The tolerability of oral iron supplementation for the treatment of iron deficiency anemia is disputed.
Our aim was to quantify the odds of GI side-effects in adults related to current gold standard oral iron therapy, namely ferrous sulfate.
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 (IV) iron. Random effects meta-analysis modelling was undertaken and study heterogeneity was summarised using I2 statistics.
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 IV 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 IV 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 IV 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.
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.
Citation: Tolkien Z, Stecher L, Mander AP, Pereira DIA, Powell JJ (2015) Ferrous Sulfate Supplementation Causes Significant Gastrointestinal Side-Effects in Adults: A Systematic Review and Meta-Analysis. PLoS ONE 10(2): e0117383. doi:10.1371/journal.pone.0117383
Academic Editor: Pavel Strnad, RWTH Aachen, GERMANY
Received: July 28, 2014; Accepted: December 23, 2014; Published: February 20, 2015
Copyright: © 2015 Tolkien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The UK Medical Research Council (MRC) (U105960399 and G0800860) funded this work but had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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.
In the UK, iron deficiency anemia (IDA) affects around 4.7 million people every year [1,2]. Groups mostly at risk include those with increased iron demands, for example children and pregnant women [3,4,5], and especially those with increased iron loses, for example pre-menopausal women  and patients with inflammatory bowel disease (IBD) [7,8].
First-line treatment is oral therapy with ferrous iron (Fe(II)) salts . For example, in 2012 more than 6.8 million prescriptions were filled for oral iron in England and 97.6% of them were for simple Fe(II) salts . Gastrointestinal side-effects are the most commonly reported adverse effects associated with oral iron treatment and include nausea, flatulence, abdominal pain, diarrhoea, constipation, and black or tarry stools [11,12,13,14,15]. For very many years patient side-effects have been the main concern with oral iron therapy  but, recently, studies have consistently shown that soluble oral iron also negatively impacts the colonic microbiota, promoting the presence of potentially pathogenic bacteria at the expense of beneficial bacteria [17,18,19]. Most recently there have been concerns over ‘available’ iron in the colon as a risk factor for inflammatory signalling and colorectal carcinogenesis [18,20]. Nonetheless, irrespective of the mechanistic foundation of the GI side-effects that appear to be related to oral iron therapy, the impact results in non-adherence in up to 50% of patients. This leads to significant treatment failures and unnecessary follow-up investigations [11,21,22,23,24,25,26,27,28,29,30].
In trying to capture the true incidence of GI side-effects with oral iron therapy, discrepancies between studies and limitations of study design have made overall conclusions difficult to reach [11,14,15]. A recent review has tried to capture data for adverse events from studies with oral iron supplementation in patients without gastrointestinal disease and reported overall adverse event incidences of 32.3% for ferrous sulfate, 47% for ferrous fumarate and 30.9% for ferrous gluconate . However, the meta-analysis reported herein has refined the study eligibility criteria in relation to the prior review . Notably, we have only included randomized controlled studies with a ferrous sulfate intervention arm; we restricted adverse events to the common focus of concern with therapeutic oral iron, namely GI side-effects, and we have only included studies with a common comparator arm, which was either placebo or intravenous iron.
Since ferrous sulfate is the gold standard (most commonly prescribed) oral iron therapy in the UK and many other countries [10,31], our aim was to quantify the odds ratio for oral ferrous sulfate- associated gastrointestinal side-effects versus placebo or IV iron. To this end, we have carried out a systematic review and meta-analysis of all published randomized controlled trials (RCTs) reporting gastrointestinal-specific side-effects that have included ferrous sulfate against placebo or IV iron. We have performed sub-group analysis for pregnant women and patients with IBD since these are two population groups at higher risk of iron deficiency anemia and for whom sufficient robust data were likely to be available [14,32,33]. Finally, we explored whether the iron dose is associated with the odds of gastrointestinal side-effects using meta-regression analysis.
The following bibliographic online databases were searched (last search in March 2014) for all dates up to and including December 2013: MEDLINE via PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Cochrane Library (http://www.thecochranelibrary.com/), EMBASE (http://www.elsevier.com/online-tools/embase), ISI web of Science (http://wok.mimas.ac.uk/), SCOPUS (http://www.scopus.com/), Current Controlled Trials (CCT) (http://www.controlled-trials.com/), International Standard Randomized Controlled Trial Number (ISRCTN) Register (http://www.controlled-trials.com/isrctn/), WHO International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/), ProQuest Dissertations and Thesis (http://www.proquest.co.uk/en-UK/catalogs/databases/), ClinicalTrials.gov (http://clinicaltrials.gov/).
Publications reporting randomized controlled studies with ferrous sulfate were identified by using the search terms ferrous, ferrous sulphate, ferrous sulfate, iron supplement, ferrous salt, iron, paired with the terms randomized controlled trial, randomized controlled trial, controlled trial, controlled clinical study. No limits on language or publication type were imposed. Please refer to S1 File in the online issue for the full search strategy.
Additionally, the following Institutions were contacted (in January 2012) via email to request any additional studies not identified through the electronic search: WHO department of Nutrition for Health and Development (NHD) as well as 12 WHO regional offices (Africa, Americas, South East Asia, Europe, Eastern Mediterranean, Western Pacific, International Agency Research on Cancer (IARC), Centre for Health Development, Lyon office, Mediterranean Centre for Health Risk Reduction, Office at United Nations), Center for Disease Control and Prevention, United Nations Children’s Fund (UNICEF), World Food Programme (WFP), the Micronutrient Initiative, and Sight and Life Foundation. No protocol exists for this systematic review.
Studies were selected for analysis if they met the following criteria: (1) the study was an RCT conducted in adult human participants with either a parallel or crossover design, (2) the study included an arm/group with ferrous sulfate, (3) the study included a comparator arm/group with either placebo or intravenous iron and (4) gastrointestinal side-effects were recorded separately for each arm (i.e. ferrous sulfate and comparator). Where co-interventions were administered with the ferrous sulfate arm (for example ascorbic acid or folic acid) the studies were only included if the same co-intervention was administered in the comparator arm and when in the authors’ view the co-interventions should not influence side-effects in either arm.
Selection and data extraction
Titles of all records retrieved were initially screened by ZT. All potentially relevant studies were then further screened as abstracts by three independent assessors. Three authors (ZT, LS and DP) independently screened full texts of all potentially relevant papers to ensure they met the inclusion criteria.
