The Effect of Parenteral or Oral Iron Supplementation on Fatigue, Sleep, Quality of Life and Restless Legs Syndrome in Iron-Deficient Blood Donors: A Secondary Analysis of the IronWoMan RCT

Susanne Macher, Cornelia Herster, Magdalena Holter, Martina Moritz, Eva Maria Matzhold, Tatjana Stojakovic, Thomas R Pieber, Peter Schlenke, Camilla Drexler, Karin Amrein, Susanne Macher, Cornelia Herster, Magdalena Holter, Martina Moritz, Eva Maria Matzhold, Tatjana Stojakovic, Thomas R Pieber, Peter Schlenke, Camilla Drexler, Karin Amrein

Abstract

Background: Besides anemia, iron deficiency may cause more subtle symptoms, including the restless legs syndrome (RLS), the chronic fatigue syndrome (CFS) or sleeping disorders. Objective: The aim of this pre-planned secondary analysis of the IronWoMan randomized controlled trial (RCT) was to compare the frequency and severity of symptoms associated with iron deficiency before and after (intravenous or oral) iron supplementation in iron deficient blood donors.

Methods/design: Prospective, randomized, controlled, single-centre trial. (ClinicalTrials.gov: NCT01787526).

Setting: Tertiary care center in Graz, Austria.

Participants: 176 (138 female and 38 male) whole-blood and platelet apheresis donors aged ≥ 18 and ≤ 65 years with iron deficiency (ferritin ≤ 30ng/mL at the time of blood donation).

Interventions: Intravenous iron (1 g ferric carboxymaltose, n = 86) or oral iron supplementation (10 g iron fumarate, 100 capsules, n = 90).

Measurements: Clinical symptoms were evaluated by a survey before iron therapy (visit 0, V0) and after 8-12 weeks (visit 1, V1), including questions about symptoms of restless legs syndrome (RLS), chronic fatigue syndrome (CFS), sleeping disorders, quality of life and symptoms like headaches, dyspnoea, dizziness, palpitations, pica and trophic changes in fingernails or hair.

Results: We found a significant improvement in the severity of symptoms for RLS, fatigue and sleep quality (p < 0.001). Furthermore, a significant decrease in headaches, dyspnoea, dizziness and palpitations was reported (p < 0.05). There was no difference between the type of iron supplementation (intravenous versus oral) and clinical outcome data.

Conclusion: Iron supplementation in iron-deficient blood donors may be an effective strategy to improve symptoms related to iron deficiency and the wellbeing of blood donors.

Keywords: RLS; blood donor; fatigue; iron deficiency; iron supplementation.

Conflict of interest statement

KA has received speaker and advisory board fees from Vifor Pharma and Fresenius Kabi. The study was supported by Vifor Pharma, Austria and G.L. Pharma, Austria.

Figures

Figure 1
Figure 1
Study flowchart.
Figure 2
Figure 2
Bar diagram showing the number of study participants (x-axis) who indicate the frequency of their restless legs syndrome (RLS) at the two time points before (V0, dark bars) and after IV or oral iron therapy (V1, bright bars) on the y-axis. The decrease in the RLS occurrence between V0 and V1 was statistically significant (p < 0.001, n = 31).
Figure 3
Figure 3
Comparison of median and 1st/3rd quartiles for the fatigue scales before (V0) and after (V1) IV or oral iron therapy. For the 4 scales general, physical, emotional and mental a lower level indicates an improvement, for the scale vigor a higher level indicates an improvement (* p < 0.001 for all, n = 160).
Figure 4
Figure 4
Bar diagrams indicating the percentage of study participants on the x-axis with the different response alternatives according to the Jenkins scale for sleeping behavior on the y-axis before (V0, dark bars) and after iron therapy (V1, bright bars). For all 4 quality of sleep items, there was a statistically significant improvement between V0 and V1 (p < 0.05 for all, n = 160).
Figure 5
Figure 5
Bar diagram indicating the percentage of study participants on the x-axis with the appropriate symptoms indicated on the y-axis before (V0, dark bars) and after iron therapy (V1, bright bars). (* p = 0.02, ** p = 0.005, *** p < 0.001, n = 161–165).
Figure 6
Figure 6
Bar diagram indicating the percentage of study participants (x-axis) rating the quality of their life between very poor and very good (y-axis) before (V0, dark bars) and after iron therapy (V1, bright bars). (no statstically significant differences, n = 168).

