Impact of Iron Supplementation on Patient Outcomes in Women Undergoing Gynecological Procedures: Systematic Review and Meta-Analysis of Randomized Trials
Authors: Sirotich Emily , Jamula Erin , Wang Andrea , Arnold Donald M. , Zeller Michelle P. 
Published: February 2020

Background. Perioperative red blood cell (RBC) transfusion is associated with poor patient outcomes. RBC transfusion rates have been decreasing across different types of surgeries as a results of implementing Patient Blood Management (PBM) strategies; while RBC transfusion rates in gynecologic surgeries have remained static. Women are at increased risk of anemia, specifically iron deficiency anemia from gynecologic blood loss putting them at increased risk of requiring perioperative RBC transfusion. PBM encourages preoperative iron supplementation to optimize patients' hemoglobin (Hb) levels; however, evidence specific to gynecological procedures is lacking. This systematic review was conducted to address the question: Does the use of iron supplementation during the perioperative period impact patient outcomes in women undergoing gynecological procedures when compared to no treatment, placebo, or standard of care?
Methods. MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science were searched up to July 2019. Additional records were identified through searching theses, conference proceedings, trials, and grey literature. All randomized controlled trials (RCTs) comparing an intervention group provided with iron supplementation perioperatively to women undergoing gynecological procedures with a comparator were included. Two authors independently assessed studies for inclusion and risk of bias using the Cochrane Risk of Bias tool, extracted data, and evaluated the certainty of evidence using the GRADE approach. Data were pooled using the random-effects (DerSimonian and Laird) method of meta-analysis.
Results. A total of eleven RCTs met inclusion criteria. Two RCTs were then excluded; one RCT compared iron supplementation to no intervention but subset data for gynecology patients was unavailable and the full text of another RCT was unavailable. Seven RCTs (n=447) were amenable to meta-analysis; however iron supplementation was used in both treatment arms: four compared iron with erythropoietin stimulating agents (ESA) to iron alone and three compared iron with gonadotropin-releasing hormone (GnRH) analogue/agonist to iron alone. Six studies were judged to be overall low risk of bias and one to be at high risk of bias.
RBC Transfusions: There was a statistically significant reduction in RBC transfusions during the perioperative period when iron was used in combination with a blood optimization compound (BOC) compared to iron alone (RR 0.33; 95%CI 0.16 to 0.70; p=0.003) (Figure 1).
Preoperative Hb Level: Women who had taken a BOC plus iron had a median preoperative Hb level of 12.87g/dl [95% CI 11.13, 14.61 g/dl]), which was significantly higher (Δ1.16 g/dl; 95% CI 1.01, 1.31g/dl; p&lt;0.00001) than those who took oral iron supplements alone.
Postoperative Hb Level: Among 336 women in six RCTs, women who had taken a BOC in addition to iron had a postoperative Hb of 11.53g/dl (95% CI 6.92 g/dl, 16.14g/dl). This was significantly higher (Δ0.96 g/dl; 95% CI 0.45 g/dl, 1.47 g/dl; p&lt;0.00001) than those who took iron supplements alone.
Adverse Events (AEs): Five studies including 289 participants reported the incidence of AEs. The addition of a BOC did not have a statistically significant effect on the occurrence of AEs (RR 0.98; 95%CI 0.83, 1.17; p=0.85).
One RCT with available data compared iron supplementation to placebo. Meta-analysis was not possible; however, the study found a significant increase in postoperative Hb and decrease in RBC transfusions in patients receiving iron supplementation compared to placebo.
Conclusion. Perioperative use of iron in combination with a BOC in women undergoing gynecological procedures may reduce the need for perioperative RBC transfusions and improve preoperative Hb levels with high certainty of evidence. There was very low certainty of evidence for the impact of iron plus BOC on postoperative Hb levels and the number of AEs. The results of this systematic review suggest that the use of perioperative iron with BOC may improve patient outcomes. Lack of RCTs comparing iron to placebo is a limitation. More studies are needed to address the role of perioperative iron supplementation for gynecological procedures, including evaluating different routes of administration. Analysis of existing observational studies may offer additional data to supplement the results of this meta-analysis.

Disclosures
Arnold: Rigel: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Principia: Consultancy. Zeller:Pfizer: Other: Advisory Board; Canadian Blood Services: Consultancy; Ontario Ministry of Health and Long Term Care: Consultancy.