Data were extracted independently by two authors (ZT and LS) and discrepancies were resolved before data were compiled into a database that included the following fields: (1) patient population, (2) inclusion age criteria, (3) mean age, (4) participant numbers, (5) commercial name for ferrous sulfate (if any), (6) ferrous sulfate dose, (7) frequency of dose, (8) equivalent iron content, (9) duration of the intervention, (10) hemoglobin changes from baseline to end of the intervention, (11) gastrointestinal side-effects reported, (12) comparator group (placebo or intravenous iron), (13) co-interventions. In most studies, patient numbers used for the meta-analysis were those that were randomized, with the exception of studies that specified a subset safety population (i.e. if it was stated that there was only a subset of patients where adverse effects were assessed). If side-effects were reported multiple times during the trial, then only measures at the end of the intervention period were included in the meta-analysis. Data were extracted at the participant level, i.e the number and/or percentage of participants with at least one GI side-effect within a study arm. The ‘total number of participants’ was taken to be the number within the safety (i.e. side-effect assessment) population when specified, otherwise it was taken as the number of participants randomized. Some studies reported the number of participants experiencing each type of GI side-effect and not overall. In these cases, the commonest GI symptom was deemed (conservatively) to represent the number of participants that experienced GI side-effects. For example, in the study of Mirrezaie et al , 5 participants in the ferrous sulfate arm reported heartburn, 17 reported nausea, 2 reported abdominal cramps and 1 reported constipation, so the number of participants in the ferrous sulfate arm with a GI side-effect was taken to be 17.
The generated database for all of the above is available upon request.
Studies that met the eligibility criteria were included in the meta-analysis. The random-effects model proposed by DerSimonian and Laird  was used for the meta-analysis. The odds in each arm were calculated as p/(1-p) where p is the proportion with GI side- effects. The odds ratio (OR) was calculated as the odds in the ferrous sulfate arm divided by the odds in the comparator arm. The meta-analyses used study specific log odds ratios as the outcome and the resulting pooled estimates were converted to OR. Values for the OR above 1 indicate that ferrous sulfate is associated with more side-effects in comparison to either placebo or intravenous iron. Risk of bias in individual studies was assessed independently by two co-authors based upon the Cochrane Collaboration’s Tool . Furthermore, we assessed risk of bias connected to how the studies obtained information about gastrointestinal adverse-events (questionnaire, face to face interviews, spontaneous reporting by participants etc.). Publication bias was assessed by ‘funnel plots’ of the effect [log (OR)] against its standard error. The symmetry of the plots was assessed visually to look for asymmetry. Heterogeneity was assessed using the I2 statistic and substantial heterogeneity exists when I2>50% . Subgroup analyses were carried out for two pre-defined subgroups, namely pregnant women and patients with inflammatory bowel disease. When zero GI side-effects were reported for the placebo or IV comparator arm a standard correction of adding 0.5 of a side-effect to each arm was used to enable calculation of the study-specific log OR. However, since this was a relatively common occurrence in the studies with an IV iron comparator, the meta-analysis was repeated excluding those studies where less than one gastrointestinal side-effect was reported in the IV iron arm.
We produced forest plots to visualise the ORs and 95% CIs of each study, each subgroup and all studies combined. For studies with a cross-over design both cross-over periods were treated independently in the analysis because there was insufficient information regarding individual tabulation of side-effects to apply the methodology proposed by Elbourne et al. .
Furthermore, meta-regression analyses were conducted to determine if the odds of gastrointestinal side-effects with ferrous sulfate was greater with higher doses. We produced bubble plots where individual studies are represented by circles, with the size of the circle being inversely proportional to the variance of the estimated odds ratio used in the meta-regression (i.e. the larger the circle, the more precise is the estimated OR). For the most commonly reported gastrointestinal side effects in the oral ferrous sulfate group, a random-effects meta-analysis (using log-transformed odds) was performed. This provided a pooled estimate of the incidence of each symptom in participants taking oral ferrous sulfate.
Meta-analyses were done with STATA 13 (StataCorp LP, Texas, USA).
A total of 44 studies with publication dates ranging from 1966 to 2013 met the inclusion criteria (Fig. 1). One study was excluded from the final meta-analysis because it was conducted in critically ill surgical patients in intensive care so ferrous sulfate was mixed in the enteral feed rather than being delivered in pure supplemental form as in the other studies . Tables 1 and 2 summarise the characteristics of the 43 studies (n = 6831 participants overall) included in the meta-analyses. Twenty studies (n = 3168 participants) evaluated side-effects associated with oral ferrous sulfate (20–222 mg Fe/day) against a placebo comparator (Table 1) and 23 studies (n = 3663 participants) evaluated side-effects with oral ferrous sulfate (100–400 mg Fe/day) against an intravenous iron comparator (Table 2). We conducted 2 independent meta-analysis, one for the placebo-controlled trials and one for the IV iron-controlled trials, due to clear differences in trial design and study populations, namely: (i) the placebo-controlled trials were generally double-blind with healthy non-anaemic participants whilst (ii) the IV iron-controlled trials were open-label with moderate-severely anaemic patients. The result of the assessment of risk of bias for the individual studies is presented in Table A in S1 File. Included is also the assessment of variability in the methodology used to collate information for gastrointestinal-related adverse-effects.
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.
Publication bias was investigated with ‘funnel plots’, see Figure A in S1 File. The outliers in the funnel plots corresponded to studies reporting zero GI side-effects either in the IV iron-arm (9 studies) or placebo-arm (2 studies) (refer to Tables 1 and 2) and to 1 small (n = 10) placebo-comparator study . The pattern of the remaining studies, although not following the expected funnel shape, is symmetrical and therefore does not provide evidence of publication bias.
Ferrous sulfate versus placebo
For the 20 trials that included placebo as the comparator a significant increase in the incidence of gastrointestinal side-effects was observed with ferrous sulfate OR = 2.32 [95% CI 1.74–3.08, p<0.0001, I2 = 53.6%] (Fig. 2). Nineteen of these 20 placebo-controlled trials were conducted in healthy non-anaemic individuals and therefore hemoglobin repletion was not a primary outcome. The only placebo-controlled trial in anaemic participants was carried out in patients who became anaemic following joint replacement surgery and reported an average increase in hemoglobin of 1.94 g/dl (range -0.3 to +4.2) following 6 weeks of ferrous sulfate therapy compared to an increase of 1.63 g/dl (range -1 to + 3.6) with placebo .
