Nicholson Lily, Axon Emma, Daru Jahnavi, Rogozińska Ewelina
Medical Research Council Clinical Trials Unit, Institute for Clinical Trials and Methodology, University College London, London, UK.
Methods & Evidence Synthesis Development, Cochrane, London, United Kingdom.
Cochrane Database Syst Rev. 2024 Dec 9;12(12):CD016136. doi: 10.1002/14651858.CD016136.
Intravenous iron is increasingly used to treat iron-deficient anaemia (IDA) in pregnancy. A previous network meta-analysis suggested that intravenous irons have a greater effect on haematological parameters than oral irons; however, the impact on serious pregnancy complications such as postpartum haemorrhage (PPH) or the need for blood transfusion was unclear. Since then, several new randomised controlled trials (RCTs) have been conducted.
To evaluate the effect and safety of intravenous versus oral iron preparations for treating IDA in pregnancy.
We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and the WHO ICTRP) for eligible studies. The latest search was performed on 19 March 2024.
We included RCTs in pregnant women with confirmed IDA (haemoglobin (Hb) level < 11 g/dL as per World Health Organization (WHO) criteria) comparing intravenous (iron sucrose, ferric carboxymaltose, ferric derisomaltose, ferumoxytol) and oral (ferrous sulfate, ferrous fumarate, ferrous gluconate) iron preparations.
Our outcomes were antenatal and postnatal Hb levels, antenatal and postnatal anaemia status, PPH, blood transfusion, maternal satisfaction, maternal well-being, breastfeeding, maternal mortality, maternal morbidity, and adverse events (AEs).
We used the Cochrane RoB 1 tool to assess risk of bias in the included RCTs.
We followed standard Cochrane methods. Two review authors independently assessed studies for eligibility and scientific rigour, evaluated the risk of bias of included studies, and extracted data. Where appropriate, we pooled data using a fixed-effect model in the first instance. We reported dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs) and continuous data as mean differences (MDs) with 95% CIs. We assessed the certainty of the evidence using the GRADE approach.
We included 13 RCTs (3939 participants) mainly conducted in India and Africa (8/13). Gestational age at baseline ranged from 13 to 37 weeks, and Hb levels ranged from 5.0 to just below 11.0 g/dL. The most frequently compared preparations were intravenous iron sucrose versus oral ferrous sulfate (5/13). Most RCTs were at low risk of bias, and the certainty of evidence ranged from moderate to very low, mainly due to concerns over attrition bias, imprecision, and inconsistency.
Antenatal outcomes Compared with oral iron, intravenous iron likely slightly increases Hb level three to six weeks after treatment start (MD 0.49, 95% CI 0.28 to 0.69; 11 RCTs; 2935 participants; moderate-certainty evidence) and likely reduces anaemia status three to six weeks after treatment start (RR 0.81, 95% CI 0.77 to 0.86; 5 RCTs; 2189 participants; moderate-certainty evidence). Compared with oral iron, intravenous iron likely slightly increases Hb level around birth (MD 0.55, 95% CI 0.33 to 0.77; 6 RCTs; 1574 participants; moderate-certainty evidence) and likely reduces anaemia status around birth (RR 0.85, 95% CI 0.77 to 0.93; 4 RCTs; 1240 participants; moderate-certainty evidence). Postpartum outcomes Compared with oral iron, intravenous iron may slightly increase Hb level postpartum (MD 0.54, 95% CI 0.41 to 0.68; 3 RCTs; 1950 participants; low-certainty evidence). It may also reduce anaemia status (RR 0.66, 95% CI 0.59 to 0.73; 3 RCTs; 1950 participants; low-certainty evidence) and severe anaemia postpartum (RR 0.16, 95% CI 0.03 to 0.84; 2 RCTs; 1581 participants; very low-certainty evidence), although the evidence for the latter outcome is very uncertain. Compared with oral iron, intravenous iron may result in little to no difference in PPH (RR 1.44, 95% CI 0.50 to 4.20; 3 RCTs; 2251 participants; low-certainty evidence) and likely results in little to no difference in the need for blood transfusion (RR 0.97, 95% CI 0.58 to 1.60; 6 RCTs; 2592 participants; moderate-certainty evidence) or rates of breastfeeding (RR 1.04, 95% CI 0.97 to 1.12; 1 RCT; 404 participants; moderate-certainty evidence). No trials reported on maternal satisfaction or maternal well-being. Adverse outcomes Compared with oral iron, intravenous iron may have little to no effect on maternal mortality, but the evidence is very uncertain (RR 0.91, 95% CI 0.13 to 6.39; 4 RCTs; 2152 participants; very low-certainty evidence). Compared with oral iron, intravenous iron likely does not increase maternal morbidity: severe infections (RR 1.01, 95% CI 0.47 to 2.18; 1 RCT; 1881 participants; moderate-certainty evidence) and prolonged hospital stay (RR 0.86, 95% CI 0.62 to 1.21; 1 RCT; 1764 participants; moderate-certainty evidence) and may not increase admissions to the intensive care unit (ICU) (RR 1.99, 95% CI 0.18 to 21.87; 2 RCTs; 2069 participants; low-certainty evidence). Compared with oral iron, intravenous iron likely does not increase AEs (RR 1.05, 95% CI 0.82 to 1.35; 1 RCT; 349 participants; moderate-certainty evidence) and may not increase serious AEs (RR 1.25, 95% CI 0.61 to 2.59; 1 RCT; 1934 participants; low-certainty evidence). However, individual AEs were inconsistently reported across trials.
