Treatment for women with postpartum iron deficiency anaemia.
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.
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.
A Cochrane Information Specialist searched for all published, unpublished, and ongoing trials, without language or publication status restrictions.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.
We included published, unpublished, and ongoing randomised controlled trials (RCTs) that compared treatments for postpartum iron deficiency anaemia with placebo, no treatment, or alternative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.
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.
We assessed risk of bias in the included studies using the Cochrane RoB 1 tool.
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.
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.
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.
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.
This Cochrane review had no dedicated funding.
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].
Jensen MCH
，Holm C
，Jørgensen KJ
，Schroll JB
... -
《Cochrane Database of Systematic Reviews》
Antioxidants for female subfertility.
M.G. Showell, R. Mackenzie‐Proctor, V. Jordan, and R.J. Hart, “Antioxidants for Female Subfertility,” Cochrane Database of Systematic Reviews, no. 8 (2020): CD007807, https://doi.org/10.1002/14651858.CD007807.pub4 This Editorial Note is for the above article, published online on August 27, 2020, in Cochrane Library (cochranelibrary.com), and has been issued by the Publisher, John Wiley & Sons Ltd, in agreement with Cochrane. The Editorial note has been agreed due to concerns discovered by the Cochrane managing editor regarding the retraction of six studies in the Review (Badawy et al. 2006, 10.1016/j.fertnstert.2006.02.097; El Refaeey et al. 2014, 10.1016/j.rbmo.2014.03.011; El Sharkwy & Abd El Aziz 2019a, https://doi.org/10.1002/ijgo.12902; Gerli et al. 2007, https://doi.org/10.26355/eurrev_202309_33752, full text: https://europepmc.org/article/MED/18074942; Ismail et al. 2014, http://dx.doi.org/10.1016/j.ejogrb.2014.06.008; Hashemi et al. 2017, https://doi.org/10.1080/14767058.2017.1372413). In addition, expressions of concern have been published for two studies (Jamilian et al. 2018, https://doi.org/10.1007/s12011-017-1236-3; Zadeh Modarres 2018, https://doi.org/10.1007/s12011-017-1148-2). The retracted studies will be moved to the Excluded Studies table, and their impact on the review findings will be investigated and acted on accordingly in a future update. Initial checks indicate that removal of the six retracted studies did not make an appreciable difference to the results. Likewise, the studies for which Expressions of Concern were issued will be moved to the Awaiting classification table; they did not report any review outcomes, so removal will have no impact on the review findings.
A couple may be considered to have fertility problems if they have been trying to conceive for over a year with no success. This may affect up to a quarter of all couples planning a child. It is estimated that for 40% to 50% of couples, subfertility may result from factors affecting women. Antioxidants are thought to reduce the oxidative stress brought on by these conditions. Currently, limited evidence suggests that antioxidants improve fertility, and trials have explored this area with varied results. This review assesses the evidence for the effectiveness of different antioxidants in female subfertility.
To determine whether supplementary oral antioxidants compared with placebo, no treatment/standard treatment or another antioxidant improve fertility outcomes for subfertile women.
We searched the following databases (from their inception to September 2019), with no language or date restriction: Cochrane Gynaecology and Fertility Group (CGFG) specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL and AMED. We checked reference lists of relevant studies and searched the trial registers.
We included randomised controlled trials (RCTs) that compared any type, dose or combination of oral antioxidant supplement with placebo, no treatment or treatment with another antioxidant, among women attending a reproductive clinic. We excluded trials comparing antioxidants with fertility drugs alone and trials that only included fertile women attending a fertility clinic because of male partner infertility.
We used standard methodological procedures expected by Cochrane. The primary review outcome was live birth; secondary outcomes included clinical pregnancy rates and adverse events.