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).
Ferrous sulfate versus IV iron
For the 23 studies that included intravenous iron as the comparator a significant increase in the incidence of gastrointestinal side-effects was observed with ferrous sulfate with an OR = 3.05 [95% CI 2.07–4.48, p<0.0001, I2 = 41.6%] (Fig. 3A). Furthermore, mean hemoglobin increase was reported for 20 of the 23 eligible IV iron-controlled trials (Fig. 3B and Table B in S1 File). Overall, for these 20 trials, the mean increase in hemoglobin for the ferrous sulfate arm was lower than for the IV iron arm although formal comparative analysis was not undertaken being outside the a priori objectives of our analysis (Fig. 3B).
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).
The IBD subgroup analysis (4 studies, n = 669 participants) also showed a significantly higher incidence of gastrointestinal side-effects in the ferrous sulfate arm than in the IV iron arm with OR = 3.14 [95% CI 1.34–7.36, p = 0.008, I2 = 0%] (Fig. 3A). The same was observed in the pregnancy subgroup analysis (5 studies, n = 561 participants), with OR = 9.44 [95% CI 2.23–39.93, p = 0.002, I2 = 33.4%] (Fig. 3A).
Nine out of the 23 IV-iron comparator studies reported zero GI side-effects in the IV-iron arm so, as detailed in Methods, we added the standard correction of 0.5 of a side-effect to each arm to enable calculation of the study-specific log odds ratio. Nevertheless, when we excluded these 9 studies from the meta-analysis the same overall effect was observed with an OR = 2.41 (95% CI 1.66–3.50, p<0.0001, I2 = 42.1%) for ferrous sulfate (seeFigure B in S1 File).
Ferrous sulfate in pregnancy: placebo- and IV iron-controlled trials combined
The subgroup analysis of RCTs in pregnancy generated contrasting results for the placebo-controlled and the IV iron-controlled trials although the number of trials were small (n = 2 and n = 5 respectively, Figs. 2 & 3). Combining data from the 7 RCTs (n = 1028 participants) demonstrated the same detrimental effect of ferrous sulfate with high heterogeneity across studies (OR = 3.33, 95% CI 1.19–9.28, p = 0.02, I2 = 66.1%) (Fig. 4).
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.
Individual gastrointestinal symptoms reported
Thirty three of the 43 studies reported incidences of individual gastrointestinal symptoms (Table 3). The most commonly reported symptoms were constipation, nausea and diarrhoea. For the 27 studies that reported constipation, the pooled estimate of incidence in the FeSO4 arm was 12% [95% CI 10%-15%]. Similarly, for the 30 studies that reported nausea the pooled estimate of incidence in the FeSO4 arm was 11% [95% CI 8%-14%] and for the 25 studies that reported diarrhoea the pooled estimate of incidence was 8% [95%CI 6%-11%].
Meta-regression of dose-response effect showed no significant association between dose and gastrointestinal side-effects for both the placebo-controlled [slope = 0.003 (95% CI: -0.001–0.007), p = 0.17] and the IV iron-controlled [slope = -0.002 (95% CI: -0.01–0.01), p = 0.77] RCTs (Fig. 5). Indeed, for an iron dose increase of 30 mg, it is estimated that the OR would only change by a factor of 1.08 (95% CI 0.96–1.22) for the placebo comparator trials and 0.96 (95% CI 0.70–1.31) for the IV-iron comparator trials.
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.
WHO considers IDA as one of the most expensive diseases in the world due to lost productivity and the sheer numbers of the population affected (ca. 1 billion) . First-line treatment is oral therapy with ferrous iron salts, but a substantial proportion of patients suffer from gastrointestinal side-effects, resulting in non-adherence and treatment failure [22,23,24,27,28,30,43]. Gastrointestinal symptoms most probably result from a combination of two factors: (i) free radical generation through iron-induced redox cycling in the gut lumen and at the mucosal surface which can promote inflammation [18,44,45,46] and (ii) changes to the microbiota composition or metabolism [17,18,19,47]. Ferrous sulfate remains the most commonly prescribed oral iron therapeutic .
We report the first meta-analysis of randomized controlled trials investigating the gastrointestinal side-effects associated with ferrous sulfate supplementation. In our analysis, IV iron was used purely as a comparator arm for gastrointestinal side-effects associated with oral iron for the trials that did not include a placebo arm. The discussion of the side-effects, other than gastrointestinal, associated with IV iron was, therefore, beyond the scope of this analysis.
Significant heterogeneity was observed in both the placebo-controlled studies analysis (I2 = 53.6%, p = 0.002) and the IV iron-controlled studies analysis (I2 = 41.6%, p = 0.02) mainly due to differences in patient population and methodology used to collate gastrointestinal adverse-effects. We have accounted for this heterogeneity by using random-effects modelling . Even though we did not anticipate publication bias to impact the analyses presented here due to the fact that GI adverse-effects was not the primary outcome in most of the studies included in the meta-analysis, we have produced ‘funnel plots’ for visualisation of any asymmetry due to non-publication of studies with negative effects (Figure A in S1 File). The perceived outliers in these plots correspond to studies with zero events in the comparator arms and to one small study with only 10 subjects. The pattern of the remaining studies in the ‘funnel plots’ did not reveal asymmetry and, therefore, there is no indication of publication bias.
Due to the heterogeneity of the study populations in both trial types we have kept the analyses separate overall but there was no change in our findings if the data were combined (see Figure C in S1 File). In order to minimize side-effect reporting bias, we have only included controlled trials with a comparator arm that included an intervention, either placebo or intravenous iron, since gastrointestinal symptoms are common even in the general population and are known to be influenced by psychological factors [48,49,50,51]. Both placebo-controlled and IV iron-controlled meta-analysis have shown that ferrous sulfate is associated with increased gastrointestinal side-effects.