References

    1. Diaz J.R., de las Cagigas A., Rodriguez R. Micronutrient deficiencies in developing and affluent countries. Eur. J. Clin. Nutr. 2003;57(Suppl. 1):S70–S72. doi: 10.1038/sj.ejcn.1601820.
    1. Kassebaum N.J., Jasrasaria R., Naghavi M., Wulf S.K., Johns N., Lozano R., Regan M., Weatherall D., Chou D.P., Eisele T.P., et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123:615–624. doi: 10.1182/blood-2013-06-508325.
    1. Andrews N.C. Disorders of iron metabolism. N. Engl. J. Med. 1999;341:1986–1995. doi: 10.1056/NEJM199912233412607.
    1. Earley C.J., Heckler D., Allen R.P. The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med. 2004;5:231–235. doi: 10.1016/j.sleep.2004.03.002.
    1. Kryger M.H., Otake K., Foerster J. Low body stores of iron and restless legs syndrome: A correctable cause of insomnia in adolescents and teenagers. Sleep Med. 2002;3:127–132. doi: 10.1016/S1389-9457(01)00160-5.
    1. Sun E.R., Chen C.A., Ho G., Earley C.J., Allen R.P. Iron and the restless legs syndrome. Sleep. 1998;21:371–377. doi: 10.1093/sleep/21.4.381.
    1. Koo B.B., Bagai K., Walters A.S. Restless legs syndrome: Current concepts about disease pathophysiology. Tremor Other Hyperkinetic Mov. 2016;6:401.
    1. Afari N., Buchwald D. Chronic fatigue syndrome: A review. Am. J. Psychiatry. 2003;160:221–236. doi: 10.1176/appi.ajp.160.2.221.
    1. Verdon F., Burnand B., Stubi C.L., Bonard C., Graff M., Michaud A., Bischoff T., De Vevey M., Studer J.P., Herzig L., et al. Iron supplementation for unexplained fatigue in non-anaemic women: Double blind randomised placebo controlled trial. BMJ. 2003;326:1124. doi: 10.1136/bmj.326.7399.1124.
    1. Houston B.L., Hurrie D., Graham J., Perija B., Rimmer E., Rabbani R., Bernstein C.N., Turgeon A.F., Fergusson D.A., Houston D.S., et al. Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: A systematic review of randomised controlled trials. BMJ Open. 2018;8:e019240. doi: 10.1136/bmjopen-2017-019240.
    1. Krayenbuehl P.A., Battegay E., Breymann C., Furrer J., Schulthess G. Intravenous iron for the treatment of fatigue in nonanemic, premenopausal women with low serum ferritin concentration. Blood. 2011;118:3222–3227. doi: 10.1182/blood-2011-04-346304.
    1. Pollitt E. Iron deficiency and cognitive function. Annu. Rev. Nutr. 1993;13:521–537. doi: 10.1146/annurev.nu.13.070193.002513.
    1. Carter R.C., Jacobson J.L., Burden M.J., Armony-Sivan R., Dodge N.C., Angelilli M.L., Lozoff B., Jacobson S.W. Iron deficiency anemia and cognitive function in infancy. Pediatrics. 2010;126:e427–e434. doi: 10.1542/peds.2009-2097.
    1. Hercberg S., Preziosi P., Galan P. Iron deficiency in Europe. Public Health Nutr. 2001;4:537–545. doi: 10.1079/PHN2001139.
    1. Ghaffari S., Pourafkari L. Koilonychia in iron-deficiency anemia. New Engl. J. Med. 2018;379:e13. doi: 10.1056/NEJMicm1802104.
    1. Rushton D.H. Nutritional factors and hair loss. Clin. Exp. Dermatol. 2002;27:396–404. doi: 10.1046/j.1365-2230.2002.01076.x.
    1. Germain M., Delage G., Robillard P., Katz L.M., Gregoire Y. The association between frequency of blood donation and the occurrence of low birthweight, preterm delivery, and stillbirth: A retrospective cohort study. Transfusion. 2016;56:2760–2767. doi: 10.1111/trf.13762.
