Supplemental Material can be found at: http://jn.nutrition.org/content/suppl/2014/05/11/jn.113.18958 9.DCSupplemental.html
The Journal of Nutrition Nutritional Epidemiology
Iron Supplementation Benefits Physical Performance in Women of Reproductive Age: A Systematic Review and Meta-Analysis1–3 Sant-Rayn Pasricha,4,5* Michael Low,6 Jane Thompson,7 Ann Farrell,8 and Luz-Maria De-Regil9
Abstract Animal and human observational studies suggest that iron deficiency impairs physical exercise performance, but findings from randomized trials on the effects of iron are equivocal. Iron deficiency and anemia are especially common in women of reproductive age (WRA). Clear evidence of benefit from iron supplementation would inform clinical and public health guidelines. Therefore, we performed a systematic review and meta-analysis to determine the effect of iron supplementation compared with control on exercise performance in WRA. We searched the Cochrane Central Register of Clinical Trials, MEDLINE, Scopus (comprising Embase and MEDLINE), WHO regional databases, and other sources in July 2013. Randomized controlled trials that measured exercise outcomes in WRA randomized to daily oral iron supplementation vs. control were eligible. Random-effects meta-analysis was used to calculate mean differences (MDs) and standardized MDs (SMDs). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 6757 titles screened, 24 eligible studies were identified, 22 of which contained extractable data. Only 3 studies were at overall low risk of bias. Iron supplementation improved both maximal exercise performance, demonstrated by an increase in maximal oxygen consumption (VO2 max) [for relative VO2 max, MD: 2.35 mL/(kg min); 95% CI: 0.82, 3.88; P = 0.003, 18 studies; for absolute VO2 max, MD: 0.11 L/min; 95% CI: 0.03, 0.20; P = 0.01, 9 studies; for overall VO2 max, SMD: 0.37; 95% CI: 0.11, 0.62; P = 0.005, 20 studies], and submaximal exercise performance, demonstrated by a lower heart rate (MD: 24.05 beats per minute; 95% CI: 27.25, 20.85; P = 0.01, 6 studies) and proportion of VO2 max (MD: 22.68%; 95% CI: 24.94, 20.41; P = 0.02, 6 studies) required to achieve defined workloads. Daily iron supplementation significantly improves maximal and submaximal exercise performance in WRA, providing a rationale to prevent and treat iron deficiency in this group. This trial was registered with PROSPERO (http://www. crd.york.ac.uk/PROSPERO/prospero.asp) as CRD42013005166. J. Nutr. 144: 906–914, 2014.
Introduction Women of reproductive age (WRA)10 are at high risk of iron deficiency and iron deficiency anemia due to menstrual blood losses. Iron deficiency occurs when iron losses or requirements 1
S.-R.P. was supported by a Victoria Fellowship by the Government of Victoria, a CRB Blackburn Scholarship by the Royal Australasian College of Physicians, an Overseas Research Experience Scholarship by the University of Melbourne, and a National Health and Medical Research Council CJ Martin Early Career Fellowship. 2 S.-R. Pasricha is a coinvestigator on an unrestricted research grant from Vifor Pharma. M. Low, J. Thompson, A. Farrell, and L.-M. De-Regil, no conflicts of interest. 3 Supplemental Figures 1–3 and Supplemental Tables 1–3 are available from the "Online Supporting Material" link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org. 10 Abbreviations used: HR, heart rate; MD, mean difference; RCT, randomized controlled trial; SMD, standardized mean difference; WRA, women of reproductive age; VO2 max, maximal oxygen consumption; VT, ventilatory threshold. * To whom correspondence should be addressed. E-mail: sant-rayn.pasricha@ unimelb.edu.au.
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exceed iron intake, resulting in deficient tissue iron and iron stores, and may eventually produce iron deficiency anemia, in which hemoglobin concentrations are reduced. Female athletes are at particular risk because of diets deficient in iron, increased losses due to gastrointestinal bleeding, and reduced iron absorption due to subclinical inflammation (1). Iron deficiency and anemia are also highly prevalent among WRA in low- and middleincome settings, in which inadequate dietary iron content, consumption of poorly bioavailable iron, and parasitic infection with chronic blood loss contribute to the problem (2). Approximately 496 million nonpregnant women are anemic worldwide, with the prevalence approaching 50% in Africa and South Asia. Approximately 50% of anemia in nonpregnant women is thought to be amenable to iron (3). Iron is essential for a range of functions relating to physical activity and exercise (4). Iron deficiency has been considered to impair physical exercise performance (5) and, consequently,
ã 2014 American Society for Nutrition. Manuscript received December 11, 2013. Initial review completed January 25, 2014. Revision accepted March 7, 2014. First published online April 9, 2014; doi:10.3945/jn.113.189589.
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4 Nossal Institute for Global Health, School of Population Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia; 5Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; 6Department of Clinical Haematology and Bone Marrow Transplant, The Alfred Hospital, Melbourne, VIC, Australia; 7School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia; 8Monash Health, Clayton, VIC, Australia; and 9The Micronutrient Initiative, Ottawa, ON, Canada
Materials and Methods Protocol. The protocol of this review was registered with PROSPERO (http:// www.crd.york.ac.uk/PROSPERO/prospero.asp) as CRD42013005166 (11). Information sources. We searched the following electronic databases: 1) MEDLINE; 2) Scopus; 3) Cochrane Central Register of Clinical Trials (CENTRAL); 4) WHO regional databases (AIM, AFROMED, LILACS, IMSEAR, WPRIM, and IMEMR); 5) the Proquest Digital Thesis database; and 6) OpenSIGLE (for gray literature). Electronic searches were undertaken on 28 July 2013. We also reviewed reference lists of identified articles and other systematic reviews. No language or date restrictions were applied. We searched the WHO International Clinical Trials Registry Platform for potentially eligible unpublished or ongoing trials. MEDLINE and Scopus search strategies are presented in the online material (Supplemental Fig. 1). Study eligibility criteria. RCTs with randomization at any level were eligible if they administered oral iron supplementation daily (at least 5 d/wk) vs. control. Trials giving iron in combination with multiple micronutrients (excluding folate or vitamin C), parenteral iron, or iron by central or pointof-use fortification were excluded. Studies that included a cointervention were included only if the cointervention was applied identically in both study arms. Trials were eligible if they were performed in WRA (women beyond menarche and before menopause who are not pregnant or lactating). If this criterion was not explicitly stated, we included studies if results for females aged 12–50 y could be extracted separately or if >50% of participants fulfilled this criterion. Sensitivity analyses were performed if marginal decisions were made. Studies meeting these criteria were eligible regardless of participant baseline iron or hemoglobin status, training history, or socioeconomic or geographic setting. We excluded studies targeting individuals with disorders affecting iron metabolism, including malabsorptive conditions, excessive blood loss, and inflammatory bowel disease, as well as individuals with medical conditions, including cancer, infectious diseases, or cardiac, renal, or liver failure. Outcomes. We specifically considered peak (maximal) exercise performance [e.g., maximal oxygen consumption (VO2 max) or peak, maximal heart rate (HR) or work rate, ventilatory threshold (VT), blood lactate] and submaximal exercise performance [e.g., efficiency (HR, %VO2 max), respiratory exchange ratio, endurance time]. VO2 max reflects the maximal capacity of an individual to use oxygen during exercise, reached when oxygen consumption reaches a plateau despite increases in exercise workload. It may be approximated by measurement of the VO2 peak, reflecting the maximal oxygen consumption obtained by an individual in a particular test (without necessarily demonstrating a plateau) (12). Absolute VO2 max, measured in liters per minute, does not account for the weight of the individual, whereas relative VO2 max is adjusted for the weight of the individual (mililiters of oxygen per kilogram of body mass per minute) and may
better correlate with peak exercise performance (13). The respiratory exchange ratio is the ratio between oxygen inhaled and carbon dioxide exhaled in a single breath. VT is the point during incremental exercise when ventilation increases out of proportion to oxygen uptake. Data extraction and management. References were managed using Endnote software. Two authors (S.-R.P., J.T.) screened references identified by the search, excluded those in which the title and abstract indicated clear ineligibility, and then assessed full-text papers against the inclusion criteria for eligibility. Two authors extracted data independently (S.-R.P. and either M.L. or A.F.). Data were analyzed using Review Manager (RevMan 5.1, 2011; The Nordic Cochrane Centre). Discrepancies were resolved through discussion. Assessment of risk of bias in included studies. Risk of bias was assessed by 2 authors independently (S.-R.P. and either M.L. or A.F.) using the Cochrane risk-of-bias tool, which addresses selection, performance, attrition, detection, and reporting bias through evaluation of reported sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other possible sources (14). Studies were considered at high overall risk of bias if randomization or allocation concealment was judged as being at high (or unclear) risk of bias or were either not blinded or had high or imbalanced attrition rates; otherwise, they were considered at low overall risk of bias. For outcomes containing >10 trials, funnel plots were examined for asymmetry to identify publication bias. Synthesis of results. Meta-analysis was undertaken for outcomes reported by at least 2 studies. Mean difference (MD) and standardized mean difference (SMD; in which effect size is normalized to the standard deviation of the measurement scale) were determined for continuous data measured on the same scale and different scales, respectively. Statistically significant differences were defined when the 95% CI for the effect size did not cross 0 with P < 0.05. Heterogeneity was quantified with the I2 test. Significant heterogeneity was considered to exist when I2 exceeded 50% and was explored by predefined subgroup analysis for outcomes containing $5 studies. Subgroups included the following: 1) age (adolescence, adulthood); 2) baseline anemia status (anemic, non-anemic, mixed/unspecified, as defined by trial authors); 3) baseline iron status (iron deficient, non-iron deficient, mixed/unspecified, as defined by trial authors); 4) dose of elemental iron per day (100 mg); 5) duration of supplementation (3 mo); and 6) training status of women (trained: participants recruited because of a high level of physical fitness due to either membership of a defined sporting team or achievement of a defined high standard of physical performance, and both competitive and recreational athletes were included; women were also included in this group if they underwent a defined physical training program as part of the study). Differences between subgroup strata were formally investigated using the x2 and I2 methods of Borenstein et al. (15) in subgroups in which $2 strata contained $3 trials each. We anticipated clinical, methodologic, and thus statistical heterogeneity between studies, so all data were combined using random-effects meta-analysis with calculation of t2.