Overall, daily ferrous sulfate supplementation was associated with 2.6 times the odds of GI side-effects compared to placebo or IV-iron in participants who were not pregnant and did not have IBD (Figs. 2 & 3). In pregnancy, adherence with ferrous sulfate has been reported as only 70–90% due to adverse-effects [27,28,43]. Two recent Cochrane reviews provide the most comprehensive analysis of oral iron therapy in pregnancy [14,15] and draw on data from 11 trials (n = 4418 participants) reporting side-effects. Pena-Rosas et al. have shown that pregnant women receiving oral iron supplements were, overall, more likely than controls (albeit not quite statistically significantly so) to report side effects (25.3% versus 9.91%: RR 2.36; 95% CI 0.96–5.82), particularly at doses ≥ 60 mg of elemental iron . Pregnant women receiving intermittent oral iron supplementation had less side effects (mean RR 0.56; 95% CI 0.37–0.84) than those receiving daily iron supplements . Herein we only considered the 7 eligible trials in pregnant women (n = 1028 participants) that have used oral ferrous sulfate and our findings also show that ferrous sulfate is associated with a significant increase in the incidence of gastrointestinal side-effects (OR = 3.33, p = 0.02, Fig. 4), but there is marked heterogeneity in the data.
It is well recognized that inflammatory conditions of the GI tract significantly reduce adherence with oral iron in comparison to the general population, with reports of 52% IBD patients reducing dose or withdrawing from ferrous sulfate treatment due to poor tolerability . Indeed, the four eligible RCTs in IBD patients showed that in this population ferrous sulfate is associated with a significant increase in the incidence of GI side-effects (OR = 3.14, p = 0.008, Fig. 3) in comparison to intravenous iron. However, in the IV iron-controlled studies all subjects were considerably ill with moderate-severe anemia and/or other underlying conditions and, therefore, the comparison with an ‘otherwise healthy’ population group was not possible.
Even following considerable efforts through local and national libraries we could not obtain the full text for 88 studies (Table C in S1 File). The vast majority of these papers were old and not available in English translation, and for many there was no abstract available. Nonetheless, based on a rate of inclusion of 2% from full-text (Fig. 1), we estimate that only 1–2 studies would have been eligible for inclusion from the 88 references that were not obtained. Even though this remains a minor weakness of the present meta-analysis, it would be surprising if data from these few anticipated, additional eligible trials would have changed our findings.
Even though we strived to include in this meta-analysis only robustly designed trials, one limitation remains in relation to blinding of the treatments. First, IV versus oral iron trials are difficult to blind due to the nature of the different interventions. None of the IV iron-controlled studies were blinded and, therefore, we have judged this to represent a high risk of bias in relation to reporting of the main outcome of the present analysis (i.e. GI adverse-effects) (Table A in S1 File). However, we do acknowledge that for the vast majority of the studies the primary outcome measures were biochemical parameters (e.g. hemoglobin) and this is unlikely to have been impacted to the same extent by the lack of blinding.
Secondly, the placebo-controlled trials were not truly blind studies as blackened stools are commonly reported with oral iron [52,53] and in none of the trials included in our meta-analysis was use of a ‘stool darkener’ reported for the placebo arm. Therefore, patients would mostly have been aware when they were taking oral iron and perception of gastrointestinal symptoms could have been altered in a manner that even robust meta-analysis cannot account for. To support the double-blind design in future placebo-controlled clinical trials investigating gastrointestinal symptoms with oral iron it would be preferable to use a stool darkener
It is generally considered that (i) doses ≤ 50–60 mg iron/day generate less side-effects than higher doses and that (ii) iron given in controlled release formulations is better tolerated [27,54,55]. However, our meta-regression analysis shows that there is no statistically significant dose-response effect or threshold whether considered as amount of iron per day (Fig. 5, Figure D-A in S1 File) or per dose (Figure D-B in S1 File). A limitation of this analysis, however, is that data are not uniformly spread across iron dosage, particularly for the intravenous iron-controlled trials that mostly used ~200mg Fe/day (see Fig. 5B). Nonetheless, if there is a benefit in terms of lower side-effects with lower doses of ferrous sulfate then the threshold appears very low (i.e. ≤ 20 mg iron per dose or per day, Figure D in S1 File).
A recent review of 111 studies (10695 participants) with different oral iron preparations has suggested that slow-release ferrous sulfate is better tolerated than regular gastric release ferrous iron salts . This review has included all types of studies ranging from observational to RCT. In contrast, we restricted the work here to meta-analysis of RCTs with robust trial design which still included data from 6831 participants. In this case, subgroup analysis of the 6 included studies that used modified-release ferrous sulfate [56,57,58,59,60,61] in fact shows an OR = 3.60 (95% CI 1.32–9.87, p = 0.01, I2 = 46.2%) compared to OR = 2.53 (95% CI 1.99–3.21, p<0.0001, I2 = 49.6%) for the 37 studies that have used conventional delivery of oral ferrous sulfate (see Figure C in S1 File). Four of the studies with modified-release ferrous sulfate [56,57,58,61] reported zero GI side-effects in the IV iron arm so these data should be interpreted with caution. Nonetheless, our findings do not support the idea that modified-release oral ferrous sulfate markedly modifies its side-effects.
In summary, our analyses show that: (i) ferrous sulfate causes significant gastrointestinal side-effects in adults in all the population groups investigated, with the caveat of potential biases associated with study blinding that are inherent to interventions with oral iron, as discussed above; (ii) the OR of side-effects in IBD is higher than in non-IBD and non-pregnant participants but overall numbers were small and significance not established; (iii) the pregnancy subgroup analysis revealed considerable heterogeneity; (iv) there is no evidence for dose effect; (v) there is no evidence that modified-release ferrous sulfate causes less side-effects than conventional gastric release ferrous sulfate.
S1 PRISMA Checklist. PRISMA checklist.
S1 File. Figure A, Funnel plots of effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects against standard error.
Figure B, Forest plot for the effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects in IV iron-controlled RCTs. Figure C, Forest plot for the effect of daily ferrous sulfate supplementation on the incidence of gastrointestinal side-effects. Figure D, Meta-regression analysis of the association between iron dosage and the odds ratio of gastrointestinal side-effects. Methods A. Table A, Assessment of ‘risk of bias’ according to the Cochrane Collaboration’s tool. Table B, Mean hemoglobin increase (g/dl) reported in IV iron-controlled RCTs (n = 3267). Table C, References identified in the systematic search for which full-text could not be obtained.
