Purpose: Iron-deficiency anemia in pregnancy is generally defined by a hemoglobin concentration < 11 g/dL. It affects up to 25% of all pregnancies in the United States. Typically, pregnant women take iron supplements to improve iron status in the blood. However, at least in non-anemic, non-pregnant young women, there is a decreasing absorbance of iron with increasing frequency of iron doses. Additionally, oral iron supplements are associated with gastrointestinal side effects. Thus, it has been suggested that once-daily or every-other-day iron supplements may paradoxically provide better treatment of iron-deficiency anemia than more frequent supplementation. The purpose of this study was to investigate whether once- versus twice-daily iron supplementation in anemic pregnant women is more effective and additionally, whether more frequent iron supplementation would increase gastrointestinal side effects.

Methods: Anemic pregnant women participated in a randomized controlled study at the University of Missouri to investigate the effects of once- versus twice-daily iron supplementation during pregnancy. Blood was drawn from patients between 14- and 28-weeks’ gestation, and if hemoglobin results indicated that the subject was anemic, they were invited to participate in the study. All subjects were randomly assigned to one of two treatment groups. Both groups took one pill in the morning and one pill in the evening. The morning pill was a 325 mg ferrous sulfate iron supplement. The evening pill was either a second 325 mg ferrous sulfate iron supplement (group 2) or a placebo containing cellulose (group 1). Maternal blood was collected at enrollment for assessment of hemoglobin and at delivery, for assessment of hemoglobin and hematocrit. Additionally, a cord blood sample was collected at delivery and hemoglobin was recorded 24 hours postpartum. Subjects were also given validated questionnaires regarding the incidence and intensity of gastrointestinal symptoms including nausea, heartburn, and abdominal pain, and their impact on daily activities. A sample size calculation based on the effects of iron supplementation in non-pregnant women predicted that seventeen participants would be needed in each treatment arm. However, accrual was halted prematurely due to the move of the principal investigator to another institution. In total, twenty subjects were randomized in the study. The gastrointestinal symptom questionnaire was not completed by one subject and delivery data were not available for a separate subject, who did not deliver at the University of Missouri.

Results: In the group that received an iron supplement twice daily, there were significantly higher hemoglobin [Group 1: mean 10.8 g/dL, 95% CI 10.4-11.2; Group 2: mean 11.7 g/dL, 95% CI 11.0-12.3; p=0.03] and hematocrit [Group 1: mean 32.3, (31.4-33.3); Group 2: mean 34.6, (33.2-36.0); p=0.02] values at delivery. However, at baseline, prior to randomization, group 2 also showed evidence of higher hemoglobin and hematocrit levels than group 1 (p<0.1). Changes in hemoglobin [Group 1: mean 0.8 g/dL, (0.5-1.1); Group 2: mean 1.1 g/dL, (0.7-1.6); p=0.26] and hematocrit [Group 1: mean 2.5, (1.4-3.6); Group 2: mean 3.3, (2.2-4.4); p=0.31] levels from baseline to delivery did not differ between the groups. Estimated blood loss at delivery [Group 1: mean 605.0 ml, (267.3-942.7); Group 2: mean 483.3 ml, (352.7-614.0); p=0.54] did not differ between the groups, nor did 24-hour postpartum hematocrit [Group 1: mean 29.7, (28.6-30.8); Group 2: mean 30.7, (28.1-33.3); p=0.50]. Only one participant overall, who was in group 1, required a transfusion at delivery. This incidence was too small to detect a difference between the treatment groups. There were no significant differences in the incidence or severity of gastrointestinal side effects, which were higher in the group that received once-daily iron. [Group 1: mean 1.9 symptoms, (0.8-3.0); Group 2: mean 1.2 symptoms, (0.3-2.2); p=0.37]. The intensity and inconvenience of side effects were nearly identical, for nausea [Group 1 Intensity: mean 0.6, (0.2-1.0); Group 2 Intensity: mean 0.7, (-0.1-1.4); p=0.88] [Group 1 Inconvenience: mean 0.6, (0.1-1.1); Group 2 Inconvenience: mean 0.6, (-0.2-1.3); p=0.92], heartburn [Group 1 Intensity: mean 0.6, (0.2-1.0); Group 2 Intensity: mean 0.1, (-0.1-0.3); p=0.07) [Group 1 Inconvenience: mean 0.7, (0.2-1.2); Group 2 Inconvenience: mean 0.1, (-0.1-0.3); p=0.06], and abdominal pain [Group 1 Intensity: mean 0.3, (0.0-0.6); Group 2 Intensity: mean 0.3, (-0.2-0.7); p=0.86] [Group 1 Inconvenience: mean 0.3, (0.0-0.6); Group 2 Inconvenience: mean 0.2, (-0.2-0.7); p=0.77].

Conclusion: This small study suggests that administering iron twice a day may provide superior treatment for iron status in pregnant women with anemia compared to once-a-day administration, without worsening gastrointestinal side effects.