Is It Safe to Correct Iron Deficiency Anemia with Intravenous Iron in Pregnancy? a Systematic Review and Meta-Analysis

Background: Iron deficiency anemia is common among pregnant patients. There is lack of consensus on the approach to management of iron deficiency anemia in pregnancy and controversy remains surrounding the risks associated with its correction. Previous systematic reviews have examined the effectiveness of various management strategies for iron deficiency anemia in pregnancy; however, severe adverse maternal and neonatal effects have not been systematically described. The aim of this systematic review and meta-analysis was to evaluate for adverse maternal and neonatal effects with intravenous (IV) versus oral iron in pregnancy.

Methods: A comprehensive search in MEDLINE, Embase, and CENTRAL from database inception to January 2024 was performed. Articles were eligible for inclusion if they were 1) randomized controlled trials or cohort studies; 2) included pregnant individuals with iron deficiency anemia; 3) comparing patients who received IV iron with those who received oral iron and 4) examining for severe adverse effects in mothers and neonates. IV iron formulations with known safety concerns such as high molecular weight iron dextran were excluded. The primary outcome was preterm birth. Secondary outcomes included neonatal outcomes (e.g., intrauterine growth restriction (IUGR), Apgar scores, admission to the neonatal intensive care unit, stillbirths and neonatal deaths) and maternal outcomes (e.g., red blood cell (RBC) transfusions, postpartum hemorrhage, maternal intensive care unit admission, hysterectomy, unplanned C-section, postpartum depression and maternal death). Data from included studies were extracted by two reviewers independently and in-duplicate, using a standardized data collection form. Disagreements were adjudicated by a third reviewer. Risk of bias assessments were conducted using standard study design specific tools. Inverse variance random effect meta-analyses were used to pool effect estimates using RevMan 5.4.

Results: A total of 1,568 citations were initially obtained of which 28 studies met inclusion criteria and 24 were randomized controlled trials. In total, 3,402 pregnant patients received IV iron and 3,640 pregnant patients received oral iron. All studies administered IV iron or oral iron within the second or third trimester of pregnancy. The most frequently reported IV iron formulations were iron sucrose and ferric carboxymaltose. The most frequently reported oral iron formulation was ferrous sulphate. There was no difference in risk of premature birth between IV and oral iron formulation groups (risk ratio (RR): 0.98, 95% Cl: 0.83 to 1.15, p=0.78, I²=0%). Rates of IUGR (RR:0.88, 95% Cl: 0.74 to 1.03, p=0.12, I²=0%), stillbirths (RR:0.93, 95% Cl: 0.56 to 1.52, p=0.76, I²=0%) and neonatal deaths (RR: 0.72, 0.45 to 1.17, p=0.19, I²=0%) were also similar between IV and oral formulation groups. Rates of adverse maternal outcomes (RBC transfusion (RR:1.00, 95% Cl: 0.57 to 1.76, p=1.00, I²=17%), postpartum hemorrhage (RR: 0.92, 95% Cl: 0.62 to 1.35, p=0.65, I²=0%), unplanned C-sections (RR: 1.33, 95% Cl: 0.99 to 1.78, p=0.06, I²=0%)) were also similar between formulation groups. No studies examined for differences in rates of postpartum depression. Meta-analyses could not be generated for Apgar score <7 at 5 minutes, admissions to the neonatal intensive care unit, maternal admissions to the intensive care unit and maternal death due to an insufficient number of studies reporting these outcomes.

Conclusions: This systematic review and meta-analysis found no difference in risk of adverse neonatal nor maternal outcomes for IV iron compared with oral iron when used to treat iron deficiency anemia of pregnancy. This suggests that IV iron should not be avoided in pregnancy for fear of severe adverse neonatal or maternal events, and provided if deemed clinically appropriate.

Fralick:Signal 1: Membership on an entity's Board of Directors or advisory committees. Kuderer:Astra Zeneca: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Beyond Springs: Consultancy; G1 Therapeutics: Consultancy; Sandoz: Consultancy; Seattle Genetics: Consultancy; Fresenious: Consultancy. Sholzberg:Pfizer: Research Funding; Octapharma: Research Funding.