This work is a publication of the UK Medical Research Council (MRC) (U105960399 and G0800860). We thank Connie Pscheidt, Kellie Hamill, Lemuel Valdez and Rene Tshulu for their help with sourcing the papers included in this analysis. ZT acknowledges the MRC for the PhD studentship.
Conceived and designed the experiments: ZT DIAP JJP. Performed the experiments: ZT LS. Analyzed the data: ZT LS APM DIAP. Wrote the paper: DIAP JJP. Critical Revision of manuscript: LS APM. Primary responsibility for final content: DIAP. Read and approved the final manuscript: ZT LS APM DIAP JJP.
- 1. WHO (2008) Global database on anaemia. Available: http://who.int/vmnis/anaemia/data/database/countries/en/
- 2. Adamson EA, Bailey GR, Richards N, Wilson H (2008) Prevalence of anaemia in an inner city primary school population. Arch Dis Child 93: 453. doi: 10.1136/adc.2007.116301. pmid:18426951
- 3. Hercberg S, Preziosi P, Galan P (2001) Iron deficiency in Europe. Public Health Nutr 4: 537–545. pmid:11683548 doi: 10.1079/phn2001139
- 4. Pavord S, Myers B, Robinson S, Allard S, Strong J, et al. (2012) UK guidelines on the management of iron deficiency in pregnancy. Br J Haematol 156: 588–600. pmid:22512001 doi: 10.1111/j.1365-2141.2011.09012.x
- 5. Abdullah K, Kendzerska T, Shah P, Uleryk E, Parkin PC (2012) Efficacy of oral iron therapy in improving the developmental outcome of pre-school children with non-anaemic iron deficiency: a systematic review. Public Health Nutr: 1–10.
- 6. Pasricha SRS, De-Regil LM (2012) Daily iron supplementation for improving iron status and health among menstruating women (Protocol). Cochrane Database of Syst Rev 4: CD009747. doi: 10.1002/14651858.cd009747
- 7. Gasche C, Lomer MC, Cavill I, Weiss G (2004) Iron, anaemia, and inflammatory bowel diseases. Gut 53: 1190–1197. pmid:15247190 doi: 10.1136/gut.2003.035758
- 8. Gasche C, Berstad A, Befrits R, Beglinger C, Dignass A, et al. (2007) Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases. Inflamm Bowel Dis 13: 1545–1553. pmid:17985376 doi: 10.1002/ibd.20285
- 9. Cook JD (2005) Diagnosis and management of iron-deficiency anaemia. Best Pract Res Clin Haematol 18: 319–332. pmid:15737893 doi: 10.1016/j.beha.2004.08.022
- 10. NHS (2012) GP prescribing data. Available: http://www.hscic.gov.uk/gpprescribingdata
- 11. Cancelo-Hidalgo MJ, Castelo-Branco C, Palacios S, Haya-Palazuelos J, Ciria-Recasens M, et al. (2013) Tolerability of different oral iron supplements: a systematic review. Curr Med Res Opin 29: 291–303. doi: 10.1185/03007995.2012.761599. pmid:23252877
- 12. Ojukwu JU, Okebe JU, Yahav D, Paul M (2009) Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas. Cochrane Database Syst Rev 3: CD006589. doi: 10.1002/14651858.CD006589.pub2. pmid:19588399
- 13. Okebe JU, Yahav D, Shbita R, Paul M (2011) Oral iron supplements for children in malaria-endemic areas. Cochrane Database Syst Rev 10: CD006589. doi: 10.1002/14651858.CD006589.pub3. pmid:21975754
- 14. Pena-Rosas JP, De-Regil LM, Dowswell T, Viteri FE (2012) Daily oral iron supplementation during pregnancy. Cochrane Database Syst Rev 12: CD004736. doi: 10.1002/14651858.CD004736.pub4. pmid:23235616
- 15. Pena-Rosas JP, De-Regil LM, Dowswell T, Viteri FE (2012) Intermittent oral iron supplementation during pregnancy. Cochrane Database Syst Rev 7: CD009997. doi: 10.1002/14651858.CD009997. pmid:22786531
- 16. Hallberg L, Ryttinger L, Solvell L (1966) Side-effects of oral iron therapy. A double-blind study of different iron compounds in tablet form. Acta Med Scand Suppl 459: 3–10. pmid:5957969 doi: 10.1111/j.0954-6820.1966.tb19403.x
- 17. Kortman GA, Boleij A, Swinkels DW, Tjalsma H (2012) Iron availability increases the pathogenic potential of Salmonella typhimurium and other enteric pathogens at the intestinal epithelial interface. PLoS One 7: e29968. doi: 10.1371/journal.pone.0029968. pmid:22272265
- 18. Werner T, Wagner SJ, Martinez I, Walter J, Chang JS, et al. (2011) Depletion of luminal iron alters the gut microbiota and prevents Crohn's disease-like ileitis. Gut 60: 325–333. doi: 10.1136/gut.2010.216929. pmid:21076126
- 19. Zimmermann MB, Chassard C, Rohner F, N'Goran E K, Nindjin C, et al. (2010) The effects of iron fortification on the gut microbiota in African children: a randomized controlled trial in Cote d'Ivoire. Am J Clin Nutr 92: 1406–1415. doi: 10.3945/ajcn.110.004564. pmid:20962160
- 20. Radulescu S, Brookes MJ, Salgueiro P, Ridgway RA, McGhee E, et al. (2012) Luminal iron levels govern intestinal tumorigenesis after apc loss in vivo. Cell Rep 2: 270–282. doi: 10.1016/j.celrep.2012.07.003. pmid:22884366
- 21. Ahn E, Pairaudeau N, Cerat Y, Couturier B, Fortier A, et al. (2006) A randomized cross over trial of tolerability and compliance of a micronutrient supplement with low iron separated from calcium vs high iron combined with calcium in pregnant women [ISRCTN56071145]. BMC Pregnancy and Childbirth 6. pmid:17190589
- 22. Coplin M, Schuette S, Leichtmann G, Lashner B (1991) Tolerability of iron: a comparison of bis-glycino iron II and ferrous sulfate. Clinical Therapeutics 13: 606–612. pmid:1799918
- 23. Habib F, Habib Zein Alabdin E, Alenazy M, Nooh R (2009) Compliance to iron supplementation during pregnancy. Journal of Obstetrics and Gynaecology 29: 487–492. doi: 10.1080/01443610902984961. pmid:19697194
- 24. Hallberg L, Ryttinger L, Solvell L (1966) Side-effects of oral iron therapy. A double-blind study of different iron compounds in tablet form. Acta medica Scandinavica Supplementum 180: 3–10. doi: 10.1111/j.0954-6820.1966.tb19403.x
- 25. Langstaff R, Geisser P, Heil W, Bowdler J (1993) Treatment of iron-deficiency anaemia: A lower incidence of adverse effects with Ferrum Hausmann than ferrous sulphate. Br J Clin Res 4: 191–198.
