Abstract
Rationale
Postpartum iron deficiency anaemia is caused by antenatal iron deficiency or excessive blood loss at delivery and might affect up to 50% of labouring women in low‐ and middle‐income countries. Effective and safe treatment during early motherhood is important for maternal well‐being and newborn care. Treatment options include oral iron supplementation, intravenous iron, erythropoietin, and red blood cell transfusion.
Objectives
To assess the benefits and harms of the available treatment modalities for women with postpartum iron deficiency anaemia. These include intravenous iron, oral iron supplementation, red blood cell transfusion, and erythropoietin.
Search methods
A Cochrane Information Specialist searched for all published, unpublished, and ongoing trials, without language or publication status restrictions. We searched databases including CENTRAL, MEDLINE, Embase, CINAHL, LILACS, WHO ICTRP, and ClinicalTrials.gov, together with reference checking, citation searching, and contact with study authors to identify eligible studies. We applied date limits to retrieve new records since the last search on 9 April 2015 until 11 April 2024.
Eligibility criteria
We included published, unpublished, and ongoing randomised controlled trials (RCTs) that compared treatments for postpartum iron deficiency anaemia with placebo, no treatment, or alternative treatments. Cluster‐randomised trials were eligible for inclusion. We included RCTs regardless of blinding. Participants were women with postpartum haemoglobin ≤ 12 g/dL, treated within six weeks after childbirth. We excluded non‐randomised, quasi‐randomised, and cross‐over trials.
Outcomes
The critical outcomes of this review were maternal mortality and fatigue. The important outcomes included persistent anaemia symptoms, persistent postpartum anaemia, psychological well‐being, infections, compliance with treatment, breastfeeding, length of hospital stay, serious adverse events, anaphylaxis or evidence of hypersensitivity, flushing/Fishbane reaction, injection discomfort/reaction, constipation, gastrointestinal pain, number of red blood cell transfusions, and haemoglobin levels.
Risk of bias
We assessed risk of bias in the included studies using the Cochrane RoB 1 tool.
Synthesis methods
Two review authors independently performed study screening, risk of bias assessment, and data extraction. We contacted trial authors for supplementary data when necessary. We screened all trials for trustworthiness and scientific integrity using the Cochrane Trustworthiness Screening Tool.
We conducted meta‐analyses using a fixed‐effect model whenever feasible to synthesise outcomes. In cases where data were not suitable for meta‐analysis, we provided a narrative summary of important findings. We evaluated the overall certainty of the evidence using GRADE.
Included studies
We included 33 RCTs with a total of 4558 postpartum women. Most trials were at high risk of bias for several risk of bias domains.
Synthesis of results
Most of the evidence was of low or very low certainty. Imprecision due to few events and risk of bias due to lack of blinding were the most important factors.
Intravenous iron versus oral iron supplementation
The evidence is very uncertain about the effect of intravenous iron on mortality (risk ratio (RR) 2.95, 95% confidence interval (CI) 0.12 to 71.96; P = 0.51; I² = not applicable; 3 RCTs; 1 event; 572 women; very low‐certainty evidence). One woman died of cardiomyopathy, and another developed arrhythmia, both in the groups treated with intravenous iron.
Intravenous iron probably results in a slight reduction in fatigue within 8 to 28 days (standardised mean difference −0.25, 95% CI −0.42 to −0.07; P = 0.006; I² = 47%; 2 RCTs; 515 women; moderate‐certainty evidence).
Breastfeeding was not reported.
Oral iron probably increases the risk of constipation compared to intravenous iron (RR 0.12, 95% CI 0.06 to 0.21; P < 0.001; I² = 0%; 10 RCTs; 1798 women; moderate‐certainty evidence).
The evidence is very uncertain about the effect of intravenous iron on anaphylaxis or hypersensitivity (RR 2.77, 95% CI 0.31 to 24.86; P = 0.36; I² = 0%; 12 RCTs; 2195 women; very low‐certainty evidence). Three women treated with intravenous iron experienced anaphylaxis or hypersensitivity.
The trials that reported on haemoglobin at 8 to 28 days were too heterogeneous to pool. However, 5 of 6 RCTs favoured intravenous iron, with mean changes in haemoglobin ranging from 0.73 to 2.10 g/dL (low‐certainty evidence).
Red blood cell transfusion versus intravenous iron
No women died in the only trial that reported on mortality (1 RCT; 7 women; very low‐certainty evidence).
The evidence is very uncertain about the effect of red blood cell transfusion on fatigue at 8 to 28 days (mean difference (MD) 1.20, 95% CI −2.41 to 4.81; P = 0.51; I² = not applicable; 1 RCT; 13 women; very low‐certainty evidence) and breastfeeding more than six weeks postpartum (RR 0.43, 95% CI 0.12 to 1.57; P = 0.20; I² = not applicable; 1 RCT; 13 women; very low‐certainty evidence).
Constipation and anaphylaxis were not reported.
Red blood cell transfusion may result in little to no difference in haemoglobin within 8 to 28 days (MD −1.00, 95% CI −2.02 to 0.02; P = 0.05; I² = not applicable; 1 RCT; 12 women; low‐certainty evidence).
Intravenous iron and oral iron supplementation versus oral iron supplementation
Mortality and breastfeeding were not reported.
One trial reported a greater improvement in fatigue in the intravenous and oral iron group, but the effect size could not be calculated (1 RCT; 128 women; very low‐certainty evidence).
Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone (RR 0.21, 95% CI 0.07 to 0.69; P = 0.01; I² = not applicable; 1 RCT; 128 women; low‐certainty evidence).
There were no anaphylaxis or hypersensitivity events in the trials (2 RCTs; 168 women; very low‐certainty evidence).
Intravenous iron and oral iron may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days (MD 0.00, 95% CI −0.48 to 0.48; P = 1.00; I² = not applicable; 1 RCT; 60 women; low‐certainty evidence).
Red blood cell transfusion versus no transfusion
Mortality, fatigue at day 8 to 28, constipation, anaphylaxis, and haemoglobin were not reported.
Red blood cell transfusion may result in little to no difference in breastfeeding more than six weeks postpartum (RR 0.91, 95% CI 0.78 to 1.07; P = 0.24; I² = not applicable; 1 RCT; 297 women; low‐certainty evidence).
Oral iron supplementation versus placebo or no treatment
Mortality, fatigue, breastfeeding, constipation, anaphylaxis, and haemoglobin were not reported.
Two trials reported on gastrointestinal symptoms, but did not report results by study arm.
Authors' conclusions
Intravenous iron probably reduces fatigue slightly in the early postpartum weeks (8 to 28 days) compared to oral iron tablets, but probably results in little to no difference after four weeks. It is very uncertain if intravenous iron has an effect on mortality and anaphylaxis/hypersensitivity. Breastfeeding was not reported. Intravenous iron may increase haemoglobin slightly more than iron tablets, but the data were too heterogeneous to pool. However, changes in haemoglobin levels are a surrogate outcome, and treatment decisions should preferentially be based on patient‐relevant outcomes. Iron tablets probably result in a large increase in constipation compared to intravenous iron.
The effect of red blood cell transfusion compared to intravenous iron on mortality, fatigue, and breastfeeding is very uncertain. No studies reported on constipation or anaphylaxis/hypersensitivity. Red blood cell transfusion may result in little to no difference in haemoglobin at 8 to 28 days.
The effect of intravenous iron and oral iron supplementation on mortality, fatigue, breastfeeding, and anaphylaxis/hypersensitivity is very uncertain or unreported. Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone, and in little to no difference in haemoglobin.
The effect of red blood cell transfusion compared to non‐transfusion on mortality, fatigue, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported. Red blood cell transfusion may result in little to no difference in breastfeeding.
The effect of oral iron supplementation on mortality, fatigue, breastfeeding, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported.
Funding
This Cochrane review had no dedicated funding.
Registration
Protocol and previous versions are available:
Protocol (2013) [DOI: 10.1002/14651858.CD010861]
Original review (2004) [DOI: 10.1002/14651858.CD004222.pub2]
Review update (2015) [DOI: 10.1002/14651858.CD010861.pub2]
Plain language summary
What are the effects of treatment for women with iron deficiency anaemia after childbirth?
Key messages
Intravenous (given through a vein) iron probably reduces tiredness slightly at 8 to 28 days compared to oral (by mouth) iron supplements, but we are uncertain if intravenous iron and oral iron supplements compared to oral iron supplements alone affects tiredness at 8 to 28 days.
We are very uncertain about the effect of red blood cell transfusion compared to intravenous iron on tiredness at 8 to 28 days, and there was no information on red blood cell transfusion compared to no transfusion on tiredness at 8 to 28 days.
Death of the mother was either not reported, or the evidence was very uncertain for all comparisons. For oral iron compared to placebo (dummy treatment) or no treatment, there was no information on tiredness at 8 to 28 days.
What is iron deficiency anaemia?
Anaemia is a condition where the blood contains less than normal haemoglobin (low blood count), as shown in blood tests. Haemoglobin is the molecule within red blood cells that carries oxygen from the lungs to the tissues. Haemoglobin is a protein that consists of peptides and iron. Insufficient iron intake, problems with absorption of iron in the gut, or iron loss (bleeding) can cause iron deficiency anaemia. Symptoms of anaemia include tiredness, shortness of breath, dizziness, and difficulty getting breastfeeding started. Women may bleed severely at childbirth, and many pregnant women already have low iron stores or anaemia, or both, which can worsen as a result of bleeding. Severe anaemia has been linked to death of the mother after childbirth. Iron deficiency anaemia after childbirth is more likely to occur in low‐income countries.
How is postpartum iron deficiency anaemia treated?
Treatment for iron deficiency anaemia includes oral iron supplements or intravenous iron. Studies have found a risk of serious allergic reactions with intravenous iron. Another option is to restore red blood cells through transfusion with blood from a blood donor.
What did we want to find out?
We wanted to know if one treatment was better than another in relieving anaemia symptoms, and whether the treatment options were safe.
What did we do?
We searched medical databases for studies looking at available treatments for women with anaemia after childbirth. We screened studies for trustworthiness and included studies we considered trustworthy. The most important outcomes were fatigue (tiredness) and death.
What did we find?
We included 33 studies with a total of 4558 women and performed seven treatment comparisons.
Eighteen trials (3026 women) compared intravenous iron with oral iron supplements. It is unclear if intravenous iron affects the number of deaths. Only one woman died, and she had received intravenous iron. Based on two studies (515 women), we found that intravenous iron probably reduces fatigue slightly within 8 to 28 days compared to oral iron supplements. No studies examined whether intravenous iron affects breastfeeding. Constipation was probably more frequent in women treated with oral iron supplements than in those receiving intravenous iron (10.7% versus < 1%). It is unclear if intravenous iron has an effect on allergic reactions (anaphylaxis (severe allergic reaction) or hypersensitivity occurred in three women who received intravenous iron). Intravenous iron may increase haemoglobin levels, but important differences among the studies prevented an estimate of the exact effect.
Two studies compared red blood cell transfusions with intravenous iron. It is unclear if red blood cell transfusion affects the number of deaths, fatigue at 8 to 28 days, and breastfeeding. No studies looked at if intravenous iron affects constipation or allergic reactions. Red blood cell transfusion may result in little to no difference in haemoglobin.
Three studies compared intravenous iron and oral iron supplements to oral iron supplementation alone. No studies looked at if intravenous iron and oral iron supplements affects the number of deaths or breastfeeding. It is unclear if intravenous iron and oral iron supplements affects allergic reactions or fatigue. Intravenous iron and oral iron supplementation may reduce constipation compared to oral iron alone (1 study; 128 women) and may result in little to no difference in haemoglobin levels at 8 to 28 days.
One study compared red blood cell transfusions to no transfusions. No studies looked at if red blood cell transfusions affect the number of deaths, fatigue, constipation, allergic reactions, or haemoglobin levels. Red blood cell transfusion may result in little to no difference in breastfeeding beyond six weeks postpartum (1 study; 297 women).
Three studies compared oral iron supplements to placebo. No studies looked at if oral iron supplements affect the number of deaths, fatigue, breastfeeding, allergic reactions, or haemoglobin levels within 8 to 28 days. Two studies reported on constipation not for both groups.
What are the limitations of the evidence?
We have low to very low confidence in the evidence because the women in the studies knew which treatment they received, which could have influenced the results. Also, few studies reported on outcomes that are important to patients. Only 8 of 33 included studies reported on fatigue.
How up‐to‐date is this evidence?
The evidence is current to April 2024.
Summary of findings
Summary of findings 1. Summary of findings table ‐ Intravenous iron compared with oral iron for women with postpartum iron deficiency anaemia.
| Intravenous iron compared with oral iron for women with postpartum iron deficiency anaemia | ||||||
| Patient or population: women with postpartum iron deficiency anaemia Setting: obstetric care units Intervention: intravenous iron Comparison: oral iron | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with oral iron | Risk with intravenous iron | |||||
| Maternal mortality assessed with: as reported by trial authors follow‐up: 12 weeks | 0 per 1000 | 0 per 1000 (0 to 0) | RR 2.95 (0.12 to 71.96) | 572 (3 RCTs) | ⊕⊝⊝⊝ Very lowa | 1 maternal death was reported among the women that received intravenous iron. |
| Fatigue 8 to 28 days assessed with: Fatigue Linear Analog Scale Assessment and physical fatigue subscale of the Multidimensional Fatigue Inventory | ‐ | SMD 0.25 lower (0.42 lower to 0.07 lower) | ‐ | 515 (2 RCTs) | ⊕⊕⊕⊝ Moderateb | Intravenous iron probably results in a slight reduction in fatigue at 8 to 28 days. |
| Breastfeeding ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Constipation follow‐up: 12 weeks | 108 per 1000 | 13 per 1000 (6 to 23) | RR 0.12 (0.06 to 0.21) | 1798 (10 RCTs) | ⊕⊕⊕⊝ Moderateb | Oral iron probably results in a large increase in constipation compared to intravenous iron. |
| Anaphylaxis or evidence of hypersentitivity assessed with: as defined by trial authors follow‐up: 1 days | 0 per 1000 | 0 per 1000 (0 to 0) | RR 2.77 (0.31 to 24.86) | 2195 (12 RCTs) | ⊕⊝⊝⊝ Very lowa,c | 1 case of anaphylaxis reaction and 2 cases of hypersensitivity occurred in the group treated with intravenous iron. |
| Haemoglobin (g/dL) 8 to 28 days assessed with: as reported by trial authors | The studies were too heterogeneous to pool, and the heterogeneity could not be explained. However, 5 out of 6 RCTs showed a benefit from intravenous iron, with mean changes in haemoglobin ranging from 0.73 to 2.10 g/dL. | 666 (6 RCTs) | ⊕⊕⊝⊝ Lowc,d | |||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio; SMD: standardised mean difference | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_450047466737500956. | ||||||
a Downgraded three levels due to imprecision: very few events. b Downgraded one level due to risk of bias: open‐label design combined with a subjective outcome measure. c The outcome is unlikely to be influenced by risk of bias, therefore we did not downgrade the certainty of the evidence for this outcome: open‐label design combined with an objective outcome measure. d Downgraded two levels due to inconsistency and high heterogeneity, which prevented data pooling.
Summary of findings 2. Summary of findings table ‐ Red blood cell transfusion compared with intravenous iron for women with postpartum iron deficiency anaemia.
| Red blood cell transfusion compared with intravenous iron for women with postpartum iron deficiency anaemia | ||||||
| Patient or population: women with postpartum iron deficiency anaemia Setting: obstetric care units Intervention: red blood cell transfusion Comparison: intravenous iron | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with intravenous iron | Risk with red blood cell transfusion | |||||
| Maternal mortality follow‐up: 12 weeks | Not pooled | Not pooled | Not pooled | 13 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | No events |
| Fatigue 8 to 28 days assessed with: physical fatigue score as measured by a subscale of the Multidimensional Fatigue Inventory | The mean fatigue 8 to 28 days was 13.3 | MD 1.2 higher (2.41 lower to 4.81 higher) | ‐ | 13 (1 RCT) | ⊕⊝⊝⊝ Very lowc,d | The evidence is very uncertain about the effect of red blood cell transfusion on fatigue at 8 to 28 days. |
| Breastfeeding > 6 weeks postpartum assessed with: not specified by trial author | 667 per 1000 | 287 per 1000 (80 to 1000) | RR 0.43 (0.12 to 1.57) | 13 (1 RCT) | ⊕⊝⊝⊝ Very lowc,d | The evidence is very uncertain about the effect of red blood cell transfusion on breastfeeding > 6 weeks postpartum. |
| Constipation ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured thisoutcome. |
| Anaphylaxis or evidence of hypersensitivity ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Haemoglobin (g/dL) 8 to 28 days assessed with: not specified by trial author | The mean haemoglobin (g/dL) 8 to 28 days was 11.7 | MD 1 lower (2.02 lower to 0.02 higher) | ‐ | 12 (1 RCT) | ⊕⊕⊝⊝ Lowd | Red blood cell transfusion may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_450047524518495009. | ||||||
a The outcome is unlikely to be influenced by risk of bias, therefore we did not downgrade the certainty of the evidence for this outcome: open‐label design combined with an objective outcome measure. b Downgraded three levels due to imprecision: very few events. c Downgraded one level due to risk of bias: open‐label design combined with a subjective outcome measure/adverse event. d Downgraded two levels due to imprecision: very broad confidence intervals or few events.
