trial [abstract]. Perinatal Society of Australia and New Zealand 7th Annual Congress; 2003 March 9-12; Tasmania, Australia. 2003:P99.
Menendez 1994 {published data only}
  • Menendez C, Todd J, Alonso PL, Francis N, Lulat S, Ceesay S, et al. The effects or iron supplementation during pregnancy, given by traditional birth attendants, on the prevalence of anaemia and malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene 1994;88:590-3.
  • Menendez C, Todd J, Alonso PL, Francis N, Lulat S, Ceesay S, et al. The response to iron supplementation of pregnant women with the haemoglobin genotype AA or AS. Transactions of the Royal Society of Tropical Medicine and Hygiene 1995;89(3):289-92.
Milman 1991 {published data only}
  • Milman N, Agger AO, Nielsen OJ. Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled study in 207 Danish women. Danish Medical Bulletin 1991;38(6):471-6.
  • Milman N, Agger AO, Nielson OJ. Iron status markers and serum erythropoietin in 120 mothers and newborn infants: effect of iron supplementation in normal pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1994;73:200-4.
  • Milman N, Byg KE, Agger AO. Hemoglobin and erythrocyte indices during normal pregnancy and postpartum in 206 women with and without iron supplementation. Acta Obstetricia et Gynecologica Scandinavica 2000;79(2):89-98.
  • Milman N, Graudal N, Agger AO. Iron status markers during pregnancy. No relationship between levels at the beginning of the second trimester, prior to delivery and post partum. Journal of Internal Medicine 1995;237:261-7.
  • Milman N, Graudal N, Nielsen OJ, Agger AO. Serum erythropoietin during normal pregnancy: relationship to hemoglobin and iron status markers and impact of iron supplementation in a longitudinal, placebo-controlled study on 118 women. International Journal of Hematology 1997;66(2):159-68.
  • Milman N, Graudal NA, Agger AO. Iron status markers during normal pregnancy in 120 women. No clinically useful relationship between levels in the second trimester, later in pregnancy, and post partum. Ugeskrift for Laeger 1995;157:6571-5.
Ortega-Soler 1998 {unpublished data only}
  • Ortega-Soler CR, Langini SH, Fleishman S, Lopez LB, Garcia M, Guntin R, et al. Iron nutritional status in pregnant women with and without iron supplementation [Estado nutricional con respecto al hierro (Fe) en gestantes con y sin suplementacion]. Personal communication 1998.
Paintin 1966 {published and unpublished data}
  • Paintin DB, Thompson AM, Hytten FE. Personal communication 1986.
  • Paintin DB, Thomson AM, Hytten FE. Iron and haemoglobin level in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1966;73:181-90.
Pita Martin 1999 {published and unpublished data}
  • Pita Martin de Portela ML. Personal communication March 22 2004.
  • Pita Martin de Portela ML, Langini SH, Fleischman S, Garcia M, Lopez LB, Guntin R, et al. Effect of iron supplementation and its frequency during pregnancy. Medicina 1999;59:430-6.
Preziosi 1997 {published data only}
  • Preziosi P, Prual A, Galan P, Daouda H, Boureima H, Hercberg S. Effect of iron supplementation on the iron status of pregnant women: consequences for newborns. American Journal of Clinical Nutrition 1997;66:1178-82.
Pritchard 1958 {published data only}
  • Pritchard J, Hunt C. A comparison of the hematologic responses following the routine prenatal administration of intramuscular and oral iron. Surgery Gynecology and Obstetrics 1958;106:516-8.
Puolakka 1980 {published data only}
  • Puolakka J, Janne O, Pakarinen A, Jarvinen PA, Vihko R. Serum ferritin as a measure of iron stores during and after normal pregnancy with and without iron supplement. Acta Obstetricia et Gynecologica Scandinavica 1980;95:43-51.
Ridwan 1996 {published and unpublished data}
  • Ridwan E, Schultink W, Dillon D, Gross R. Effects of weekly iron supplementation on pregnant indonesian women are similar to those of daily supplementation. American Journal of Clinical Nutrition 1996;63(6):884-90.