- 26. Saha L, Pandhi P, Gopalan S, Malhotra S, Saha PK (2007) Comparison of efficacy, tolerability, and cost of iron polymaltose complex with ferrous sulphate in the treatment of iron deficiency anemia in pregnant women. MedGenMed 9: 1. pmid:18311352
- 27. Souza AI, Batista Filho M, Bresani CC, Ferreira LOC, Figueiroa JN (2009) Adherence and side effects of three ferrous sulfate treatment regimens on anemic pregnant women in clinical trials. Cad Saude Publica 25: 1225–1233. pmid:19503953 doi: 10.1590/s0102-311x2009000600005
- 28. Zaim M, Piselli L, Fioravant iP, Kanony-Truc C(2011) Efficacy and tolerability of a prolonged release ferrous sulphate formulation in iron deficiency anaemia: a non-inferiority controlled trial. Eur J Nutr 51: 221–229. doi: 10.1007/s00394-011-0210-7. pmid:21643774
- 29. Lindgren S, Wikman O, Befrits R, Blom H, Eriksson A, et al. (2009) Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients: A randomized, controlled, evaluator-blind, multicentre study. Scandinavian Journal of Gastroenterology 44: 838–845. doi: 10.1080/00365520902839667. pmid:19330567
- 30. Lindgren S, Wikman O, Befrits R, Blom H, Eriksson A, et al. (2009) Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients: A randomized, controlled, evaluator-blind, multicentre study. Scand J Gastroenterol 44: 838–845. doi: 10.1080/00365520902839667. pmid:19330567
- 31. Santiago P (2012) Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview. Scientific World Journal 2012: 846824. doi: 10.1100/2012/846824. pmid:22654638
- 32. Gasche C, Evstatiev R, Haas T, Kaser A, Knoflach P, et al. (2011) [Diagnosis and treatment of iron deficiency and anaemia in inflammatory bowel diseases. Consensus of the Austrian IBD Working Party]. Z Gastroenterol 49: 627–632. doi: 10.1055/s-0031-1273324. pmid:21526463
- 33. Stein J, Hartmann F, Dignass AU (2010) Diagnosis and management of iron deficiency anemia in patients with IBD. Nat Rev Gastroenterol Hepatol 7: 599–610. doi: 10.1038/nrgastro.2010.151. pmid:20924367
- 34. Mirrezaie SM, Parsi R, Torabgahromi SA, Askarian M (2008) Low dose, short-term iron supplementation in female blood donors of childbearing age: A randomized, double-masked, placebo-controlled study. Iranian Journal of Medical Sciences 33: 138–143.
- 35. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Controlled Clinical Trials 7: 177–188. pmid:3802833 doi: 10.1016/0197-2456(86)90046-2
- 36. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, et al. (2011) The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343: d5928. doi: 10.1136/bmj.d5928. pmid:22008217
- 37. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560. pmid:12958120 doi: 10.1136/bmj.327.7414.557
- 38. Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, et al. (2002) Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 31: 140–149. pmid:11914310 doi: 10.1093/ije/31.1.140
- 39. Pieracci F, Henderson P, Rodney J, Holena D, Genisca A, et al. (2009) Randomized, double-blind, placebo-controlled trial of effects of enteral iron supplementation on anemia and risk of infection during surgical critical illness. Surgical infections 10: 9–19. doi: 10.1089/sur.2008.043
- 40. Pereira D, Couto Irving SS, Lomer MC, Powell JJ (2014) A rapid, simple questionnaire to assess gastrointestinal symptoms after oral ferrous sulphate supplementation. BMC Gastroenterol 14: 103. doi: 10.1186/1471-230X-14-103. pmid:24899360
- 41. Sutton PM, Cresswell T, Livesey JP, Speed K, Bagga T (2004) Treatment of anaemia after joint replacement. A double-blind, randomised, controlled trial of ferrous sulphate versus placebo. J Bone Joint Surg Br 86: 31–33. pmid:14765861
- 42. WHO (2008) The global burden of disease: 2004 update. Geneva: WHO. 1–146 p. pmid:25506952
- 43. Saha L, Pandhi P, Gopalan S, Malhotra S, Saha P (2007) Comparison of efficacy, tolerability, and cost of iron polymaltose complex with ferrous sulphate in the treatment of iron deficiency anemia in pregnant women. MedGenMed: Medscape general medicine 9: 1. pmid:18311352
- 44. Carrier J, Aghdassi E, Cullen J, Allard JP (2002) Iron supplementation increases disease activity and vitamin E ameliorates the effect in rats with dextran sulfate sodium-induced colitis. J Nutr 132: 3146–3150. pmid:12368409
- 45. Lund EK, Wharf SG, Fairweather-Tait SJ, Johnson IT (1999) Oral ferrous sulfate supplements increase the free radical-generating capacity of feces from healthy volunteers. Am J Clin Nutr 69: 250–255. pmid:9989688
- 46. Orozco MN, Solomons NW, Schumann K, Friel JK, de Montenegro AL (2010) Antioxidant-rich oral supplements attenuate the effects of oral iron on in situ oxidation susceptibility of human feces. J Nutr 140: 1105–1110. doi: 10.3945/jn.109.111104. pmid:20392879
- 47. Dostal A, Chassard C, Hilty FM, Zimmermann MB, Jaeggi T, et al. (2012) Iron depletion and repletion with ferrous sulfate or electrolytic iron modifies the composition and metabolic activity of the gut microbiota in rats. J Nutr 142: 271–277. doi: 10.3945/jn.111.148643. pmid:22190022
- 48. Koloski NA, Talley NJ, Boyce PM (2003) Does psychological distress modulate functional gastrointestinal symptoms and health care seeking? A prospective, community Cohort study. Am J Gastroenterol 98: 789–797. pmid:12738457 doi: 10.1111/j.1572-0241.2003.07388.x
