Effects of preventive oral supplementation with iron or iron with folic acid for women following childbirth

  • Protocol
  • Intervention


  • Hannah JT Neufeld,

    1. The World Health Organization, Department of Nutrition for Health and Development, Geneva, Switzerland
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  • Luz Maria De-Regil,

    Corresponding author
    1. World Health Organization, Evidence and Programme Guidance, Department of Nutrition for Health and Development, Geneva, Switzerland
    • Luz Maria De-Regil, Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, 20 Avenue Appia, Geneva, 1211, Switzerland. deregillu@who.int.

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  • Therese Dowswell,

    1. The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK
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  • Lisa M Rogers

    1. World Health Organization, Evidence and Programme Guidance, Department of Nutrition for Health and Development, Geneva, Switzerland
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This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To examine the effects of oral iron supplementation alone or in combination with folic acid provided to women during the first six weeks postpartum on maternal and infant health outcomes.


Description of the condition

Anaemia is a condition in which the number of red blood cells and consequently their oxygen-carrying capacity is insufficient to meet physiologic needs, which vary by age, gender, altitude, smoking, and different stages of pregnancy (WHO 2001). Iron deficiency often precedes anaemia and is one of the most common forms of nutritional deficiencies, particularly among vulnerable groups such as women, children and low-income populations (WHO 2002a). Iron reserves in the body can deteriorate as a result of low dietary intake or poor absorption of iron, which is often associated with cereal based diets (WHO 2001). In addition to iron deficiency, other factors may cause anaemia including blood loss, parasitic infections and deficiencies of vitamin A, folate, vitamin B12, and riboflavin (WHO 2001). Haemoglobin concentrations are used to diagnose anaemia, while serum ferritin, an iron storage protein, and serum transferrin, an iron transport protein, are commonly used as indicators of iron status in populations (WHO 2011b; WHO 2011c).  

The postpartum period, sometimes referred as to puerperium, begins just after childbirth and includes the subsequent six weeks (WHO 2010). In normal conditions, maternal iron requirements commonly decline since this nutrient is no longer needed to support fetal and tissue growth and iron losses are reduced by the cessation of menstruation, particularly during prolonged lactation. In addition, only relatively small and decreasing amounts of iron are excreted through breast milk (Shashiraj 2006), which is considered a poor source of iron and cannot be altered by maternal supplementation (WHO 2002b).

Anaemia is one of the most common conditions in women of reproductive age and anaemia during pregnancy has been found to be one of the strongest predictors of postpartum anaemia as iron stores generally tend to remain low several months after delivery, especially if there is augmented blood loss during the delivery and no additional iron intake (Bodnar 2002; Scholl 2000). There are no global figures on the prevalence of anaemia following childbirth, but it is recognised as a common problem throughout the world (Milman 2011; Milman 2012). Studies conducted in the United States of America and in some countries in Europe have reported a prevalence of postpartum anaemia ranging from 10% to 30% (Barroso 2011; Bergmann 2010; Bodnar 2002; Simoes 2004). The prevalence may be higher in low- to middle-income countries, as suggested by data from different age groups (WHO/CDC 2008). For example, the global prevalence of anaemia in pregnant women is 42%, with the highest prevalence found in the WHO Africa region and the highest number of affected pregnant women in WHO South-East Asia region (WHO/CDC 2008).

It is possible that women suffer from multiple concomitant vitamin and mineral deficiencies, although there is not much information on their metabolism during the postpartum period. For calcium, it has been reported that parity and lactation do not affect the long-term risks of low bone density, osteoporosis, or fracture (Kovacs 2011); however, for folate, it has been reported that serum folate concentrations continue to decrease several weeks after delivery, especially when combined with inadequate dietary intakes, and under certain conditions, women may go on to develop megaloblastic anaemia (Haider 2009; Smits 2001).