Summary of findings 3. Summary of findings table ‐ Intravenous iron with oral iron compared with oral iron for women with postpartum iron deficiency anaemia.
| Intravenous iron with oral iron compared with oral iron for women with postpartum iron deficiency anaemia | ||||||
| Patient or population: women with postpartum iron deficiency anaemia Setting: Obstetric care units Intervention: intravenous iron and oral iron Comparison: oral iron | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with oral iron | Risk with intravenous iron and oral iron | |||||
| Maternal mortality ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Fatigue 8 to 28 days | In 1 study the authors state that "physical fatigue" or "total fatigue" improved more in the group treated with intravenous iron and oral iron supplementation compared to the group treated with oral iron supplementation only. Standard deviations were not available, therefore we could not carry out a statistical analysis. | 128 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | No data, as no study measured this outcome. | ||
| Breastfeeding ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Constipation assessed with: as reported by trial author follow‐up: 4 weeks | 243 per 1000 | 51 per 1000 (17 to 168) | RR 0.21 (0.07 to 0.69) | 128 (1 RCT) | ⊕⊕⊝⊝ Lowa,c | Intravenous iron and oral iron may result in a reduction in constipation compared to oral iron alone. |
| Anaphylaxis or evidence of hypersensitivity follow‐up: 1 days | Not pooled | Not pooled | Not pooled | 168 (2 RCTs) | ‐ | No events |
| Haemoglobin (g/dL) 8 to 28 days | The mean haemoglobin (g/dL) 8 to 28 days was 10.7 | MD 0 (0.48 lower to 0.48 higher) | ‐ | 60 (1 RCT) | ⊕⊕⊝⊝ Lowb | Intravenous iron and oral iron may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_450047593637217140. | ||||||
a Downgraded one level due to risk of bias: open‐label design combined with a subjective outcome measure/adverse event. b Downgraded two levels due to imprecision: very broad confidence intervals or few events. c Downgraded one level due to imprecision: broad confidence intervals or few events.
Summary of findings 4. Summary of findings table ‐ Red blood cell transfusion compared with non‐transfusion for women with postpartum iron deficiency anaemia.
| Red blood cell transfusion compared with non‐transfusion for women with postpartum iron deficiency anaemia | ||||||
| Patient or population: women with postpartum iron deficiency anaemia Setting: Obstetric care unit Intervention: red blood cell transfusion Comparison: no transfusion | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with no transfusion | Risk with red blood cell transfusion | |||||
| Maternal mortality ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Fatigue 8 to 28 days ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Breastfeeding > 6 weeks postpartum assessed with: as reported by trial authors | 706 per 1000 | 643 per 1000 (551 to 756) | RR 0.91 (0.78 to 1.07) | 297 (1 RCT) | ⊕⊕⊝⊝ Lowa,b | Red blood cell transfusion may result in little to no difference in breastfeeding > 6 weeks postpartum. |
| Constipation ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | Not relevant |
| Anaphylaxis or evidence of hypersensitivity ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Haemoglobin (g/dL) 8 to 28 days ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_450047672958321675. | ||||||
a Downgraded one level due to risk of bias: open‐label design combined with a subjective outcome measure/adverse event. b Downgraded two levels due to imprecision: very broad confidence intervals or few events.
Summary of findings 5. Summary of findings table ‐ Oral iron compared with placebo or no treatment for women with postpartum iron deficiency anaemia.
| Oral iron compared with placebo or no treatment for women with postpartum iron deficiency anaemia | ||||||
| Patient or population: women with postpartum iron deficiency anaemia Setting: Obstetric care units Intervention: oral iron Comparison: placebo or no treatment | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with placebo or no treatment | Risk with oral iron | |||||
| Maternal mortality ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Fatigue ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Breastfeeding ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| Constipation ‐ not reported | 2 studies reported on gastrointestinal symptoms, however the data were not reported by study arm. | ‐ | ‐ | No data, as no study reported this by study arm. | ||
| Anaphylaxis or evidence of hypersensitivity ‐ not reported | ‐ | ‐ | No data, as no study measured this outcome. | |||
| Haemoglobin (g/dL) 8 to 28 days ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐ | No data, as no study measured this outcome. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; RR: risk ratio | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
| See interactive version of this table: https://gdt.gradepro.org/presentations/#/isof/isof_question_revman_web_450047711138808876. | ||||||
Background
Description of the condition
Women who give birth may develop postpartum anaemia, either because of excessive bleeding during or after delivery or pre‐existing iron deficiency or anaemia in pregnancy. Severe postpartum anaemia can have serious consequences, being linked to possibly 40% of maternal perinatal deaths worldwide [1]. Anaemia also increases the risk of maternal death from other causes such as infections, malnutrition, and bleeding [2]. For some women, particularly in low‐ and middle‐income countries, postpartum anaemia is a major cause of poor health [3, 4, 5, 6] and might affect up to 50% of women giving birth [7].
Anaemia, including postpartum anaemia, is defined by a lower than normal haemoglobin value, but clinical symptoms are essential in the evaluation of its impact. Haemoglobin is the molecule contained within red blood cells that is responsible for transporting oxygen in the body. The primary cause of iron deficiency anaemia in pregnancy is the high iron demands for the development of the fetus, placenta, and increased erythropoiesis. Postpartum anaemia may be caused by low dietary iron intake before or during pregnancy, iron malabsorption, and/or blood loss during or after delivery [8, 9, 7, 10].
Postpartum anaemia can cause symptoms such as breathlessness, palpitations, tiredness, headache, dizziness as well as an increased risk of infections. All of these symptoms may impact a woman’s ability to breastfeed and care for her newborn [3, 7].
In pregnancy, the circulating blood volume increases to prepare the woman for blood loss at delivery. However, pregnant women have a physiologically normal reduction in their haemoglobin concentration, as dilution due to accumulation of fluid exceeds the increased erythropoiesis [1]. Bleeding and resorption of excess fluid from body tissues during and after delivery vary in extent between individuals [7], which can have a major impact on maternal haemoglobin concentration. It is generally accepted that a low haemoglobin concentration ‐ usually less than 12 g/L ‐ is indicative of anaemia in postpartum women, although there is considerable variation in the precise concentration that defines anaemia, and also the time after birth at which this should be measured [11, 3, 9, 12, 7, 13]. Thus, postpartum anaemia is poorly defined, and the postpartum haemoglobin level (six weeks after delivery) depends strongly on how long after delivery it is measured [6].
It should be emphasised that even though an association between low haemoglobin and clinical symptoms has been shown in population‐based observational studies, the normal range of haemoglobin is an arbitrarily defined statistical value derived from the population average, and an individual woman’s haemoglobin level does not necessarily reflect the clinical symptoms she may experience [1]. Since the correlation between the different clinical symptoms and the level of haemoglobin in postpartum anaemia is not well described, the clinical significance of a change in haemoglobin level as a result of any given treatment remains uncertain.
Postpartum iron deficiency anaemia does not have a specific code in the International Classification of Diseases (ICD‐10), but is included in the more general code 099.0 'Anaemia complicating pregnancy, childbirth and the puerperium' [14]. Currently, all definitions of postpartum anaemia and the different stages of severity are based on haemoglobin values only [15], and not on the severity of anaemia symptoms. In the postpartum period as well as in pregnancy, it remains unanswered whether any benefits of treating anaemia outweigh the harms of treatment [10]. Known harms depend on the choice of treatment and include, for example, gastrointestinal symptoms and allergic reactions.
Description of the intervention and how it might work
There are a number of treatment options for women with postpartum anaemia, and the optimal treatment, dose, and balance between benefits and harms may vary depending on the timing and severity of anaemia, clinical symptoms, harms of the intervention, available resources, and factors such as geographic location, socioeconomic status, and education. The treatment modalities described in this review include iron supplementation administered either orally or directly into a vein (intravenously), erythropoietin which stimulates red blood cell production, and substitution of red blood cells by transfusion.
Oral iron therapy
Oral iron supplementation in the form of tablets, often ferrous sulphate, has been used for many years as a treatment for iron deficiency anaemia in general [16], as well as in pregnancy [17]. Oral iron supplementation is inexpensive, readily available, and effective for treating iron deficiency, if taken appropriately.
The body has a limited capacity to absorb iron from the intestine, and prolonged treatment, often several months, is required to correct the haemoglobin level and relieve symptoms of anaemia. The intestinal absorption of oral iron supplementation results in a rise in circulating hepcidin (peptide hormone that plays an important role in iron homeostasis), which limits further iron absorption for up to 48 hours, suggesting that once‐daily or alternate‐day dosing may be more effective than traditional treatment with high doses several times a day [18]. However, data on the optimal dosing schedule for iron tablets in pregnant women and postpartum are needed [19].
Gastrointestinal adverse effects, such as constipation and nausea, are common in women treated with oral iron supplementation [20, 21]. This may affect women's compliance with treatment and consequently prevent correction of iron deficiency and anaemia.
Intravenous iron therapy
Intravenous iron has been shown to produce a more rapid increase in the haemoglobin concentration in iron deficiency across a range of clinical conditions including chronic kidney disease, inflammatory bowel disease, heart failure, and pregnancy. In the presence of inflammation, intravenous iron can bypass the ‘hepcidin block’ that limits the absorption of iron from the intestine [19].
Common side effects of intravenous iron include nausea, headaches, and flushing as well as injection site reactions, such as pain and long‐term skin miscolouration [19]. Iron is also essential for bacterial growth, and caution is advised in individuals with acute infection. However, iron is also important for an optimal functioning immune system, a dilemma which is still being debated.
Rarely, anaphylactic reactions can occur which are characterised by itching, redness, and angioedema, vascular collapse, bronchospasm, and shock [22, 23, 24, 25, 26]. Anaphylaxis is rare, and the use of new low‐molecular iron (e.g. iron sucrose, iron gluconate, ferric carboxymaltose, and ferric derisomaltose) may lower the risk of anaphylactic reaction to 24 to 68 cases per 100,000 [27].
In about 1 out of 100 patients, the administration of intravenous iron may elicit a non‐allergic Fishbane reaction [28], the symptoms of which may include facial flushing, chest pain, lower back pain, shortness of breath, and/or joint pains. It is important to distinguish between Fishbane reaction and an anaphylactic reaction, as Fishbane reaction appears without severe anaphylactic symptoms as described above and is usually settled quickly without treatment if the injection is paused and continued more slowly [28].
Intravenous iron products are considerably more expensive than oral iron and are currently only licenced to be given in specific settings (e.g. hospital outpatients or wards) where there are trained staff and equipment for managing anaphylaxis.
Erythropoietin
Erythropoietin (EPO) is a hormone produced in the kidneys when blood oxygen levels are low. It acts to stimulate the formation of red blood cells (erythropoiesis) in the bone marrow [29]. Initially, EPO was used for anaemia associated with renal disease. It was later used to treat other forms of anaemia, and has been given as an alternative to blood transfusion for the treatment of iron deficiency anaemia, including postpartum iron deficiency anaemia [3, 29]. Adverse effects of EPO treatment include mild flu‐like symptoms such as sore throat, cough, fever, muscle pains and weakness, headache, and fatigue. Uncommon but more serious adverse effects include hypertension, thromboembolic complications, seizures, and pure red‐cell aplasia [30, 31]. Research has shown an association with certain haematological cancers, which led to a US Food and Drug Administration (FDA) black box warning (label on the product warning against serious or life‐threatening risks). The use of EPO is now restricted to specific patient groups and is very rarely used in postpartum anaemic patients [32, 29].
Red blood cell transfusion
Transfusion of allogeneic blood (blood products extracted from another person) can be used in the treatment of postpartum anaemia and may be life‐saving in the case of acute or major bleeding at the time of giving birth [33]. Adverse reactions, rather than clinical benefit, have been found when transfusing patient populations with mild to moderate anaemia [34, 35, 36]. Thus, transfusion is generally not recommended following small to moderate bleeding in patients with a normal physiologic response. There are associated risks, including donor‐transmitted infections (particularly hepatitis and HIV), transfusion‐associated circulatory overload (TACO), and a variety of immunologic reactions such as fever, urticaria, anaphylaxis, transfusion‐related lung injury (TRALI) or antibody formation which may interfere with future pregnancies [37, 38, 39, 40]. Blood transfusion may rarely cause acute haemolysis (breakdown of red blood cells) if incompatible blood is administered by mistake [37]. Blood transfusions are expensive, as costs include screening for infection, cross‐matching, storage, and sterile and safe administration of blood products [41]. In low‐income countries, blood for transfusion may not be available.
Why it is important to do this review
This is an update of a Cochrane review first published in 2006, and previously updated in 2015. Postpartum iron deficiency anaemia is a common condition affecting women after childbirth and may be associated with symptoms that can influence survival, health, and the ability to care for the baby in the critical period of new motherhood. The treatment modalities available for postpartum iron deficiency anaemia vary in effectiveness and have side effects, some of which are serious. Some populations may benefit more than others, and in some situations treatment may be unnecessary, ineffective, or even harmful. Women and clinicians need reliable estimates of the effectiveness and risks of available treatments for postpartum anaemia to facilitate informed and patient‐specific decision‐making.
Conducting this review holds significant importance as it will serve as a component in the development of a comprehensive consolidated guideline for postpartum haemorrhage (PPH) within the World Health Organization (WHO) Roadmap to combat postpartum haemorrhage between 2023 and 2030 [42].
This review serves as an update to a previous review by Markova V [43].
Objectives
To assess the benefits and harms of the available treatment modalities for women with postpartum iron deficiency anaemia. These include intravenous iron, oral iron supplementation, red blood cell transfusion, and erythropoietin.
Methods
We followed the Methodological Expectations for Cochrane Intervention Reviews (MECIR) [44] when conducting the review and the PRISMA 2020 [45] for the reporting.
In the current update, we decided to focus on and present fatigue at the 8‐ to 28‐day time point in the summary of findings table. In the previous version of the review, handling of time points was not specified. The fatigue after birth will eventually resolve itself, and combining long‐term data with short‐term data could potentially dilute a clinically relevant effect. We also included haemoglobin, at the request of WHO, as a surrogate measure of anaemia.
Criteria for considering studies for this review
Types of studies
We included published, unpublished, and ongoing, parallel‐group, randomised trials that compared any treatment for postpartum iron deficiency anaemia with placebo, no treatment, or another treatment for postpartum iron deficiency anaemia, including trials described in abstracts only. Cluster‐randomised trials were eligible for inclusion. We included both open‐label trials and blinded trials, irrespective of who was blinded. We excluded non‐randomised trials, quasi‐randomised trials (alternating assignment, date of birth, order of registration, geographic location, etc.), and trials using a cross‐over design.
Types of participants
Women with a postpartum haemoglobin value of 12 g/dL (7.4 mmol/L) or less, regardless of the mode of birth (vaginal delivery, operative vaginal delivery, or caesarean section) within six weeks after delivery.
We included studies with a subset of eligible participants if data at the individual level or at the relevant group level were available.
We planned in a previous version of the review to "distinguish between socioeconomic population groups whenever possible", but since it was not clear how this would be operational, we removed this from the current version.
Types of interventions
Treatment for postpartum iron deficiency anaemia started within the first six weeks after giving birth compared with placebo, no treatment, or another treatment modality.
The currently accepted treatment for iron deficiency anaemia includes blood transfusion, iron supplementation administered orally or parenterally, either alone or in combination with folate, and/or erythropoietin.
Folate supplementation was not considered as an independent treatment for iron deficiency anaemia, but was accepted as a part of other types of treatment for postpartum iron deficiency anaemia.
In the previous version of the review, all interventions and comparisons were included, but we decided to collapse some of the interventions in order to better guide clinicians. We decided to investigate the following comparisons, which are the only ones of interest in this review.
Comparison 1: Intravenous iron versus oral iron supplementation
Comparison 2: Red blood cell transfusion versus intravenous iron
Comparison 3: Intravenous iron and oral iron supplementation versus oral iron supplementation
Comparison 4: Red blood cell transfusion versus no transfusion
Comparison 5: Oral iron supplementation versus placebo or no treatment
Comparison 6: Erythropoietin (regardless of route) versus intravenous or oral iron supplementation
Comparison 7: Erythropoietin (regardless of route) versus placebo
Any new treatment modalities appropriate for iron deficiency anaemia will be included in future updates.
Outcome measures
Critical outcomes
Maternal mortality: we considered that no women died only if: a) this was stated explicitly, or b) no dropouts occurred during follow‐up, or c) contact authors provided this information on request. We considered mortality to be present only if: a) stated explicitly in a published report or b) contact authors provided this information on request. We assessed mortality as not reported if a) there was no mention of dropouts or their causes, b) all dropouts were not accounted for, c) dropouts were not explicitly reported to be alive at the end of the follow‐up period.
Fatigue: as reported by the woman ‐ verbalisation of fatigue or lack of energy and inability to maintain usual routines; measured by a scale or questionnaire; or as defined by the trial authors, within the first week postpartum, 8 to 28 days postpartum, and more than 28 days postpartum when available.
Important outcomes
Persistent anaemia symptoms during treatment. Any of the following symptoms: dyspnoea, tachypnoea, tachycardia, palpitations, orthostatic dizziness, syncopation, paleness.
Persistent postpartum anaemia, defined as haemoglobin < 9 g/dL at end of treatment.
Psychological well‐being, including cognitive performance, measured by the Blues Questionnaire [46], Self‐report symptom inventory 90 (SCL‐90‐R) [47], SF‐36 (Medical Outcomes Study Short Form) [48], or similar questionnaire; or as defined by the trial authors. Only short‐term results, thus the minimal time from baseline.
Urinary tract infection, endometritis, or other infections (as defined by the trial authors).
Compliance to treatment (as defined by the trial authors).