    1. Conrad M.E., Crosby W.H., Jacobs A., Kaltwasser J.P., Nusbacher J. The Hippocratian principle of ‘primum nil nocere’ demands that the metabolic state of a donor should be normalized prior to a subsequent donation of blood or plasma. How much blood, relative to his body weight, can a donor give over a certain period, without a continuous deviation of iron metabolism in the direction of iron deficiency? Vox Sang. 1981;41:336–343.
    1. Page E.A., Coppock J.E., Harrison J.F. Study of iron stores in regular plateletpheresis donors. Transfus. Med. 2010;20:22–29. doi: 10.1111/j.1365-3148.2009.00979.x.
    1. Spencer B.R., Kleinman S., Wright D.J., Glynn S.A., Rye D.B., Kiss J.E., Mast A.E., Cable R.G., REDS-II RISE Analysis Group Restless legs syndrome, pica, and iron status in blood donors. Transfusion. 2013;53:1645–1652. doi: 10.1111/trf.12260.
    1. Bryant B.J., Yau Y.Y., Arceo S.M., Hopkins J.A., Leitman S.F. Ascertainment of iron deficiency and depletion in blood donors through screening questions for pica and restless legs syndrome. Transfusion. 2013;53:1637–1644. doi: 10.1111/trf.12061.
    1. Semmelrock M.J., Raggam R.B., Amrein K., Avian A., Schallmoser K., Lanzer G., Semmelrock H.J., Prueller F., Berghold A., Rohde E. Reticulocyte hemoglobin content allows early and reliable detection of functional iron deficiency in blood donors. Clin. Chim. Acta. 2012;413:678–682. doi: 10.1016/j.cca.2011.12.006.
    1. Simon T.L. Iron, iron everywhere but not enough to donate. Transfusion. 2002;42:664. doi: 10.1046/j.1537-2995.2002.00121.x.
    1. Simon T.L., Garry P.J., Hooper E.M. Iron stores in blood donors. JAMA. 1981;245:2038–2043. doi: 10.1001/jama.1981.03310450030018.
    1. Brittenham G.M. Iron deficiency in whole blood donors. Transfusion. 2011;51:458–461. doi: 10.1111/j.1537-2995.2011.03062.x.
    1. Cable R.G., Glynn S.A., Kiss J.E., Mast A.E., Steele W.R., Murphy E.L., Wright D.J., Sacher R.A., Gottschall J.L., Vij V., et al. Iron deficiency in blood donors: Analysis of enrollment data from the REDS-II Donor Iron Status Evaluation (RISE) study. Transfusion. 2011;51:511–522. doi: 10.1111/j.1537-2995.2010.02865.x.
    1. Finch C.A., Cook J.D., Labbe R.F., Culala M. Effect of blood donation on iron stores as evaluated by serum ferritin. Blood. 1977;50:441–447. doi: 10.1182/blood.V50.3.441.441.
    1. Baart A.M., van Noord P.A., Vergouwe Y., Moons K.G., Swinkels D.W., Wiegerinck E.T., de Kort W.L., Atsma F. High prevalence of subclinical iron deficiency in whole blood donors not deferred for low hemoglobin. Transfusion. 2012;53:1670–1677. doi: 10.1111/j.1537-2995.2012.03956.x.
    1. Pedrazzini B., Waldvogel S., Vaucher P., Cornuz J., Heinzer R., Tissot J.D., Favrat B. Prevalence of restless legs syndrome in female blood donors 1 week after blood donation. Vox Sang. 2014;107:44–49. doi: 10.1111/vox.12123.
    1. Birgegard G., Schneider K., Ulfberg J. High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: Intravenous iron sucrose substitution more effective than oral iron. Vox Sang. 2010;99:354–361. doi: 10.1111/j.1423-0410.2010.01368.x.
    1. Silber M.H., Richardson J.W. Mayo Clinic Proceedings. Volume 78. Elsevier; Amsterdam, The Netherlands: 2003. Multiple blood donations associated with iron deficiency in patients with restless legs syndrome; pp. 52–54.
    1. Drexler C., Macher S., Lindenau I., Holter M., Moritz M., Stojakovic T., Pieber T.R., Schlenke P., Amrein K. High-dose intravenous versus oral iron in blood donors with iron deficiency: The IronWoMan randomized, controlled clinical trial. Clin. Nutr. 2020;39:737–745. doi: 10.1016/j.clnu.2019.03.025.