The consequences of iron deficiency and anaemia during the postpartum period can be serious and have long-term health implications for the mother and her child. Mothers with depleted iron reserves at the time of delivery and following child birth may experience fatigue, altered cognition and depressive symptoms (Breymann 2010). These changes in the mother's emotional and cognitive functioning may in turn affect the interactions with her baby, and have a potentially negative impact on infant behaviour and development (Murray-Kolb 2009). If iron stores are not restored soon after delivery, the negative consequences of postpartum iron deficiency and anaemia may permeate other stages of the reproductive cycle, particularly among those women with short inter-pregnancy intervals (less than 18 months), leading to continued adverse maternal and infant outcomes (Conde-Agudelo 2000; Khoshnood 1998; King 2003; Zhu 1999).

Description of the intervention

Oral iron supplementation refers to the delivery of iron compounds directly to the oral cavity, either as a tablet (regular or dispersible), capsule or liquid. This intervention has been proposed as an efficient and effective approach in public health programmes aimed at improving pregnancy outcomes and enhancing maternal and infant health in different age groups (WHO 2001).

A dosage of 60 mg of elemental iron plus 400 µg (0.4 mg) of folic acid per day is recommended universally for pregnant women, to be continued for three months postpartum, particularly in regions where the prevalence of anaemia is above 40% (WHO 2001). Other international organisations recommend that women who have been identified as having anaemia throughout the third trimester of pregnancy, or who suffer excessive blood loss at delivery or multiple births, should receive supplemental iron up to six weeks postpartum with an oral dose of 60 to 120 mg of elemental iron daily until the anaemia is resolved (CDC 1998; IOM 1990).

How the intervention might work

Iron is absorbed by intestinal cell luminal and basal transporters. It is then bound to proteins that transport it to the bone marrow, muscle and other tissue, where it is taken up by specific receptors and utilised for biologic functions or stored (Andrews 1999). Daily iron supplementation has proven to be effective for increasing haemoglobin concentrations among pregnant and non pregnant women (Fernandez 2011; Pena-Rosas 2009; Yakoob 2011). Some trials suggest that this supplementation regimen could also be effective during the postpartum period although the literature on the contribution of other vitamins and minerals to the women's haematological status and health during the postpartum period is still limited (Correia-Santos 2011; Mitra 2011).

The oral consumption of iron tablets may be associated with unpleasant and sometimes distressing side-effects such as diarrhoea, constipation, nausea and vomiting (WHO 2001). These symptoms increase in severity according to the amount of elemental iron released and whether or not the supplement is taken on an empty stomach or with a meal. The tolerable upper limits for the intake of iron during pregnancy and lactation has been set in 45 mg/day of elemental iron and is based on the gastrointestinal side-effects associated with supplementation (IOM 2001). Alternative intermittent supplementation regimens such as weekly iron-folic acid supplementation have been recommended to prevent anaemia in menstruating women (WHO 2011a). Although their efficacy has not been proven during the postpartum period, they might represent a good alternative to increase iron stores and minimise the negative effects associated with daily supplementation.

In addition to the possible distressing side-effects, daily iron supplementation may be associated with a reduction of zinc and copper absorption, increased oxidative stress and a higher risk of infections. It is plausible that when either zinc or copper are consumed together with iron, their absorption may be impaired due to competition for the same intestinal absorption pathway, but the results are inconsistent (Casanueva 2003; Chung 2002; Gropper 2002; O'Brien 2000; Solomons 1986). It has also been suggested that the iron-rich environment resulting from continued high-dose iron supplementation may cause cell damage (Casanueva 2003; Viteri 2005); however, the clinical significance of this still remains unclear. Finally, it has been proposed that additional iron may exacerbate infections, particularly malaria in areas where it is endemic, as more iron may be available for the parasite's growth, although the mechanisms whereby this may occur are not fully understood (Ekvall 2000; NIH 2011; Oppenheimer 2001). Among pregnant women, some trials have reported an increased risk of infection following iron supplementation but a systematic assessment of the evidence has failed to demonstrate this association (Pena-Rosas 2009).