Breastfeeding (at hospital discharge; six weeks postpartum; six months postpartum).
Length of hospital stay.
Adverse events/side effects during treatment. We predefined reporting of serious adverse events, anaphylaxis or hypersensitivity, flushing/Fishbane reaction, injection discomfort/reaction, constipation and gastrointestinal pain.
Number of red blood cell transfusions (number of transfused women and number of red blood cell units per woman).
Haemoglobin as continuous outcome (g/dL); within the first week postpartum, 8 to 28 days postpartum, and more than 28 days postpartum.
For outcomes other than psychological well‐being, we did not apply any restrictions regarding follow‐up periods in order to avoid excluding data on any long‐term benefits or harms. We did not apply language restrictions.
On advice from the WHO, we added the outcomes 'persistent postpartum anaemia, defined as haemoglobin < 9 g/dL at end of treatment' and 'haemoglobin as continuous outcome (g/dL)' in the current review. We also added the predefined list of adverse events in the current version to prioritise the most important adverse events.
Search methods for identification of studies
The following methods section is based on a standard template used by Cochrane.
Electronic searches
In collaboration with Cochrane Information Specialists, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 3, 2024), Ovid MEDLINE ALL, Ovid Embase, LILACS (Latin American and Caribbean Health Science Information database), and CINAHL via EBSCOhost (Cumulative Index to Nursing and Allied Health Literature) using predefined search strategies (for detailed search strategies, please refer to Supplementary material 1), together with reference checking, citation searching, and contact with study authors to identify eligible studies. We applied date limits to retrieve records added to the databases since the last search on 9 April 2015. Searches for this update therefore covered the period from 9 April 2015 to 11 April 2024.
In addition, we searched ClinicalTrials.gov (clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (trialsearch.who.int) on 11 April 2024 for unpublished, planned, and ongoing trial reports.
If papers were not accessible, we contacted the relevant authors and organisations. We did not apply any language or date restrictions.
Compared to the previous version of this review, we did not search Cochrane Pregnancy and Childbirth Group’s Trials Register as it is no longer being updated. We have added ClinicalTrials.gov since the previous version.
Searching other resources
We retrieved additional relevant references cited in papers identified through the above search strategy and searched for the full texts of trials initially identified as abstracts.
For randomised trials published only as abstracts, we sought information from primary authors to investigate whether these studies met our eligibility criteria before including them.
Data collection and analysis
Selection of studies
Two review authors (MJ and CH) independently assessed the titles and abstracts of studies identified by the search for potential relevance. We used Covidence for screening studies [49]. We obtained the full texts of studies deemed potentially relevant, and the same two review authors assessed the full‐text reports for inclusion in the review Studies for which CH was a co‐author were assessed by MJ and JBS. Any disagreements were resolved through discussion or in consultation with a third review author (JBS or KJ).
Data extraction and management
We used Covidence [49] to extract data. The previous version of the review used a Microsoft Excel sheet. At least two review authors independently extracted data from eligible studies using a blank electronic form, blinded to each other's results (MJ and CH, KJ, or JBS). Any discrepancies were resolved through discussion or in consultation with another review author if necessary. Data extraction for studies for which CH was a co‐author was performed by MJ and JBS. We exported data into RevMan software [50]. The previous version of the review entered data manually. When information was unclear, we contacted the authors of the original studies to provide further details.
When we identified trials with more than two study arms, we included only the relevant arms in our meta‐analysis. The remaining arm(s) was described and compared with the control arm. If comparisons in the trial could not be included in a meta‐analysis, but the trial otherwise fulfilled our inclusion criteria, we described the results in separate comparisons.
Outcome data
We extracted the following information from each included study at minimum.
Number of participants
Inclusion/exclusion criteria
Interventions being compared and their respective primary and secondary outcomes
All relevant arm‐level data (e.g. number of events and number of participants for binary outcomes and means and standard deviations (SDs) per study arm for continuous outcomes, number of dropouts)
Data on potential effect modifiers
We extracted from each included study the following population characteristics that may act as effect modifiers.
Study setting: high‐ versus low‐income populations; high versus low education status
Type of intravenous iron therapy: iron sucrose versus iron carboxymaltose
Dose administered: high versus low dose
Duration of treatment: four weeks versus longer
Presence of an adjunct to oral iron supplementation: folate versus no folate
Source of funding: public versus corporate
Mode of birth (vaginal versus caesarean section)
PPH (bleeding > 500 mL)
Other data
We extracted the following additional information from each included study.
Country or countries in which the study was performed
Date of publication and dates of recruitment
Type of publication (full text, abstract, unpublished data)
Trial registration reference
Author contact information
Risk of bias assessment in included studies
Two review authors (MJ and CH, KJ, or JBS) independently assessed the risk of bias for each included study using the Cochrane RoB 1 tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions and a risk of bias table [51]. We assessed each of the following domains as low, high, or unclear: selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. Any disagreements were resolved by discussion or by involving a third review author (KJ or JBS). Studies for which CH was a co‐author were assessed by MJ, KJ, and JBS.
We explored the impact of bias through sensitivity analysis.
In addition to the risk of bias assessment, we performed a research integrity assessment to establish the integrity and authenticity of studies using the Cochrane Trustworthiness Screening Tool, developed by Cochrane Pregnancy and Childbirth (see below).
Screening eligible studies for scientific integrity/trustworthiness
Two review authors (MJ and CH, KJ, or JBS) evaluated all studies meeting the inclusion criteria against predefined criteria to determine, based on the available information, whether they were sufficiently trustworthy to be included in the analyses. Studies for which CH was a co‐author were assessed by MJ, KJ, and JBS. Trustworthiness was not assessed in the previous version of the review and was a requirement from the WHO. The criteria were as follows.
Research governance
No prospective trial registration for studies published after 2010 without plausible explanation.
When requested, trial authors refuse to provide/share the protocol or ethics approval letter (or both).
Trial authors refuse to engage in communication with the Cochrane review authors.
Trial authors refuse to provide trial data upon request with no justifiable reason.
Baseline characteristics
Characteristics of the study participants are too similar (distribution of mean (SD) excessively narrow or excessively wide).
Feasibility
Implausible numbers (e.g. 500 women with severe cholestasis of pregnancy recruited in 12 months).
(Close to) zero losses to follow‐up without plausible explanation.
Results
Implausible results (e.g. massive risk reduction for main outcomes with small sample size).
Unexpectedly even numbers of women ‘randomised’, including a mismatch between the numbers and the methods, e.g. if it is stated that no blocking was used, but there are still equal numbers; or it is stated that blocks of four were used, but the final numbers differ by six.
Where a study was classified as being at ‘high risk’ for one or more of the above criteria, we would attempt to contact the study authors to address any possible lack of information and concerns. If adequate information remained unavailable, we would categorise the study as ‘awaiting classification’ and describe in detail the concerns and communications with the author (or lack thereof). The process is described fully in Figure.
1.
Using the Cochrane Pregnancy and Childbirth criteria for assessing the trustworthiness of a study.
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as a summary risk ratio (RR) with 95% confidence intervals (CIs) from a meta‐analysis, if possible.
Continuous outcome data
For continuous outcome data, we used the mean difference (MD) if outcomes were measured in the same way between trials. We planned to use the standardised mean difference (SMD) to combine trial results that measured the same outcome but used different methods.
Unit of analysis issues
Cluster‐randomised trials
We planned to include cluster‐randomised trials in the analyses along with individually randomised trials; however, none were identified.
If in future updates cluster‐randomised trials are included, we will adjust sample sizes using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions [52], employing an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), from a similar trial, or from a study of a similar population. If ICC is used from other sources, we planned to report this and perform a sensitivity analysis to investigate the effect of variation in the ICC.
Multi‐armed trials
We planned to include studies with more than two intervention groups in a meta‐analysis and omit groups that were not relevant to the comparison being made. If there were still more than two comparisons, we planned to combine relevant intervention groups into one group and also combine control groups into one group in accordance with the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions.
Dealing with missing data
We noted the level of attrition for each included study. We planned to explore the impact of including studies with high levels of missing data (more than 10%) in the overall assessment of treatment effect through sensitivity analysis, using our critical outcomes (maternal mortality and fatigue).
For all outcomes, we carried out analyses, to the greatest degree possible, on an intention‐to‐treat basis, that is we attempted to include all participants randomised to each group in the analyses, and all participants were analysed in the group to which they were allocated, regardless of whether they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus the number of participants whose outcome data were known to be missing.
Reporting bias assessment
We planned to investigate reporting biases (e.g. publication bias) if 10 or more studies were included in a meta‐analysis, using funnel plots and assessing the asymmetry of the funnel plot visually. However, no analysis included at least 10 trials.
In future updates, if asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate this.
Synthesis methods
We performed statistical analyses using RevMan software [50]. We used a fixed‐effect model for our meta‐analyses as the main approach. We also performed a sensitivity analysis using a random‐effects model and reported the results if they were sensitive to the statistical approach.
We presented the results of random‐effects meta‐analyses as the average treatment effect with 95% CIs, and the estimates of Tau² and I².
Investigation of heterogeneity and subgroup analysis
We assessed statistical heterogeneity in each meta‐analysis using the I² statistic. We regarded heterogeneity as substantial if I² was greater than 50%. If heterogeneity was substantial, we investigated it using subgroup and sensitivity analyses. We planned to carry out the following subgroup analyses, if possible.
Study setting: high‐ versus low‐income populations; high versus low education status
Type of intravenous iron therapy: iron sucrose versus iron carboxymaltose
Dose administered: high versus low dose
Duration of treatment: four weeks versus longer
Presence of an adjunct to oral iron supplementation: folate versus no folate
Source of funding: public versus corporate
Mode of birth (vaginal versus caesarean section)
PPH (bleeding > 500 mL)
We assessed potential subgroup differences by interaction tests available within RevMan [50] and reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.
In the previous version of the review, the authors had already planned six subgroup analyses, and WHO requested that we introduce mode of birth and PPH. The number of subgroups should be reduced in future versions of the review.
We conducted subgroup analyses but did not interpret them due to small numbers of studies within each subgroup.
Equity‐related assessment
Though incidence of PPH is similar around the world, maternal mortality and severe morbidity due to PPH are concentrated in low‐resource settings and disproportionately affect women who are socially disadvantaged. Recognising that context may influence the implementation of an intervention, we extracted data on country or countries in which trials were conducted (as a proxy for resource level) and considered how contextual factors may influence the transferability and applicability of results in the interpretation of the evidence.
Sensitivity analysis
We planned to carry out a sensitivity analysis based on risk of bias, excluding trials with a high risk of selection, performance, and detection bias. However, all studies had at least one high‐risk domain in these categories, precluding this analysis.
We also planned to carry out sensitivity analyses to explore the effects of random‐effects analyses for outcomes with statistical heterogeneity and the effects of any assumptions made such as the value of the ICC used for cluster‐randomised trials.
We planned sensitivity analyses only for our critical outcomes (maternal mortality and fatigue). If sufficient data become available, we will attempt to carry out sensitivity analyses for all comparisons in future updates.
Certainty of the evidence assessment
We assessed the certainty of the evidence using the GRADE approach for the critical outcomes, as outlined in the GRADE Handbook [53].
We imported data from RevMan to GRADEpro GDT to create a summary of findings table [54]. A summary of the intervention effect and a measure of certainty for each of the critical outcomes was produced using the GRADE approach. The GRADE approach uses five domains (study limitations, consistency of effect, imprecision, indirectness, publication bias, and overall risk of bias) to assess the certainty of the body of evidence for each outcome. The evidence can be downgraded from high certainty by one level for serious (or by two or three levels for very serious) limitations, based on the five GRADE domains.
Two review authors (MJ and JBS) independently assessed the certainty of the evidence, with any disagreements resolved through discussion or consultation with a third review author where necessary (KJ). We assessed the certainty of the evidence for each outcome as high, moderate, low, or very low, in accordance with the GRADE approach, as explained below.
High certainty: we are very confident that the true effect lies close to that of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
We chose the comparisons included in the summary of findings tables based on their relevance to current treatment standards according to clinical experts in our author team. We chose not to report a summary of findings table for the interventions with erythropoietin as we found it was the least clinical meaningful intervention and due to lack of space.
Intravenous iron versus oral iron supplementation
Red blood cell transfusion versus intravenous iron
Intravenous iron and oral iron supplementation versus oral iron supplementation
Red blood cell transfusion versus no transfusion
Oral iron supplementation versus placebo or no treatment
We planned to include the following outcomes in the summary of findings tables of the review, using GRADEpro GDT [54].
Maternal mortality
Fatigue (8 to 28 days)
Breastfeeding
Constipation (for oral iron substitution)
Anaphylaxis or evidence of hypersensitivity (for intravenous iron)
Haemoglobin (8 to 28 days)
For the treatment‐specific outcomes listed above (constipation and allergic reactions), the results were included in the summary of findings tables if the specific treatment was present in only one study arm.
Consumer involvement
A consumer peer review was conducted. Furthermore, the review has benefited from active engagement with the guideline group and a diverse range of stakeholders, including representatives from the WHO. Their input during the PICO design phase has contributed to enhancing the relevance of the review.
Results
Description of studies
For an individual description of the studies, see Supplementary material 2, Supplementary material 3, Supplementary material 4, and Supplementary material 5.
Results of the search
Searches for this update encompassed the period from 9 April 2015 to 11 April 2024. We applied date limits to retrieve records added to the databases since the last search. We employed new search strategies for CENTRAL, MEDLINE, Embase, CINAHL, and ClinicalTrials.gov, as previous search results were obtained through the Cochrane Pregnancy and Childbirth Group's Trials Register, and no strategies were available. The search strategies from the last review were applied for LILACS and WHO ICTRP.
Our searches identified a total of 2317 records. A PRISMA flow chart illustrating the screening process for this update, along with the number of trials brought forward from the previous version, is provided in Figure [43]. We identified 11 new trials based on full‐text assessment (Akhtar 2018 [55]; Bombac Tavcar 2024 [56, 57]; Calje 2023 [58]; Damineni 2016 [59]; ElKhouly 2017 [60, 61]; Holm 2017 [62, 63, 64, 65]; Holm 2017a [66]; Iyoke 2017 [67]; Saad 2023 [68, 69]; Suneja 2019 [70, 71]; Yefet 2021 [72, 73]).
2.
Study flow diagram.
Additionally, through trial registration, one trial was identified as eligible for inclusion but was subsequently stopped and therefore excluded (Chaudhuri 2013 [74]). We categorised another trial as awaiting classification due to methodological uncertainties about randomisation (Hye 2022 [75]), and we received no response from the authors. We flagged one trial for potential issues through the Trustworthiness Screening Tool because it lacked a protocol and a full‐text article, with only an abstract available (Abbas 2019 [76]). The author did not respond to our request for additional information or provide an explanation, and the author has several retracted studies [77]. We therefore categorised the trial as awaiting classification; please refer to Supplementary material 4.
Finally, four additional trials are awaiting classification due to unresolved concerns about the similarity of their data (Amina 2022 [78]; Batool 2018 [79]; Janjua 2018 [80]; Razzaq 2017 [81]). We have not received answers from any of the authors.
Eight trials are currently ongoing (Afolabi 2022 [82]; Chua 2017 [83, 84]; Lee 2020 [85, 86]; McClure 2022 [87, 88]; Nair 2021 [89]; Paily 2020 [90, 91]; Srivastava 2023 [92, 93]; Takeshi 2021 [94, 95]); please refer to Supplementary material 5.
Furthermore, some trials appeared in our electronic search that were already included in previous versions of this review. They were manually marked as duplicates.
We found no additional randomised controlled trials (RCTs) through screening the citation lists of relevant publications.
We attempted to contact the trial authors for additional information or clarification of methods used for several of the included trials and those for which eligibility was unclear. We received additional information, including on the current status of the trial, from the authors of five trials (Chaudhuri 2013; Holm 2017; Paily 2020; Suneja 2019; Takeshi 2021)
The full search strategy is provided in Supplementary material 1.
Included studies
Design and sample sizes
We included 33 RCTs with a total of 4558 women (Akhtar 2018; Beard 2005 [96, 97, 98]; Bhandal 2006 [20, 99]; Bombac Tavcar 2024; Breymann 1996 [100, 101]; Breymann 2000 [102]; Breymann 2008 [23]; Calje 2023; Damineni 2016; ElKhouly 2017; Froessler 2013 [103]; Guerra 2012 [104]; Holm 2017; Holm 2017a; Iyoke 2017; Jain 2013 [105]; Krafft 2011 [106]; Krauss 1972 [107]; Lebrecht 1995 [108]; Makrydimas 1998 [109]; Meyer 1995 [110]; Mumtaz 2011 [111]; Perello 2014 [112, 113]; Prick 2014 [114, 115, 116, 117, 118, 119, 120]; Saad 2023; Seid 2008 [25, 121]; Suneja 2019; Tam 2005 [122]; Van Wyck 2007 [123]; Verma 2011 [124]; Wagstrom 2007 [125]; Westad 2008 [126, 127]; Yefet 2021).
Participants
All the participants were women with postpartum anaemia who received treatment within six weeks of giving birth. The included trials were conducted in 23 countries: Australia, China, Denmark, Egypt, Germany, Greece, India, Israel, Mexico, the Netherlands, New Zealand, Nigeria, Norway, Pakistan, Poland, Romania, Russia, Slovenia, South Africa, Spain, Sweden, Switzerland, and the United Kingdom. The mean age of women ranged from 24 to 30 years.