  • Schultink W, Ridwan E, Dillon D, Gross R. Individual patient data (as supplied 12 January 2004). Data on file.
Robinson 1998 {published and unpublished data}
  • Robinson JS. Individual patient data (as supplied 11 March 2004). Data on file.
  • Robinson JS. Working with traditional birth attendants to improve iron tablet utilization by pregnant women. MotherCare Technical Working Paper #7. Arlington, VA 1998.
  • Robinson JS, Sopacua J, Napitapulu J. Using traditional birth attendants to improve iron tablet utilization by pregnant women. Maluku Province, Indonesia. Draft paper. Mother Care Project. Project Concern International San Diego CA 1999.
  • Robinson JS, Yip R. Weekly versus daily iron tablet supplementation in pregnant women in Indonesia. Draft paper 2000.
Romslo 1983 {published data only}
  • Romslo I, Haram K, Sagen N, Augensen K. Iron requirements in normal pregnancy as assessed by serum ferritin, serum transferrin saturation and erythrocyte protoporphyrin determinations. British Journal of Obstetrics and Gynaecology 1983;90:101-7.
Svanberg 1975 {published data only}
  • Svanberg B, Arvidsson B, Norrby A, Rybo G, Solvell L. Absorption of supplemental iron during pregnancy - a longitudinal study with repeated bone marrow studies and absorption measurements. Acta Obstetricia et Gynecologica Scandinavica 1975;48:87-108.
Taylor 1982 {published data only}
  • Taylor DJ, Mallen C, McDougall N, Lind T. Personal communication 1982.
  • Taylor DJ, Mallen C, McDougall N, Lind T. Effect of iron supplementation on serum ferritin levels during and after pregnancy. British Journal of Obstetrics and Gynaecology 1982;89:1011-7.
Tura 1989 {published data only}
  • Tura S, Carenza L, Baccarani M, Bagnara M, Bocci A, Bottone P, et al. Therapy and iron supplements with ferritin during pregnancy. A randomized prospective study of 458 cases. Recenti Progessi in Medicina 1989;80:607-14.
Van Eijk 1978 {published data only}
  • Van Eijk HG, Kroos MJ, Hoogendoorn GA, Wallenburg HC. Serum ferritin and iron stores during pregnancy. Clinica Chimica Acta 1978;83(1-2):81-91.
Wallenburg 1983 {published data only}
  • Buytaert G, Wallenburg HCS, Van Eijk HG, Buytaert P. Iron supplementation during pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 1983;15:11-6.
  • Wallenburg HCS, Van Eijk HG. Effect of oral iron supplementation during pregnancy on maternal and fetal iron status. Journal of Perinatal Medicine 1984;12:7-12.
Willoughby 1967 {published data only}
  • Willoughby MLN. An investigation of folic acid requirements in pregnancy. II. British Journal of Haematology 1967;13:503-9.
Wills 1947 {published data only}
  • Wills L, Hill G, Bingham K, Miall M, Wrigley J. Haemoglobin levels in pregnancy: the effect of the rationing scheme and routine administration of iron. British Journal of Nutrition 1947;1:126-38.
Winichagoon 2003 {unpublished data only}
  • Winichagoon P, Lertmullikaporn N, Chitcumroonchokechai C, Thamrongwarangkul T. Daily versus weekly iron supplementation to pregnant women in rural northeast Thailand. Personal communication 2003.
Young 2000 {published data only}
  • Young MW, Lupafya E, Kapenda E, Bobrow EA. The effectiveness of weekly iron supplementation in pregnant women of rural northern Malawi. Tropical Doctor 2000;30(2):84-8.
Yu 1998 {published and unpublished data}
  • Yu KH, Yoon, JS. Individual patient data (as supplied 11 March 2004). Data on file.
  • Yu KH, Yoon JS. The effect of weekly iron supplementation on iron and zinc nutritional status in pregnant women. Korean Journal of Nutrition 1998;31(8):1270-82.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Aaseth 2001 {published data only}
  • Aaseth J, Thomassen Y, Ellingsen DG, Stoa-Birketvedt G. Prophylactic iron supplementation in pregnant women in Norway. Journal of Trace Elements in Medicine & Biology 2001;15(2-3):167-74.