From the implementation perspective, the period immediately following childbirth may represent a unique opportunity to reach women as they often remain in close contact with healthcare providers. This continuity of care would permit ease of coverage, accessibility, as well as consistency in dosing schedules.

Why it is important to do this review

Iron deficiency and anaemia are important public health problems worldwide, particularly among women of reproductive age. The period following childbirth should not be considered a time of low risk for iron deficiency and anaemia, especially for women living in resource-poor environments who tend to suffer higher rates of morbidity and mortality associated with anaemia (Bodnar 2005; WHO/CDC 2008; WHO 2002a).

Iron supplementation alone or in combination with other nutrients has proven to be efficacious during pregnancy and among other age groups, but as yet there has been no systematic assessment of the benefits or harms of this public health intervention following childbirth, to inform policy making and health practitioners. The potential health gains from improved iron status support the systematic investigation and assessment of iron supplementation during what has previously been a neglected period of the lifecycle.

This review contributes to the body of evidence formed by various Cochrane reviews examining iron and folic acid supplementation as a public health intervention in pregnant and non pregnant women (De-Regil 2010; Fernandez 2011; Haider 2006; Haider 2009; Pena-Rosas 2009; Picciano 2009). It complements the findings of a previously published review that looked at the oral, intravenous or subcutaneous administration of iron, folic acid, erythropoietin or blood transfusion for therapeutic purposes among women with postpartum anaemia (Dodd 2004).


To examine the effects of oral iron supplementation alone or in combination with folic acid provided to women during the first six weeks postpartum on maternal and infant health outcomes.


Criteria for considering studies for this review

Types of studies

Randomised and quasi-randomised studies with randomisation at either individual or cluster level. Studies using a cross-over design will be excluded.

Types of participants

Postpartum adolescent or adult women randomised to receive iron supplements during the first six weeks after giving birth.

We will not include trials focusing specifically on women diagnosed with a particular disease (e.g. women with HIV, tuberculosis) nor those studies in which the intervention was given exclusively during pregnancy, even if such trials report outcomes relating to the postnatal period.

Types of interventions

We will include interventions involving oral supplements of iron alone or combined with other micronutrients provided on a daily or intermittent basis. Therefore, we will examine the following comparisons.

  1. Any oral supplements containing iron versus no iron.

  2. Any oral supplements containing iron + folic acid versus no iron + folic acid.

  3. Oral supplements with iron alone versus no treatment/placebo.

  4. Oral supplements with iron + folic acid versus no treatment/placebo.

  5. Oral supplements with iron + folic acid versus oral supplements with folic acid alone (without iron).

  6. Oral supplements with iron + folic acid + other vitamins and minerals versus oral supplements with folic acid + other vitamins and minerals (without iron).

  7. Oral supplements with iron + folic acid + other vitamins and minerals versus oral supplements with other vitamins and minerals (without iron + folic acid).

We will include studies that examined interventions where iron supplementation was combined with co-interventions such as deworming, education or other approaches only if the co-interventions were the same in both the intervention and comparison groups. 

We will exclude studies examining tube feeding, parenteral nutrition or supplementary food-based interventions such as mass fortification of staple or complementary foods, home fortification with micronutrient powders, lipid-based supplements or Foodlets tablets, or biofortification.

Types of outcome measures

Primary outcomes
Maternal outcomes
  1. Anaemia (haemoglobin (Hb) below a cut-off defined by trialists, taking into account age, altitude and smoking).*

  2. Haemoglobin (in g/L).*

  3. Iron deficiency (as measured by trialists by using indicators of iron status, such as ferritin or transferrin).*

  4. Ferritin (in μg/L).*

  5. Side-effects during the intervention period (constipation, teeth staining, gastrointestinal discomfort).*

  6. Infection (any, as defined by trialists).

Infant outcomes
  1. Infant mortality (deaths occurring during the intervention period).