Interventions
Intravenous iron versus oral iron supplementation
Intravenous iron (either iron carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose) was compared with oral ferrous sulphate provided as tablets in 18 trials including a total of 3026 women (Akhtar 2018; Bhandal 2006; Bombac Tavcar 2024; Breymann 2008; Damineni 2016; ElKhouly 2017; Froessler 2013; Guerra 2012; Holm 2017; Iyoke 2017; Jain 2013; Mumtaz 2011; Saad 2023; Seid 2008; Suneja 2019; Van Wyck 2007; Verma 2011; Westad 2008). One trial added oral iron to those originally assigned to receive intravenous iron after four weeks (Westad 2008).
Five trials (Breymann 2008; Holm 2017; Seid 2008; Van Wyck 2007; Westad 2008), corresponding to 28% of all trials, were industry funded.
The follow‐up periods varied from 14 days to 9 months among the trials. Socioeconomic status was only clearly stated as being low in one trial (Froessler 2013). We did not make assumptions regarding socioeconomic status based on geography.
Intravenous iron versus red blood cell transfusion
Red blood cell transfusion was compared with intravenous iron treatment in two trials involving 39 women (Calje 2023; Holm 2017a). The follow‐up period in both trials was 12 weeks. One trial was industry funded (Holm 2017a).
Intravenous iron and oral iron supplementation versus oral iron supplementation
In three trials (Breymann 2000; Perello 2014; Westad 2008), intravenous and oral iron supplementation was compared to oral iron supplementation in a total of 229 women. Two trials were industry funded (Perello 2014; Westad 2008).
Red blood cell transfusion versus no transfusion
Red blood cell transfusion was compared with no transfusion in one trial with 519 women (Prick 2014). 'Standard of care' after childbirth was permitted in this comparison (e.g. oral iron tablets). The treatment of the non‐intervention arm was decided by the clinicians. This trial reported on all predefined outcomes for this review except maternal mortality. The follow‐up period was six weeks.
Oral iron supplementation versus placebo or no treatment
Oral iron tablets was compared with either placebo or no treatment in three trials with a total of 315 women (Beard 2005; Krauss 1972; Tam 2005). The preparations used in each trial contained various additives, such as vitamin C, vitamin B, and folic acid. Follow‐up varied from 30 days to 9 months among trials. One RCT only included women of low socioeconomic status (Beard 2005). The remaining trials did not provide this information. The trial by Krauss 1972 included three study arms. The trial by Tam 2005 was based on two anaemic study groups (one treated and one given placebo) and one non‐anaemic group. We included the trial based on the intervention, which fulfilled our criteria; however, the majority of the results were combined for both anaemic groups, thus not distinguishing between the treated and untreated group.
Intravenous iron and oral iron supplementation versus oral iron supplementation
Intravenous iron in combination with oral iron tablets was compared with intravenous placebo and oral iron treatment in two trials with a total of 112 women (Breymann 2000; Perello 2014). Follow‐up was two and six weeks, respectively.
Erythropoietin (regardless of route) and iron versus intravenous or oral iron supplementation
Erythropoietin and intravenous iron were compared with intravenous iron alone in two trials with a total of 100 women (Krafft 2011; Wagstrom 2007). In the trial by Wagstrom 2007, EPO was given subcutaneously in two different doses in two different groups (total of 40,000 units (U) and 20,000 U). In Krafft 2011, EPO was given intravenously. Follow‐up was two weeks in both trials.
Erythropoietin combined with intravenous iron followed by oral iron supplementation was compared with intravenous iron alone followed by oral iron supplementation in three trials with a total of 186 women (Breymann 1996; Breymann 2000; Lebrecht 1995). Two of the trials had three study arms (Breymann 1996; Breymann 2000); in one trial, EPO was given either subcutaneous or intravenous (Breymann 1996), and one trial also had a study arm that only received oral iron tablets (Breymann 2000). We compared study arms with similar treatment across trials.
Subcutaneous EPO and oral iron tablets were compared with oral iron tablets in one trial with 40 women (Makrydimas 1998). Follow‐up was 40 days.
Wagstrom 2007 was the only industry‐funded trial.
Erythropoietin (regardless of route) versus placebo
Intravenous EPO was compared with placebo in one trial with 71 women (Meyer 1995). Follow‐up was five days.
Outcomes
All the included publications reported at least one of our prespecified clinical outcome measures. Thirty‐three trials also reported other laboratory parameters besides haemoglobin, such as ferritin, mean corpuscular volume (MCV), mean corpuscular volume concentration (MCHC), transferrin, C‐reactive protein (CRP), etc.
Of all the included trials, information was reported, or study authors provided additional data on, maternal mortality eight trials (Breymann 2000; Guerra 2012; Holm 2017; Holm 2017a; Krafft 2011; Lebrecht 1995; Makrydimas 1998; Van Wyck 2007), fatigue in eight trials (Bombac Tavcar 2024; Calje 2023; Holm 2017; Holm 2017a; Prick 2014; Van Wyck 2007; Westad 2008; Yefet 2021), anaemia symptoms in three trials (Perello 2014; Prick 2014; Tam 2005), psychological well‐being in seven trials (Beard 2005; Meyer 1995; Perello 2014; Prick 2014; Van Wyck 2007; Wagstrom 2007; Westad 2008; Yefet 2021), infections in six trials (Breymann 2008; Guerra 2012; Krafft 2011; Prick 2014; Van Wyck 2007; Wagstrom 2007), compliance in 14 trials (Bhandal 2006; Breymann 2008; Damineni 2016; Guerra 2012; Iyoke 2017; Jain 2013; Krafft 2011; Prick 2014; Saad 2023; Suneja 2019; Van Wyck 2007; Verma 2011; Westad 2008; Yefet 2021), breastfeeding in six trials (Calje 2023; Krafft 2011; Makrydimas 1998; Prick 2014; Tam 2005; Yefet 2021), length of hospital stay in four trials (Makrydimas 1998; Perello 2014; Prick 2014; Verma 2011), and adverse events during treatment in 30 trials. The trials that did not report on adverse events were Beard 2005, Meyer 1995, and Akhtar 2018. Thirteen trials reported on the use of blood transfusions as a rescue treatment (Bhandal 2006; Bombac Tavcar 2024; Breymann 1996; Breymann 2000; Breymann 2008; Froessler 2013; Holm 2017; Krafft 2011; Makrydimas 1998; Perello 2014; Prick 2014; Wagstrom 2007; Westad 2008).
We chose not to consider placebo treatment as a type of intervention, based on the lack of evidence for a substantial placebo effect [128]. Groups with inactive placebo were therefore considered comparable with groups not receiving treatment. We also chose not to distinguish between subcutaneous and intravenous EPO administration, as we did not expect the effect to be influenced by the route of administration.
The included trials are described in detail in Supplementary material 2. Only the preplanned outcomes chosen for this review were described and analysed. For an 'Overview of included studies and syntheses' table, please refer to Table.
1. Overview of Synthesis and Included Studies (OSIS) table for the review ‘Treatment for women with postpartum iron deficiency anaemia’.
| Study name; year; country of conduct | Study design | Population (sample size: intervention/control) | Laboratory value inclusion criteria | Outcome domain | Outcome measure | Follow‐up time points | Method of synthesis |
| Intravenous iron versus oral iron supplementation | |||||||
| Akhtar 2018 Pakistan |
RCT | 60: 30/30 | Hb < 10 g/dL to 7 mg/dL and ferritin level < 15 μg/L at 24 to 48 hours of delivery and women |
|
|
15 days 40 days |
|
| Bhandal 2006 UK |
RCT | 44: 22/22 | Hb < 90 g/L |
|
|
5 days 14 days 40 days |
|
| Bombac Tavcar 2024 Slovenia |
RCT | 300: 3 study arms 100/100/100 | Hb levels between 70 and 100 g/L within 48 h after childbirth |
|
|
6 weeks |
|
| Breymann 2008 Switzerland |
RCT | 329: 231/118 | Hb < 105 g/L |
|
|
2 weeks 4 weeks 12 weeks |
|
| Damineni 2016 India |
RCT | 98: 47/51 | Hb between 7 and 10 g/dL and peripheral smear showing microcytic hypochromic anaemia on the first postpartum day |
|
|
1 week 6 weeks |
|
| ElKhouly 2017 Egypt |
RCT | 252: 176/176 | Hb between 7 and 10 g/dL and peripheral smear showing microcytic hypochromic anaemia on the first postpartum day |
|
|
5 days 14 days 40 days |
|
| Froessler 2013 Australia |
RCT | 90: 37/53 | Hb < 110 g/L and ferritin < 12 μg/L either antepartum or within 72 hours postpartum, following caesarean section and vaginal delivery with blood loss > 500 mL |
|
|
1 day 14 days 42 days |
|
| Guerra 2012 Spain |
RCT | 13: 6/7 | Hb 70 to 100 g/L, and ferritin > 15 µg/L at 24 hours postpartum |
|
|
7 days 14 days 42 days |
|
| Holm 2017 Denmark |
RCT | 200: 100/100 | PPH ≥ 700 and ≤ 1000 mL or PPH > 1000 mL and Hb > 6.5 g/dL (4.0 mmol/L) measured at > 12 hours after delivery |
|
|
3 days 1 week 3 weeks 8 weeks 12 weeks |
|
| Iyoke 2017 Nigeria |
RCT | 284: 142/142 | Hb 6 to 7.9 g/dL with features of iron deficiency (red cell hypochromia and microcytosis with or without anisocytosis and poikilocytosis) |
|
|
6 weeks |
|
| Jain 2013 India |
RCT | 46: 23/23 | Hb < 80 g/L within 48 hours postpartum |
|
|
7 days 14 days |
|
| Mumtaz 2011 Pakistan |
RCT | 80: 40/40 | Hb < 90 g/L, ferritin < 15 μg/dL at 24 to 48 hours postpartum |
|
|
7 days 14 days 40 days |
|
| Saad 2023 USA |
RCT | 40: 20/20 | Hb levels below 9 g/dL on postpartum day 1 |
|
|
6 weeks |
|
| Seid 2008 USA |
RCT | 291: 143/148 | Hb < 100 g/L 10 days or less postpartum on 2 or more laboratory tests conducted at least 12 hours apart |
|
|
42 days |
|
| Suneja 2019 India |
RCT | 140: 70/70 | Hb 7 to 10 g/dL, peripheral smear showing microcytic hypochromic anaemia or red cell indices suggestive of iron deficiency anaemia (PCV < 36%, MCV < 80 fL, MCH < 27 pg, and MCHC < 33 g/dL) with negative NESTROF test |
|
|
6 weeks |
|
| Van Wyck 2007 USA |
RCT | 361: 182/179 | Hb ≤ 100 g/L |
|
|
42 days |
|
| Verma 2011 India |
RCT | 150: 75/75 | Hb < 80 g/L 24 hours after delivery |
|
|
7 days 15 days 30 days |
|
| Westad 2008 (< 4 weeks) Norway |
RCT | 128: 58/70 | Hb 65 to 85 g/L |
|
|
4 weeks 8 weeks 12 weeks |
|
| Intravenous iron versus red blood cell transfusion | |||||||
| Calje 2023 New Zealand |
RCT | 26: data extracted from 2 study arms: 8/10 | Hb 65 to 79 g/L ≤ 7 days of birth |
|
|
1 week 6 weeks 12 weeks |
|
| Holm 2017a Denmark |
RCT | 13: 7/6 | Hb between 5.6 and 8.1 g/dL (3.5 and 5.0 mmol/L ‐ in Denmark Hb is expressed in mmol/L) measured at least 12 h after delivery |
|
|
1 week 3 weeks 8 weeks 12 weeks |
|
| Intravenous iron and oral iron supplementation versus oral iron supplementation | |||||||
| Breymann 2000 Switzerland |
RCT | 60: data extracted from 2 study arms: 20/20 | Hb < 100 g/L 24 to 72 hours postpartum |
|
|
4 days 7 days 14 days |
|
| Perello 2014 Spain |
RCT | 72: 36/38 | Hb 60 to 80 g/L within the 48 hours after delivery |
|
|
1 week 2 weeks 6 weeks |
|
| Westad 2008 (> 4 weeks ‐ see first comparison for details) Norway |
RCT | ‐ | Hb 65 to 85 g/L | ‐ | ‐ | ‐ | ‐ |
| Red blood cell transfusion versus no transfusion | |||||||
| Prick 2014 Netherlands |
RCT | 521: 259/262 | Hb 48 to 79 g/L 12 to 24 hours postpartum, postpartum haemorrhage (> 1000 mL and/or a decrease in Hb > 19 g/L) |
|
|
3 days 1 week 3 weeks 6 weeks |
|
| Oral iron supplementation versus placebo or no treatment | |||||||
| Beard 2005 South Africa |
RCT | 64: 34/30 | Hb 90 to 115 g/L, and at least 2 of the following: MCV < 80 fL, TSAT < 15%, serum ferritin < 12 µg/L |
|
|
10 weeks 9 months |
|
| Krauss 1972 Germany |
RCT | 101: data extracted from 2 study arms: 34/34 | Hb values for inclusion in this study were not defined. Table 1 shows that the mean Hb in all groups was < 120 g/L prior to treatment. |
|
|
6 days 30 days |
|
| Tam 2005 China |
RCT | 150: 75/75 | Hb 80 to 99 g/L 2 days postpartum |
|
|
6 weeks |
|
| Erythropoietin (regardless of route) and iron versus intravenous or oral iron supplementation | |||||||
| Breymann 1996 Switzerland |
RCT | 90: data extracted from 2 study arms: 30/30 | Hb < 100 g/L 48 to 72 hours after delivery |
|
|
1 day 4 days 14 days 42 days |
|
| Krafft 2011 Switzerland |
RCT | 40: 20/20 | Prepartal Hb > 100 g/L, followed by severe postpartum anaemia, defined by an Hb < 85 g/L 24 to 48 hours after delivery |
|
|
4 days 8 days 15 days |
|
| Lebrecht 1995 Germany |
RCT | 36: 24/12 | Hb < 90 g/L on second day postpartum |
|
|
3 days 4 days 7 days 14 days 28 days |
|
| Makrydimas 1998 Greece |
RCT | 40: 20/20 | Hb < 100 g/L on first day postpartum |
|
|
1 day 3 days 5 days 10 days 15 days 40 days |
|
| Wagstrom 2007 Sweden |
RCT | 60: data extracted from 2 study arms: 20/20 | Hb < 80 g/L within 72 hours after delivery |
|
|
3 days 7 days 14 days |
|
| Erythropoietin (regardless of route) versus placebo | |||||||
| Meyer 1995 Switzerland |
RCT | 71: 35/36 | Hb < 100 g/L |
|
|
5 days |
|
EPDS: Edinburgh Postnatal Depression Scale Hb: haemoglobin IQR: interquartile range MCH: mean corpuscular haemoglobin MCHC: mean corpuscular haemoglobin concentration MCV: mean corpuscular volume MFI: Multidimensional Fatigue Inventory NESTROF: Naked‐Eye Single Tube Red Cell Osmotic Fragility PSQ: Perceived Stress Questionnaire PCV: packed cell volume PPH: postpartum haemorrhage RCT: randomised controlled trial SD: standard deviation SF‐36: 36‐Item Short Form Health Survey STAI: State‐Trait Anxiety Inventory TSAT: transferrin saturation
Excluded studies
We excluded 12 studies identified in this updated search. Reasons for exclusion were wrong comparator (Garg 2015 [129]; Hamm 2021 [130]; Karwasara 2023 [131]; Prakash 2023 [132]; Rush 2023 [133]; Saroj 2023 [134]; Wajid 2021 [135]), wrong patient population (Jose 2023 [136]; Vanobberghen 2021 [137]), wrong study design (Calje 2022 [138]; Sirsam 2022 [139]), and one study was terminated prematurely due to "some institutional issues" (Chaudhuri 2013). Combined with 17 excluded studies from the previous review, there were a total of 29 excluded studies.
For further details, please see Supplementary material 3.
Screening eligible studies for trustworthiness
We screened all trials for trustworthiness and scientific integrity using the Cochrane Trustworthiness Screening Tool. We contacted the authors of the five studies that were either awaiting classification or classified as high risk of bias for additional information. One study lacked a protocol and full text (Abbas 2019), and the author, who has several retracted studies [77], did not respond to our request for additional information. Four studies are awaiting classification due to unresolved concerns about the similarity of their content, data presentation, and methodology (Amina 2022; Batool 2018; Janjua 2018; Razzaq 2017).
All studies included in the review or assessed as ongoing after the trustworthiness assessment were judged as being at low risk based on research governance, baseline characteristics, feasibility, and results.
Ongoing studies
We identified a total of eight ongoing studies, of which six were found in the WHO ICTRP, one in ClinicalTrials.gov (McClure 2022), and one reported as pilot study (Nair 2021). Protocols were made available between 2017 and 2023, and the countries include Nigeria, Australia, Korea, a multicentre study in eight low‐income countries, Malaysia, Japan, and two studies in India.
A full list of ongoing studies can be found in Supplementary material 5.
Risk of bias in included studies
The risk of bias assessment is summarised in Figure and Figure.
3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Random sequence generation
We assessed 20 trials as at low risk of bias (Akhtar 2018; Bhandal 2006; Bombac Tavcar 2024; Calje 2023; ElKhouly 2017; Froessler 2013; Guerra 2012; Holm 2017; Holm 2017a; Iyoke 2017; Jain 2013; Krafft 2011; Perello 2014; Prick 2014; Seid 2008; Tam 2005; Van Wyck 2007; Wagstrom 2007; Westad 2008; Yefet 2021). We assessed 13 trials as at unclear risk of bias, as the random sequence generation method was not described (Beard 2005; Breymann 1996; Breymann 2000; Breymann 2008; Damineni 2016; Krauss 1972; Lebrecht 1995; Makrydimas 1998; Meyer 1995; Mumtaz 2011; Saad 2023; Suneja 2019; Verma 2011).