Abel 2000 {published data only}
  • Abel R, Rajaratnam J, Kalaimani A, Kirubakaran S. Can iron status be improved in each of the three trimesters? A community base study. European Journal of Clinical Nutrition 2000;54:490-3.
Afifi 1978 {published data only}
  • Afifi AM. Plexafer-F in the management of latent iron deficiency in pregnancy. Journal of International Medical Research 1978;6:34-40.
Babior 1985 {published data only}
  • Babior BM, Peters WA, Briden PM, Cetrulo CL. Pregnant women's absorption of iron from prenatal supplements. Journal of Reproductive Medicine 1985;30:355-7.
Bergsjo 1987 {published data only}
  • Bergsjo P. The effects of iron supplementation in pregnancy. Personal communication 1987.
Blot 1980 {published data only}
  • Blot I, Tchernia G, Chenayer M, Hill C, Hajeri H, Leluc R. Iron deficiency in the pregnant woman. Its repercussions on the newborn. The influence of systematic iron treatment. Journal de Gynecologie, Obstetrique et Biologie de la Reproduction 1980;9:489-95.
Brown 1972 {published data only}
  • Brown GM, Dawson DW. Prevention of anaemia in pregnancy. Current Medical Research and Opinion 1972;1:93-9.
Burslem 1968 {published data only}
  • Burslem RW, Poller L, Wacks H. A trial of slow release ferrous sulphate (Ferrogradumet) in prevention of iron deficiency in pregnancy. Acta Haematologica 1968;40:200-4.
Cantlie 1971 {published data only}
  • Cantlie GSD, De Leeuw NKM, Lowenstein L. Iron and folate nutrition in a group of private obstetrical patients. American Journal of Clinical Nutrition 1971;24:637-41.
Carrasco 1962 {published data only}
  • Carrasco E, Jose F, Samson G, Germar E, Padilla B. Effect of D-sorbitol on the absorption and transfer of nutrients from mother to fetus. American Journal of Clinical Nutrition 1962;11:533-6.
Casanueva 2003a {unpublished data only}
  • Casanueva E. Weekly iron-folate (Fe-fol) supplementation during pregnancy in Mexican women. Personal communication 2003.
  • Casanueva E, Viteri FE, Mares-Galindo M, Meza-Camacho C, Loria A, Schnaas L, et al. Weekly iron as a safe alternative to daily supplementation for nonanemic pregnant women. Archives of Medical Research 2006 in press.
Chanarin 1965 {published data only}
  • Chanarin I, Rothman D, Berry V. Iron deficiency and its relation to folic acid status in pregnancy: results of a clinical trial. BMJ 1965;1:480-5.
Chawla 1995 {published data only}
  • Chawla PK, Puri R. Impact of nutritional supplements on hematological profile of pregnant women. Indian Pediatrics 1995;32:876-80.
Christian 2003 {published data only}
  • Christian P, Khatry SK, Katz J, Pradhan EK, LeClerq SC, Shrestha SR, et al. Effects of alternative maternal micronutrient supplements on low birth weight in rural Nepal: double blind randomised community trial. BMJ 2003;326(7389):571.
Dawson 1987 {published data only}
  • Dawson EB, McGanity WJ. Protection of maternal iron stores in pregnancy. Journal of Reproductive Medicine 1987;32(6 Suppl):478-87.
Dommisse 1983 {published data only}
  • Dommisse J, Bell DJH, Du Toit ED, Midgley V, Cohen M. Iron-storage deficiency and iron supplementation in pregnancy. South African Medical Journal 1983;64:1047-51.
Edgar 1956 {published data only}
  • Edgar W, Rice HM. Administration of iron in antenatal clinics. Lancet 1956;1:599-602.
Ekstrom 1996 {published data only}
  • Ekstrom EM, Kavishe FP, Habicht J, Frongillo EA, Rasmussen KM, Hemed L. Adherence to iron supplementation during pregnancy in Tanzania: determinants and hematologic consequences. American Journal of Clinical Nutrition 1996;64:368-74.