AUTHORS' CONCLUSIONS: Intravenous iron likely slightly increases Hb levels and likely reduces anaemia in pregnancy compared to oral iron. Hb levels postpartum may be slightly increased with intravenous iron, but the effect on postpartum severe anaemia status is very uncertain. Intravenous iron may result in little to no difference in PPH, and blood transfusion rates are likely unaffected by route of administration. Synthesis of adverse outcomes proved challenging due to their rarity and suboptimal reporting. The effects of intravenous iron on maternal mortality and admissions to the ICU are very uncertain, and there is likely little to no difference between groups in severe infections and prolonged hospital stay. Intravenous iron likely does not increase AEs and may not increase serious AEs; however, the 95% CIs in both cases include potential harm. Furthermore, this finding should be treated cautiously due to the varied adverse event profiles of both types of iron preparations. Data from the ongoing multicentre trials may address some of the identified evidence gaps. However, there is a clear need to strengthen the co-ordination of research efforts around clinically important time points of outcome measure, homogeneity of their definition, and safety reporting.
This Cochrane Review was partially funded by the WHO and was supported by the UK Medical Research Council funding.
Registration (2024): PROSPERO, CRD42024523791 via www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024523791.
静脉注射铁剂越来越多地用于治疗孕期缺铁性贫血（IDA）。此前的一项网状Meta分析表明，静脉注射铁剂对血液学参数的影响大于口服铁剂；然而，其对产后出血（PPH）或输血需求等严重妊娠并发症的影响尚不清楚。自那时以来，已经进行了几项新的随机对照试验（RCT）。
评估静脉注射与口服铁剂治疗孕期IDA的效果和安全性。
我们检索了Cochrane系统评价数据库、MEDLINE、Embase以及两个试验注册库（ClinicalTrials.gov和世界卫生组织国际临床试验注册平台）以查找符合条件的研究。最近一次检索于2024年3月19日进行。
我们纳入了确诊为IDA（根据世界卫生组织（WHO）标准，血红蛋白（Hb）水平<11 g/dL）的孕妇的RCT，比较静脉注射（蔗糖铁、羧基麦芽糖铁、异麦芽糖酐铁、铁氧还蛋白）和口服（硫酸亚铁、富马酸亚铁、葡萄糖酸亚铁）铁剂。
我们的结局指标包括产前和产后Hb水平、产前和产后贫血状态、PPH、输血、产妇满意度、产妇健康状况、母乳喂养、产妇死亡率、产妇发病率和不良事件（AE）。
我们使用Cochrane偏倚风险1工具评估纳入的RCT中的偏倚风险。
我们遵循Cochrane标准方法。两位综述作者独立评估研究的纳入资格和科学严谨性，评估纳入研究的偏倚风险，并提取数据。在适当情况下，我们首先使用固定效应模型汇总数据。我们将二分数据报告为风险比（RR）及95%置信区间（CI），将连续数据报告为平均差（MD）及95%CI。我们使用GRADE方法评估证据的确定性。
我们纳入了13项RCT（3939名参与者），主要在印度和非洲进行（13项中的8项）。基线时的孕周范围为13至37周，Hb水平范围为5.0至略低于11.0 g/dL。最常比较的制剂是静脉注射蔗糖铁与口服硫酸亚铁（13项中的5项）。大多数RCT的偏倚风险较低，证据的确定性从中度到极低，主要是由于对失访偏倚、不精确性和不一致性的担忧。
产前结局与口服铁剂相比，静脉注射铁剂可能在治疗开始后三至六周使Hb水平略有升高（MD 0.49，95%CI 0.28至0.69；11项RCT；2935名参与者；中度确定性证据），并可能在治疗开始后三至六周降低贫血状态（RR 0.81，95%CI 0.77至0.86；5项RCT；2189名参与者；中度确定性证据）。与口服铁剂相比，静脉注射铁剂可能在出生时使Hb水平略有升高（MD 0.55，95%CI 0.33至0.77；6项RCT；1574名参与者；中度确定性证据），并可能在出生时降低贫血状态（RR 0.85，95%CI 0.77至0.93；4项RCT；1240名参与者；中度确定性证据）。产后结局与口服铁剂相比，静脉注射铁剂可能使产后Hb水平略有升高（MD 0.54，95%CI 0.41至0.68；3项RCT；1950名参与者；低确定性证据）。它也可能降低贫血状态（RR 0.66，9