- 49. Sobieraj DM, Coleman SM, Coleman CI (2011) US prevalence of upper gastrointestinal symptoms: a systematic literature review. Am J Manag Care 17: e449–458. pmid:22200062
- 50. Heading RC (1999) Prevalence of upper gastrointestinal symptoms in the general population: a systematic review. Scand J Gastroenterol Suppl 231: 3–8. pmid:10565617
- 51. Portincasa P, Maggipinto A, Berardino M, Bonfrate L, Costin S, et al. (2009) Assessing gastrointestinal symptoms and perception, quality of life, motility, and autonomic neuropathy in clinical studies. J Gastrointestin Liver Dis 18: 205–211. pmid:19565052
- 52. Rimon E, Kagansky N, Kagansky M, Mechnick L, Mashiah T, et al. (2005) Are we giving too much iron? Low-dose iron therapy is effective in octogenarians. Am J Med 118: 1142–1147. pmid:16194646 doi: 10.1016/j.amjmed.2005.01.065
- 53. Roth JL, Pugh LC (1998) Side effects of alternative iron supplementation: a pilot study. Pa Nurse 53: 16–18. pmid:10614442
- 54. Liguori L (1993) Iron protein succinylate in the treatment of iron deficiency: controlled, double-blind, multicenter clinical trial on over 1,000 patients. Int J Clin Pharmacol Ther Toxicol 31: 103–123. pmid:8468108
- 55. McDiarmid T, Johnson ED (2002) Clinical inquiries. Are any oral iron formulations better tolerated than ferrous sulfate? J Fam Pract 51: 576. pmid:12100787
- 56. Bayoumeu F, Subiran-Buisset C, Baka NE, Legagneur H, Monnier-Barbarino P, et al. (2002) Iron therapy in iron deficiency anemia in pregnancy: Intravenous route versus oral route. American Journal of Obstetrics and Gynecology 186: 518–522. pmid:11904617 doi: 10.1067/mob.2002.121894
- 57. Bencaiova G, von Mandach U, Zimmermann R (2009) Iron prophylaxis in pregnancy: Intravenous route versus oral route. European Journal of Obstetrics Gynecology and Reproductive Biology 144: 135–139. doi: 10.1016/j.ejogrb.2009.03.006. pmid:19406557
- 58. Strickland ID, Chaput de Saintonge DM, Boulton FE, Francis B, Roubikova J, et al. (1977) The therapeutic equivalence of oral and intravenous iron in renal dialysis patients. Clin Nephrol 7: 55–57. pmid:321170
- 59. Waldvogel S, Pedrazzini B, Vaucher P, Bize R, Cornuz J, et al. (2012) Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: a randomized controlled trial. BMC Med 10: 8. doi: 10.1186/1741-7015-10-8. pmid:22272750
- 60. Vaucher P, Druais PL, Waldvogel S, Favrat B (2012) Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ 184: 1247–1254. doi: 10.1503/cmaj.110950. pmid:22777991
- 61. Guerra Merino S, López Picado A, Muñoz Hernández H, Marín Mesa JM, Lete Lasa I, et al. (2012) Randomized clinical trial to evaluate the effectiveness of two routes of iron administration, oral and intravenous, in the treatment of postpartum iron deficiency anemia. Ensayo clínico aleatorizado para evaluar la efectividad de dos vías de administración de hierro, oral e intravenosa, en el tratamiento de la anemia ferropénica posparto 39: 190–195. doi: 10.1016/j.gine.2011.03.008
- 62. Baykan A, Yalcin SS, Yurdakok K (2006) Does maternal iron supplementation during the lactation period affect iron status of exclusively breast-fed infants? Turkish Journal of Pediatrics 48: 301–307. pmid:17290563
- 63. Cook J, Carriaga M, Kahn S, Schalch W, Skikne B (1990) Gastric delivery system for iron supplementation. Lancet 335: 1136–1139. pmid:1971872 doi: 10.1016/0140-6736(90)91135-w
- 64. Davis BJ, Rajput A, Rajput ML, Aul EA, Eichhorn GR (2000) A randomized, double-blind placebo-controlled trial of iron in restless legs syndrome. European Neurology 43: 70–75. pmid:10686463 doi: 10.1159/000008138
- 65. Fouad GT, Evans M, Sharma P, Baisley J, Crowley D, et al. (2013) A randomized, double-blind clinical study on the safety and tolerability of an iron multi-amino acid chelate preparation in premenopausal women. J Diet Suppl 10: 17–28. doi: 10.3109/19390211.2012.758217. pmid:23387416
- 66. Ganzoni AM, Toendury G, Rhyner K (1974) Oral iron therapy: tolerance for iron sulfate and iron sulfate + succinic acid, and influence on hemoglobin concentration of healthy subjects. <ORIGINAL> ORALE EISENMEDIKATION. VERTRAGLICHKEIT VON EISENSULFAT UND EISENSULFAT + BERNSTEINSAURE, EINFLUSS AUF DIE HAMOGLOBINKONZENTRATION GESUNDER. Dtsch Med Wochenschr (Deutsche Medizinische Wochenschrift) 99: 1175–1178. pmid:4600156
- 67. Gordeuk VR, Brittenham GM, Hughes MA, Keating LJ (1987) Carbonyl iron for short-term supplementation in female blood donors. Transfusion 27: 80–85. pmid:3810831 doi: 10.1046/j.1537-2995.1987.27187121482.x
- 68. Levy F, Andersen P, Ekren T (1978) Absorption and side-effects after peroral administration of sustained release iron tablets. Ferro-Retard Compared with Ferronicum and Duroferon Duretter. Acta Medica Scandinavica 204: 303–310. pmid:358765 doi: 10.1111/j.0954-6820.1978.tb08444.x
- 69. Maghsudlu M, Nasizadeh S, Toogeh G, Zandieh T, Parandoush S, et al. (2008) Short-term ferrous sulfate supplementation in female blood donors. Transfusion 48: 1192–1197. doi: 10.1111/j.1537-2995.2007.01671.x. pmid:18363581
- 70. Meier PR, Nickerson HJ, Olson KA, Berg RL, Meyer JA (2003) Prevention of iron deficiency anemia in adolescent and adult pregnancies. Clin Med Res 1: 29–36. pmid:15931282 doi: 10.3121/cmr.1.1.29