Allocation concealment
We assessed 20 trials as at low risk of bias (Beard 2005; Bhandal 2006; Breymann 1996; Breymann 2000; Froessler 2013; Guerra 2012; Krafft 2011; Perello 2014; Prick 2014; Tam 2005 Van Wyck 2007 Bombac Tavcar 2024; Calje 2023; ElKhouly 2017; Holm 2017; Holm 2017a; Iyoke 2017; Wagstrom 2007; Westad 2008; Yefet 2021). We assessed 13 trials as at unclear risk of bias, as the allocation concealment method was not described (Akhtar 2018; Breymann 2008; Damineni 2016; Jain 2013; Krauss 1972; Lebrecht 1995; Makrydimas 1998; Meyer 1995; Mumtaz 2011; Saad 2023; Seid 2008; Suneja 2019; Verma 2011).
Blinding
Performance bias
We assessed one trial as at low risk of bias (Perello 2014), as blinding was clearly described and considered adequate, and it was clear who was blinded.
We assessed six trials as at unclear risk of bias. Three placebo‐controlled trials described the blinding method as double‐blind, but it was unclear who was blinded (Lebrecht 1995; Meyer 1995; Saad 2023). In the trial reported by Beard 2005, it was unclear if all treatment components (iron, folate, vitamin C) were prepared in a single tablet and whether this tablet resembled the placebo tablet. In Tam 2005, it was reported that although the trial was double‐blinded, the participants reported stool discolourations when receiving active treatment. In Calje 2023, all participants underwent an intravenous infusion (either red blood cell transfusion, iron, or both), which reduces the likelihood of potential differences in co‐intervention, as the route of administration, preparation, and aftercare were similar.
We assessed the majority of the trials as at high risk of bias due to their open‐label design, which is likely to influence subjective outcomes and adverse events (Akhtar 2018; Bhandal 2006; Bombac Tavcar 2024; Breymann 1996; Breymann 2000; Breymann 2008; Damineni 2016; ElKhouly 2017; Froessler 2013; Guerra 2012; Holm 2017; Holm 2017a; Iyoke 2017; Jain 2013; Krafft 2011; Krauss 1972; Makrydimas 1998; Mumtaz 2011; Prick 2014; Seid 2008; Suneja 2019; Van Wyck 2007; Verma 2011; Wagstrom 2007; Westad 2008; Yefet 2021).
Detection bias
We assessed seven trials as at unclear risk of bias. Three trials were described as double‐blinded, but it was unclear who was blinded (Lebrecht 1995; Meyer 1995; Saad 2023). In Perello 2014, it was unclear whether personnel who handled self‐rated questionnaires were blinded. In Tam 2005, it was unclear whether participants could identify their treatment based on alterations in stool colour. Since the outcomes relied on subjective participant reports, the risk of detection bias hinged on participants' awareness of the connection between iron therapy and stool discolouration, as well as clinicians' knowledge of any discolouration when recording other outcomes. In Beard 2005, it was not clear from the study description who was blinded and whether the placebo tablet and treatment were sufficiently similar to prevent participants from guessing the group assignment. In Akhtar 2018, blinding procedures were unclear.
We assessed 25 trials as at high risk of bias due to their open‐label trial design (Bhandal 2006; Bombac Tavcar 2024; Breymann 1996; Breymann 2000; Breymann 2008; Calje 2023; Damineni 2016; ElKhouly 2017; Froessler 2013; Guerra 2012; Holm 2017; Holm 2017a; Iyoke 2017; Jain 2013; Krafft 2011; Krauss 1972; Makrydimas 1998; Mumtaz 2011; Prick 2014; Seid 2008; Suneja 2019; Van Wyck 2007; Verma 2011; Wagstrom 2007; Westad 2008; Yefet 2021). Maternal mortality is likely not affected by a lack of blinding. However, this outcome was rarely reported. Haemoglobin and other laboratory values were also considered unlikely to be influenced by lack of blinding.
Incomplete outcome data
Twenty‐nine trials reported information on dropouts and withdrawals after randomisation (Beard 2005; Bhandal 2006; Bombac Tavcar 2024; Breymann 2000; Breymann 2008; Calje 2023; Damineni 2016; ElKhouly 2017; Froessler 2013; Guerra 2012; Holm 2017; Holm 2017a; Iyoke 2017; Jain 2013; Krafft 2011; Krauss 1972; Lebrecht 1995; Makrydimas 1998; Mumtaz 2011; Perello 2014; Prick 2014; Saad 2023; Seid 2008; Suneja 2019; Tam 2005; Van Wyck 2007; Wagstrom 2007; Westad 2008; Yefet 2021). Three trial authors provided additional information on dropout rates (Froessler 2013; Van Wyck 2007; Wagstrom 2007).
Dropout rates varied greatly across trials. They were lower than 5% in eight trials (Bhandal 2006; Breymann 2000; Holm 2017; Holm 2017a; Krafft 2011; Lebrecht 1995; Makrydimas 1998; Seid 2008), between 5% and 9.9% in four trials (Damineni 2016; Krauss 1972; Mumtaz 2011; Van Wyck 2007), between 10% and 19.9% in 10 trials (Bombac Tavcar 2024; ElKhouly 2017; Froessler 2013; Guerra 2012; Iyoke 2017; Jain 2013; Perello 2014; Suneja 2019; Tam 2005; Wagstrom 2007), and 20% or more in seven trials (Beard 2005; Breymann 2008; Calje 2023; Prick 2014; Saad 2023; Westad 2008; Yefet 2021). In four trials, information was insufficient to calculate the dropout rates after randomisation (Akhtar 2018; Breymann 1996; Meyer 1995; Verma 2011).
We assessed 14 trials as at low risk of bias because the dropout rate was low or equally distributed across groups (Bhandal 2006; Bombac Tavcar 2024; Breymann 2000; ElKhouly 2017; Holm 2017; Holm 2017a; Iyoke 2017; Jain 2013; Krafft 2011; Krauss 1972; Lebrecht 1995; Makrydimas 1998; Mumtaz 2011; Seid 2008).
We assessed six trials as at unclear risk of bias. In one trial, the reasons for dropouts were not explained (Guerra 2012). In three trials, it was not mentioned whether any participants dropped out after randomisation (Akhtar 2018; Breymann 1996; Verma 2011). In Calje 2023, only five out of eight participants in the intravenous arm completed the trial, and it is unclear how this could have affected the final results. In Yefet 2021, there was a relatively large dropout rate, although it appeared to be balanced. A subanalysis of the baseline characteristics of women who completed the trial versus those who were lost to follow‐up found no substantial difference between them, hence our judgement of unclear risk of attrition bias.
We assessed 13 trials as at high risk of bias due to a high dropout rate or unequal distribution across groups, or both (Beard 2005; Breymann 2008; Damineni 2016; Froessler 2013; Meyer 1995; Perello 2014; Prick 2014; Saad 2023; Suneja 2019; Tam 2005; Van Wyck 2007; Wagstrom 2007; Westad 2008).
Selective reporting
In the previous update of this review, strict criteria were applied when evaluating reporting bias due to the critical importance of mortality. Consequently, only two trials were rated as having a low risk of reporting bias (Krafft 2011; Van Wyck 2007). In the current update, an additional six trials were assessed as having a low risk of reporting bias due to comprehensive reporting of all outcomes prespecified in their protocols or trial registrations (Bombac Tavcar 2024; Calje 2023; Holm 2017; Holm 2017a; Saad 2023; Yefet 2021).
We assessed six trials as at unclear risk of bias due to lack of reporting on some preplanned outcomes, unspecified adverse events, or retrospective publication of their protocol (Breymann 2000; Damineni 2016; ElKhouly 2017; Guerra 2012; Iyoke 2017; Suneja 2019)
We assessed 19 trials as at high risk of bias, primarily due to lack of reporting on harms of use, adverse events, and mortality (Akhtar 2018; Beard 2005; Bhandal 2006; Breymann 1996; Breymann 2008; Froessler 2013; Jain 2013; Krauss 1972; Meyer 1995; Mumtaz 2011; Perello 2014; Prick 2014; Seid 2008; Tam 2005; Verma 2011; Wagstrom 2007; Westad 2008), and in two trials there was a lack of data to support conclusions on quality of life (Lebrecht 1995; Makrydimas 1998). The Verma 2011 trial did not report on many preplanned outcomes.
Other potential sources of bias
We assessed seven trials as at unclear risk of other bias. In Krauss 1972, the haemoglobin level for inclusion was not stated. Three of the newly included trials in this update were sponsored by pharmaceutical companies (Holm 2017; Holm 2017a; Yefet 2021): Pharmacosmos A/S, the manufacturer of iron isomaltoside (Monofer), and Altman Health, the market leader in Israel for dietary supplements. In Holm 2017, no oral iron supplementation was provided. Instead, participants were recommended to continue their oral iron supplementation as they had during pregnancy, following the Danish Health and Medicines Authority's guideline of 40 to 50 mg daily. Alternatively, they were advised to take 100 mg of oral iron supplementation once or twice daily for a variable period. Relying on women to acquire oral iron supplementation themselves could weaken adherence in the control arm. However, it could also be seen as a pragmatic trial, though this may favour the intravenous iron treatment.
The authors of Bombac Tavcar 2024 received fees from Ewopharma for leading a workshop on anaemia in pregnancy and postpartum after study completion. We assessed the risk of other potential sources of bias as unclear in Akhtar 2018 due to poor reporting and in Suneja 2019 due to several years of delayed publication. An explanation is provided in Supplementary material 2.
We assessed three trials as at high risk of bias because of significant errors in the published reports (Mumtaz 2011; Van Wyck 2007; Verma 2011). For further description, please see Supplementary material 2.
Synthesis of results
Comparison 1: Intravenous iron versus oral iron supplementation
Intravenous iron treatment was compared with oral iron supplementation in 18 trials with a total of 3026 women (Akhtar 2018; Bhandal 2006; Bombac Tavcar 2024; Breymann 2008; Damineni 2016; ElKhouly 2017; Froessler 2013; Guerra 2012; Holm 2017; Iyoke 2017; Jain 2013; Mumtaz 2011; Saad 2023; Seid 2008; Suneja 2019; Van Wyck 2007; Verma 2011; Westad 2008). Intravenous iron was in the form of either iron carboxymaltose (six trials), iron dextran (two trials), iron isomaltoside (one trial), or iron sucrose (nine trials). Doses differed across trials, with a total dose range of 300 mg to 2500 mg. In several trials, doses were individually calculated using the Ganzoni formula, estimating the iron deficit in each participant. Oral iron supplementation was given as ferrous sulphate, typically using a fixed dose. Treatment regimens differed between trials with regard to doses, number of iron tablets per day, and number of days of treatment. Non‐elemental iron doses ranged from 100 mg to 325 mg per tablet from one to three times a day. See Table; for outcomes not presented here, refer to Supplementary material 8.
Critical outcomes
Maternal mortality
The evidence is very uncertain about the effect of intravenous iron on mortality (risk ratio (RR) 2.95, 95% confidence interval (CI) 0.12 to 71.96; P = 0.51; I² = not applicable; 3 RCTs; 572 women; very low‐certainty evidence; Analysis 1.1). There was one maternal death in the group receiving intravenous iron, caused by peripartum cardiomyopathy 13 days postpartum, making it unclear whether this death was caused by the study medication (Van Wyck 2007). The corresponding author of another trial reported that no women died (Guerra 2012). There were no deaths reported in the trial of Holm 2017 (unpublished data). The occurrence of deaths in the remaining trials was uncertain.
Fatigue
Intravenous iron probably results in a slight reduction in fatigue on day 0 to 7 (mean difference (MD) −1.60, 95% CI −2.71 to −0.49; P = 0.005; I² = not applicable; 1 RCT; 193 women; moderate‐certainty evidence; Analysis 1.2).
Two trials were eligible for meta‐analysis of fatigue on day 8 to 28 postpartum. Intravenous iron probably results in a slight reduction in fatigue on day 8 to 28 (standardised mean difference (SMD) −0.25, 95% CI −0.42 to −0.07; P = 0.006; I² = 47%; 2 RCTs; 515 women; moderate‐certainty evidence; Analysis 1.3).
Intravenous iron probably results in little to no difference in fatigue after 28 days (SMD −0.10, 95% CI −0.24 to 0.04; P = 0.17; I² = 0%; 3 RCTs; 783 women; moderate‐certainty evidence; Analysis 1.4).
Four trials reported fatigue. Van Wyck 2007 used the Fatigue Linear Analog Scale Assessment [140] for a mean total fatigue score. In Bombac Tavcar 2024, fatigue was assessed using the Multidimensional Fatigue Inventory (MFI) [141]. In Holm 2017, fatigue was measured by the physical fatigue subscale of the MFI, allowing a maximum change of 16 points.
In all trials, a higher score indicated a higher level of fatigue. Two trials reported an improvement in fatigue in the group receiving intravenous treatment (Holm 2017; Westad 2008). However, in Holm 2017, a clinically significant decrease in the fatigue scale was predefined as a reduction of 1.8 points on the MFI. The trial did not meet this criterion within one week postpartum, showing only a 1.6‐point reduction. The other two trials showed no difference in fatigue (Bombac Tavcar 2024; Van Wyck 2007).
Westad 2008 used the Fatigue Score [142]. It was not possible to obtain SDs from Westad 2008 (SDs were only available for baseline data), thus preventing inclusion of this trial in a meta‐analysis. The trial found improvement in fatigue in the group receiving intravenous treatment after 4, 8, and 12 weeks.
Important outcomes
Persistent anaemia symptoms
Not reported.
Persistent postpartum anaemia
Not reported.
Psychological well‐being
Two trials reported psychological well‐being (Van Wyck 2007; Westad 2008). Both trials used the SF‐36, where higher scores indicate better health state [48]. There was no overall difference in psychological well‐being (see below).
It was not possible to carry out a meta‐analysis, as SDs were only available for baseline data for the trial by Westad 2008. This trial reported on four out of eight SF‐36 items. In the published report, the authors found no between‐group difference, given as a change from baseline, in week four.
Van Wyck 2007 provided raw means on all eight items of the SF‐36: 'physical function', 'physical role', 'bodily pain', 'social function', 'mental health', 'general health', 'vitality', and 'emotional role'. Intravenous iron may result in little to no difference in psychological well‐being at two weeks compared with oral iron supplementation (MD −1.20, 95% CI −4.84 to 2.44; P = 0.52; I² = not applicable; 1 RCT; 321 women; low‐certainty evidence; Analysis 1.5).
Urinary tract infections, endometritis, or other infections
Intravenous iron may result in a slight increase to no difference in infections compared to oral iron supplementation (RR 1.49, 95% CI 0.93 to 2.38; I² = 72%; 3 RCTs; 718 women; low‐certainty evidence; Analysis 1.6).
Infections were analysed as a total of events for each group. The results diverged: in the trial by Breymann 2008, infections were more frequent in the group treated with intravenous iron, whereas there was no difference between groups in the trial by Van Wyck 2007. In Guerra 2012, there were no events of infection.
Compliance to treatment
Ten trials reported compliance (Bhandal 2006; Breymann 2008; Damineni 2016; Guerra 2012; Jain 2013; Saad 2023; Suneja 2019; Van Wyck 2007; Verma 2011; Westad 2008).
Intravenous iron may increase compliance (RR 1.17, 95% CI 1.13 to 1.22; P < 0.001; I² = 77%; 7 RCTs; 1011 women; low‐certainty evidence; Analysis 1.7).
Of the trials reporting on compliance eligible for meta‐analysis, 566 of 572 women were compliant in receiving the intravenous iron (98.95%). In comparison, 369 of 439 women were compliant with their prescribed oral iron supplementation (84.05%).
Compliance was mainly defined as receiving all the preplanned intravenous infusions or the entire single‐dose infusion. In the groups treated with oral iron supplementation, compliance was mostly monitored by returned blister packs used to assess adherence to therapy. Compliance varied greatly among the trials and was influenced by whether the trial took measures to motivate participants to take their prescribed tablets. Some trials sent reminders to women, while others did not. Additionally, the reporting of reasons for non‐compliance (e.g. side effects) was not always present.
Jain 2013 and Verma 2011 did not provide data eligible for analysis. Jain 2013 reported 100% compliance in the groups treated with oral iron supplementation, confirmed by pill count, but did not specify compliance for the group treated with intravenous iron. Verma 2011 mentioned that compliance was better in the group receiving intravenous iron compared to the group treated with oral iron supplementation, but did not provide specific data.
Breastfeeding
Not reported.
Length of hospital stay
Length of hospital stay was generally not reported. Verma 2011 noted that hospital stays were longer in the groups treated with intravenous iron, but data were not available.
Adverse events
Serious adverse events
Intravenous iron may result in little to no difference in serious adverse events (RR 1.11, 95% CI 0.52 to 2.37; I² = 0%; 4 RCTs; 913 women; low‐certainty evidence; Analysis 1.8).
One woman who received intravenous iron developed cardiac arrhythmia during the iron infusion in the trial by Froessler 2013. The woman was excluded from the trial. However, upon investigation, the arrhythmia appeared to be unrelated, as it had occurred previously. Although the trial did not classify it as a serious adverse event, we evaluated it as such and reported it narratively.