Fenton 1977 {published data only}
  • Fenton V, Cavill I, Fisher J. Iron stores in pregnancy. British Journal of Haematology 1977;37:145-9.
Fleming 1974 {published data only}
  • Fleming AF, Martin JD, Hahnel R, Westlake AJ. Effects of iron and folic acid antenatal supplements on maternal haematology and fetal wellbeing. Medical Journal of Australia 1974;2:429-36.
Fleming 1986 {published data only}
  • Fleming AF. Anaemia in pregnancy in the Guinea Savanna of Nigeria. In: Ludwig H, Thomsen K editor(s). Gynecology and Obstetrics. Berlin: Springer-Verlag, 1986:122-4.
  • Fleming AF, Ghatoura GBS, Harrison KA, Briggs ND, Dunn DT. The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Annals of Tropical Medicine and Parasitology 1986;80:211-33.
  • Harrison KA, Fleming AF, Briggs ND, Rossiter CE. Child-bearing, health and social priorities: a survey of 22,774 consecutive hospital births in Zaria, Northern Nigeria. 5. Growth during pregnancy in Nigerian teenage primigravidae. British Journal of Obstetrics and Gynaecology 1985;92(5):32-9.
Fletcher 1971 {published data only}
  • Fletcher J, Gurr A, Fellingham F, Prankerd T, Brant H, Menzies D. The value of folic acid supplements in pregnancy. Journal of Obstetrics and Gynaecology of the British Empire 1971;78:781-5.
Foulkes 1982 {published data only}
  • Foulkes J, Goldie DJ. The use of ferritin to assess the need for iron supplements in pregnancy. Journal of Obstetrics and Gynaecology 1982;3:11-6.
Freire 1989 {published data only}
  • Freire WB. Hemoglobin as a predictor of response to iron therapy and its use in screening and prevalence estimates. American Journal of Clinical Nutrition 1989;50:1442-9.
Gomber 2002 {published data only}
  • Gomber S, Agarwal KN, Mahajan C, Agarwal N. Impact of daily versus weekly hematinic supplementation on anemia in pregnant women. Indian Pediatrics 2002;39(4):339-46.
Goonewardene 2001 {published data only}
  • Goonewardene M, Liyanage C, Fernando R. Intermittent oral iron supplementation during pregnancy. Ceylon Medical Journal 2001;46(4):132-5.
Gringras 1982 {published data only}
  • Gringras M. A comparison of two combined iron-folic acid preparations in the prevention of anaemia in pregnancy. Journal of International Medical Research 1982;10:268-70.
Groner 1986 {published data only}
  • Groner JA, Holtzman NA, Charney E, Mellits ED. A randomized trial of oral iron on tests of short-term memory and attention span in young pregnant women. Journal of Adolescent Health Care 1986;7:44-8.
Guldholt 1991 {published data only}
  • Guldholt IS, Trolle BG, Hvidman LE. Iron supplementation during pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1991;70:9-12.
Hampel 1974 {published data only}
  • Hampel K, Roetz R. Influence of a long-time substitution with a folate-iron combination in pregnancy on serum folate and serum iron and on hematological parameters. Geburtshilfe und Frauenheilkunde 1974;34:409-17.
Hawkins 1987 {published data only}
  • Hawkins DF. Relative efficacy of sustained release iron and iron with folic acid treatment in pregnancy. Personal communication 1987.
Hemminki 1989 {published data only (unpublished sought but not used)}
  • Hemminki E, Merilainen J. Long-term effects of iron prophylaxis during pregnancy. International Journal of Gynecology & Obstetrics 1994;46:3.
  • Hemminki E, Merilainen J. Long-term follow-up of mothers and their infants in a randomized trial on iron prophylaxis during pregnancy. American Journal of Obstetrics and Gynecology 1995;173:205-9.
  • Hemminki E, Rimpela U. A randomized comparison of routine vs selective iron supplementation during pregnancy. Journal of the American College of Nutrition 1991;10:3-10.