Results Study flow is presented in Figure 1. A total of 6757 titles were screened for eligibility. The WHO International Clinical Trials Registry Platform identified no unpublished or ongoing potentially eligible studies. After screening, 36 references were identified for full-text review. Five were excluded because they were not RCTs (16–20) [including 1 that was a quasi-RCT (19)], and 1 was excluded because the intervention was not an eligible iron supplement (21). One full-text paper could not be sourced (22). Twenty-nine references comprising 24 studies were considered eligible for inclusion. The full eligibility screen is presented in Supplemental Table 1. Two ostensibly eligible Iron supplementation and physical performance
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economic productivity, particularly in manual workers (6,7), especially female manual workers. These detrimental effects are considered important justifications to prevent or treat iron deficiency in women. The WHO recommends distribution of iron supplements to all women in populations in which the prevalence of anemia (in women) exceeds 20% (8). Likewise, the International Olympic Committee recommends screening female athletes for iron deficiency to target iron supplementation, with a view to improving performance (9). However, randomized controlled trials (RCTs) investigating effects of iron supplementation on exercise performance have been small generally with equivocal results (10). This limits the capacity of primary and specialist clinicians and policymakers to anticipate potential benefits when considering strategies to prevent and treat iron deficiency. Therefore, we performed a systematic review and meta-analysis of RCTs to evaluate the effects of daily iron supplementation on physical performance in WRA.
studies were crossover trials that did not report on outcomes at the end of the first parallel time course, so data could be not extracted (23,24). Data were thus extracted from 22 studies (Table 1) recruiting 911 participants, of whom 464 were randomly assigned to take daily iron supplementation and 447 to the control group. Characteristics of included studies are summarized in Table 1. Authors provided additional information for 2 trials (7,10). Risk of bias of included studies is summarized in Supplemental Figure 2. Only 3 studies were considered to be at overall low risk of bias (10,25,26). Findings from meta-analysis are summarized in Table 2. A comprehensive summary of results for all outcomes including subgroup analysis when appropriate is presented in Supplemental Table 2. Four trials were funded or supported by pharmaceutical companies (26–29), but only Jensen et al. (27) identified benefit from iron on exercise outcomes. Funding sources are presented in Supplemental Table 3. Maximal exercise performance Maximal aerobic capacity was measured in different studies using VO2 max or VO2 peak, which we combined by metaanalysis (termed hereafter as VO2 max). Both absolute and relative VO2 max were reported in eligible studies. Relative VO2 max was reported in 18 studies recruiting 620 participants. Meta-analysis revealed a beneficial effect from iron [MD: 2.31 mL/(kg min) (95% CI: 0.83, 3.80), P = 0.002, I2 = 71%] (Fig. 2a). The funnel plot showed no asymmetry to indicate publication bias (Supplemental Fig. 3). When the 20 anemic participants from the single trial recruiting iron-deficient anemic women (30) were removed from the analysis, the beneficial effect from iron remained significant [MD: 2.18 (95% CI: 0.57, 3.79), P = 0.008, I2 = 72%], as it did when the 1 trial that recruited 42% male participants (31) was excluded [MD: 2.25 (95% CI: 0.70, 3.80)]. The effect was seen in irondeficient women, although there was also a benefit in women for 908
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Other maximal exercise variables. There were no differences evident between women randomly assigned to take iron and control in other peak exercise variables, including respiratory exchange ratio or time (duration of maximal exercise) to exhaustion (Table 2). One study reported effects of iron supplementation on muscle fatigability in non-anemic iron-depleted women: women randomly assigned to take iron experienced reduced attenuation of maximal voluntary contractions compared with women randomly assigned to the control group (P < 0.01) (32). One study reported the effects of iron on VT in peak exercise: women randomly assigned to take iron had significantly higher VT [31.54 vs. 24.27 mL/(kg min) and 74.13% vs. 63.04% of VO2 max, both P < 0.05] (33). Submaximal exercise No studies reporting submaximal exercise outcomes were considered at low overall risk of bias. Efficiency: HR. Six studies recruiting 172 participants reported HR during submaximal exercise (28,33–36). Women administered iron had a significantly lower HR during submaximal exercise compared with women randomly assigned to the control group [MD: 24.05 beats per minute (95% CI: 27.25, 20.85), P = 0.01, I2 = 0%] (Fig. 3a). The reduction was seen only in trained women. All studies reporting this outcome were performed in irondeficient women. Efficiency: percentage of VO2 max. Six studies comprising 167 participants reported on percentage of VO2 max required by participants as they undertook a defined submaximal exercise
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FIGURE 1 Study flow for selection of trials included in the systematic review. RCT, randomized controlled trial.
whom iron status had not been determined at recruitment. The effect was seen in trained [MD: 2.28 (95% CI: 1.35, 3.21), P < 0.00001, I2 = 10%] but not in nontrained [MD: 2.32 (23.38, 8.02), P = 0.43, I2 = 93%] women. When only the 3 studies at low risk of bias were included, no benefit from iron on VO2 max was seen [MD: 0.94 (95% CI: 22.06, 3.93), P = 0.54, I2 = 0%, 207 participants]. Analysis by age, dose, and type of iron compound could not be performed because of insufficient data in the subgroups. Absolute VO2 max was reported by 9 studies recruiting 316 women, all of whom were iron deficient. Meta-analysis identified a benefit from iron among women randomly assigned to receive iron [MD: 0.11 L/min (95% CI: 0.03, 0.20), P = 0.01, I2 = 0%] (Fig. 2b). This effect was seen in anemic but not non-anemic women. The benefit from iron was seen only in trained women. No studies at overall low risk of bias reported this outcome. When all studies reporting VO2 max were combined (20 studies, 737 participants, inclusion of relative VO2 max data if both absolute and relative data were reported), the SMD between iron and control was 0.35 (95% CI: 0.12, 0.58) (P = 0.004, I2 = 52%). When the 64 anemic women were removed from the analysis, a beneficial effect from iron remained [SMD: 0.26 (95% CI: 0.05, 0.47), P = 0.01, I2 = 38%]. Subgroup analysis showed that iron supplementation clearly benefited VO2 max in anemic women and in both iron-deficient women and women in whom baseline iron status was not established. Nonsignificant evidence of benefit was seen in participants who were nonanemic or in whom baseline anemia status was not established. Iron improved VO2 max in trained but not nontrained women. For each of these subgroups, there was no evidence of a significant difference in effect between subgroup strata (Supplemental Table 2).