Anaphylaxis or evidence of hypersensitivity
Twelve trials reported anaphylaxis (Bhandal 2006; Bombac Tavcar 2024; Breymann 2008; Damineni 2016; Froessler 2013; Holm 2017; Iyoke 2017; Jain 2013; Saad 2023; Seid 2008; Van Wyck 2007; Verma 2011).
The evidence is very uncertain about the effect of intravenous iron on anaphylaxis or hypersensitivity (RR 2.77, 95% CI 0.31 to 24.86; I² = 0%; 12 RCTs; 2195 women; very low‐certainty evidence; Analysis 1.9). Three of 1086 women who received intravenous iron experienced anaphylaxis (one woman) or hypersensitivity (two women).
The trials reporting on cases of severe allergic reactions, Breymann 2008 and Verma 2011, used iron carboxymaltose and iron sucrose, respectively.
Flushing/Fishbane reaction
Five trials reported flushing/Fishbane reaction (Bhandal 2006; Bombac Tavcar 2024; Holm 2017; Mumtaz 2011; Saad 2023). Eleven of 355 women who received intravenous iron experienced flushing or Fishbane reaction.
No women who received oral iron supplementation experienced flushing or Fishbane reaction. Intravenous iron probably increases flushing/Fishbane reaction (RR 5.74, 95% CI 1.38 to 23.91; I² = 0%; 5 RCTs; 619 women; moderate‐certainty evidence; Analysis 1.10).
In a clinical context, it is important to distinguish flushing/Fishbane reactions from genuine anaphylactic reactions. The trials defined the outcome somewhat differently. In Mumtaz 2011 and Bhandal 2006, the adverse event was reported as facial flushing, described as a warm, tingling sensation and redness of the facial skin. There were no haemodynamic disturbances observed either during or after infusion.
In Holm 2017, two women experienced acute back, neck, and chest pain during infusion that abated spontaneously over a few minutes (categorised as Fishbane reaction).
No treatment was given for either reaction, and the infusion could be continued (but one woman did not want to).
Injection site discomfort/reaction
Intravenous iron probably increases the risk of injection site discomfort/reaction (RR 7.10, 95% CI 1.95 to 25.84; I² = 0%; 6 RCTs; 1212 women; moderate‐certainty evidence; Analysis 1.11).
A total of 21 of 710 women experienced some kind of injection site discomfort, discolouration, or skin reaction/rash. All reactions were mild and transient.
Obviously, no women experienced this adverse effect in the group treated with oral iron supplementation.
Constipation, nausea, and gastrointestinal pain
Overall, gastrointestinal symptoms were probably less frequent in the group treated with intravenous iron.
Oral iron supplementation probably results in a large increase in constipation compared to intravenous iron (RR 0.12, 95% CI 0.06 to 0.21; I² = 0%; 10 RCTs; 1798 women; moderate‐certainty evidence; Analysis 1.12).
Women receiving intravenous iron probably experience less nausea (RR 0.18, 95% CI 0.09 to 0.37; I² = 0%; 8 RCTs; 1303 women; moderate‐certainty evidence; Analysis 1.13) and may experience little to no difference in gastrointestinal pain (RR 0.49, 95% CI 0.18 to 1.36; I² = 36%; 5 RCTs; 797 women; low‐certainty evidence; Analysis 1.14) compared to oral iron supplementation.
Number of red blood cell‐transfused women
Intravenous iron may make little to no difference to the number of red blood cell transfusions (RR 0.75, 95% CI 0.23 to 2.40; P = 0.63; I² = 0%; 5 RCTs; 938 women; low‐certainty evidence; Analysis 1.15). The number of units of red blood cell transfused was not reported systematically.
Haemoglobin (g/dL)
Most trials reported on haemoglobin levels. However, not all reported results could be included in our analysis, as some trials provided data as mean and range, while others reported it as a rate of efficacy (e.g. haemoglobin rise of 3.5 g/dL).
Seven trials reported haemoglobin values (g/dL) at day 0 to 7 (Akhtar 2018; Bhandal 2006; Damineni 2016; ElKhouly 2017; Guerra 2012; Holm 2017; Jain 2013). The trials were too heterogeneous to combine (I² = 93%; 7 RCTs; 756 women; low‐certainty evidence; Analysis 1.16). We investigated whether heterogeneity could be explained by type of intravenous iron or dosage, but this was not the case (Analysis 7.1). When trials with unclear risk of bias for allocation were excluded in Analysis 1.16, the heterogeneity disappeared, but the effect of intravenous iron within one week was slightly smaller (MD 0.15, 95% CI 0.04 to 0.25; P = 0.005; I² = 0%; 4 RCTs; 565 women; low‐certainty evidence; Analysis 8.1) compared to oral iron supplementation.
Six trials reported haemoglobin values (g/dL) within 8 to 28 days post‐intervention/postpartum (Akhtar 2018; Bhandal 2006; ElKhouly 2017; Guerra 2012; Holm 2017; Jain 2013). The trials were too heterogeneous to combine (I² = 93%; 6 RCTs; 666 women; low‐certainty evidence; Analysis 1.17), and the heterogeneity could not be explained by either intravenous iron type or dosage (Analysis 7.2) or risk of bias for allocation concealment (Analysis 8.2). However, five of six trials showed a benefit of intravenous iron compared to oral iron supplementation, with mean changes in haemoglobin ranging from 0.73 to 2.10 g/dL. Guerra 2012 appeared to be an outlier, but excluding the study did not explain the heterogeneity, as I² remained unchanged.
Nine trials reported haemoglobin values (g/dL) four weeks post‐intervention/postpartum (Akhtar 2018; Bhandal 2006; Bombac Tavcar 2024; Damineni 2016; ElKhouly 2017; Guerra 2012; Holm 2017; Iyoke 2017; Suneja 2019). Again, the trials were too heterogeneous to combine (I² = 97%; 9 RCTs; 1333 women; low‐certainty evidence; Analysis 1.18), and the heterogeneity could not be explained by either intravenous iron type or dosage (Analysis 7.3) or risk of bias for allocation concealment (Analysis 8.3). However, six of nine trials showed a benefit of intravenous iron compared to oral iron supplementation, with mean changes in haemoglobin ranging from 0.40 to 1.89 g/dL. Guerra 2012 appeared to be an outlier, but excluding the study did not explain the heterogeneity, as I² remained unchanged.
It is noteworthy that the two largest trials in this comparison showed conflicting results after 28 days (ElKhouly 2017; Iyoke 2017), with ElKhouly 2017 finding an MD of 1.35 (95% CI 1.24 to 1.46), and Iyoke 2017 finding no difference between groups in mean level of haemoglobin after 28 days (MD 0.09, 95% CI −0.05 to 0.23). The only important clinical difference between the trials was that Iyoke 2017 included Short Message Service (SMS) reminders to motivate the group treated with oral iron supplementation to take their pills.
The high level of heterogeneity observed in the trials could be attributed to clinical heterogeneity, which encompasses variations in participant characteristics, interventions (e.g. different types of intravenous iron, total iron dose, iron dosage regimens, and methods used by authors to ensure participant compliance in the groups treated with oral iron supplementation, baseline haemoglobin), and the outcomes measured (e.g. the various time points that were pooled) across the trials.
Comparison 2: Red blood cell transfusion versus intravenous iron
Red blood cell transfusion was compared with intravenous iron treatment in two trials with a total of 39 women (Calje 2023; Holm 2017a). The number of red blood cell units was determined by the responsible clinician, often with 1 to 2 units of red blood cells being given. The comparators in the trials were iron carboxymaltose and iron isomaltoside, respectively.
We extracted data only from the two relevant arms in the trial by Calje 2023 (red blood cell transfusion and intravenous iron, respectively). The third and last study arm did not fit into any comparison in this review (intravenous iron combined with red blood cell transfusion). See Table; for outcomes not presented here, refer to Supplementary material 9.
Critical outcomes
Maternal mortality
No deaths were reported in the trial by Holm 2017a (not estimable; Analysis 2.1).
Fatigue
The evidence is very uncertain about the effect of red blood cell transfusion on fatigue on day 0 to 7 (SMD −0.04, 95% CI −0.77 to 0.68; P = 0.90; I² = 0%; 2 RCTs; 29 women; very low‐certainty evidence; Analysis 2.2), day 8 to 28 (MD 1.20, 95% CI −2.41 to 4.81; P = 0.51; I² = not applicable; 1 RCT; 13 women; very low‐certainty evidence; Analysis 2.3), and after 28 days (SMD −0.52, 95% CI −1.29 to 0.25; P = 0.18; I² = 0%; 2 RCTs; 29 women; very low‐certainty evidence; Analysis 2.4) compared to intravenous iron.
Important outcomes
Persistent anaemia symptoms
Not reported.
Persistent postpartum anaemia
Not reported.
Psychological well‐being
No studies reported psychological well‐being. However, Holm 2017a and Calje 2023 used the Edinburgh Postnatal Depression Scale (EPDS) [143] to estimate and examine the risk of depression; no difference was found between groups in depression scores at any time point.
Both trials were pilot trials and feasibility studies, limiting their power.
Urinary tract infections, endometritis, or other infections
Not reported.
Compliance to treatment
Not reported
Breastfeeding
The number of participants for this outcome in Calje 2023 was very small. The evidence is very uncertain about the effect of red blood cell transfusion on breastfeeding at hospital discharge (RR 0.88, 95% CI 0.63 to 1.23; P = 0.46; I² = not applicable; 1 RCT; 16 women; very low‐certainty evidence; Analysis 2.5) and more than six weeks postpartum (RR 0.43, 95% CI 0.12 to 1.57; P = 0.20; I² = not applicable; 1 RCT; 13 women; very low‐certainty evidence; Analysis 2.6).
Length of hospital stay
Not reported.
One case of Fishbane reaction, in the group treated with intravenous iron, was reported in Holm 2017a. The reaction was characterised by acute back, neck, and chest pain during infusion that abated spontaneously over a few minutes. The evidence is very uncertain about the effect of red blood cell transfusion on flushing/Fishbane reaction (RR 0.38, 95% CI 0.02 to 7.93; P = 0.53; I² = not applicable; 1 RCT; 13 women; very low‐certainty evidence; Analysis 2.7).
Adverse events
Anaphylaxis or evidence of hypersensitivity
Not reported.
Flushing/Fishbane reaction
Not reported.
Injection discomfort/reaction
Two cases were reported in Holm 2017a in the group treated with intravenous iron: application site discolouration and infusion site irritation, respectively. No data were reported for this outcome in the group receiving red blood cell transfusion. One case of application site discolouration was also reported in Calje 2023.
Constipation, nausea, and gastrointestinal pain
Not reported, and likely less relevant in this comparison.
Number of red blood cell‐transfused women
In Holm 2017a, one woman in the intravenous iron group and two women in the red blood cell transfusion group were excluded from the final analysis due to receiving 'off‐protocol' red blood cell transfusion during the follow‐up period. However, statistical analysis in this comparison seems redundant, as red blood cell transfusion was the intervention in one of the study arms.
In Calje 2023, none of the women randomised to receive intravenous iron received 'off‐protocol' red blood cell transfusion.
Haemoglobin (g/dL)
Red blood cell transfusion may result in little to no difference in haemoglobin (g/dL) at 0 to 7 days (MD 0.57, 95% CI −0.18 to 1.31; P = 0.14; I² = 43%; 2 RCTs; 27 women; low‐certainty evidence; Analysis 2.8).
Red blood cell transfusion may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days (MD −1.00, 95% CI −2.02 to 0.02; P = 0.05; I² = not applicable; 1 RCT; 12 women; low‐certainty evidence; Analysis 2.9).
Intravenous iron may result in a slight increase in haemoglobin (g/dL) at more than 28 days compared with red blood cell transfusion (MD −1.04, 95% CI −1.70 to −0.38; P = 0.002; I² = 0%; 2 RCTs; 29 women; low‐certainty evidence; Analysis 2.10), revealing a potential long‐term effect of intravenous iron in terms of haemoglobin rise.
Comparison 3: Intravenous iron and oral iron supplementation versus oral iron supplementation
We included three trials (229 women) in this comparison (Breymann 2000; Perello 2014; Westad 2008). One trial administered placebo EPO in the intervention arm (Breymann 2000), and another trial administered placebo intravenous iron in the comparator arm (Perello 2014), resulting in the comparison of intravenous and oral iron supplementation versus oral iron supplementation. Given the lack of evidence against a substantial placebo effect [128] , and the similar active treatments in these two trials, we found them comparable. In the last trial (Westad 2008), Group A received intravenous iron immediately after giving birth and started iron tablet therapy after four weeks, while Group B began receiving oral iron supplementation immediately after delivery. See Table; for outcomes not presented here, refer to Supplementary material 10.
Critical outcomes
Maternal mortality
Not reported.
Fatigue
Not reported in Breymann 2000 and Perello 2014.
The authors of Westad 2008 state that "physical fatigue" or "total fatigue" improved more in the group treated with intravenous iron and oral iron supplementation (Group A) compared to the group treated with oral iron supplementation only (Group B) at weeks 4, 8, and 12. At 12 weeks, the group treated with intravenous iron and oral iron supplementation had a mean change from baseline in total fatigue of 7. In contrast, the group treated with oral iron supplementation had a baseline change of 4.69 (t‐value = 2.38, P = 0.02). Standard deviations were not available for fatigue at 8 and 12 weeks, precluding statistical analysis.
Important outcomes
Persistent anaemia symptoms
One trial evaluated anaemia symptoms by the number of women who scored severity ≥ 7 on a visual analogue scale (VAS) (higher score indicates higher severity) (Perello 2014). There was no statistical difference between groups at any time point. An analysis of persistent anaemia symptoms at six weeks follow‐up is shown; evidence for the effect is very uncertain (RR 3.00, 95% CI 0.33 to 27.50; P = 0.33; I² = not applicable; 1 RCT; 72 women; very low‐certainty evidence; Analysis 3.1).
Persistent postpartum anaemia
Not reported.
Psychological well‐being
Westad 2008 found no difference between groups in SF‐36 scores at week eight according to the published report. Standard deviations were not available for analysis.
Perello 2014 measured depression symptoms using the EPDS [143] and the State‐Trait Anxiety Inventory (STAI) [144]. Although we did not consider this psychological well‐being, the trial did not show a difference between groups at one‐week follow‐up.
Urinary tract infections, endometritis, or other infections
Not reported.
Compliance to treatment
Compliance to treatment with oral iron supplementation was assessed by counting returned pills in Westad 2008. Compliance was reported as less than 50% of the recommended dose in both groups. However, intravenous iron probably results in higher compliance (RR 1.90, 95% CI 1.49 to 2.42; P < 0.001; I² = not applicable; 1 RCT; 90 women; moderate‐certainty evidence; Analysis 3.2).
Breastfeeding
Not reported.
Length of hospital stay
Length of hospitalisation was reported by Perello 2014. Intravenous iron may result in a little to no difference in length of hospital stay (MD −0.30, 95% CI −1.02 to 0.42; P = 0.41; I² = not applicable; 1 RCT; 72 women; low‐certainty evidence; Analysis 3.3).
Adverse events
Adverse events were given as the number of women who scored severity ≥ 7 on the VAS in one trial (Perello 2014). The trial found no difference between groups at any time point.
In Westad 2008, adverse events did not differ between groups, except for constipation (see below).
Anaphylaxis or evidence of hypersensitivity
No cases of anaphylaxis were reported in either group in Breymann 2000 and Westad 2008, rendering the data ineligible for analysis (not estimable; Analysis 3.4).
Flushing/Fishbane reaction
Three cases of warm flushes were reported in Breymann 2000, but not by study arm.
Injection discomfort
Not reported.
Constipation, nausea, and gastrointestinal pain
In Westad 2008, constipation was seen more in the groups treated with oral iron supplementation compared to the intravenous iron group, which had a delayed start of iron tablet therapy at four weeks. Intravenous and oral iron may result in a reduction in constipation compared to oral iron alone (RR 0.21, 95% CI 0.07 to 0.69; P = 0.01; I² = not applicable; 1 RCT; 128 women; low‐certainty evidence; Analysis 3.5).
No studies reported nausea. Five cases of gastrointestinal pain were reported in Breymann 2000, but not by study arm.
Number of red blood cell‐transfused women
Intravenous and oral iron may result in little to no difference in number of red blood cell‐transfused women (RR 0.53, 95% CI 0.21 to 1.35; P = 0.19; I² = 0%; 3 RCTs; 240 women; low‐certainty evidence; Analysis 3.6).
Haemoglobin (g/dL)
Perello 2014 was the only trial to report haemoglobin values (g/dL) within one‐week post‐intervention and at day 8 to 28 postpartum.
Intravenous and oral iron may result in little to no difference in haemoglobin (g/dL) at 0 to 7 days (MD −0.10, 95% CI −0.64 to 0.44; P = 0.72; I² = not applicable; 1 RCT; 60 women; low‐certainty evidence; Analysis 3.7). Intravenous and oral iron may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days (MD 0.00, 95% CI −0.48 to 0.48; P = 1.00; I² = not applicable; 1 RCT; 60 women; low‐certainty evidence; Analysis 3.8). Westad 2008 contributed to the analysis conducted for the period exceeding 28 days postpartum. Intravenous and oral iron may result in little to no difference in haemoglobin (g/dL) at more than 28 days (MD 0.20, 95% CI −0.20 to 0.59; P = 0.16; I² = not applicable; 2 RCTs; 153 women; low‐certainty evidence; Analysis 3.9).
