By Rebecca H. Allen, MD, MPH, Editor
SYNOPSIS: In this systematic review and meta-analysis, among all populations, intravenous iron was associated with a slight increased risk of infection (relative risk, 1.17; 95% confidence interval, 1.04-1.31) compared to oral iron or no iron. However, there was no difference in mortality or length of hospital stay.
SOURCE: Shah AA, Donovan K, Seeley C, et al. Risk of infection associated with administration of intravenous iron: A systematic review and meta-analysis. JAMA Netw Open 2021;4:e2133935.
Intravenous (IV) iron is superior to oral iron in many ways for the treatment of anemia and has become used more commonly in pregnant patients. However, there is biologic plausibility that intravenous iron, by increasing the levels of circulating unbound iron, may contribute to pathogen growth and, therefore, increase infection risk.1
The authors of this study sought to evaluate this association by performing a systematic review and meta-analysis of all randomized clinical trials (RCTs) from 1966 onward that compared IV iron with oral iron, no iron, or placebo, as well as non-randomized trials that met certain criteria (reporting data on infection, at least two comparable groups, and published since 2007) among all populations. The primary outcome was the proportion of patients who developed an infection. Other endpoints included mortality, requirement for red blood cell transfusion, hospital length of stay, and hemoglobin level.
The authors identified 154 RCTs (32,920 participants) and eight non-randomized controlled trials (7,146 participants) to include. The median number of participants in the RCTs was 111 (interquartile range, 14-2,534). The most common setting was obstetrics (39 RCTs, 9,993 participants), followed by surgery (27 RCTs, 4,223 participants), and chronic kidney disease (22 RCTs, 6,013 participants). The most common IV iron preparations studied were iron sucrose and ferric carboxymaltose. For the primary outcome of infection, IV iron was associated with a slightly elevated risk compared with oral iron or no iron (relative risk [RR], 1.17; 95% confidence interval [CI], 1.04-1.31). This risk did not appear to be influenced by anemia levels at study enrollment. The subgroup of patients with inflammatory bowel disease had the highest risk of infection (RR, 1.73; 95% CI, 1.11-2.71). IV iron was associated with improved hemoglobin levels in the meta-analysis compared with oral iron or no iron (mean difference, 0.57 g/dL; 95% CI, 0.50 g/dL to 0.64 g/dL) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89). There was no effect on mortality or hospital length of stay.
COMMENTARY
This study resulted in a headline that IV iron increases the risk of infection. But is that really the case? This is a systematic review and meta-analysis that necessarily depends on the quality of the studies included. The primary outcome was judged to be based on moderate quality evidence. However, the authors acknowledge that the studies had inconsistent and variable reporting of infection as an outcome. Furthermore, grouping obstetrics, surgical, and other types of patients together seems to muddle the picture. The actual increased RR of 1.17 is quite small and in the realm of statistical noise.
Because newer preparations are available that are less likely to cause allergic reactions, the use of IV iron has become more popular in clinical medicine and relevant to obstetric providers in prenatal care. Pregnancy is a state in which increased iron is required (approximately 1,000 mg) to support the increase in red blood cell mass, fetal and placental growth, and blood loss at delivery.2 Therefore, pregnant women routinely are screened for anemia. The first-line therapy for iron-deficiency anemia in pregnancy is, of course, oral iron supplementation, above the amount available in a prenatal vitamin. However, gastrointestinal side effects often limit adherence to oral iron. New guidelines actually recommend administering oral iron every other day to increase absorption and limit side effects.2
Among prenatal patients who are anemic as the result of iron deficiency and cannot tolerate oral iron or are unable to raise hemoglobin levels with oral iron, IV iron is an effective option that typically is given in the third trimester. In contrast to other clinical states, during pregnancy there is a limited period of time available to raise hemoglobin levels prior to delivery. Intravenous iron actually has been shown to raise hemoglobin and ferritin levels faster and to a greater extent compared to oral iron.2 The logistics of administering IV iron are more complex than oral iron, but most infusion centers are able to accommodate this. In my institution, we are referring pregnant women with anemia and low ferritin levels who are not responding to oral iron for IV iron more commonly than in the past, without a hematology consultation. Different IV iron formulations are available and often are dictated by the formulation covered by the patient’s insurance.
Although IV iron theoretically may increase the risk of infection, there are so many variables that come into play in any clinical scenario, it would be difficult to assign a cause-and-effect relationship. The recent Clinical Expert Series on Iron Deficiency Anemia in Pregnancy published in Obstetrics and Gynecology did not mention the risk of infection at all.2 Furthermore, the risks of not treating anemia in pregnancy with the anticipated delivery blood loss must be balanced against the slight theoretical risk of infection. Most experts believe any increased risk is negligible and would only withhold IV iron for a patient with an active infection. Therefore, this would not apply to the vast majority of prenatal patients. In conclusion, this systematic review and meta-analysis will not change my clinical practice.
REFERENCES
- Youssef LA, Spitalnik SL. Iron: A double-edged sword. Transfusion 2017;57:2293-2297.
- James AH. Iron deficiency anemia in pregnancy. Obstet Gynecol 2021;138:663-674.