909
18–33 y 18–41 y
18–35 y 19–44 y
Finland
Germany
United States
United States
United States United States
United States
China
United States
Israel United States Canada
Serbia
United States
United States
Japan
Fogelholm et al. (25)
Friedmann et al. (31)
Hinton (34); Brownlie et al. (53,54) Hinton and Sinclair (33)
Jensen et al. (27) Klingshirn et al. (37)
LaManca and Haymes (28) Li et al. (7,55); Li (50)
Lyle et al. (56)
Magazanik et al. (57) McClung et al. (38) Newhouse et al. (29)
Radjen et al. (30)
Rajaram et al. (58)
Rowland et al. (35)
Taniguchi et al. (59)
18–22 y
Adolescents
College age
16–25 y
19 y Mean age: 21 y 18–40 y
College age
18–25 y 22–39 y
13–25 y (58% females)
17–31 y
.18 y
United States
DellaValle (52)
18–45 y
Participant age
Mexico
Country
Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 6 mg/L)
Anemia status unknown; iron status unknown Anemia status unknown; iron status unknown Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 20 mg/L) Iron deficiency anemia (Hb , 120 g/L, ferritin , 12 mg/L, transferrin saturation , 16%) Non-anemic iron deficiency (Hb . 120 g/L, ferritin , 12 mg/L, transferrin saturation . 16%); anemia status unknown; iron status unknown
Anemia status unknown; iron status unknown
1 mg/d elemental iron as ferric ammonium citrate + vitamin C (n value not stated, assume 27)
325 mg/d elemental iron as FeSO4 (n = 7)
Iron deficiency anemia (n = 10); non-anemic iron deficiency (n = 9); 50 mg/d elemental iron as FeSO4 (low-iron diet) (n = 16)
15 mg/d elemental iron as FeSO4 (n = 13) 15 mg/d elemental iron as FeSO4 (n = 86) 100 mg elemental iron twice per day as FeSO4 (n = 19) 50 mg/d elemental iron as FeSO4
60 mg/d (non-anemic, mild anemic) or 120 mg/d (moderate anemia) elemental iron as FeSO4 (n = 40) 10 or 50 mg/d elemental iron as FeSO4 + low-iron diet + exercise regimen
50 mg/d elemental iron as FeSO4 (n = 10)
12 wk
7 wk 9 wk 8 wk 8 wk
Placebo + unrestricted diet + exercise regimen Placebo (n = 15) Placebo (n = 85) Placebo (n = 21) Placebo
Placebo + vitamin C (n value not stated, assume 27)
9 wk
4 wk
24 wk
12 wk
Placebo (n = 40)
Iron deficiency anemia (n = 10); non-anemic iron deficiency (n = 8); placebo (normal-iron diet) (n = 13) Placebo (n = 7)
8 wk
12 wk 8 wk
6 wk
6 wk
12 wk
8 wk
6 wk
6 wk
Duration
Placebo (n = 10)
Placebo (n = 6) Placebo (n = 9)
Placebo (n = 10)
30 mg/d elemental iron as FeSO4 (n = 10)
50 mg/d elemental iron as FeSO4 (n = 7) 50 mg/d elemental iron as FeSO4 (n = 9)
Placebo (n = 20)
20 mg/d elemental iron as FeSO4 (n = 22)
Placebo + vitamin C supplement (n = 17) Placebo (n = 20)
100 mg/d elemental iron as FeSO4, with vitamin C supplement (n = 14) 200 mg/d elemental iron as FeSO4 (n = 20)
Placebo (n = 10) Placebo (n = 19)
10 mg/d elemental iron as FeSO4 (n = 10)
Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); mixed iron status: 58% iron depleted (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 25 mg/L) Non-anemic (Hb . 117 g/L for females, 135 g/L for males); iron depleted (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 16 mg/L) Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 16 mg/L or raised sTfR or sTfR-F index) Non-anemic Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 20 mg/L) Anemia status unknown; iron depleted (ferritin , 20 mg/L) Iron deficient (ferritin , 12 mg/L); non-anemic (n = 18); anemic (Hb , 120 g/L) (n = 22)
Control
30 mg/d elemental iron as FeSO4 (n = 21)
Intervention
Baseline anemia, iron deficiency status
Included studies evaluating effects of daily iron supplementation on physical exercise performance in women of reproductive age1
Brutsaert et al. (32)
Study (ref)
TABLE 1
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Iron supplementation and physical performance
(Continued)
U, U, H, H, U, L
U, U, L, U, U, L
U, U, H, H, L, L
U, U, L, U, U, L
U, U, L, U, L, L U, U, L, U, L, L U, U, L, U, L, L
U, U, H, H, H, L
U, U, L, U, L, L
U, U, L, U, U, L
U, U, L, U, U, L U, U, L, U, U, L
U, U, L, L, U, L
U, U, L, U, L, L
U, U, U, U, H, L
L, U, L, U, L, L
L, L, L, L, L, L
U, U, L, U, U, L
Risk of bias2
8 wk Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 16 mg/L) 19–36 y United States Zhu et al. (36); Zhu and Hass (63)
Not reported Japan
1 Overall risk of bias was defined as follows: 1) high risk if randomization or allocation concealment judged as being at high risk of bias (or unclear) or were either not blinded or had high or imbalanced attrition rates; 2) otherwise, low risk of bias. H, high risk of bias; Hb, hemoglobin; L, low risk or bias; ref, reference; sTfR, soluble transferrin receptor; sTfR-F, soluble transferrin receptor/log(ferritin) index; U, unclear risk of bias. 2 The letters correspond to random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessors, incomplete outcome data, and selective reporting, respectively.
U, U, L, U, L, L
U, U, L, U, U, L 8 wk
Multivitamin alone (n = 6) Placebo (n = 17)
Adolescents Australia
Walsh and McNaughton (60,61) Yoshida et al. (62)
18–50 y Switzerland Waldvogel et al. (26)
Anemia status unknown; iron status unknown
12 wk Placebo (n = 10)
150 mg/d iron; formulation not stated (n = 10) 60 mg/d elemental iron as ferrous ammonium citrate + multivitamin (n = 6) 135 mg/d elemental iron as FeSO4 (n = 20)
U, U, L, U, L, L
4 wk Placebo (n = 76) 80 mg/d elemental iron as FeSO4 (n = 78)
Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 30 mg/L) Anemia status unknown; iron status unknown
L, L, L, U, L, L
Risk of bias2 Duration Control Intervention Baseline anemia, iron deficiency status Participant age Country Study (ref)
Continued TABLE 1
Pasricha et al.
Other submaximal outcomes. No differences between women randomly assigned to the iron and control groups were seen in energy consumption (kilojoules per minute), work (watts), or respiratory exchange ratio during submaximal exercise (Table 2). One study reported an improvement in 3.2 km (2 miles) run time among iron-deficient anemic female soldiers randomly assigned to take iron, although data for the overall group were not presented (38). Other outcomes Although not a prespecified outcome, we collected data on reported adverse events that were reported in detail by only 1 trial (26): women randomly assigned to take iron experienced increased undesirable gastrointestinal events (P = 0.001), ‘‘hard stools’’ (P = 0.015), and ‘‘any events’’ (P = 0.002).
