Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis

Zoe Tolkien, Lynne Stecher, Adrian P Mander, Dora I A Pereira, Jonathan J Powell, Zoe Tolkien, Lynne Stecher, Adrian P Mander, Dora I A Pereira, Jonathan J Powell

Abstract

Background: The tolerability of oral iron supplementation for the treatment of iron deficiency anemia is disputed.

Objective: Our aim was to quantify the odds of GI side-effects in adults related to current gold standard oral iron therapy, namely ferrous sulfate.

Methods: Systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating GI side-effects that included ferrous sulfate and a comparator that was either placebo or intravenous (i.v.) iron. Random effects meta-analysis modelling was undertaken and study heterogeneity was summarised using I2 statistics.

Results: Forty three trials comprising 6831 adult participants were included. Twenty trials (n = 3168) had a placebo arm and twenty three trials (n = 3663) had an active comparator arm of i.v. iron. Ferrous sulfate supplementation significantly increased risk of GI side-effects versus placebo with an odds ratio (OR) of 2.32 [95% CI 1.74-3.08, p<0.0001, I2 = 53.6%] and versus i.v. iron with an OR of 3.05 [95% CI 2.07-4.48, p<0.0001, I2 = 41.6%]. Subgroup analysis in IBD patients showed a similar effect versus i.v. iron (OR = 3.14, 95% CI 1.34-7.36, p = 0.008, I2 = 0%). Likewise, subgroup analysis of pooled data from 7 RCTs in pregnant women (n = 1028) showed a statistically significant increased risk of GI side-effects for ferrous sulfate although there was marked heterogeneity in the data (OR = 3.33, 95% CI 1.19-9.28, p = 0.02, I2 = 66.1%). Meta-regression did not provide significant evidence of an association between the study OR and the iron dose.

Conclusions: Our meta-analysis confirms that ferrous sulfate is associated with a significant increase in gastrointestinal-specific side-effects but does not find a relationship with dose.

Conflict of interest statement

Competing Interests: ZT, LS, APM declare no conflict of interest. DIAP and JJP declare no conflict of interest but wish to note that they have consulted on iron supplementation and are inventors on a patent detailing novel Fe(III) poly oxo-hydroxide structures that may have potential as commercial dietary supplements [Powell J, Bruggraber S, Faria N, Pereira D, inventors; Ligand modified poly oxo-hydroxy metal ion materials, their uses and processes for their preparation. U.K. patent WO/2008/096130 2008]. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1. Study flow diagram.
Fig 1. Study flow diagram.
RCT, randomized controlled trial; ICU, intensive care unit. (1) This study was carried out by the co-authors and is currently submitted for publication and under review. A list compiling the 88 references that were not obtained is provided in Table A in S1 File.
Fig 2. Forest plot for the effect…
Fig 2. Forest plot for the effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects in placebo-controlled RCTs.
Data for random-effects meta-analysis are shown. For each study the closed diamond represents the mean estimated effect and the horizontal lines the 95% CI. The grey shaded area surrounding each closed diamond represents the weight of each study in the analysis. Weight was assigned based on the (inverse of) the sum of the within-study variance and between study variance. Open diamonds represent the subgroup mean difference and pooled overall mean differences as shown. Test for overall effect: z-score = 7.54 (other), 0.20 (pregnant), 5.79 (overall); p-value <0.0001 (other), = 0.8 (pregnant), <0.0001 (overall). OR, odds ratio; CI, confidence interval. Data shown for 20 RCTs (n = 3168).
Fig 3. Effect of daily ferrous sulfate…
Fig 3. Effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects and hemoglobin repletion in intravenous iron-controlled RCTs.
A, Forest plot for random-effects meta-analysis of the effect of ferrous sulfate supplementation on the incidence of gastrointestinal side-effects against intravenous iron. For each study the closed diamond represents the mean estimated effect and the horizontal lines the 95% CI. The grey shaded area surrounding each closed diamond represents the weight of each study in the analysis. Weight was assigned based on (inverse of) the sum of the within-study variance and between study variance. Open diamonds represent the subgroup mean difference and pooled overall mean differences as shown. Test for overall effect: z-score = 4.36 (other), 3.05 (pregnant), 2.63 (IBD), 5.67(overall); p-value <0.0001 (other), = 0.002 (pregnant), = 0.008 (IBD), <0.0001 (overall). OR, odds ratio; CI, confidence interval. B, Hemoglobin increase in both ferrous sulfate (FeSO4) and intravenous iron (IV iron) arms from baseline (open circles) to end of study intervention (closed circles). Data shown for 20 RCTs (n = 3261).
Fig 4. Forest plot for the effect…
Fig 4. Forest plot for the effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects in pregnant women.
Data for random-effects subgroup meta-analysis are shown (7RCTs, n = 1028). For each study the closed diamond represents the mean estimated effect and the horizontal lines the 95% CI. The grey shaded area surrounding each closed diamond represents the weight of each study in the analysis. Weight was assigned based on (inverse of) the sum of the within-study variance and between study variance. Open diamonds represent the subgroup mean difference and pooled overall mean differences as shown. Test for overall effect: z-score = 2.29; p = 0.02. OR, odds ratio; CI, confidence interval.
Fig 5. Meta-regression analysis of the association…
Fig 5. Meta-regression analysis of the association between daily iron dose and the odds ratio of gastrointestinal side-effects.
A, data from 20 placebo-controlled RCTs (n = 3168); B, data from 23 IV iron-controlled RCTs (n = 3663). Individual studies are represented by circles, with the size of the circle being inversely proportional to the variance of the estimated effect (i.e the larger the circle, the more precise the estimated effect). The dotted lines represent the regression line for the analysis. Closed circles, studies with modified release ferrous sulfate; open circles, studies with conventional ferrous sulfate (i.e. not modified-release). All studies used daily posology.

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