  • Hemminki E, Rimpela U. Iron supplementation, maternal packed cell volume, and fetal growth. Archives of Disease in Childhood 1991;66:422-5.
  • Hemminki E, Rimpela U, Yla-Outinen A. Iron prophylaxis during pregnancy and infections. International Journal of Vitamin and Nutrition Research 1991;61:370-1.
  • Hemminki E, Uski A, Koponen P, Rimpela U. Iron supplementation during pregnancy - experiences of a randomized trial relying on health service personnel. Controlled Clinical Trials 1989;10:290-8.
Hermsdorf 1986 {published data only}
  • Hermsdorf J, Ring D, Retzke U, Bruschke G. Oral iron prophylaxis during pregnancy. A longitudinal study about hematologic and clinical parameters in treated and non-treated pregnant women. Proceedings of 10th European Congress of Perinatal Medicine; 1986 August 12-16; Leipzig, Germany. 1986:84.
Horgan 1966 {published data only}
  • Horgan M, Woodliff M, Mangion J. A combined iron and folic-acid preparation in the prophylaxis of anaemia of pregnancy. Practitioner 1966;197:683-6.
Iyengar 1970 {published data only}
  • Iyengar L, Apte SV. Prophylaxis of anemia in pregnancy. American Journal of Clinical Nutrition 1970;23:725-30.
Kann 1988 {published data only}
  • Kann J, Lyon JA, Bon C. Availability of iron from four prenatal multivitamin/multimineral products. Clinical Therapeutics 1988;10:287-93.
Madan 1999 {published data only}
  • Madan N, Prasannaraj P, Rusia U, Sundaram KR, Nath LM, Sood SK. Monitoring oral iron therapy with protoporphyrin/heme ratios in pregnant women. Annals of Hematology 1999;78(6):279-83.
McKenna 2002 {published data only (unpublished sought but not used)}
  • McKenna D, Spence D, Dornan J. A randomised, double-blind, placebo-controlled trial investigating the place of spatone-iron plus as a prophylaxis against iron deficiency in pregnancy [abstract]. Journal of Obstetrics and Gynaecology 2002;22(2 Suppl):S45.
  • McKenna D, Spence D, Haggan SE, McCrum E, Dornan JC, Lappin TR. A randomized trial investigating an iron-rich natural mineral water as a prophlylaxis against iron deficiency in pregnancy. Clinical and Laboratory Haematology 2003;25:99-103.
Menon 1962 {published data only}
  • Menon MKK, Rajan L. Prophylaxis of anaemia in pregnancy. Journal of Obstetrics and Gynaecology of the British Commonwealth 1962;12:382-9.
Morgan 1961 {published data only}
  • Morgan EH. Plasma-iron and haemoglobin levels in pregnancy. Lancet 1961;1:9-12.
  • Morgan EH. Plasma-iron and haemoglobin levels in pregnancy. Personal communication January 19 1987.
Morrison 1977 {published data only}
  • Morrison J, Bell J, Chang AMZ, Larkin PK. A comparative trial of haematinic supplements in pregnancy. Medical Journal of Australia 1977;1:482-4.
Mumtaz 2000 {published data only}
  • Mumtaz Z, Shahab S, Butt N, Rab MA, DeMuynck A. Daily iron supplementation is more effective than twice weekly iron supplementation in pregnant women in Pakistan in a randomized double-blind clinical trial. Journal of Nutrition 2000;130(11):2697-702.
Nogueira 2002 {published data only}
  • Nogueira NDN, Macedo ADS, Parente JV, Cozzolino SMF. Nutritional profile of newborns of adolescent mothers supplemented with iron, in different concentrations, zinc and pholic acid. Revista de Nutricao 2002;15:193-200.
  • Nogueira Ndo N, Parente JV, Cozzolino SM. Changes in plasma zinc and folic acid concentrations in pregnant adolescents submitted to different supplementation regimens. Cadernos de Saude Publica 2003;19(1):155-60.