  2. Mental development and motor skill development (as assessed by trialists, including Bayley Mental Development Index (MDI), Bayley Psychomotor Development Index (PDI), Stanford-Binet Test, DENVER II Developmental Screening Test).

  3. Growth (height-for-age Z-scores and weight-for-age Z-scores).

* Outcomes that will be included in the 'Summary of findings' tables.

Secondary outcomes
  1. Iron-deficiency anaemia (defined by the presence of anaemia plus iron deficiency, diagnosed with an indicator of iron status selected by trialists).

  2. Work/physical capacity (as defined by trialists).

  3. Depression (as defined by trialists).

  4. Severe anaemia (Hb lower than 80 g/L).

  5. All-cause mortality (deaths during the trial).

For populations in malaria-endemic areas, we will report two additional outcomes:

  • malaria incidence;

  • malaria severity.

With the exception of side effects and mortality, outcome measurements will be considered at the end of the intervention or at the closest measurement to the end of the intervention.

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register. The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. handsearches of 30 journals and the proceedings of major conferences;

  4. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts;

  5. International Clinical Trials Registry Platform.

Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords. 

We will search the International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned trials and the Networked Digital Library of Theses and Dissertations (NDLTD) for grey literature.

We will not apply any language or date restrictions.

Searching other resources

For assistance in identifying ongoing or unpublished studies, we will contact authors and known experts to identify any additional or unpublished data. We will also contact the Departments of Nutrition for Health and Development and regional offices of the World Health Organization (WHO), and the nutrition section of the Centers for Disease Control and Prevention (CDC), The United States National Institutes of Health (NIH); the United Nations Children's Fund (UNICEF), the World Food Programme (WFP), the Micronutrient Initiative (MI) and Sight and Life Foundation.

Data collection and analysis

Selection of studies

Review authors will assess the potential eligibility of the identified references by conducting relevance screening. One review author will assess all references beginning with titles and abstracts while the other three will assess one third of the articles each. All four review authors will then independently determine inclusion of the screened references using the inclusion criteria previously discussed using full text of reports and published articles. We will resolve disagreements through discussion to reach consensus and will document reasons for excluding trials during this process.

If any additional information is required to determine eligibility, for example, if trials are published only as abstracts, we will attempt to contact the primary author of the publication to obtain relevant information. Studies will await assessment, however, if there is insufficient information available for us to accurately assess risk of bias.

Articles in English, French and Spanish will be reviewed by the review team, however, if a relevant study is published in another language, then, where possible, we will commission a full translation of the paper.

Data extraction and management

For eligible studies, two review authors will independently extract data using a form designed for this review. LM De Regil (LMD) will extract data from all the studies and the remaining authors will each extract a third. LMD will enter data into the Review Manager software (RevMan 2011) and the same review author who extracted one-third of the data in duplicate will carry out checks for accuracy. We will resolve any disagreements through discussion or if necessary, consult with an external party.

We will complete the data collection form electronically and record information as follows.

(1) Trial methods
  • Study design

  • Unit and method of allocation

  • Masking of participants and outcome assessors

  • Exclusion of participants after randomisation and proportion of losses at follow-up

(2) Participants
  • Location of the study

  • Sample size

  • Age

  • Socioeconomic status (as defined by trialists and where such information was available)

  • Baseline status of anaemia

  • Inclusion and exclusion criteria as described in the Criteria for considering studies for this review

(3) Intervention
  • Iron and folic acid dosage

  • Type of iron compound

  • Supplementation regimen

  • Duration of the intervention

  • Co-intervention

(4) Comparison group
  • Type of comparison (no intervention, placebo or same supplement without iron or iron + folic acid)

(5) Outcomes

We will collect both prespecified and non-prespecified outcome data, although we will not use the latter to underpin the conclusions of the review. We will make it clear in the results section if we report findings for any non-prespecified outcomes.

If there is insufficient information to complete the extraction form, we will attempt to contact the authors of the original research to provide further details.