Discussion Daily oral iron supplementation in WRA improves both maximal and submaximal exercise performance. These benefits are clearest in iron-deficient and trained women. Our findings have implications for clinical management of patients, nutritional optimization for athletes, and rationale and design of public health anemia control programs. These results also begin to define the physiologic deficits induced by iron deficiency. To our knowledge, this is the first published meta-analysis to provide evidence of beneficial effects of iron supplementation on physical performance. Gera et al. (39) reviewed effects of iron administration on physical performance in children but included only 3 studies, which was too few for meta-analysis. An unpublished meta-analysis by Casgrain et al. (40) that evaluated effects of iron (through different delivery strategies) on physical performance (in males and females) performed a meta-analysis of 8 studies reporting VO2 max, finding a significant benefit from iron [MD: 1.61 mL/(kg min) (95% CI: 0.39, 2.83)] . These authors also identified a significant reduction in HR during submaximal exercise [4 studies, MD: 25.57 beats per minute (95% CI: 210.38, 20.76)]. Iron supplementation benefits maximal aerobic capacity (VO2 max) and efficiency of submaximal exercise (i.e., reduces the required percentage of VO2 max and HR), with 1 study also suggesting that it improves strength. The physiologic mechanism for these effects may reflect a range of processes. Raised hemoglobin concentrations may improve oxygen-carrying capacity and hence tissue oxygenation during exercise. Meta-analysis of hemoglobin data from studies reporting on VO2 max in this review showed a clear increase in hemoglobin with iron compared with control [MD: 6.79 g/L (95% CI: 4.29, 9.30), 19 studies]. Animal studies suggest that even non-anemic iron deficiency severely affects exercise performance in rats, restored by iron repletion (41). Iron is important in muscle metabolism with critical roles in the mitochondrial respiratory chain (cytochrome oxidase) and myoglobin (4,42). Improved tissue iron may thus improve tissue oxygen utilization and hence exercise performance, even in non-anemic individuals. Our findings indicate that prevention and treatment of iron deficiency could improve performance in female athletes who compete in a wide range of sports requiring either or all of endurance, maximal power output, and strength. The magnitude of increase in
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load (34–37). Iron reduced the percentage of VO2 max required [22.68% (95% CI: 24.94, 20.41), I2 = 46%, P = 0.02] (Fig. 3b). The reduction was seen only in trained women. All studies reporting this outcome were performed in iron-deficient women.
TABLE 2 Summary of effects of daily iron supplementation on exercise performance in women of reproductive age1 Outcome
1
I2
Participants
n
n
18 9 20 4 5 4 2
620 316 737 112 152 106 49
2.35 (0.82, 3.88) 0.11 (0.03, 0.20) 0.34 (0.11, 0.57) 0.01 (20.02, 0.03) 1.27 (21.08, 3.61) 20.00 (20.72, 0.72) 1.09 (20.48, 2.66)
0.003 0.01 0.004 0.60 0.29 1.00 0.17
71 0 52 0 0 0 41
6 6 5 3 3 3
172 167 136 98 99 52
24.05 (27.25, 20.85) 22.68 (24.94, 20.41) 20.01 (20.02, 0.01) 20.48 (21.65, 0.68) 26.64 (219.15, 5.88) 1.23 (20.41, 2.87)
0.01 0.02 0.28 0.42 0.30 0.14
0 46 0 67 10 0
%
SMD, standardized mean difference; VO2 max, maximal oxygen consumption.
relative VO2 max from iron [0.82–3.88 mL/(kg min)] is in the range of improvements that can be achieved by exercise training (43). Female athletes experience a higher prevalence of iron
deficiency compared with the general population (44) because of inadequate iron intake in athletes attempting to achieve or maintain a defined body weight and composition, foot-strike
FIGURE 2 Effects of daily iron supplementation on maximal exercise performance in women of reproductive age. Daily iron supplementation improved relative VO2 max, maximal oxygen consumption. (A) and absolute VO2 max (B). IV, inverse variance; Random, random effects; VO2 max, maximal oxygen consumption. Iron supplementation and physical performance
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Maximal exercise Relative VO2 max, mL/(kg min) Absolute VO2 max, L/min VO2 max, all studies, SMD Respiratory exchange ratio Heart rate, beats/min Blood lactate at longest time point, mmol/L Time to exhaustion, min Submaximal exercise Heart rate, beats/min %VO2 max Respiratory exchange ratio Energy consumption, kJ/min Workload, W Time to exhaustion, min
Difference [mean (95% CI)]
P-effect
Trials
hemolysis, and increased iron losses in sweat, urine, and feces (44). Iron status may also be impaired in athletes by highaltitude training with enhanced erythropoiesis, gastrointestinal bleeding after severe endurance exercise (45), and elevated hepcidin after exercise (46). Hepcidin regulates systemic iron homeostasis and is induced by inflammation [including intensive exercise (47)] and storage iron; suppressed hepcidin facilitates iron absorption and utilization, whereas elevated hepcidin prevents it (48), suggesting that restitution of iron stores with oral iron may be less effective in the immediate postexercise period. Our data indicate that detection, treatment, and prevention of iron deficiency in this population can improve physical performance. Iron supplementation was shown clearly in trials and metaanalyses to benefit hemoglobin and iron stores (49), but evidence for benefits on functional outcomes, which are a key rationale for controlling iron deficiency, has been difficult to ascertain. Measurement of exercise performance (e.g., VO2 max) has been consistent over time and between studies, enabling meta-analysis, unlike other variables (e.g., cognitive performance, psychologic health, fatigue) that have been measured in different studies using differing techniques and scales. Therefore, to the best of our knowledge, this is 1 of the first reports to document a nonhematologic benefit from iron. Improvements in physical performance from iron supplementation may extend to broader benefits. For example, Li et al. (7) showed that female cotton-mill workers randomly assigned to take iron experienced improved productivity and earnings and also had reduced HR during work compared with women in the control group (potentially reflecting our finding that iron reduces HR during submaximal exercise). Unpublished data from the same trial (included in this metaanalysis) revealed a significant improvement in absolute VO2 max in women randomly assigned to take iron (42,50). Given the beneficial effect from iron supplementation in women in whom baseline iron or anemia status was not measured, our data support, in populations in which iron deficiency and 912
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anemia are highly prevalent, implementation of public health measures to alleviate the burden of iron deficiency (such as daily or intermittent iron supplementation, staple food fortification, and deworming) (2) and, in settings in which iron deficiency is less prevalent, clinical measures to prevent, detect, and treat iron deficiency in individuals at risk (51), especially athletes. Our conclusions are limited by heterogeneity and the paucity of highly eligible quality trials. We found that only 3 studies could be considered at low overall risk of bias: only a minority of studies reported methodology for randomization and allocation concealment. However, it is possible that other studies indeed used appropriate methods for prevention of bias but did not present these in the manuscript. Heterogeneity appears partially explained by variation in baseline anemia, iron deficiency, and training status of participants in trials. Few trials reported adverse effects. Estimates from our meta-analysis suggest that studies would need to recruit at least 142 participants to each arm (assuming a power of 0.80 to detect the difference). However, individual studies had an average size of just 41 participants, and 17 of the 22 included studies allocated #20 women to each arm. Combination of studies using meta-analysis has been useful in increasing the power to detect clinically significant differences in exercise-related outcomes. However, additional evidence is required to clarify the effects of iron on other exercise variables, such as endurance, and for other functional outcomes, including work performance and productivity and adverse effects. Our data establish evidence of a beneficial effect from iron supplementation on exercise performance in women. Effect estimates can be used to determine the expected benefit to individual women and perhaps populations from alleviation of iron deficiency. They may also be used to guide iron deficiency prevention programs, especially among physically active women, and to design adequately powered RCTs to confirm our observations in specific settings. Acknowledgments The authors thank Mrs. Maggie Low, University of Adelaide, for assistance with locating publications. The authors would like
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FIGURE 3 Effects of daily iron supplementation on submaximal exercise performance in women of reproductive age. Daily iron supplementation reduced heart rate (A) and percentage of maximal oxygen consumption needed to achieve a defined submaximal exercise load (B). IV, inverse variance; Random, random effects.
to thank Dr. Juan-Pablo Pena-Rosas, Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, for his support. S.-R.P. and L.-M.D.-R. designed the research; S.-R.P., M.L., A.F., and J.T. conducted the research; S.-R.P. and L.-M.D.-R. analyzed the data and performed the statistical analysis; S.-R.P. and L.-M.D.-R. wrote the paper; and S.-R.P. had primary responsibility for the final content. All authors read and approved the final version of the manuscript.