Pena-Rosas 2003 {published data only}
  • Pena-Rosas JP, Nesheim M, Garcia-Casal MN, Crompton DWT, Sanjur D, Viteri FE, et al. Intermittent iron supplementation regimens are able to maintain safe maternal hemoglobin concentrations during pregnancy in venezuela. Journal of Nutrition 2004;134(5):1099-104.
Quintero 2004 {unpublished data only}
  • Quintero Gutierrez AG, Gonzalez Rosendo G, Cedillo Espana F, Rivera-Dommarco J. Single weekly iron supplementation in pregnant women. Personal communication February 17 2004.
Ramakrishnan 2003 {published data only}
  • Ramakrishnan U, Gonzalez-Cossio T, Neufeld LM, Rivera J, Martorell R. Multiple micronutrient supplementation during pregnancy does not lead to greater infant birth size than does iron-only supplementation: a randomized controlled trial in a semirural community in mexico. American Journal of Clinical Nutrition 2003;77(3):720-5.
Rayado 1997 {published data only}
  • Rayado B, Carrillo JA, Fernandez-Esteban JA, Gomez-Cedillo A, Martin M, Coronel P. A comparative study of 2 ferrous proteins in the prevention of iron deficiency anaemia during pregnancy. Clinica e Investigacion En Ginecologia y Obstetricia 1997;24:46-50.
Reddaiah 1989 {published data only}
  • Reddaiah VP, Raj PP, Ramachandran K, Nath LM, Sood SK, Madan N, et al. Supplementary iron dose in pregnancy anemia prophylaxis. Indian Journal of Pediatrics 1989;56:109-14.
Roztocil 1994 {published data only}
  • Roztocil A, Charvatova M, Harastova L, Zahradkova J, Studenik P, Sochorova V, et al. Anti-anemia therapy with prophylactic administration of fe2+ in normal pregnancy and its effect on prepartum hematologic parameters in the mother and neonate. Ceska Gynekologie 1994;59(3):130-3.
Rybo 1971 {published data only}
  • Rybo G, Solvell L. Side-effect studies on a new sustained release iron preparation. Scandinavian Journal of Hematology 1971;8(4):257-64.
Sandstad 2003 {published data only}
  • Sandstad B, Borch-Iohnson B, Andersen GM, Dahl-Jorgensen B, Froysa I, Leslie C, et al. Selective iron supplementation based on serum ferritin values early in pregnancy: are the Norwegian recommendations satisfactory?. Acta Obstetricia et Gynecologica Scandinavica 2003;82:537-42.
Shatrugna 1999 {published data only}
  • Shatrugna V, Raman L, Kailash U, Balakrishna N, Rao KV. Effect of dose and formulation on iron tolerance in pregnancy. National Medical Journal of India 1999;12(1):18-20.
Siega-Riz 2004 {published data only}
  • Bodnar LM, Davidian M, Siega-Riz AM, Tsiatis AA. Marginal structural models for analyzing causal effects of time-dependent treatments: an application in perinatal epidemiology. American Journal of Epidemiology 2004;159(10):926-34.
  • Siega-Riz A, Hartzema A, Turnbull C, Thorp JJ, McDonald T. A trial of selective versus routine iron supplementation to prevent third trimester anemia during pregnancy [abstract]. American Journal of Obstetrics and Gynecology 2001; Vol. 185, issue 6 Suppl:S119.
Simmons 1993 {published data only}
  • Simmons WK, Cook JD, Bingham KC, Thomas M, Jackson J, Jackson M, et al. Evaluation of a gastric delivery system for iron supplementation in pregnancy. American Journal of Clinical Nutrition 1993;58:622-6.
Sjostedt 1977 {published data only}
  • Sjostedt JE, Manner P, Nummi S, Ekenved G. Oral iron prophylaxis during pregnancy - a comparative study on different dosage regimens. Acta Obstetricia et Gynecologica Scandinavica 1977;66:3-9.
Sood 1979 {published data only}
  • Sood SK, Ramachandran K, Rani K, Ramalingaswami V, Mathan VI, Ponniah J, et al. WHO sponsored collaborative studies on nutritional anaemia in India. The effect of parenteral iron administration in the control of anaemia of pregnancy. British Journal of Nutrition 1979;42:399-406.