Assessment of risk of bias in included studies

Using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and with reference to points (1) to (6) below, two of the review authors will independently evaluate risk of bias or study quality, with any disagreements resolved by discussion or in consultation with a third assessor. We will discuss any discrepancies in quality ratings to come to a shared agreement.

We will report this assessment in the 'Description of studies' and 'Risk of bias' tables. We will explicitly mention when authors provide us with additional information on their trials.

(1) Sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence. We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear.   

 (2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal the allocation sequence and assess whether the intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes);

  • unclear.   

(3) Blinding (checking for possible performance and detection bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. For interventions involving the provision of iron supplements it may be possible to blind women, clinical staff and outcome assessors to group allocation by providing placebo preparations.

We will assess blinding separately for different classes of outcomes and will note where there is an attempt at partial blinding.

We will assess the risk of performance bias associated with blinding as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

We will assess the risk of detection bias associated with blinding as:

  • low, high or unclear risk of bias for outcome assessors.

Whilst assessed separately, we will combine the results into a single evaluation of risk of bias associated with blinding (Higgins 2011).

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We will assess losses to follow up and post-randomisation exclusions systematically for each trial.

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions are reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. We will assess methods as:

  • low risk of bias (less than 20% of cases lost to follow-up and balanced in numbers across intervention groups);

  • high risk of bias (20% or more cases lost to follow-up or outcome data imbalanced in numbers across intervention groups);

  • unclear.

(5) Selective reporting bias

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review were reported);

  • high risk of bias (where not all the study’s prespecified outcomes were reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported);

  • unclear.

(6) Other sources of bias

We will assess whether each study was free of other problems that could put it at risk of bias. We will note for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study is free of other problems that could put it at risk of bias:

  • low risk of further bias;

  • high risk of further bias;

  • unclear whether there is a risk of further bias.

(7) Overall risk of bias

We will summarise the risk of bias at two levels: within studies (across domains) and across studies.

For the first, we will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking Sensitivity analysis

For the assessment across studies, the main findings of the review will be set out in 'Summary of findings' (SoF) tables prepared using GRADE profiler software (GRADEpro 2008). The primary outcomes for each comparison will be listed with estimates of relative effects along with the number of participants and studies contributing data for those outcomes. For each individual outcome, the quality of the evidence will be assessed by two review authors using the GRADE approach (Balshem 2010; Higgins 2011), which involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. The results will be expressed as one of four levels of quality (high, moderate, low or very low). This assessment will be restricted to the randomised clinical trials included in this review.

Measures of treatment effect

Dichotomous data

For dichotomous outcomes, we will present the results as average risk ratios, using 95% confidence intervals.

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way at the end of the intervention. If trials do not provide this information but report the mean change, we will include these data as suggested by Higgins 2011. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster-randomised trials

Cluster-randomised trials will be included in the analysis, along with individually-randomised trials. To take account of design effect, we will adjust their sample sizes using the methods described in the Handbook (Higgins 2011). If possible, we will use an estimate of the intracluster correlation coefficient (ICC) derived either from the trial, or another source. If ICCs from other sources are used, we will report this and will conduct sensitivity analyses to examine the impact of variation in the ICC. If both cluster- and individually-randomised trials are identified, the relevant information will be synthesised provided there is little heterogeneity between study designs, and we consider interaction between the effect of intervention and choice of randomisation unit is unlikely (Higgins 2011).

Cross-over trials

We will not include cross-over trials.

Studies with more than two treatment groups

For studies with more than two intervention groups (multi-arm studies), we will include the directly relevant arms only. If we identify studies with various relevant arms, we will combine the groups into a single pair-wise comparison (Higgins 2011) and include the disaggregated data in the corresponding subgroup category. If the control group is shared by two or more study arms, we will divide the control group over the number of relevant subgroup categories to avoid double counting the participants (for dichotomous data, we will divide the events and the total population while for continuous data we will assume the same mean and standard deviation but will divide the total population). The details will be described in the 'Characteristics of included studies' tables.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess methodological heterogeneity by examining the methodological characteristics and risk of bias of the studies, and clinical heterogeneity by examining the similarity between the types of participants, the interventions and the outcomes.

