Daily versus Alternate-Day Iron Supplementation for Pregnant Women with Iron Deficiency Anemia: A Randomized Controlled Trial

Abstract

This study aimed to evaluate the most effective regimen to raise hemoglobin (Hb) by comparing alternate-day dosing of iron to daily dosing in pregnant women with iron deficiency anemia. Women with Hb < 11.0 g/dL and ferritin ≤ 25 µg/L between 12^0/7 and 34^0/7 weeks' gestation were recruited. A total of 88 patients were randomized using block randomization with 1:1 allocation to receive either 1 tablet of 325 mg ferrous sulfate on consecutive days or 2 tablets every other day. The primary outcome, the change in Hb after 6 weeks of treatment was assessed using an analysis of covariance to adjust for baseline level. Secondary outcomes included change in ferritin, hepcidin, side effects, and compliance. Patients completed a questionnaire to assess for adverse symptoms and adherence was monitored by installing a pill reminder app on smartphones of patients. A total of 88 patients were consented. The daily iron group had a greater proportion of nulliparous women (40 vs. 7%). Most patients (98%) had mild anemia (Hb: 9–10.9 g/dL) at recruitment, with a median gestational age of 28.1 weeks (interquartile range [IQR]: 25.6, 30.9) and median duration of treatment of 42 days (IQR: 35, 45). At 6 weeks, the daily iron group had a mean increase in Hb of 0.8 ± 0.9 g/dL, whereas the alternate-day iron group had a mean increase of 0.5 ± 1.0 g/dL (baseline adjusted difference of means: −0.3 [95% confidence interval: −0.7, 0.1], p = 0.15). Frequency of adverse effects attributable to iron were similar between groups. Patient self-reported compliance to treatment was also similar between groups. Among those that used the app, compliance was higher among the daily group compared with the alternate daily group (median: 95.5% [IQR: 75, 100] vs. 85% [IQR: 40, 92]), although this difference was not statistically significant (p = 0.07). This trial suggests that there are no significant differences between alternate-day iron supplementation and daily iron supplementation for treating iron deficiency anemia.

Key Points

• Intermittent iron provides no additional benefit compared to daily iron in the treatment of anemia.

• Patient compliance to treatment was similar between the groups.

• The frequency of side effects was not significantly different between the groups.

Keywords

anemia - alternate - daily - deficiency - dosing - intermittent - iron - pregnancy - regimen

Publication History

Received: 09 January 2024

Accepted: 25 August 2024

Accepted Manuscript online:
29 August 2024

Article published online:
23 September 2024

• References

• 1 Sloan NL, Jordan E, Winikoff B. Effects of iron supplementation on maternal hematologic status in pregnancy. Am J Public Health 2002; 92 (02) 288-293
• 2 Khalafallah AA, Dennis AE. Iron deficiency anaemia in pregnancy and postpartum: pathophysiology and effect of oral versus intravenous iron therapy. J Pregnancy 2012; 2012: 630519
• 3 Breymann C, Bian XM, Blanco-Capito LR, Chong C, Mahmud G, Rehman R. Expert recommendations for the diagnosis and treatment of iron-deficiency anemia during pregnancy and the postpartum period in the Asia-Pacific region. J Perinat Med 2011; 39 (02) 113-121
• 4 Allen LH. Anemia and iron deficiency: effects on pregnancy outcome. Am J Clin Nutr 2000; 71 (05) 1280S-1284S
• 5 Smith C, Teng F, Branch E, Chu S, Joseph KS. Maternal and perinatal morbidity and mortality associated with anemia in pregnancy. Obstet Gynecol 2019; 134 (06) 1234-1244
• 6 Breymann C. Iron deficiency anemia in pregnancy. Semin Hematol 2015; 52 (04) 339-347
• 7 Koenig MD, Tussing-Humphreys L, Day J, Cadwell B, Nemeth E. Hepcidin and iron homeostasis during pregnancy. Nutrients 2014; 6 (08) 3062-3083
• 8 McCabe GBGP. Efficacy of Intermittent Iron Supplementation in the Control of Iron Deficiency Anaemia in Developing Countries: An Analysis of Experience; Final Report to the Micronutrient Initiative. Ottawa: Micronutrient Initiative; 1999
• 9 Peña-Rosas JP, De-Regil LM, Dowswell T, Viteri FE. Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev 2012; 7 (07) CD009997
• 10 Stoffel NU, Cercamondi CI, Brittenham G. et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol 2017; 4 (11) e524-e533
• 11 Stoffel NU. et al. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anemic women. . Haematologica 2019
• 12 Ganz T. Hepcidin and iron regulation, 10 years later. Blood 2011; 117 (17) 4425-4433
• 13 Cancelo-Hidalgo MJ, Castelo-Branco C, Palacios S. et al. Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin 2013; 29 (04) 291-303
• 14 Gofrit SG, Ohayon-Cohen S, Tsur AM. et al. Compliance compromises an interventional study on iron supplementation in female combatants. . J R Army Med Corps 2019
• 15 Grover V, Aggarwal OP, Gupta A, Kumar P, Tiwari RS. Effect of Daily and alternate day iron and folic acid supplementation to pregnant females on weight of the new born. Indian J Community Med 1998; 23 (04) 165-168
• 16 Schoorl M, Schoorl M, van der Gaag D, Bartels PC. Effects of iron supplementation on red blood cell hemoglobin content in pregnancy. Hematol Rep 2012; 4 (04) e24
• 17 Kaundal R, Bhatia P, Jain A. et al. Randomized controlled trial of twice-daily versus alternate-day oral iron therapy in the treatment of iron-deficiency anemia. Ann Hematol 2020; 99 (01) 57-63