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The Journal of Nutrition Nutritional Epidemiology
Iron Supplementation Benefits Physical Performance in Women of Reproductive Age: A Systematic Review and Meta-Analysis1–3 Sant-Rayn Pasricha,4,5* Michael Low,6 Jane Thompson,7 Ann Farrell,8 and Luz-Maria De-Regil9
Abstract Animal and human observational studies suggest that iron deficiency impairs physical exercise performance, but findings from randomized trials on the effects of iron are equivocal. Iron deficiency and anemia are especially common in women of reproductive age (WRA). Clear evidence of benefit from iron supplementation would inform clinical and public health guidelines. Therefore, we performed a systematic review and meta-analysis to determine the effect of iron supplementation compared with control on exercise performance in WRA. We searched the Cochrane Central Register of Clinical Trials, MEDLINE, Scopus (comprising Embase and MEDLINE), WHO regional databases, and other sources in July 2013. Randomized controlled trials that measured exercise outcomes in WRA randomized to daily oral iron supplementation vs. control were eligible. Random-effects meta-analysis was used to calculate mean differences (MDs) and standardized MDs (SMDs). Risk of bias was assessed using the Cochrane risk-of-bias tool. Of 6757 titles screened, 24 eligible studies were identified, 22 of which contained extractable data. Only 3 studies were at overall low risk of bias. Iron supplementation improved both maximal exercise performance, demonstrated by an increase in maximal oxygen consumption (VO2 max) [for relative VO2 max, MD: 2.35 mL/(kg min); 95% CI: 0.82, 3.88; P = 0.003, 18 studies; for absolute VO2 max, MD: 0.11 L/min; 95% CI: 0.03, 0.20; P = 0.01, 9 studies; for overall VO2 max, SMD: 0.37; 95% CI: 0.11, 0.62; P = 0.005, 20 studies], and submaximal exercise performance, demonstrated by a lower heart rate (MD: 24.05 beats per minute; 95% CI: 27.25, 20.85; P = 0.01, 6 studies) and proportion of VO2 max (MD: 22.68%; 95% CI: 24.94, 20.41; P = 0.02, 6 studies) required to achieve defined workloads. Daily iron supplementation significantly improves maximal and submaximal exercise performance in WRA, providing a rationale to prevent and treat iron deficiency in this group. This trial was registered with PROSPERO (http://www. crd.york.ac.uk/PROSPERO/prospero.asp) as CRD42013005166. J. Nutr. 144: 906–914, 2014.
Introduction Women of reproductive age (WRA)10 are at high risk of iron deficiency and iron deficiency anemia due to menstrual blood losses. Iron deficiency occurs when iron losses or requirements 1
S.-R.P. was supported by a Victoria Fellowship by the Government of Victoria, a CRB Blackburn Scholarship by the Royal Australasian College of Physicians, an Overseas Research Experience Scholarship by the University of Melbourne, and a National Health and Medical Research Council CJ Martin Early Career Fellowship. 2 S.-R. Pasricha is a coinvestigator on an unrestricted research grant from Vifor Pharma. M. Low, J. Thompson, A. Farrell, and L.-M. De-Regil, no conflicts of interest. 3 Supplemental Figures 1–3 and Supplemental Tables 1–3 are available from the "Online Supporting Material" link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org. 10 Abbreviations used: HR, heart rate; MD, mean difference; RCT, randomized controlled trial; SMD, standardized mean difference; WRA, women of reproductive age; VO2 max, maximal oxygen consumption; VT, ventilatory threshold. * To whom correspondence should be addressed. E-mail: sant-rayn.pasricha@ unimelb.edu.au.
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exceed iron intake, resulting in deficient tissue iron and iron stores, and may eventually produce iron deficiency anemia, in which hemoglobin concentrations are reduced. Female athletes are at particular risk because of diets deficient in iron, increased losses due to gastrointestinal bleeding, and reduced iron absorption due to subclinical inflammation (1). Iron deficiency and anemia are also highly prevalent among WRA in low- and middleincome settings, in which inadequate dietary iron content, consumption of poorly bioavailable iron, and parasitic infection with chronic blood loss contribute to the problem (2). Approximately 496 million nonpregnant women are anemic worldwide, with the prevalence approaching 50% in Africa and South Asia. Approximately 50% of anemia in nonpregnant women is thought to be amenable to iron (3). Iron is essential for a range of functions relating to physical activity and exercise (4). Iron deficiency has been considered to impair physical exercise performance (5) and, consequently,
ã 2014 American Society for Nutrition. Manuscript received December 11, 2013. Initial review completed January 25, 2014. Revision accepted March 7, 2014. First published online April 9, 2014; doi:10.3945/jn.113.189589.
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4 Nossal Institute for Global Health, School of Population Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia; 5Medical Research Council (MRC) Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK; 6Department of Clinical Haematology and Bone Marrow Transplant, The Alfred Hospital, Melbourne, VIC, Australia; 7School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, SA, Australia; 8Monash Health, Clayton, VIC, Australia; and 9The Micronutrient Initiative, Ottawa, ON, Canada
Materials and Methods Protocol. The protocol of this review was registered with PROSPERO (http:// www.crd.york.ac.uk/PROSPERO/prospero.asp) as CRD42013005166 (11). Information sources. We searched the following electronic databases: 1) MEDLINE; 2) Scopus; 3) Cochrane Central Register of Clinical Trials (CENTRAL); 4) WHO regional databases (AIM, AFROMED, LILACS, IMSEAR, WPRIM, and IMEMR); 5) the Proquest Digital Thesis database; and 6) OpenSIGLE (for gray literature). Electronic searches were undertaken on 28 July 2013. We also reviewed reference lists of identified articles and other systematic reviews. No language or date restrictions were applied. We searched the WHO International Clinical Trials Registry Platform for potentially eligible unpublished or ongoing trials. MEDLINE and Scopus search strategies are presented in the online material (Supplemental Fig. 1). Study eligibility criteria. RCTs with randomization at any level were eligible if they administered oral iron supplementation daily (at least 5 d/wk) vs. control. Trials giving iron in combination with multiple micronutrients (excluding folate or vitamin C), parenteral iron, or iron by central or pointof-use fortification were excluded. Studies that included a cointervention were included only if the cointervention was applied identically in both study arms. Trials were eligible if they were performed in WRA (women beyond menarche and before menopause who are not pregnant or lactating). If this criterion was not explicitly stated, we included studies if results for females aged 12–50 y could be extracted separately or if >50% of participants fulfilled this criterion. Sensitivity analyses were performed if marginal decisions were made. Studies meeting these criteria were eligible regardless of participant baseline iron or hemoglobin status, training history, or socioeconomic or geographic setting. We excluded studies targeting individuals with disorders affecting iron metabolism, including malabsorptive conditions, excessive blood loss, and inflammatory bowel disease, as well as individuals with medical conditions, including cancer, infectious diseases, or cardiac, renal, or liver failure. Outcomes. We specifically considered peak (maximal) exercise performance [e.g., maximal oxygen consumption (VO2 max) or peak, maximal heart rate (HR) or work rate, ventilatory threshold (VT), blood lactate] and submaximal exercise performance [e.g., efficiency (HR, %VO2 max), respiratory exchange ratio, endurance time]. VO2 max reflects the maximal capacity of an individual to use oxygen during exercise, reached when oxygen consumption reaches a plateau despite increases in exercise workload. It may be approximated by measurement of the VO2 peak, reflecting the maximal oxygen consumption obtained by an individual in a particular test (without necessarily demonstrating a plateau) (12). Absolute VO2 max, measured in liters per minute, does not account for the weight of the individual, whereas relative VO2 max is adjusted for the weight of the individual (mililiters of oxygen per kilogram of body mass per minute) and may
better correlate with peak exercise performance (13). The respiratory exchange ratio is the ratio between oxygen inhaled and carbon dioxide exhaled in a single breath. VT is the point during incremental exercise when ventilation increases out of proportion to oxygen uptake. Data extraction and management. References were managed using Endnote software. Two authors (S.-R.P., J.T.) screened references identified by the search, excluded those in which the title and abstract indicated clear ineligibility, and then assessed full-text papers against the inclusion criteria for eligibility. Two authors extracted data independently (S.-R.P. and either M.L. or A.F.). Data were analyzed using Review Manager (RevMan 5.1, 2011; The Nordic Cochrane Centre). Discrepancies were resolved through discussion. Assessment of risk of bias in included studies. Risk of bias was assessed by 2 authors independently (S.-R.P. and either M.L. or A.F.) using the Cochrane risk-of-bias tool, which addresses selection, performance, attrition, detection, and reporting bias through evaluation of reported sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other possible sources (14). Studies were considered at high overall risk of bias if randomization or allocation concealment was judged as being at high (or unclear) risk of bias or were either not blinded or had high or imbalanced attrition rates; otherwise, they were considered at low overall risk of bias. For outcomes containing >10 trials, funnel plots were examined for asymmetry to identify publication bias. Synthesis of results. Meta-analysis was undertaken for outcomes reported by at least 2 studies. Mean difference (MD) and standardized mean difference (SMD; in which effect size is normalized to the standard deviation of the measurement scale) were determined for continuous data measured on the same scale and different scales, respectively. Statistically significant differences were defined when the 95% CI for the effect size did not cross 0 with P < 0.05. Heterogeneity was quantified with the I2 test. Significant heterogeneity was considered to exist when I2 exceeded 50% and was explored by predefined subgroup analysis for outcomes containing $5 studies. Subgroups included the following: 1) age (adolescence, adulthood); 2) baseline anemia status (anemic, non-anemic, mixed/unspecified, as defined by trial authors); 3) baseline iron status (iron deficient, non-iron deficient, mixed/unspecified, as defined by trial authors); 4) dose of elemental iron per day (100 mg); 5) duration of supplementation (3 mo); and 6) training status of women (trained: participants recruited because of a high level of physical fitness due to either membership of a defined sporting team or achievement of a defined high standard of physical performance, and both competitive and recreational athletes were included; women were also included in this group if they underwent a defined physical training program as part of the study). Differences between subgroup strata were formally investigated using the x2 and I2 methods of Borenstein et al. (15) in subgroups in which $2 strata contained $3 trials each. We anticipated clinical, methodologic, and thus statistical heterogeneity between studies, so all data were combined using random-effects meta-analysis with calculation of t2.