For statistical heterogeneity, we will examine the forest plots from meta-analyses to look for heterogeneity among studies, We will also evaluate the T², I² and Chi² statistics and regard heterogeneity as substantial if I² is greater than 30% and either T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. If we identify substantial unexplained heterogeneity, we will explore this by carrying out Sensitivity analysis (e.g. by temporarily removing studies at high risk of bias to examine the impact on results).

Assessment of reporting biases

Where we suspect reporting bias (see 'Selective reporting bias' above), we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for asymmetry. For continuous outcomes, we will use the test proposed by Egger 1997. and for dichotomous outcomes we will use the test proposed by Harbord 2006. If asymmetry is detected in any of these tests or is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out meta-analysis using the generic inverse-variance method in RevMan 2011. We have carried out other reviews on this topic and we anticipate some heterogeneity because of some differences in the interventions and populations examined in different trials. Therefore, we will use random-effects meta-analysis for combining data to produce an overall summary. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If we do not think that an average treatment effect is clinically meaningful, we will not combine trials.

Subgroup analysis and investigation of heterogeneity

When data are available or appropriate, we will carry out the following subgroup analyses on primary outcomes:

  1. by supplementation scheme: daily versus intermittent (up to three times a week on non consecutive days);

  2. by duration of supplementation: three months or less versus more than three months;

  3. by prenatal supplementation with iron alone or in combination with other micronutrients: yes versus no or unknown;

  4. by breastfeeding practice: exclusive versus mixed versus no breastfeeding or unknown;

  5. by malaria status of the study site at the time of the trial: endemic versus not endemic/not reported.

We will not conduct a subgroup analyses for those outcomes with three or fewer trials. We will examine differences between subgroup categories by visual inspection of the subgroup categories’ confidence intervals; non-overlapping confidence intervals suggesting a statistically significant difference in treatment effect between the subgroups. We will also formally investigate the differences between two or more subgroup categories (Borenstein 2008).

Sensitivity analysis

We will carry out sensitivity analysis to examine the effects of removing studies at high risk of bias (studies with poor or unclear sequence generation and allocation concealment and either high levels of attrition or inadequate blinding) from the analyses. If we identify and include any cluster trials, we will carry out sensitivity analysis using a range of ICC values. We will carry out sensitivity analysis for primary outcomes only.


We would like to thank the Cochrane Pregnancy and Childbirth group for their support during the development of this protocol. As part of the pre-publication editorial process, this protocol has been commented on by two peers (an editor and referee who is external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser. We are grateful for their feedback.

The World Health Organization (WHO) retains copyright and all other rights in the manuscript of this Protocol as submitted for publication, including any revisions or updates to the manuscript which WHO may make from time to time.


Appendix 1. Search terms used for additional author searching

We will search the WHO International Clinical Trials Registry Platform (ICTRP) for any ongoing or planned trials and the Networked Digital Library of Theses and Dissertations (NDLTD) for grey literature using the terms "iron and pregnancy", "iron and pregnant", "iron and postpartum", and "iron and puerperium", "iron and postnatal"

Contributions of authors

All four authors contributed to the development of this protocol.

Disclaimer: Hannah Neufeld, Luz Maria De-Regil and Lisa Rogers are currently staff members of the World Health Organization (WHO). The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy or views of WHO.

Declarations of interest

None known.

Sources of support

Internal sources

  • Evidence and Programme Guidance Unit, Department of Nutrition for Health and Development, World Health Organization, Switzerland.

  • The University of LIverpool, UK.

External sources

  • Government of Luxembourg, Luxembourg.

    WHO acknowledges the Government of Luxembourg for their financial support to the Micronutrients Unit to assist with conducting systematic reviews on micronutrient interventions.