Iron-deficiency anemia (IDA) is a common, undertreated problem in pregnancy. According to
data from the U.S. National Health and Nutrition Examination Survey (NHANES), 25% of
pregnant women in the U.S. have iron deficiency, with rates of 7%, 24%, and 39% in the
first, second, and third trimesters, respectively. The prevalence of IDA is estimated at
16.2% overall and up to 30% at delivery. Iron deficiency is associated with significant
adverse maternal and fetal outcomes including blood transfusion, cesarean delivery,
depression, preterm birth, and low birth weight. Moreover, iron-deficient mothers are at
risk of delivering iron-deficient neonates who, despite iron repletion, remain at risk
for delayed growth and development. While treatment with iron supplementation is
recommended during pregnancy, questions remain about the optimal route of delivery. Oral
iron therapy, the current standard, is often suboptimal: up to 70% of patients experience
significant gastrointestinal side effects (nausea, constipation, diarrhea, indigestion,
and metallic taste) that prevent adherence to treatment, resulting in persistent anemia.
Intravenous (IV) iron is an attractive alternative because it mitigates the adherence and
absorption challenges of oral iron. However, IV iron costs more, and there are historical
concerns about adverse reactions.
The American College of Obstetricians and Gynecologists (ACOG) recommends oral iron for
the treatment of IDA in pregnancy, with IV iron reserved for the restricted group of
patients. Our preliminary data show that this approach leads to 30% of patients with
persistent IDA at delivery and an associated 3 to 6-fold increased risk of peripartum
blood transfusion. ACOG's preferential recommendation of oral iron is based on paucity of
data on the benefits and safety of IV iron, compared with oral iron, in pregnancy. Our
published systematic review and meta-analysis showed that IV iron is associated with
greater increase in maternal hemoglobin (Hb), but most of the primary trials were
conducted in developing countries, included small sample sizes (50 - 252), and did not
assess meaningful maternal and neonatal outcomes. The current Cochrane review noted that
despite the high incidence and disease burden associated with IDA in pregnancy, there is
paucity of quality trials assessing clinical maternal and neonatal effects of iron
administration in women with anemia. The authors called for "large, good quality trials
assessing clinical outcomes." The only large randomized trial of IV versus oral iron,
conducted in India, showed no difference in a maternal composite outcome, but it is
limited by use of iron sucrose which required five infusions, resulting in a wide range
of iron doses (200 - 1600 mg). In addition, the primary composite outcome included some
components not directly related to anemia. In contrast, our pilot trial of a single
infusion of 1000 mg of IV low molecular weight iron dextran in pregnant women in the U.S.
with moderate-to-severe IDA significantly reduced the rate of maternal anemia at delivery
and showed promise for improving maternal morbidity by reducing rates of blood
transfusion.
This is the first definitive double blind, placebo controlled, multicenter randomized
trial in pregnant women in the U.S. (N=746) to test the central hypothesis that IV iron
in pregnant women with moderate-to-severe IDA (Hb<10 g/dL and ferritin<30 ng/mL) at 13 -
30 weeks will be effective, safe and cost-effective in reducing severe maternal
morbidity-as measured by peripartum blood transfusion-and will also improve offspring
neurodevelopment. A multidisciplinary team of investigators in the U.S., will pursue the
following specific aims:
Primary Aim: Evaluate the effectiveness and safety of IV iron, compared with oral iron,
in reducing the rate of peripartum blood transfusion in pregnant women with
moderate-to-severe IDA.
Secondary Aim 1: Estimate the cost-effectiveness of IV iron , compared with oral iron, in
pregnant women with moderate-to-severe IDA as measured by incremental cost per Quality
Adjusted Life-year (QALY).
Secondary Aim 2: Assess the effect of IV iron, compared with oral iron, on offspring
brain myelin content and neurodevelopment.