Results Study flow is presented in Figure 1. A total of 6757 titles were screened for eligibility. The WHO International Clinical Trials Registry Platform identified no unpublished or ongoing potentially eligible studies. After screening, 36 references were identified for full-text review. Five were excluded because they were not RCTs (16–20) [including 1 that was a quasi-RCT (19)], and 1 was excluded because the intervention was not an eligible iron supplement (21). One full-text paper could not be sourced (22). Twenty-nine references comprising 24 studies were considered eligible for inclusion. The full eligibility screen is presented in Supplemental Table 1. Two ostensibly eligible Iron supplementation and physical performance
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economic productivity, particularly in manual workers (6,7), especially female manual workers. These detrimental effects are considered important justifications to prevent or treat iron deficiency in women. The WHO recommends distribution of iron supplements to all women in populations in which the prevalence of anemia (in women) exceeds 20% (8). Likewise, the International Olympic Committee recommends screening female athletes for iron deficiency to target iron supplementation, with a view to improving performance (9). However, randomized controlled trials (RCTs) investigating effects of iron supplementation on exercise performance have been small generally with equivocal results (10). This limits the capacity of primary and specialist clinicians and policymakers to anticipate potential benefits when considering strategies to prevent and treat iron deficiency. Therefore, we performed a systematic review and meta-analysis of RCTs to evaluate the effects of daily iron supplementation on physical performance in WRA.
studies were crossover trials that did not report on outcomes at the end of the first parallel time course, so data could be not extracted (23,24). Data were thus extracted from 22 studies (Table 1) recruiting 911 participants, of whom 464 were randomly assigned to take daily iron supplementation and 447 to the control group. Characteristics of included studies are summarized in Table 1. Authors provided additional information for 2 trials (7,10). Risk of bias of included studies is summarized in Supplemental Figure 2. Only 3 studies were considered to be at overall low risk of bias (10,25,26). Findings from meta-analysis are summarized in Table 2. A comprehensive summary of results for all outcomes including subgroup analysis when appropriate is presented in Supplemental Table 2. Four trials were funded or supported by pharmaceutical companies (26–29), but only Jensen et al. (27) identified benefit from iron on exercise outcomes. Funding sources are presented in Supplemental Table 3. Maximal exercise performance Maximal aerobic capacity was measured in different studies using VO2 max or VO2 peak, which we combined by metaanalysis (termed hereafter as VO2 max). Both absolute and relative VO2 max were reported in eligible studies. Relative VO2 max was reported in 18 studies recruiting 620 participants. Meta-analysis revealed a beneficial effect from iron [MD: 2.31 mL/(kg min) (95% CI: 0.83, 3.80), P = 0.002, I2 = 71%] (Fig. 2a). The funnel plot showed no asymmetry to indicate publication bias (Supplemental Fig. 3). When the 20 anemic participants from the single trial recruiting iron-deficient anemic women (30) were removed from the analysis, the beneficial effect from iron remained significant [MD: 2.18 (95% CI: 0.57, 3.79), P = 0.008, I2 = 72%], as it did when the 1 trial that recruited 42% male participants (31) was excluded [MD: 2.25 (95% CI: 0.70, 3.80)]. The effect was seen in irondeficient women, although there was also a benefit in women for 908
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Other maximal exercise variables. There were no differences evident between women randomly assigned to take iron and control in other peak exercise variables, including respiratory exchange ratio or time (duration of maximal exercise) to exhaustion (Table 2). One study reported effects of iron supplementation on muscle fatigability in non-anemic iron-depleted women: women randomly assigned to take iron experienced reduced attenuation of maximal voluntary contractions compared with women randomly assigned to the control group (P < 0.01) (32). One study reported the effects of iron on VT in peak exercise: women randomly assigned to take iron had significantly higher VT [31.54 vs. 24.27 mL/(kg min) and 74.13% vs. 63.04% of VO2 max, both P < 0.05] (33). Submaximal exercise No studies reporting submaximal exercise outcomes were considered at low overall risk of bias. Efficiency: HR. Six studies recruiting 172 participants reported HR during submaximal exercise (28,33–36). Women administered iron had a significantly lower HR during submaximal exercise compared with women randomly assigned to the control group [MD: 24.05 beats per minute (95% CI: 27.25, 20.85), P = 0.01, I2 = 0%] (Fig. 3a). The reduction was seen only in trained women. All studies reporting this outcome were performed in irondeficient women. Efficiency: percentage of VO2 max. Six studies comprising 167 participants reported on percentage of VO2 max required by participants as they undertook a defined submaximal exercise
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FIGURE 1 Study flow for selection of trials included in the systematic review. RCT, randomized controlled trial.
whom iron status had not been determined at recruitment. The effect was seen in trained [MD: 2.28 (95% CI: 1.35, 3.21), P < 0.00001, I2 = 10%] but not in nontrained [MD: 2.32 (23.38, 8.02), P = 0.43, I2 = 93%] women. When only the 3 studies at low risk of bias were included, no benefit from iron on VO2 max was seen [MD: 0.94 (95% CI: 22.06, 3.93), P = 0.54, I2 = 0%, 207 participants]. Analysis by age, dose, and type of iron compound could not be performed because of insufficient data in the subgroups. Absolute VO2 max was reported by 9 studies recruiting 316 women, all of whom were iron deficient. Meta-analysis identified a benefit from iron among women randomly assigned to receive iron [MD: 0.11 L/min (95% CI: 0.03, 0.20), P = 0.01, I2 = 0%] (Fig. 2b). This effect was seen in anemic but not non-anemic women. The benefit from iron was seen only in trained women. No studies at overall low risk of bias reported this outcome. When all studies reporting VO2 max were combined (20 studies, 737 participants, inclusion of relative VO2 max data if both absolute and relative data were reported), the SMD between iron and control was 0.35 (95% CI: 0.12, 0.58) (P = 0.004, I2 = 52%). When the 64 anemic women were removed from the analysis, a beneficial effect from iron remained [SMD: 0.26 (95% CI: 0.05, 0.47), P = 0.01, I2 = 38%]. Subgroup analysis showed that iron supplementation clearly benefited VO2 max in anemic women and in both iron-deficient women and women in whom baseline iron status was not established. Nonsignificant evidence of benefit was seen in participants who were nonanemic or in whom baseline anemia status was not established. Iron improved VO2 max in trained but not nontrained women. For each of these subgroups, there was no evidence of a significant difference in effect between subgroup strata (Supplemental Table 2).