    1. Iron Deficiency is a Common Disorder in General Population and Independently Predicts All-Cause Mortality: Results from the Gutenberg Health Study. [(accessed on 25 March 2020)]; Available online: .
    1. Macher S., Drexler C., Lindenau I., Sareban N., Schlenke P., Amrein K. High-dose intravenously administered iron versus orally administered iron in blood donors with iron deficiency: Study protocol for a randomised, controlled trial. Trials. 2016;17:527. doi: 10.1186/s13063-016-1648-y.
    1. Allen R.P., Picchietti D., Hening W.A., Trenkwalder C., Walters A.S., Montplaisi J. Restless legs syndrome: Diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101–119. doi: 10.1016/S1389-9457(03)00010-8.
    1. Stein K.D., Jacobsen P.B., Blanchard C.M., Thors C. Further validation of the multidimensional fatigue symptom inventory-short form. J. Pain Symptom Manag. 2004;27:14–23. doi: 10.1016/j.jpainsymman.2003.06.003.
    1. Vahtera J., Pentti J., Helenius H., Kivimaki M. Sleep disturbances as a predictor of long-term increase in sickness absence among employees after family death or illness. Sleep. 2006;29:673–682. doi: 10.1093/sleep/29.5.673.
    1. Jenkins C.D., Stanton B.A., Niemcryk S.J., Rose R.M. A scale for the estimation of sleep problems in clinical research. J. Clin. Epidemiol. 1988;41:313–321. doi: 10.1016/0895-4356(88)90138-2.
    1. Chalmers R.P. mirt: A multidimensional item response theory package for the R environment. J. Stat. Softw. 2012;48:1–29. doi: 10.18637/jss.v048.i06.
    1. Pratt J.J., Khan K.S. Non-anaemic iron deficiency—A disease looking for recognition of diagnosis: A systematic review. Eur. J. Haematol. 2016;96:618–628. doi: 10.1111/ejh.12645.
    1. Camaschella C. Iron deficiency. Blood. 2019;133:30–39. doi: 10.1182/blood-2018-05-815944.
    1. Camaschella C. New insights into iron deficiency and iron deficiency anemia. Blood Rev. 2017;31:225–233. doi: 10.1016/j.blre.2017.02.004.
    1. Allen R.P., Stillman P., Myers A.J. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: Prevalence and characteristics. Sleep Med. 2010;11:31–37. doi: 10.1016/j.sleep.2009.03.007.
    1. Godau J., Klose U., Di Santo A., Schweitzer K., Berg D. Multiregional brain iron deficiency in restless legs syndrome. Mov. Disord. 2008;23:1184–1187. doi: 10.1002/mds.22070.
    1. Connor J.R., Ponnuru P., Wang X.S., Patton S.M., Allen R.P., Earley C.J. Profile of altered brain iron acquisition in restless legs syndrome. Pt 4Brain. 2011;134:959–968. doi: 10.1093/brain/awr012.
    1. Wang J., O’Reilly B., Venkataraman R., Mysliwiec V., Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med. 2009;10:973–975. doi: 10.1016/j.sleep.2008.11.003.
    1. Silber M.H., Becker P.M., Earley C., Garcia-Borreguero D., Ondo W.G., Medical Advisory Board of the Willis. Ekbom Disease Foundation . Mayo Clinic Proceedings. Volume 88. Elsevier; Amsterdam, The Netherlands: 2013. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome; pp. 977–986.
    1. Winkelman J.W., Armstrong M.J., Allen R.P., Chaudhuri K.R., Ondo W., Trenkwalder C., Zee P.C., Gronseth G.S., Gloss D., Zesiewicz T. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology. 2016;87:2585–2593. doi: 10.1212/WNL.0000000000003388.