Steer 1992 {published data only}
  • Steer PJ. Trial to assess the effects of iron and folate supplementation on pregnancy outcome [trial abandoned]. Personal communication 1992.
Stone 1975 {published data only}
  • Stone M, Elder MG. The relative merits of a slow-release and a standard iron preparation during pregnancy. Current Medical Research and Opinion 1975;3:469-72.
Suharno 1993 {published data only}
  • Suharno D, West CE, Karyadi D, Hautvast JGA. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet 1993;342:1325-8.
Tampakoudis 1996 {published data only}
  • Tampakoudis P, Tantanassis T, Tsatalas K, Lazaridis E, Tsalikis T, Venetis C, et al. A randomized trial on the effect of oral supplementation with iron protein succinylate in singleton pregnancies. The role of maternal erythropoietin as a marker. Prenatal and Neonatal Medicine 1996;1 Suppl 1:181.
Tan 1995 {published data only}
  • Tan CH, Ng KB. The effect of oral iron on the haemoglobin concentration during the second half of pregnancy. 27th British Congress of Obstetrics and Gynaecology 1995 July 4-7; Dublin, Ireland. Royal College of Obstetricians & Gynaecologists, 1995:101.
Thane-Toe 1982 {published data only}
  • Thane-Toe, Thein-Than. The effects of oral iron supplementation on ferritin levels in pregnant Burmese women. American Journal of Clinical Nutrition 1982;35:95-9.
Tholin 1995 {published data only}
  • Tholin K, Sandstrom B, Palm R, Hallmans G. Changes in blood manganese levels during pregnancy in iron supplemented and non supplemented women. Journal of Trace Elements in Medicine and Biology 1995;9(1):13-7.
Thomsen 1993 {published data only}
  • Thomsen JK, Prien-Larsen JC, Devantier A, Fogh-Andersen N. Low dose iron supplementation does not cover the need for iron during pregnancy. Acta Obstetricia et Gynecologica Scandinavica 1993;72:93-8.
Vogel 1963 {published data only}
  • Vogel L, Steingold L, Suchet J. Iron therapy in the treatment of anaemia in pregnancy. Lancet 1963;1:1296-9.
Willoughby 1966 {published data only}
  • Willoughby M, Jewell F. Investigation of folic acid requirements in pregnancy. BMJ 1966;2:1568-71.
Willoughby 1968 {published data only}
  • Willoughby MLN, Jewell FG. Folate status throughout pregnancy and in postpartum period. BMJ 1968;4:356-60.
Wu 1998 {published data only}
  • Wu Y, Weng L, Wu L. Clinical experience with iron supplementation in pregnancy. Chung-Hua Fu Chan Ko Tsa Chih [Chinese Journal of Obstetrics & Gynecology] 1998;33(4):206-8.
Zittoun 1983 {published data only}
  • Zittoun J, Blot I, Hill C, Zittoun R, Papiernik E, Tchernia G. Iron supplements vs placebo during pregnancy: its effects on iron and folate status on mothers and newborns. Annals of Nutrition and Metabolism 1983;27:320-7.

References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Angeles-Agdeppa 2003 {published data only (unpublished sought but not used)}
  • Angeles-Agdeppa I. The effects of a community-based weekly iron-folate supplementation on hemoglobin and iron status of pregnant and non-pregnant women in Philippines. Meeting on weekly iron/folic acid supplementation for preventing anaemia in women of reproductive age in the Western Pacific Region Report. Manila, Philippines, February 2004.
Berger 2003 {published data only (unpublished sought but not used)}
  • Berger J. Effectiveness of weekly iron/folate supplementation on anaemia and iron status in women of reproductive age in rural Viet Nam. Meeting on weekly iron/folic acid supplementation for preventing anaemia in women of reproductive age in the Western Pacific Region Report. Manila, Philippines, February 2004.
