Anemia is a common complication during pregnancy, and is associated with preterm birth, low birth weight, and maternal morbidity and mortality. Since iron deficiency (ID) is the most common cause of anemia in pregnant women, iron tablets are usually prescribed as treatment. Most iron dosages are given as 80 mg tablets, which often cause adverse gastrointestinal side effects and impairment of mineral absorption. To minimize these adverse events, upper limits of 45 mg of iron are recommended. However, little is known about alternatives to high dose iron administration to treat anemia during pregnancy. Therefore, a recent study was undertaken to assess the efficacy and side effects of low- vs. high-dose iron administration to treat anemia during pregnancy.

In the study, 179 women at mid-pregnancy were allocated into groups receiving ferrous sulfate containing 20, 40, or 80 mg of elemental iron. The dose was taken daily for 8 weeks or until birth occurred. The study’s primary outcomes were hemoglobin (Hb) level, incidence of anemia at the end of treatment, and adverse gastrointestinal effects. A clear dose-response of increasing Hb with iron dosage was shown, and fewer women receiving 80 mg presented with ID at the end of treatment compared with the lower dosages. Despite a higher mean Hb level and an improved iron status in the 80 mg group, there was no difference in the incidence of anemia among all three groups. Also, adverse gastrointestinal events such as nausea, abdominal discomfort, and constipation were significantly more frequent in the 80 mg group, furthering the issue of clinical benefit vs. patient comfort.

From these results, the authors conclude that lowering the dose of iron provides the same clinical benefits in terms of anemia treatment, but with less adverse events. However, study limitations warrant further investigation into the potential benefits of higher Hb doses. Although several trials have examined Hb cutoff points in relation to adverse pregnancy outcomes, this present study does not have the statistical power to determine if higher Hb levels have an effect on pregnancy outcomes. On the other hand, some studies have indicated a risk of hemoconcentration and other adverse effects in pregnant women treated with higher dosages of iron supplements. More research will be needed to determine the appropriate levels of iron supplements and Hb levels to achieve optimal pregnancy outcomes.

Zhou SJ, Gibson RA, Crowther CA, Makrides M. Should we lower the dose of iron when treating anaemia in pregnancy? A randomized dose-response trial. Eur J Clin Nutr. 2007 Oct 10.

NAAC Expert Commentary:
Iron deficiency anemia (IDA) reportedly affects 20-40% of pregnant women. Although IDA has been associated with multiple maternal and fetal morbidities, little evidence exists to confirm a direct cause and effect relationship. Because of these concerns and because of the approximately 5% incidence of postpartum hemorrhage and its consequent risks, including transfusion—most experts believe anemia in pregnancy should be treated. However, oral iron replacement is poorly tolerated by many patients and therefore, compliance with treatment regimens may be poor.

In the controlled trial, Zhou et al demonstrated that a single 20 mg daily-dose of elemental iron given as ferrous sulfate produced a similar correction of mild to moderate IDA with fewer gastrointestinal side effects than an 80 mg daily-dose. However, iron stores and Hb levels were higher in patients that received the higher iron dose.

The authors were correct to question the clinical equivalence of anemia correction in the three groups, given the expected differences in Hb levels and iron stores. For example, although anemia correction was similar in all groups, women with lower Hb levels and iron stores might suffer prolonged or greater postpartum anemia following blood loss at delivery. Women with lower Hb levels and lower iron stores might benefit from higher Hb and iron levels due to administering a higher iron dose. Similarly, women with lower Hb levels at delivery have a greater risk of requiring a blood transfusion, which might be preventable by establishing higher Hb levels. Although the general rule in medicine is to prescribe the lowest dose of medication that will accomplish the therapeutic goal, there may be benefit in using the higher doses.

Participants in all three arms of the study were highly compliant in taking their medication, despite side effects. It may be difficult to compare this level of compliance among volunteer subjects to the reality of patients prescribed a supplement that is difficult to tolerate. Despite receiving only a single 20 mg daily-dose of elemental iron, even patients in the low dose iron group suffered a 46% incidence of uncomfortable side effects. Had they not been enrolled in a study, many of these women might have discontinued their treatment. Real world compliance with oral iron regimens is low (60%), emphasizing the need for better tolerated preparations and/or dosing schedules. This study provides good information about efficacy and side effects of three dosing protocols for ferrous sulfate, but further research is needed to identify a more ideal protocol for iron replacement in IDA.

Last Modified: September 4, 2008