Daily Versus Non-Daily Oral Iron Supplementation for the Treatment of Iron Deficiency Anemia: A Systematic Review and Meta-Analysis of Randomized Trials

Introduction

Iron deficiency anemia (IDA) is a leading cause of disability worldwide affecting approximately 1.2 billion people. The primary treatment for IDA is oral iron supplementation, which is often accompanied by adverse side effects such as nausea and epigastric pain which may be dose-dependent and can lead to poor compliance. Given that the efficacy and safety of different iron supplementation regimens for managing IDA is not clear, we conducted a systematic review and meta-analysis to compare the effectiveness and tolerability of daily versus non-daily oral iron supplementation.

Methods

Following PRISMA guidelines, MEDLINE, EMBASE, and CENTRAL were systematically searched (via Ovid) from inception to September 2022, supplemented by targeted searching of Google Scholar and the reference lists of relevant studies, to identify randomized controlled trials comparing daily (seven days a week) versus non-daily iron supplementation for the management of IDA. The primary outcome was the mean difference in hemoglobin (Hb) levels (in g/L) before and after iron supplementation. Secondary outcomes included percentual correction of baseline Hb, and tolerability and side-effect profile. The quality of the studies was evaluated using the Jadad score and the Revised Cochrane Risk of Bias Tool for Randomized Trials. The primary meta-analysis for the mean difference between baseline and end-of-treatment Hb was done using the generic inverse variance method under a random effects model. To account for potential differences in Hb laboratory methods or reference ranges among different populations, we conducted a meta-analysis for the standardized mean differences calculated using the Hedges g statistic under a random effects model. Heterogeneity was assessed using Cochran's Q and Higgin's I² statistics and sensitivity analyses was also conducted for different dosing regimens for the non-daily group. This review is registered with the International Prospective Register of Systematic Review (CRD42024403539).

Results

Study Characteristics

Of the 6659 identified citations, 106 underwent full-text evaluation, and we included 19 studies involving 2783 patients. The trials were conducted in various countries, including India, Bangladesh, Jordan, Pakistan, Turkey, Brazil, China, Indonesia, Kenya, and Malawi. The study populations included children and adolescents (n=11), pregnant females (n=6), premenopausal females (n=1), and patients greater than 15 years of age (n=1). Regarding non-daily regimes used, 8/19 studies assessed once weekly iron, 2/19 assessed alternate days, 6/19 assessed twice weekly, and 3/19 evaluated both once weekly and twice weekly. Study quality was, in general, low.

Primary Outcome

The pooled mean difference in Hb correction over the treatment period was 3.64 g/L higher in the daily group, with sensitivity analyses showing consistent results. The primary meta-analysis did not suggest evidence of publication bias. The meta-analysis of standardized mean differences corroborated the primary findings. All comparisons showed high heterogeneity based on Cochran's Q and Higgin's I² statistics. The averages of the percent of correction of the baseline Hb 20.9% and 16.1% in the daily and non-daily groups, respectively.

Assessment of Side Effects

Side effects were reported in 11 out of 19 trials and were predominantly gastrointestinal including abdominal pain, nausea, stool consistency change, and/or darker stools, in order of prevalence. Of the 11 studies, 10 reported higher percentages of side effects in the daily group compared to non-daily. One of 11 studies assessed medication compliance revealing a 2.6-fold increase in non-compliance with iron supplementation in the daily group.

Conclusion

Both daily and non-daily oral iron supplementation effectively increase Hb concentrations in patients with IDA. Although daily supplementation results in a slightly higher Hb increase, it is only 3.64 g/L representing approximately a 5% higher correction of the baseline Hb, and it is associated with higher incidence of side effects and reduced tolerability. Consequently, non-daily iron may offer clinically comparable outcomes to daily regimens, along with additional advantages such as improved compliance, fewer side effects and lower treatment cost, and that non-daily supplementation should be considered as a preferred alternative for managing IDA effectively.

No relevant conflicts of interest to declare.