909
18–33 y 18–41 y
18–35 y 19–44 y
Finland
Germany
United States
United States
United States United States
United States
China
United States
Israel United States Canada
Serbia
United States
United States
Japan
Fogelholm et al. (25)
Friedmann et al. (31)
Hinton (34); Brownlie et al. (53,54) Hinton and Sinclair (33)
Jensen et al. (27) Klingshirn et al. (37)
LaManca and Haymes (28) Li et al. (7,55); Li (50)
Lyle et al. (56)
Magazanik et al. (57) McClung et al. (38) Newhouse et al. (29)
Radjen et al. (30)
Rajaram et al. (58)
Rowland et al. (35)
Taniguchi et al. (59)
18–22 y
Adolescents
College age
16–25 y
19 y Mean age: 21 y 18–40 y
College age
18–25 y 22–39 y
13–25 y (58% females)
17–31 y
.18 y
United States
DellaValle (52)
18–45 y
Participant age
Mexico
Country
Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 6 mg/L)
Anemia status unknown; iron status unknown Anemia status unknown; iron status unknown Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 20 mg/L) Iron deficiency anemia (Hb , 120 g/L, ferritin , 12 mg/L, transferrin saturation , 16%) Non-anemic iron deficiency (Hb . 120 g/L, ferritin , 12 mg/L, transferrin saturation . 16%); anemia status unknown; iron status unknown
Anemia status unknown; iron status unknown
1 mg/d elemental iron as ferric ammonium citrate + vitamin C (n value not stated, assume 27)
325 mg/d elemental iron as FeSO4 (n = 7)
Iron deficiency anemia (n = 10); non-anemic iron deficiency (n = 9); 50 mg/d elemental iron as FeSO4 (low-iron diet) (n = 16)
15 mg/d elemental iron as FeSO4 (n = 13) 15 mg/d elemental iron as FeSO4 (n = 86) 100 mg elemental iron twice per day as FeSO4 (n = 19) 50 mg/d elemental iron as FeSO4
60 mg/d (non-anemic, mild anemic) or 120 mg/d (moderate anemia) elemental iron as FeSO4 (n = 40) 10 or 50 mg/d elemental iron as FeSO4 + low-iron diet + exercise regimen
50 mg/d elemental iron as FeSO4 (n = 10)
12 wk
7 wk 9 wk 8 wk 8 wk
Placebo + unrestricted diet + exercise regimen Placebo (n = 15) Placebo (n = 85) Placebo (n = 21) Placebo
Placebo + vitamin C (n value not stated, assume 27)
9 wk
4 wk
24 wk
12 wk
Placebo (n = 40)
Iron deficiency anemia (n = 10); non-anemic iron deficiency (n = 8); placebo (normal-iron diet) (n = 13) Placebo (n = 7)
8 wk
12 wk 8 wk
6 wk
6 wk
12 wk
8 wk
6 wk
6 wk
Duration
Placebo (n = 10)
Placebo (n = 6) Placebo (n = 9)
Placebo (n = 10)
30 mg/d elemental iron as FeSO4 (n = 10)
50 mg/d elemental iron as FeSO4 (n = 7) 50 mg/d elemental iron as FeSO4 (n = 9)
Placebo (n = 20)
20 mg/d elemental iron as FeSO4 (n = 22)
Placebo + vitamin C supplement (n = 17) Placebo (n = 20)
100 mg/d elemental iron as FeSO4, with vitamin C supplement (n = 14) 200 mg/d elemental iron as FeSO4 (n = 20)
Placebo (n = 10) Placebo (n = 19)
10 mg/d elemental iron as FeSO4 (n = 10)
Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); mixed iron status: 58% iron depleted (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 25 mg/L) Non-anemic (Hb . 117 g/L for females, 135 g/L for males); iron depleted (ferritin , 20 mg/L) Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 16 mg/L) Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 16 mg/L or raised sTfR or sTfR-F index) Non-anemic Non-anemic (Hb . 120 g/L); iron depleted (ferritin , 20 mg/L) Anemia status unknown; iron depleted (ferritin , 20 mg/L) Iron deficient (ferritin , 12 mg/L); non-anemic (n = 18); anemic (Hb , 120 g/L) (n = 22)
Control
30 mg/d elemental iron as FeSO4 (n = 21)
Intervention
Baseline anemia, iron deficiency status
Included studies evaluating effects of daily iron supplementation on physical exercise performance in women of reproductive age1
Brutsaert et al. (32)
Study (ref)
TABLE 1
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Iron supplementation and physical performance
(Continued)
U, U, H, H, U, L
U, U, L, U, U, L
U, U, H, H, L, L
U, U, L, U, U, L
U, U, L, U, L, L U, U, L, U, L, L U, U, L, U, L, L
U, U, H, H, H, L
U, U, L, U, L, L
U, U, L, U, U, L
U, U, L, U, U, L U, U, L, U, U, L
U, U, L, L, U, L
U, U, L, U, L, L
U, U, U, U, H, L
L, U, L, U, L, L
L, L, L, L, L, L
U, U, L, U, U, L
Risk of bias2
8 wk Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 16 mg/L) 19–36 y United States Zhu et al. (36); Zhu and Hass (63)
Not reported Japan
1 Overall risk of bias was defined as follows: 1) high risk if randomization or allocation concealment judged as being at high risk of bias (or unclear) or were either not blinded or had high or imbalanced attrition rates; 2) otherwise, low risk of bias. H, high risk of bias; Hb, hemoglobin; L, low risk or bias; ref, reference; sTfR, soluble transferrin receptor; sTfR-F, soluble transferrin receptor/log(ferritin) index; U, unclear risk of bias. 2 The letters correspond to random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessors, incomplete outcome data, and selective reporting, respectively.
U, U, L, U, L, L
U, U, L, U, U, L 8 wk
Multivitamin alone (n = 6) Placebo (n = 17)
Adolescents Australia
Walsh and McNaughton (60,61) Yoshida et al. (62)
18–50 y Switzerland Waldvogel et al. (26)
Anemia status unknown; iron status unknown
12 wk Placebo (n = 10)
150 mg/d iron; formulation not stated (n = 10) 60 mg/d elemental iron as ferrous ammonium citrate + multivitamin (n = 6) 135 mg/d elemental iron as FeSO4 (n = 20)
U, U, L, U, L, L
4 wk Placebo (n = 76) 80 mg/d elemental iron as FeSO4 (n = 78)
Non-anemic (Hb . 120 g/L); iron deficient (ferritin , 30 mg/L) Anemia status unknown; iron status unknown
L, L, L, U, L, L
Risk of bias2 Duration Control Intervention Baseline anemia, iron deficiency status Participant age Country Study (ref)
Continued TABLE 1
Pasricha et al.
Other submaximal outcomes. No differences between women randomly assigned to the iron and control groups were seen in energy consumption (kilojoules per minute), work (watts), or respiratory exchange ratio during submaximal exercise (Table 2). One study reported an improvement in 3.2 km (2 miles) run time among iron-deficient anemic female soldiers randomly assigned to take iron, although data for the overall group were not presented (38). Other outcomes Although not a prespecified outcome, we collected data on reported adverse events that were reported in detail by only 1 trial (26): women randomly assigned to take iron experienced increased undesirable gastrointestinal events (P = 0.001), ‘‘hard stools’’ (P = 0.015), and ‘‘any events’’ (P = 0.002).