Comparison 4: Red blood cell transfusion versus no transfusion
Prick 2014 was the only trial to compare red blood cell transfusion to non‐intervention, that is other treatment at the clinician's discretion. The trial included 519 women. See Table; for outcomes not presented here, refer to Supplementary material 11.
Critical outcomes
Maternal mortality
Not reported.
Fatigue
There was a small and transient between‐group difference in general fatigue measured by the MFI [141] during the first week, favouring the red blood cell transfusion group. Red blood cell transfusion probably results in a slight decrease in fatigue on day 0 to 7 (MD −0.80, 95% CI −1.53 to −0.07; P = 0.03; I² = not applicable; 1 RCT; 388 women; moderate‐certainty evidence; Analysis 4.1) compared with no transfusion.
The authors provided raw means and SDs at our request.
The additional data showed that red blood cell transfusion probably results in no difference in fatigue after 28 days (MD −0.25, 95% CI −1.22 to 0.72; P = 0.61; I² = not applicable; 1 RCT; 318 women; moderate‐certainty evidence; Analysis 4.2).
Important outcomes
Persistent anaemia symptoms
Anaemia symptoms eliciting a red blood cell transfusion occurred in 28 women in the non‐intervention group. However, the frequency of anaemia symptoms (besides fatigue) was not systematically reported for the remaining, non‐transfused members of the non‐intervention group or for the group receiving red blood cell transfusion.
Persistent postpartum anaemia
Not reported.
Psychological well‐being
The authors provided SF‐36 data upon request. SF‐36 data at one‐week follow‐up were provided and analysed. For the 'general health' domain, we found that red blood cell transfusion may result in little or no difference in psychological well‐being (MD 2.18, 95% CI −1.47 to 5.83; P = 0.24; I² = not applicable; 1 RCT; 369 women; low‐certainty evidence; Analysis 4.3).
Urinary tract infections, endometritis, or other infections
Red blood cell transfusion probably results in little to no difference in infection (RR 0.93, 95% CI 0.53 to 1.61; P = 0.79; I² = not applicable; 1 RCT; 519 women; moderate‐certainty evidence; Analysis 4.4).
Compliance to treatment
Compliance with treatment was lower in the non‐intervention group, where 33 women did not comply with the allocated treatment (iron or folic acid supplementation, or both, was allowed according to local protocol) versus 7 women in the group receiving red blood cell transfusion. Red blood cell transfusion probably results in higher compliance (RR 1.11, 95% CI 1.06 to 1.17; P < 0.001; I² = not applicable; 1 RCT; 519 women; moderate‐certainty evidence; Analysis 4.5).
Breastfeeding
The breastfeeding rate at randomisation was 77% in both groups. Red blood cell transfusion may result in little to no difference in breastfeeding more than six weeks postpartum (RR 0.91, 95% CI 0.78 to 1.07; P = 0.24; I² = not applicable; 1 RCT; 297 women; low‐certainty evidence; Analysis 4.6).
Length of hospital stay
Length of hospital stay was a median of two days in both groups.
Adverse events
There was no difference between groups in the number of reported adverse events, which were alloantibody formation, rash, fever, thromboembolic events, parenteral iron intolerance, and transfusion reactions. Transfusion reactions (alloantibodies, fever) only occurred in transfused participants. However, there was no systematic investigation of the presence of new alloantibodies.
Serious adverse events
There were two pulmonary/thromboembolic events in each group. Red blood cell transfusion may result in little to no difference in serious adverse events (RR 1.01, 95% CI 0.14 to 7.13; P = 0.99; I² = not applicable; 1 RCT; 519 women; low‐certainty evidence; Analysis 4.7).
Anaphylaxis or evidence of hypersensitivity, flushing/Fishbane reaction, injection discomfort
Not reported.
Constipation, nausea, and gastrointestinal pain
Not reported.
Number of red blood cell‐transfused women
This outcome seems less relevant when red blood cell transfusion is the intervention.
In the red blood cell transfusion group, 251 women received transfusions, while 7 refused. The total number of red blood cell units given was 517 (median: 2 units per woman; interquartile range 2 to 2). In the non‐intervention group, 33 women received red blood cell transfusions, and 88 red blood cell units were given (median: 0 units per woman; interquartile range 0 to 0).
Haemoglobin (g/dL)
Red blood cell transfusion probably results in an increase in haemoglobin (g/dL) within 0 to 7 days (MD 1.61, 95% CI 0.60 to 2.62; P = 0.002; I² = not applicable; 1 RCT; 408 women; moderate‐certainty evidence; Analysis 4.8) and a likely slight increase in haemoglobin (g/dL) after 28 days (MD 0.23, 95% CI 0.00 to 0.46; P = 0.05; I² = not applicable; 1 RCT; 408 women; moderate‐certainty evidence; Analysis 4.9). This finding aligns with the small and transient improvement in fatigue of the transfusion group within the first week postpartum.
Comparison 5: Oral iron supplementation versus placebo or no treatment
Three trials compared oral iron supplementation with placebo (Beard 2005; Krauss 1972; Tam 2005). The trial by Krauss 1972 had three study arms. For this comparison, we chose the study arm that received the tablet Eryfer, containing ferrous sulphate, ascorbic acid, and sodium bicarbonate, as the intervention arm (Group S) and the placebo arm (empty preparation) as the control arm. The trials also reported on different outcomes, thereby precluding meta‐analyses for this comparison, except for haemoglobin. See Table; for outcomes not presented here, refer to Supplementary material 12.
Critical outcomes
Mortality and fatigue were not reported.
Important outcomes
Persistent anaemia symptoms
Only one trial, Tam 2005, reported on persistent anaemia symptoms, but for both study groups combined. These were dyspnoea (n = 6), palpitations (n = 6), chest discomfort (n = 3), dizziness (n = 12), and headache (n = 10).
Persistent postpartum anaemia
Not reported.
Psychological well‐being
Beard 2005 did not report on well‐being. However, the trial reported on the Digit Symbol Substitution test [145], EPDS [143], STAI [144], and Perceived Stress Questionnaire [146]. The trial found that iron treatment resulted in an improvement in previously iron‐deficient mothers' Digit Symbol test scores. Anaemic mothers who were not given iron had no change in performance on the cognitive tasks.
Urinary tract infections, endometritis, or other infections, compliance to treatment, breastfeeding, length of hospital stay
Not reported.
Adverse events
Anaphylaxis or evidence of hypersensitivity, flushing/Fishbane reaction, injection discomfort
Two trials reported adverse events (Krauss 1972; Tam 2005). Tam 2005 reported only one type of adverse event (back pain) for each study group individually, with no difference found between groups. The remaining adverse events were provided for both study groups combined, making them ineligible for meta‐analysis.
Constipation, nausea, and gastrointestinal pain
The authors of Tam 2005 stated that there was no difference between groups in nausea, vomiting, or constipation. Krauss 1972 reported that six women in each group had gastrointestinal adverse events such as constipation, low appetite, and morning sickness, but the numbers of each specific adverse event were not reported. No serious adverse events were reported.
Number of red blood cell‐transfused women
Not reported.
Haemoglobin (g/dL)
Krauss 1972 reported on haemoglobin values (g/dL) within one week post‐intervention/postpartum. Oral iron supplementation probably increases haemoglobin (g/dL) within 0 to 7 days slightly (MD 1.01, 95% CI 0.36 to 1.66; P = 0.002; I² = not applicable; 1 RCT; 64 women; moderate‐certainty evidence; Analysis 5.1). Baseline haemoglobin levels were similar before treatment start.
No trials reported haemoglobin values (g/dL) within 8 to 28 days post‐intervention/postpartum.
All three trials reported haemoglobin values (g/dL) after 28 days postpartum (Beard 2005; Krauss 1972; Tam 2005). The trials were too heterogeneous to combine (3 RCTs; 237 women; Analysis 5.2), and an insufficient number of studies precluded heterogeneity examination and subgrouping. However, all three trials showed a benefit of oral iron supplementation, with mean changes in haemoglobin ranging from 0.60 to 2.47 g/dL.
Comparison 6: Erythropoietin (regardless of route) and iron versus intravenous or oral iron supplementation
In order to conduct an adequate comparison, we considered all trials investigating the combined use of EPO with oral iron supplementation, regardless of the route of administration. The control was iron supplementation alone, regardless of the administration route. We included six trials involving a total of 256 women in this comparison (Breymann 1996; Breymann 2000; Krafft 2011; Lebrecht 1995; Wagstrom 2007). See Supplementary material 13.
Two trials compared the use of EPO in combination with intravenous iron against intravenous iron alone (Krafft 2011; Wagstrom 2007). In the trial by Wagstrom 2007, which had three study arms, data were extracted from the group receiving intravenous iron only (Group 1) and compared with the group receiving EPO and intravenous iron (Group 2).
Another trial also included three study arms (Breymann 1996). For this comparison, the arm receiving EPO, intravenous iron, and oral iron supplementation (Group 2) was selected and compared with the group receiving intravenous iron and oral iron supplementation (Group 1).
Two trials utilised EPO placebos for the control groups (Breymann 2000; Lebrecht 1995). In both trials, the intervention group received EPO, intravenous iron, and oral iron supplementation, while the control group received intravenous placebo EPO, intravenous iron, and oral iron supplementation.
In the trial by Makrydimas 1998, the effectiveness of EPO in combination with oral iron supplementation was compared to oral iron supplementation alone.
For specific information on doses, administration routes, and dosing regimens, please refer to Supplementary material 2.
Critical outcomes
Mortality and fatigue were not reported.
Important outcomes
Persistent anaemia symptoms
Not reported.
Persistent postpartum anaemia
Not reported.
Psychological well‐being
One participant in the trial conducted by Wagstrom 2007 developed postpartum depression, although this was not a prespecified outcome in the methodology outlined in our research.
Urinary tract infections, endometritis, or other infections
The evidence is very uncertain about the effect of EPO (regardless of route) and iron on infection (RR 0.75, 95% CI 0.19 to 2.93; P = 0.68; I² = not applicable; 2 RCTs; 80 women; very low‐certainty evidence; Analysis 6.1). There were events in only one trial.
Compliance to treatment
Compliance with the injection protocol was reported as 100% in both study groups by Krafft 2011, as there were no instances of women refusing or discontinuing the injections. Erythropoietin (regardless of route) and iron may result in little to no difference in compliance to treatment (RR 1.00, 95% CI 0.91 to 1.10; P = 1.00; I² = not applicable; 1 RCT; 40 women; low‐certainty evidence; Analysis 6.2).
Breastfeeding
Due to considerable heterogeneity, we could not pool the two studies that reported breastfeeding (I² = 97%; 2 RCTs; 80 women; very low‐certainty evidence; Analysis 6.3). One trial showed a very large effect (RR 1.90, 95% CI 1.21 to 2.98). However, this study had unclear risk of bias for both random sequence generation and allocation concealment (Makrydimas 1998). Both studies were at high risk of bias for blinding, and they both included 40 women. Krafft 2011 found no effect of EPO on breastfeeding (RR 1.00, 95% CI 0.91 to 1.10); this study was at low risk of bias for random sequence generation and allocation concealment.
Length of hospital stay
Length of hospital stay was reported as a median of 11 days (range 6 to 11) for the intervention group and 14 days (range 11 to 19) for the groups treated with oral iron supplementation in Makrydimas 1998. The reason for the prolonged hospitalisation was not given. The available data were not sufficient to perform a statistical analysis.
Adverse events
Anaphylaxis or evidence of hypersensitivity, injection discomfort, constipation and gastrointestinal pain
Three studies reported no serious adverse events (2 RCTs; 80 women; very low‐certainty evidence; Analysis 6.4) and no anaphylactic reactions (3 RCTs; 155 women; very low‐certainty evidence; Analysis 6.5) (Breymann 1996; Breymann 2000; Lebrecht 1995).
Two women experienced a warm sensation during iron infusion, and 10 women complained of a burning sensation during EPO injection (Breymann 1996). However, these numbers were not provided per group, thus precluding analysis.
Flushing/Fishbane reaction
Three women reported warm flush over a few minutes in Krafft 2011. The evidence is very uncertain about the effect of EPO (regardless of route) and iron on flushing/Fishbane reaction (RR 2.00, 95% CI 0.20 to 20.33; P = 0.56, I² = not applicable; 1 RCT; 40 women; very low‐certainty evidence; Analysis 6.6).
Constipation, nausea, and gastrointestinal pain
In Breymann 2000, there were five cases of gastrointestinal adverse events and three cases of warm flushes. However, these numbers were not given for individual study arms but for the groups combined.
Adverse events including gastrointestinal symptoms were not reported by Makrydimas 1998.
Number of red blood cell‐transfused women
Five trials reported number of red blood cell‐transfused women. The evidence is very uncertain about the effect of EPO (regardless of route) and iron on number of red blood cell‐transfused women (RR 0.20, 95% CI 0.01 to 3.92; P = 0.29, I² = not applicable; 5 RCTs; 240 women; very low‐certainty evidence; Analysis 6.7). Two women in the oral iron‐only group showed haemodynamic instability and received blood transfusions in the trial by Makrydimas 1998.
Haemoglobin (g/dL)
Three trials reported haemoglobin. Erythropoietin and iron probably results in little to no difference in haemoglobin (g/dL) on day 0 to 7 compared to iron treatment alone (MD 0.29, 95% CI −0.12 to 0.69; P = 0.17; I² = 0%; 3 RCTs; 110 women; moderate‐certainty evidence; Analysis 6.8)
Erythropoietin and iron probably results in little to no difference in haemoglobin (g/dL) on day 8 to 28 compared to iron treatment alone (MD 0.18, 95% CI −0.19 to 0.55; P = 0.34; I² = 0%; 3 RCTs; 110 women; moderate‐certainty evidence; Analysis 6.9).
Erythropoietin and iron may result in little to no difference in haemoglobin (g/dL) after 28 days compared to iron treatment alone (MD 0.40, 95% CI −0.21 to 1.01; P = 0.20; 1 RCT; 35 women; low‐certainty evidence; Analysis 6.10).
Comparison 7: Erythropoietin (regardless of route) versus placebo
We included one trial involving 71 women in this comparison (Meyer 1995). The trial compared intravenous EPO with placebo.
Critical outcomes
Mortality and fatigue were not reported.
Important outcomes
Psychological well‐being
According to the study authors, there was no statistical difference between groups in psychological well‐being, which was measured using selected items from the Blues Questionnaire (low score indicates absence of blues) [46] and the Self‐report symptom inventory 90 (SCL‐90‐R) (high scores indicate high levels of unfavourable symptoms) [47]. Data were not eligible for analysis.
Haemoglobin (g/dL)
The study authors found that the mean haemoglobin and mean haematocrit increased in the groups receiving recombinant human erythropoietin (rhEPO), while no changes were observed in the placebo group. However, a statistical difference in haemoglobin between groups within the very short five‐day study period was not shown. Haemoglobin was reported as a mean and range, thus precluding analysis.
Persistent anaemia symptoms, persistent postpartum anaemia, urinary tract infections, endometritis, or other infections, compliance to treatment, breastfeeding, length of hospital stay, adverse events, number of red blood cell transfusions
Not reported.
All analyses are available in Supplementary material 6, and the data package is available for download in Supplementary material 7.
Discussion
Summary of main results
This review included 33 trials with a total of 4558 women. The majority of our analyses were based on a small number of trials with high heterogeneity. Few trials reported on our critical outcomes of maternal mortality and fatigue.
Comparison 1: Intravenous iron versus oral iron supplementation
The evidence is very uncertain about the effect of intravenous iron on mortality compared to oral iron supplementation. See Table. One maternal death occurred in the groups treated with intravenous iron due to peripartum cardiomyopathy. Additionally, one woman developed arrhythmia during intravenous iron infusion. Thus, two cases of serious cardiac adverse events were observed. These events have not previously been described as adverse effects of intravenous iron treatment, even though no conclusions can be drawn regarding a causal relationship. However, we suggest that cardiac events should be carefully monitored and documented in all future trials.
Intravenous iron probably results in a slight reduction in fatigue at 8 to 28 days compared to oral iron supplementation. An SMD of −0.25 is usually considered a small effect, and it can be translated to a difference of 6 mm on a 100‐millimetre fatigue VAS.
Breastfeeding was not reported for this comparison. Oral iron supplementation probably increases the risk of constipation compared to intravenous iron.
The evidence is very uncertain about the effect of intravenous iron on anaphylaxis/hypersensitivity. Anaphylaxis was reported in 1 of a total of 1086 women who received intravenous iron. Two women experienced evidence of hypersensitivity without further specification; however, it was stated that this was not an anaphylactic reaction. Due to the low number of events statistical power is lacking, but anaphylaxis is a known dangerous side effect of intravenous iron.
Five of six trials found that haemoglobin (g/dL) at 8 to 28 days was increased with intravenous iron compared to oral iron supplementation, but the studies could not be pooled, and the overall certainty of the evidence was low.
Comparison 2: Red blood cell transfusion versus intravenous iron
It is very uncertain if red blood cell transfusion affects maternal mortality or fatigue at 8 to 28 days or breastfeeding compared to intravenous iron because the included studies only involved 39 participants. Constipation and anaphylaxis/hypersensitivity were not reported. Red blood cell transfusion may result in little or no difference in haemoglobin (g/dL) within 8 to 28 days compared with intravenous iron. See Table.
Comparison 3: Intravenous iron and oral iron supplementation versus oral iron supplementation
Maternal mortality and breastfeeding were not reported for this comparison. It is very uncertain if intravenous iron and oral iron supplementation affects fatigue at 8 to 28 days compared to oral iron supplementation. Intravenous iron and oral iron supplementation may result in fewer events of constipation compared to oral iron supplementation. Two studies reported on anaphylaxis/hypersensitivity but found no events. Intravenous iron and oral iron supplementation may result in little to no difference in haemoglobin (g/dL) at 8 to 28 days compared to oral iron supplementation. See Table.