We included 63 trials involving 7760 women. Investigators compared oral antioxidants, including: combinations of antioxidants, N-acetylcysteine, melatonin, L-arginine, myo-inositol, carnitine, selenium, vitamin E, vitamin B complex, vitamin C, vitamin D+calcium, CoQ10, and omega-3-polyunsaturated fatty acids versus placebo, no treatment/standard treatment or another antioxidant. Only 27 of the 63 included trials reported funding sources. Due to the very low-quality of the evidence we are uncertain whether antioxidants improve live birth rate compared with placebo or no treatment/standard treatment (odds ratio (OR) 1.81, 95% confidence interval (CI) 1.36 to 2.43; P < 0.001, I2 = 29%; 13 RCTs, 1227 women). This suggests that among subfertile women with an expected live birth rate of 19%, the rate among women using antioxidants would be between 24% and 36%. Low-quality evidence suggests that antioxidants may improve clinical pregnancy rate compared with placebo or no treatment/standard treatment (OR 1.65, 95% CI 1.43 to 1.89; P < 0.001, I2 = 63%; 35 RCTs, 5165 women). This suggests that among subfertile women with an expected clinical pregnancy rate of 19%, the rate among women using antioxidants would be between 25% and 30%. Heterogeneity was moderately high. Overall 28 trials reported on various adverse events in the meta-analysis. The evidence suggests that the use of antioxidants makes no difference between the groups in rates of miscarriage (OR 1.13, 95% CI 0.82 to 1.55; P = 0.46, I2 = 0%; 24 RCTs, 3229 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.00, 95% CI 0.63 to 1.56; P = 0.99, I2 = 0%; 9 RCTs, 1886 women; low-quality evidence). There was also no evidence of a difference between the groups in rates of gastrointestinal disturbances (OR 1.55, 95% CI 0.47 to 5.10; P = 0.47, I2 = 0%; 3 RCTs, 343 women; low-quality evidence). Low-quality evidence showed that there was also no difference between the groups in rates of ectopic pregnancy (OR 1.40, 95% CI 0.27 to 7.20; P = 0.69, I2 = 0%; 4 RCTs, 404 women). In the antioxidant versus antioxidant comparison, low-quality evidence shows no difference in a lower dose of melatonin being associated with an increased live-birth rate compared with higher-dose melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). This suggests that among subfertile women with an expected live-birth rate of 24%, the rate among women using a lower dose of melatonin compared to a higher dose would be between 12% and 40%. Similarly with clinical pregnancy, there was no evidence of a difference between the groups in rates between a lower and a higher dose of melatonin (OR 0.94, 95% CI 0.41 to 2.15; P = 0.89, I2 = 0%; 2 RCTs, 140 women). Three trials reported on miscarriage in the antioxidant versus antioxidant comparison (two used doses of melatonin and one compared N-acetylcysteine versus L-carnitine). There were no miscarriages in either melatonin trial. Multiple pregnancy and gastrointestinal disturbances were not reported, and ectopic pregnancy was reported by only one trial, with no events. The study comparing N-acetylcysteine with L-carnitine did not report live birth rate. Very low-quality evidence shows no evidence of a difference in clinical pregnancy (OR 0.81, 95% CI 0.33 to 2.00; 1 RCT, 164 women; low-quality evidence). Low quality evidence shows no difference in miscarriage (OR 1.54, 95% CI 0.42 to 5.67; 1 RCT, 164 women; low-quality evidence). The study did not report multiple pregnancy, gastrointestinal disturbances or ectopic pregnancy. The overall quality of evidence was limited by serious risk of bias associated with poor reporting of methods, imprecision and inconsistency.
In this review, there was low- to very low-quality evidence to show that taking an antioxidant may benefit subfertile women. Overall, there is no evidence of increased risk of miscarriage, multiple births, gastrointestinal effects or ectopic pregnancies, but evidence was of very low quality. At this time, there is limited evidence in support of supplemental oral antioxidants for subfertile women.
Showell MG
，Mackenzie-Proctor R
，Jordan V
，Hart RJ
... -
《Cochrane Database of Systematic Reviews》
ResearchGate
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