Discussion Daily oral iron supplementation in WRA improves both maximal and submaximal exercise performance. These benefits are clearest in iron-deficient and trained women. Our findings have implications for clinical management of patients, nutritional optimization for athletes, and rationale and design of public health anemia control programs. These results also begin to define the physiologic deficits induced by iron deficiency. To our knowledge, this is the first published meta-analysis to provide evidence of beneficial effects of iron supplementation on physical performance. Gera et al. (39) reviewed effects of iron administration on physical performance in children but included only 3 studies, which was too few for meta-analysis. An unpublished meta-analysis by Casgrain et al. (40) that evaluated effects of iron (through different delivery strategies) on physical performance (in males and females) performed a meta-analysis of 8 studies reporting VO2 max, finding a significant benefit from iron [MD: 1.61 mL/(kg min) (95% CI: 0.39, 2.83)] . These authors also identified a significant reduction in HR during submaximal exercise [4 studies, MD: 25.57 beats per minute (95% CI: 210.38, 20.76)]. Iron supplementation benefits maximal aerobic capacity (VO2 max) and efficiency of submaximal exercise (i.e., reduces the required percentage of VO2 max and HR), with 1 study also suggesting that it improves strength. The physiologic mechanism for these effects may reflect a range of processes. Raised hemoglobin concentrations may improve oxygen-carrying capacity and hence tissue oxygenation during exercise. Meta-analysis of hemoglobin data from studies reporting on VO2 max in this review showed a clear increase in hemoglobin with iron compared with control [MD: 6.79 g/L (95% CI: 4.29, 9.30), 19 studies]. Animal studies suggest that even non-anemic iron deficiency severely affects exercise performance in rats, restored by iron repletion (41). Iron is important in muscle metabolism with critical roles in the mitochondrial respiratory chain (cytochrome oxidase) and myoglobin (4,42). Improved tissue iron may thus improve tissue oxygen utilization and hence exercise performance, even in non-anemic individuals. Our findings indicate that prevention and treatment of iron deficiency could improve performance in female athletes who compete in a wide range of sports requiring either or all of endurance, maximal power output, and strength. The magnitude of increase in
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load (34–37). Iron reduced the percentage of VO2 max required [22.68% (95% CI: 24.94, 20.41), I2 = 46%, P = 0.02] (Fig. 3b). The reduction was seen only in trained women. All studies reporting this outcome were performed in iron-deficient women.
TABLE 2 Summary of effects of daily iron supplementation on exercise performance in women of reproductive age1 Outcome
1
I2
Participants
n
n
18 9 20 4 5 4 2
620 316 737 112 152 106 49
2.35 (0.82, 3.88) 0.11 (0.03, 0.20) 0.34 (0.11, 0.57) 0.01 (20.02, 0.03) 1.27 (21.08, 3.61) 20.00 (20.72, 0.72) 1.09 (20.48, 2.66)
0.003 0.01 0.004 0.60 0.29 1.00 0.17
71 0 52 0 0 0 41
6 6 5 3 3 3
172 167 136 98 99 52
24.05 (27.25, 20.85) 22.68 (24.94, 20.41) 20.01 (20.02, 0.01) 20.48 (21.65, 0.68) 26.64 (219.15, 5.88) 1.23 (20.41, 2.87)
0.01 0.02 0.28 0.42 0.30 0.14
0 46 0 67 10 0
%
SMD, standardized mean difference; VO2 max, maximal oxygen consumption.
relative VO2 max from iron [0.82–3.88 mL/(kg min)] is in the range of improvements that can be achieved by exercise training (43). Female athletes experience a higher prevalence of iron
deficiency compared with the general population (44) because of inadequate iron intake in athletes attempting to achieve or maintain a defined body weight and composition, foot-strike
FIGURE 2 Effects of daily iron supplementation on maximal exercise performance in women of reproductive age. Daily iron supplementation improved relative VO2 max, maximal oxygen consumption. (A) and absolute VO2 max (B). IV, inverse variance; Random, random effects; VO2 max, maximal oxygen consumption. Iron supplementation and physical performance
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Maximal exercise Relative VO2 max, mL/(kg min) Absolute VO2 max, L/min VO2 max, all studies, SMD Respiratory exchange ratio Heart rate, beats/min Blood lactate at longest time point, mmol/L Time to exhaustion, min Submaximal exercise Heart rate, beats/min %VO2 max Respiratory exchange ratio Energy consumption, kJ/min Workload, W Time to exhaustion, min
Difference [mean (95% CI)]
P-effect
Trials
hemolysis, and increased iron losses in sweat, urine, and feces (44). Iron status may also be impaired in athletes by highaltitude training with enhanced erythropoiesis, gastrointestinal bleeding after severe endurance exercise (45), and elevated hepcidin after exercise (46). Hepcidin regulates systemic iron homeostasis and is induced by inflammation [including intensive exercise (47)] and storage iron; suppressed hepcidin facilitates iron absorption and utilization, whereas elevated hepcidin prevents it (48), suggesting that restitution of iron stores with oral iron may be less effective in the immediate postexercise period. Our data indicate that detection, treatment, and prevention of iron deficiency in this population can improve physical performance. Iron supplementation was shown clearly in trials and metaanalyses to benefit hemoglobin and iron stores (49), but evidence for benefits on functional outcomes, which are a key rationale for controlling iron deficiency, has been difficult to ascertain. Measurement of exercise performance (e.g., VO2 max) has been consistent over time and between studies, enabling meta-analysis, unlike other variables (e.g., cognitive performance, psychologic health, fatigue) that have been measured in different studies using differing techniques and scales. Therefore, to the best of our knowledge, this is 1 of the first reports to document a nonhematologic benefit from iron. Improvements in physical performance from iron supplementation may extend to broader benefits. For example, Li et al. (7) showed that female cotton-mill workers randomly assigned to take iron experienced improved productivity and earnings and also had reduced HR during work compared with women in the control group (potentially reflecting our finding that iron reduces HR during submaximal exercise). Unpublished data from the same trial (included in this metaanalysis) revealed a significant improvement in absolute VO2 max in women randomly assigned to take iron (42,50). Given the beneficial effect from iron supplementation in women in whom baseline iron or anemia status was not measured, our data support, in populations in which iron deficiency and 912
Pasricha et al.
anemia are highly prevalent, implementation of public health measures to alleviate the burden of iron deficiency (such as daily or intermittent iron supplementation, staple food fortification, and deworming) (2) and, in settings in which iron deficiency is less prevalent, clinical measures to prevent, detect, and treat iron deficiency in individuals at risk (51), especially athletes. Our conclusions are limited by heterogeneity and the paucity of highly eligible quality trials. We found that only 3 studies could be considered at low overall risk of bias: only a minority of studies reported methodology for randomization and allocation concealment. However, it is possible that other studies indeed used appropriate methods for prevention of bias but did not present these in the manuscript. Heterogeneity appears partially explained by variation in baseline anemia, iron deficiency, and training status of participants in trials. Few trials reported adverse effects. Estimates from our meta-analysis suggest that studies would need to recruit at least 142 participants to each arm (assuming a power of 0.80 to detect the difference). However, individual studies had an average size of just 41 participants, and 17 of the 22 included studies allocated #20 women to each arm. Combination of studies using meta-analysis has been useful in increasing the power to detect clinically significant differences in exercise-related outcomes. However, additional evidence is required to clarify the effects of iron on other exercise variables, such as endurance, and for other functional outcomes, including work performance and productivity and adverse effects. Our data establish evidence of a beneficial effect from iron supplementation on exercise performance in women. Effect estimates can be used to determine the expected benefit to individual women and perhaps populations from alleviation of iron deficiency. They may also be used to guide iron deficiency prevention programs, especially among physically active women, and to design adequately powered RCTs to confirm our observations in specific settings. Acknowledgments The authors thank Mrs. Maggie Low, University of Adelaide, for assistance with locating publications. The authors would like
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FIGURE 3 Effects of daily iron supplementation on submaximal exercise performance in women of reproductive age. Daily iron supplementation reduced heart rate (A) and percentage of maximal oxygen consumption needed to achieve a defined submaximal exercise load (B). IV, inverse variance; Random, random effects.
to thank Dr. Juan-Pablo Pena-Rosas, Evidence and Programme Guidance, Department of Nutrition for Health and Development, World Health Organization, for his support. S.-R.P. and L.-M.D.-R. designed the research; S.-R.P., M.L., A.F., and J.T. conducted the research; S.-R.P. and L.-M.D.-R. analyzed the data and performed the statistical analysis; S.-R.P. and L.-M.D.-R. wrote the paper; and S.-R.P. had primary responsibility for the final content. All authors read and approved the final version of the manuscript.
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