    1. Allen R.P., Picchietti D.L., Auerbach M., Cho Y.W., Connor J.R., Earley C.J., Garcia-Borreguero D., Kotagal S., Manconi M., Ondo W., et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: An IRLSSG task force report. Sleep Med. 2018;41:27–44. doi: 10.1016/j.sleep.2017.11.1126.
    1. Allen R.P., Walters A.S., Montplaisir J., Hening W., Myers A., Bell T.J., Ferini-Strambi L. Restless legs syndrome prevalence and impact: REST general population study. Arch. Intern. Med. 2005;165:1286–1292. doi: 10.1001/archinte.165.11.1286.
    1. Hogl B., Kiechl S., Willeit J., Saletu M., Frauscher B., Seppi K., Müller J., Rungger G., Gasperi A., Wenning G., et al. Restless legs syndrome: A community-based study of prevalence, severity, and risk factors. Neurology. 2005;64:1920–1924. doi: 10.1212/01.WNL.0000163996.64461.A3.
    1. Barriere G., Cazalets J.R., Bioulac B., Tison F., Ghorayeb I. The restless legs syndrome. Prog. Neurobiol. 2005;77:139–165. doi: 10.1016/j.pneurobio.2005.10.007.
    1. Ulfberg J., Nystrom B. Restless legs syndrome in blood donors. Sleep Med. 2004;5:115–118. doi: 10.1016/j.sleep.2003.09.010.
    1. Burchell B.J., Allen R.P., Miller J.K., Hening W.A., Earley C.J. RLS and blood donation. Sleep Med. 2009;10:844–849. doi: 10.1016/j.sleep.2008.09.013.
    1. Waldvogel S., Pedrazzini B., Vaucher P., Bize R., Cornuz J., Tissot J.D., Favrat B. Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: A randomized controlled trial. BMC Med. 2012;10:8. doi: 10.1186/1741-7015-10-8.
    1. Fontana S., Jüni P., Niederhauser C., Keller P. Lack of effectiveness of intravenous iron infusion in healthy blood donors with low ferritin: A double-blind randomized controlled trial: P-134. Vox Sang. 2014;107:98.
    1. Yokoi K., Konomi A. Iron deficiency without anaemia is a potential cause of fatigue: Meta-analyses of randomised controlled trials and cross-sectional studies. Br. J. Nutr. 2017;117:1422–1431. doi: 10.1017/S0007114517001349.
    1. Melenovsky V., Hlavata K., Sedivy P., Dezortova M., Borlaug B.A., Petrak J., Kautzner J., Hajek M. Skeletal muscle abnormalities and iron deficiency in chronic heart failurean exercise (31)P magnetic resonance spectroscopy study of calf muscle. Circ. Heart Fail. 2018;11:e004800. doi: 10.1161/CIRCHEARTFAILURE.117.004800.
    1. Cho Y.W., Allen R.P., Earley C.J. Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome. Sleep Med. 2016;25:16–23. doi: 10.1016/j.sleep.2016.06.021.
    1. Rushton D.H. Management of hair loss in women. Dermatol. Clin. 1993;11:47–53. doi: 10.1016/S0733-8635(18)30281-X.
    1. Kantor J., Kessler L.J., Brooks D.G., Cotsarelis G. Decreased serum ferritin is associated with alopecia in women. J. Investig. Dermatol. 2003;121:985–988. doi: 10.1046/j.1523-1747.2003.12540.x.
    1. Simpson E., Mull J.D., Longley E., East J. Pica during pregnancy in low-income women born in Mexico. West. J. Med. 2000;173 doi: 10.1136/ewjm.173.1.20.
    1. Rector W.G., Jr. Pica: Its frequency and significance in patients with iron-deficiency anemia due to chronic gastrointestinal blood loss. J. Gen. Intern. Med. 1989;4:512–513. doi: 10.1007/BF02599550.
    1. Kiss J.E., Brambilla D., Glynn S.A., Mast A.E., Spencer B.R., Stone M., Kleinman S.H., Cable R.G. Oral iron supplementation after blood donation: A randomized clinical trial. JAMA. 2015;313:575–583. doi: 10.1001/jama.2015.119.

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