Comparison 4: Red blood cell transfusion versus no transfusion
Maternal mortality, fatigue at 8 to 28 days, constipation, anaphylaxis/hypersensitivity, and haemoglobin (g/dL) within 8 to 28 days were not reported for this comparison. Red blood cell transfusion may result in little to no difference in breastfeeding more than six weeks postpartum compared to no transfusion. See Table.
Comparison 5: Oral iron supplementation versus placebo or no treatment
Maternal mortality, fatigue at 8 to 28 days, breastfeeding, anaphylaxis/hypersensitivity, and haemoglobin (g/dL) within 8 to 28 days were not reported for this comparison. Constipation was reported by two studies but not separately by groups. See Table.
Limitations of the evidence included in the review
The majority of included trials had a high risk of bias in at least two domains. Specifically, blinding of participants and outcome assessors was rare. While this may not affect laboratory values, it could have influenced one of our critical outcomes, patient‐reported fatigue. However, the possibility of co‐interventions affecting the results of an objective outcome (e.g. laboratory values) cannot be entirely ruled out. Many trials did not report harmful effects, such as maternal mortality, even though this information is important when assessing drug safety. This lack of reporting on harms raises concerns that unfavourable events may have occurred but were not reported.
Many of the authors we contacted did not respond to our requests for additional information.
Using the GRADE approach, we downgraded the certainty of evidence mainly due to imprecision, indicated by broad CIs, small sample size, and few events, which lowers our confidence in the estimate. We also downgraded due to high heterogeneity (I²), in particular for haemoglobin.
The majority of trials were open‐label; we downgraded the certainty of evidence if we suspected that this could have influenced the outcomes. We did not downgrade the certainty of evidence if the outcome was unlikely to be influenced by risk of bias, for example an open‐label design combined with an objective outcome with no suspicion of relevant co‐interventions.
We did not downgrade due to indirectness.
Given that we included 33 trials, we expected to have sufficient data to perform a comprehensive meta‐analysis on clinically relevant outcomes. Surprisingly, the available literature provided sparse information on clinical outcomes, with many trials reporting on surrogate outcomes such as laboratory values. Even though fatigue is common in people with anaemia, only eight trials reported on this outcome. Also, the minimal clinically relevant difference of the various fatigue scales has yet to be established for women in the puerperium.
The identified trials provide an overall acceptable insight into various harmful symptoms, although maternal mortality was rarely reported. We found that anaphylaxis, the most feared complication of intravenous iron, is likely rare, and have confirmed that gastrointestinal adverse events associated with oral iron supplementation were common.
Only three small trials investigated the effect of oral iron supplementation versus placebo, one of which was conducted more than 50 years ago. The cost of different drugs and treatments varies depending on the setting and thus cannot be generalised. However, it is certain that intravenous iron costs substantially more than oral iron supplementation [147], and infusion often requires hospitalisation. When investigating treatment for a condition that is likely to occur in low‐income settings where nutritional factors, longer periods of breastfeeding, and the number of pregnancies per woman may differ from those in high‐income countries, special attention must be paid to the types of treatment options available in these particular settings, such as oral iron supplementation.
Most trials were conducted in high‐income countries, with only two papers explicitly indicating that participants were from low‐income settings. Notably, a large trial from a low‐income setting is currently ongoing (McClure 2022).
Clinicians should consider that women from different socioeconomic backgrounds may respond differently to the same treatment. Women in low‐income settings may be more susceptible to malnutrition and infections. These factors can affect compliance, the incidence and management of adverse effects, and overall clinical response to treatment. This is particularly important during the critical period of early motherhood.
Limitations of the review processes
We only extracted, analysed, and reported outcomes prespecified for this review, therefore the effects of the interventions on other laboratory values, such as ferritin, CRP, and haptoglobin, are not reported.
In the Methods section, we did not account for the substantial clinical heterogeneity among trials, such as type of intravenous/oral iron supplementation used, dosage regimen, total dose, motivation for compliance, and variation in follow‐up time points. This might have resulted in heterogeneity in our analyses and limited our ability to detect some relevant differences between study groups.
Some data were provided graphically in the published reports. We consistently requested such data in numerical form along with corresponding SDs. When the authors did not respond, we read the values from graphs. However, the lack of data, such as SD, prevented us from including some trials in meta‐analyses.
Moreover, the experiences and findings of larger observational studies on this topic are not accounted for in this review.
Agreements and disagreements with other studies or reviews
The previous version of this review [43] did not report on the effects of the interventions on laboratory values such as haemoglobin, but rather focused on the clinical effect of treatment. In our review we tried to cover the clinical effect of treatment (fatigue as critical outcome), but we also examined the effect on haemoglobin as an important outcome, as this was specifically requested by the WHO for an upcoming guideline. However, our assessment of an effect on fatigue was impeded by the majority of the studies focusing on laboratory values.
We identified several other review articles on treatment of anaemia, including postpartum iron deficiency anaemia [12, 147, 7, 15]. Their assessment of the severity of anaemia and treatment effects were all based on laboratory values only. The search methods used in these reviews were not clearly described.
We identified one systematic review on the benefits and harms of intravenous iron therapy, which included some clinical outcome measures in addition to haemoglobin values [148]. However, this review included all types of patients and did not perform a subgroup analysis on postpartum women, making the results uncertain for our specific population. The results showed an increased risk of infections in the groups treated with intravenous iron, but no difference in mortality, adverse events, or blood transfusions. The results on infections could not be confirmed by our meta‐analysis, but a similar trend was seen. No conclusion could be drawn, which may be due to the lower number of participants in our analysis.
One systematic review addressed the prevention and treatment of maternal anaemia and showed a lack of evidence regarding treatment of anaemia in the postnatal period. The study had poor reporting of clinical outcome measures [149].
Authors' conclusions
Implications for practice
The potential harms of intravenous iron are not fully clarified, as maternal mortality was insufficiently reported, and there were too few events to estimate an absolute risk. Intravenous iron probably reduces fatigue slightly in the early postpartum weeks (8 to 28 days) compared to oral iron supplementation, but probably shows little to no difference after four weeks. Oral iron supplementation probably results in an increase in constipation compared to intravenous iron. There were three cases of anaphylaxis/hypersensitivity in the intravenous iron group, but the evidence for this outcome is very uncertain. Intravenous iron may increase haemoglobin slightly more than oral iron supplementation, but the data were too heterogeneous to pool. Haemoglobin is a surrogate outcome, and treatment decisions should preferentially be based on patient‐relevant outcomes.
The evidence is very uncertain about the effect of red blood cell transfusion on fatigue compared with intravenous iron. While red blood cell transfusion may result in little to no difference on day 0 to 28, after day 28 intravenous iron may result in a slight increase in haemoglobin compared to red blood cell transfusion.
Maternal mortality was not reported for intravenous iron and oral iron supplementation compared to oral iron supplementation. We are very uncertain about whether intravenous iron and oral iron supplementation affects the risk of fatigue at 8 to 28 days and haemoglobin at 8 to 28 days compared to oral iron supplementation.
The effect of red blood cell transfusion compared to non‐transfusion on mortality, fatigue at 8 to 28 days, constipation, anaphylaxis/hypersensitivity, and haemoglobin is unreported. Red blood cell transfusions to alleviate mild or symptom‐free anaemia in stable patients should be weighed against the known risks of blood transfusion. Additionally, the risk of antibody formation is particularly important for future pregnancies.
Treatment choices should also take into account the socioeconomic context and healthcare facilities, particularly in low‐income settings.
The above‐mentioned treatment options have been tested in various combinations in several trials. Our analyses did not favour one combination over others. The trials provided limited information on clinical outcomes.
Implications for research
After five decades of research and 33 trials examining postpartum iron deficiency anaemia, we are still not able to clearly state how postpartum iron deficiency anaemia should be treated. This lack of robust evidence may be due to the heterogeneity of trials: the chosen interventions, the chosen outcomes, and the many different study designs. Although haemoglobin levels do not necessarily correlate with the degree of anaemia symptoms in postpartum women, scientists commonly use haemoglobin as a surrogate of treatment effectiveness.
We recommend that future trials focus on outcomes that are clinically important, such as maternal mortality, fatigue, persistence of anaemia symptoms, breastfeeding rates, psychological well‐being, and long‐term consequences for mother and child. In light of the cases of cardiac events and anaphylaxis reported in this review, there is a need to ensure a complete benefit and harm profile of intravenous iron treatment. In summary, anaemia symptoms and adverse effects of treatment should be reported to evaluate the overall clinical effect. The CONSORT statement recommends that all studies should report mortality and serious adverse events.
To ensure that future trials are applicable in different socioeconomic contexts, participants need to be diverse, and also from low‐income settings, which are traditionally underrepresented. It is important to develop a postpartum iron deficiency anaemia treatment guideline for global applicability and safety.
Multicentre trials with large populations are valuable. However, due to the risk of adverse effects on mothers, studies on red blood cell transfusion should be reserved for cases of severe postpartum bleeding or severe anaemia, with comprehensive monitoring of adverse effects, including allo‐immunisation.
In conclusion, while intravenous iron rapidly corrects postpartum iron deficiency anaemia, important gaps in knowledge about serious harms remain, and it remains uncertain if intravenous iron is more effective than iron supplementation with tablets to an extent that is clinically relevant. Addressing these gaps through well‐designed studies focusing on clinical outcomes and potential harms is essential for optimising treatment strategies and improving maternal health worldwide.
Equity‐related implications for research
More trials should be conducted in low‐ and middle‐income countries where maternal complications are frequent, including maternal deaths. Such trials should include patient‐relevant outcomes such as breastfeeding, maternal mortality, and fatigue.
Supporting Information
Supplementary materials are available with the online version of this article: 10.1002/14651858.CD010861.pub2.
Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.
Supplementary material 1 Search strategies
Supplementary material 2 Characteristics of included studies
Supplementary material 3 Characteristics of excluded studies
Supplementary material 4 Characteristics of studies awaiting classification
Supplementary material 5 Characteristics of ongoing studies
Supplementary material 6 Analyses
Supplementary material 7 Data package
Supplementary material 8 Summary of findings table. Non‐prioritised outcomes ‐ Intravenous iron compared to oral iron supplementation for women with postpartum iron deficiency anaemia
Supplementary material 9 Summary of findings table. Non‐prioritised outcomes ‐ Red blood cell transfusion compared to intravenous iron
Supplementary material 10 Summary of findings table. Non‐prioritised outcomes ‐ Intravenous iron and oral iron supplementation compared to oral iron supplementation
Supplementary material 11 Summary of findings table. Non‐prioritised outcomes ‐ Red blood cell transfusion compared to no transfusion
Supplementary material 12 Summary of findings table. Non‐prioritised outcomes ‐ Oral iron supplementation compared to placebo or no treatment
Supplementary material 13 Summary of findings. Erythropoietin (regardless of route) and iron compared to intravenous or oral iron supplementation
New search for studies and content updated (conclusions changed)
Additional information
Acknowledgements
We acknowledge the important work of the two previous review teams [30, 150].
We would like to express our appreciation to the dedicated team at Cochrane for facilitating a smooth publication from search to peer‐review.
We are also very grateful to those corresponding authors and trial investigators who took the time to answer our questions and provided the requested information for this update (Chaudhuri 2013; Paily 2020; Suneja 2019; Takeshi 2021).
We extend special thanks to the World Health Organization (WHO) for their support and encouragement in updating this review. We are grateful to WHO for recognising the importance of this review and identifying it as a priority topic for their Postpartum Haemorrhage consolidated guideline, currently in development [42]
We are also grateful for Professor Asbjørn Hróbjartsson's valuable comments on the manuscript.
Editorial and peer‐reviewer contributions
Cochrane supported the authors in the development of this review.
The following people conducted the editorial process for this article.
Sign‐off Editor (final editorial decision): Pisake Lumbiganon, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen University
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Ben Ridley, Cochrane Central Editorial Service
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments, and supported the editorial team): Lisa Wydrzynski, Cochrane Central Editorial Service
Copy Editor (copy editing and production): Lisa Winer, Cochrane Central Production Service
Peer reviewers (provided comments and recommended an editorial decision): Lumaan Sheikh, Aga Khan University Pakistan (clinical/content review), Brian Duncan (consumer review), Nuala Livingstone, Cochrane Evidence Production and Methods Directorate and Lindsay Robertson, Cochrane (methods review), Steve McDonald, Cochrane Australia (search review)
Contributions of authors
Mie Cecilie Hall Jensen revised the Methods and Background sections for the current update.
Mie Cecilie Hall Jensen and Charlotte Holm, Jeppe Bennekou Schroll, or Karsten Juhl Jørgensen independently performed study screening, risk of bias assessment, and data extraction. Mie Cecilie Hall Jensen conducted the statistical analyses, prepared the summary of findings tables with support from Jeppe Bennekou Schroll, and drafted the review.
Charlotte Holm provided expert clinical knowledge on current treatment regimens for postpartum anaemia.
Karsten Juhl Jørgensen contributed expertise in methodology.
All authors reviewed all manuscript drafts and contributed to the final preparation of the review.
Declarations of interest
Mie Cecilie Hall Jensen: received three months of monthly payments from Cochrane Denmark and Centre for Evidence‐Based Medicine Odense (CEBMO), University of Southern Denmark, Odense, Denmark, for writing this review, allowing her to take three months off from her regular full‐time job at Department of Obstetrics and Gynaecology, Amager and Hvidovre Hospital, Denmark.
Charlotte Holm: conducted two randomised controlled trials funded by Pharmacosmos A/S. Both studies were included in this review (Holm 2017; Holm 2017a). Received speaker's fee from Pharmacosmos A/S and Pierre Fabre Pharmaceuticals and participated in advisory board for Pharmacosmos A/S. However, CH did not participate in study eligibility decisions, data extraction, risk of bias assessment, or GRADE assessment of her own studies.
Karsten Juhl Jørgensen: none.
Jeppe Bennekou Schroll: is a Cochrane editor of the Gynaecology and Fertility group. JBS was not involved in the editorial process for this review.
Sources of support
Internal sources
-
Sources of support, Denmark
This was a non‐profit project and the co‐authors did not receive financial support for their efforts.
External sources
-
New Source of support, Denmark
This was a non‐profit project and the co‐authors did not receive financial support for their efforts.
Registration and protocol
Protocol (2013) [150]
Review update (2015) [43]
Original review (2004) [30]
Data, code and other materials
As part of the published Cochrane Review, the following are made available for download for users of the Cochrane Library: full search strategies for each database; full citations of each unique report for all studies included, ongoing or awaiting classification, or excluded at the full‐text screen, in the final review; study data, including study information, study arms, and study results or test data; consensus risk of bias assessments; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows. Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, Review Manager Web, using the inbuilt computation methods. Template data extraction forms from Covidence are available from the authors on reasonable request.
What's new
| Date | Event | Description |
|---|---|---|
| 13 December 2024 | New search has been performed | Search updated to 11 April 2024. 11 new trials identified. Methods changed (see Methods ). |
| 13 December 2024 | New citation required and conclusions have changed | This is an update of a Cochrane review first published in 2006, and previously updated in 2015. Conducting this review holds significant importance as it will serve as a component in the development of a comprehensive consolidated guideline for postpartum haemorrhage within the World Health Organization (WHO) Roadmap to combat postpartum haemorrhage between 2023 and 2030. In this update, we have decided to focus on and present fatigue at the 8‐ to 28‐day time point in the summary of findings table. At the request of WHO, we also included haemoglobin as a surrogate measure of anaemia. Haemoglobin was added as an outcome as requested by the WHO to ensure consistency among the Cochrane reviews that are used in the guideline on management of postpartum haemorrhage. |
History
Protocol first published: Issue 12, 2013 Review first published: Issue 8, 2015
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material 1 Search strategies
Supplementary material 2 Characteristics of included studies
Supplementary material 3 Characteristics of excluded studies
Supplementary material 4 Characteristics of studies awaiting classification
Supplementary material 5 Characteristics of ongoing studies
Supplementary material 6 Analyses
Supplementary material 7 Data package
Supplementary material 8 Summary of findings table. Non‐prioritised outcomes ‐ Intravenous iron compared to oral iron supplementation for women with postpartum iron deficiency anaemia
Supplementary material 9 Summary of findings table. Non‐prioritised outcomes ‐ Red blood cell transfusion compared to intravenous iron
Supplementary material 10 Summary of findings table. Non‐prioritised outcomes ‐ Intravenous iron and oral iron supplementation compared to oral iron supplementation
Supplementary material 11 Summary of findings table. Non‐prioritised outcomes ‐ Red blood cell transfusion compared to no transfusion
Supplementary material 12 Summary of findings table. Non‐prioritised outcomes ‐ Oral iron supplementation compared to placebo or no treatment
Supplementary material 13 Summary of findings. Erythropoietin (regardless of route) and iron compared to intravenous or oral iron supplementation
Data Availability Statement
As part of the published Cochrane Review, the following are made available for download for users of the Cochrane Library: full search strategies for each database; full citations of each unique report for all studies included, ongoing or awaiting classification, or excluded at the full‐text screen, in the final review; study data, including study information, study arms, and study results or test data; consensus risk of bias assessments; and analysis data, including overall estimates and settings, subgroup estimates, and individual data rows. Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, Review Manager Web, using the inbuilt computation methods. Template data extraction forms from Covidence are available from the authors on reasonable request.