- 71. Makrides M, Crowther C, Gibson R, Gibson R, Skeaff C (2003) Efficacy and tolerability of low-dose iron supplements during pregnancy: a randomized controlled trial. The American journal of clinical nutrition 78: 145–153. pmid:12816784
- 72. Tuomainen T-P, Nyyssonen K, Porkkala-Sarataho E, Salonen R, Baumgartner J, et al. (1999) Oral supplementation with ferrous sulfate but not with nonionic iron polymaltose complex increases the susceptibility of plasma lipoproteins to oxidation. Nutrition Research 19: 1121–1132. doi: 10.1016/s0271-5317(99)00073-1
- 73. Yalcin SS, Baykan A, Yurdakok K, Yalcin S, Gucus AI (2009) The factors that affect milk-to-serum ratio for iron during early lactation. J Pediatr Hematol Oncol (Journal of Pediatric Hematology/Oncology) 31: 85–90. doi: 10.1097/MPH.0b013e31819146c2. pmid:19194189
- 74. Agarwal R, Rizkala AR, Bastani B, Kaskas MO, Leehey DJ, et al. (2006) A randomized controlled trial of oral versus intravenous iron in chronic kidney disease. American Journal of Nephrology 26: 445–454. pmid:17035697 doi: 10.1159/000096174
- 75. Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, et al. (2004) Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol 22: 1301–1307. pmid:15051778 doi: 10.1200/jco.2004.08.119
- 76. Bhandal N, Russell R (2006) Intravenous versus oral iron therapy for postpartum anaemia. BJOG: An International Journal of Obstetrics and Gynaecology 113: 1248–1252. pmid:17004982 doi: 10.1111/j.1471-0528.2006.01062.x
- 77. Breymann C, Gliga F, Bejenariu C, Strizhova N (2008) Comparative efficacy and safety of intravenous ferric carboxymaltose in the treatment of postpartum iron deficiency anemia. Int J Gynaecol Obstet 101: 67–73. doi: 10.1016/j.ijgo.2007.10.009. pmid:18234203
- 78. Charytan C, Qunibi W, Bailie GR (2005) Comparison of intravenous iron sucrose to oral iron in the treatment of anemic patients with chronic kidney disease not on dialysis. Nephron—Clinical Practice 100: c55–c62. doi: 10.1016/j.coph.2014.12.012. pmid:25614182
- 79. Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufmane LR (2007) Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 12: 231–242. pmid:17296819 doi: 10.1634/theoncologist.12-2-231
- 80. Mudge DW, Tan KS, Miles R, Johnson DW, Badve SV, et al. (2012) A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation. Transplantation 93: 822–826. doi: 10.1097/TP.0b013e318248375a. pmid:22290270
- 81. Seid M, Derman R, Baker J, Banach W, Goldberg C, et al. (2008) Ferric carboxymaltose injection in the treatment of postpartum iron deficiency anemia: a randomized controlled clinical trial. American journal of obstetrics and gynecology 199: 435 e431–435 e437. doi: 10.1016/j.ajog.2008.07.046
- 82. Tokars ML (2010) Comparison of Safety and Efficacy of Intravenous Iron Versus Oral Iron in Chronic Renal Failure Subjects With Anemia. http://clinicaltrials.gov/ct2/show/results/NCT00236977
- 83. Van Wyck D, Roppolo M, Martinez C, Mazey R, McMurray S (2005) A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney international 68: 2846–2856. pmid:16316362 doi: 10.1111/j.1523-1755.2005.00758.x
- 84. Van Wyck D, Martens M, Seid M, Baker J, Mangione A (2007) Intravenous ferric carboxymaltose compared with oral iron in the treatment of postpartum anemia: a randomized controlled trial. Obstetrics and gynecology 110: 267–278. pmid:17666600 doi: 10.1097/01.aog.0000275286.03283.18
- 85. Van Wyck D, Mangione A, Morrison J, Hadley P, Jehle J, et al. (2009) Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion 49: 2719–2728. doi: 10.1111/j.1537-2995.2009.02327.x. pmid:19682342
- 86. Kochhar PK, Kaundal A, Ghosh P (2013) Intravenous iron sucrose versus oral iron in treatment of iron deficiency anemia in pregnancy: a randomized clinical trial. J Obstet Gynaecol Res 39: 504–510. doi: 10.1111/j.1447-0756.2012.01982.x. pmid:22925176
- 87. Vazquez Pacheco J (1980) A comparative study of i.v. iron dextran and an oral combination of ferrous sulfate, cyanocobalamin and folic acid in obstetrical patients. Investigacion Medica International 7: 129–135.
- 88. al-Momen AK, al-Meshari A, al-Nuaim L, Saddique A, Abotalib Z, et al. (1996) Intravenous iron sucrose complex in the treatment of iron deficiency anemia during pregnancy. European journal of obstetrics, gynecology, and reproductive biology 69: 121–124. pmid:8902444 doi: 10.1016/0301-2115(95)02538-3
- 89. Kulnigg S, Stoinov S, Simanenkov V, Dudar LV, Karnafel W, et al. (2008) A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: The ferric carboxymaltose (FERINJECT) randomized controlled trial. American Journal of Gastroenterology 103: 1182–1192. doi: 10.1111/j.1572-0241.2007.01744.x. pmid:18371137
- 90. Reinisch W, Staun M, Tandon RK, Altorjay I, Thillainayagam AV, et al. (2013) A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (monofer) compared with oral iron for treatment of anemia in ibd (proceed). American Journal of Gastroenterology 108: 1877–1888. doi: 10.1038/ajg.2013.335. pmid:24145678
- 91. Schroder O, Mickisch O, Mickisch O Fau—Seidler U, Seidler U Fau—de Weerth A, de Weerth A Fau—Dignass AU, et al. (2005) Intravenous iron sucrose versus oral iron supplementation for the treatment of iron deficiency anemia in patients with inflammatory bowel disease—a randomized, controlled, open-label, multicenter study. Am J Gastroenterol 100: 2503–2509. pmid:16279906 doi: 10.1111/j.1572-0241.2005.00250.x