Coelho 2000 {published data only}
  • Coelho K, Ramdas S, Pillai S. A comparative study of changes in haemoglobin with high and low dose iron preparations in pregnant women. Journal of Obstetrics and Gynecology of India 2000;50(2):37-9.
Dijkhuizen 2004 {published data only}
  • Dijkhuizen MA, Wieringa FT, West CE, Muhilal. Zinc plus beta-carotene supplementation of pregnant women is superior to beta-carotene supplementation alone in improving vitamin a status in both mothers and infants. American Journal of Clinical Nutrition 2004;80(5):1299-307.
Hosokawa 1989 {published data only}
  • Hosokawa K. Studies on anemia in pregnant women: therapeutic efficacy of iron monotherapy vs. combination therapy with iron and vitamin C. Rinsho to Kenkyu (The Japanese Journal of Clinical and Experimental Medicine) 1989;66(10):3329-35.
Kumar 2005 {published data only}
  • Kumar A, Jain S, Singh NP, Singh T. Oral versus high dose parenteral iron supplementation in pregnancy. International Journal of Gynecology & Obstetrics 2005;89:7-13.
Meier 2003 {published data only}
  • Meier PR, Nickerson HJ, Olson KA, Berg RL, Meyer JA. Prevention of iron deficiency anemia in adolescent and adult pregnancies. Clinical Medicine and Research 2003;1(1):29-36.
Milman 2005 {published data only}
  • Milman N, Bergholt T, Eriksen L, Byg KE, Graudal N, Pedersen P, et al. Iron prophylaxis during pregnancy - how much iron is needed? A randomized dose- response study of 20-80 mg ferrous iron daily in pregnant women. Acta Obstetricia et Gynecologica Scandinavica 2005;84:238-47.
Mukhopadhyay 2004 {published data only}
  • Mukhopadhyay A, Bhatla N, Kriplani A, Agarwal N, Saxena R. Erythrocyte indices in pregnancy: effect of intermittent iron supplementatiom. National Medical Journal of India 2004;17(3):135-7.
  • Mukhopadhyay A, Bhatla N, Kriplani A, Pandey RM, Saxena R. Daily versus intermittent iron supplementation in pregnant women: hematological and pregnancy outcome. Journal of Obstetrics and Gynaecology Research 2004;30(6):409-17. [MEDLINE: 15566454]
Osrin 2005 {published data only}
  • Osrin D, Vaidya A, Shrestha Y, Baniya RB, Manandhar DS, Adhikari RK, et al. Effects of antenatal multiple micronutrient supplementation on birthweight and gestational duration in Nepal: double-blind, randomised controlled trial. Lancet 2005;365:955-62.
Payne 1968 {published data only}
  • Payne RW. Prophylaxis of anaemia in pregnancy. Journal of the Royal College of General Practitioners 1968;16:353-8.
Zutshi 2004 {published data only}
  • Zutshi V, Batra S, Ahmad SS, Khera N, Chauhan G, Gandhi G, et al. Injectable iron supplementation instead of oral therapy for antenatal care. Journal of Obstetrics and Gynecology of India 2004;54(1):37-8.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
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Beard 2000
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Beaton 1999
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Bothwell 2000
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Godfrey 1991
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Koller 1979
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LeVeen 1980
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Lumley 2003
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Lund 1961
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Mahomed 1989
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Mahomed 1998
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Mahomed 2000
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Mercer 2001
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Mora 2002
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Murphy 1986
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Oppenheimer 2001
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Poulsen 1990
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Prema 1982
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RevMan 2003
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Scanlon 2000
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Scholl 1992
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Scholl 1997
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Scholl 2005
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References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
CDSR 1998
  • Mahomed K. Iron and folate supplementation in pregnancy. The Cochrane Database of Systematic Reviews 1998, Issue 3. [Art. No.: CD001135. DOI: 10.1002/14651858.CD001135.pub2]
CDSR 2000
  • Mahomed K. Iron supplementation in pregnancy. The Cochrane Database of Systematic Reviews 2000, Issue 1. [Art. No.: CD000117. DOI: 10.1002/14651858.CD000117.pub2]