Iron Deficiency in Menstruating Adult Women - Digital CSIC

ORIGINAL ARTICLE Open Access

Iron Deficiency in Menstruating Adult WomenMuch More than AnemiaM Cristina Fernandez-Jimenez MD1 Gemma Moreno MD2 Ione Wright MD3 Pei-Chun Shih PhD4

M Pilar Vaquero MD PhD3 and Angel F Remacha MD PhD5

AbstractBackground Iron deficiency anemia (IDA) is highly prevalent in women of child-bearing age However theirnonhematological symptoms have been overlooked This study aims to analyze the nonhematological featuresand symptoms of IDA in a group of women of reproductive age and the changes occurred during iron therapyMaterials and Methods IDA women underwent dietary physical activity menstrual blood loss and cognitivefunction assessment at baseline Hematological and biochemical parameters were analyzed Executive attentionwas tested by the flanker task and working memory by the 2-back task Oral iron therapy (ferrous sulfate) wasgiven to 35 women for 8 weeks and the changes in iron status biochemical markers cognitive function andnonhematological symptoms were evaluatedResults Patients presented nonhematological symptoms pica 324 cheilitis 206 restless legs syndrome(RLS) 206 diffuse hair loss 559 and ungual alterations 382 Two or more symptoms were present in588 of women Serum iron and working memory were correlated at baseline Multivariate analyses show as-sociations (odds ratio [OR] 95 confidence interval [CI]) between pica and reaction time in the working memorytest (OR 214 95 CI 119ndash387 p = 0012) RLS with total serum protein (OR 008 95 CI 006ndash092 p = 0043) andcheilitis with mean corpuscular hemoglobin (OR 0388 95 CI 0189ndash0799 p = 001) Pica cheilitis and RLS com-pletely resolved with iron therapy and ungual alterations and hair loss improved in 923 and 842 of womenrespectively Better performance in executive attention and working memory was observed after iron therapyConclusions More attention should be given to the nonhematological manifestations of IDA to improve thequality of life of menstruating women

Keywords iron deficiency anemia nonhematological symptoms cognitive function menstruation women

IntroductionIron deficiency (ID) is the most common nutritionaldeficiency in the world and is the leading cause of ane-mia in both developed and developing countries Thegreatest prevalence of iron deficiency anemia (IDA) isfound in women of reproductive age and preschoolchildren regardless of geographic region or economicstatus1

ID occurs as a spectrum beginning with tissue ironstore depletion and progressing to impaired eryth-ropoiesis and anemia Iron is an essential element re-quired for numerous vital processes including energymetabolism cell signaling gene expression and cellgrowth regulation and differentiation2 These functionsare so basic that ID has far reaching consequences onsystemic functions apart from the well-known feature

1Hematology Department Complejo Hospitalario de Toledo Toledo Spain2Hematology Department Hospital Ramon y Cajal Madrid Spain3Department of Metabolism and Nutrition Institute of Food Science Technology and Nutrition (ICTAN) Consejo Superior de Investigaciones Cientıficas (CSIC) MadridSpain4Faculty of Psychology Universidad Autonoma de Madrid Madrid Spain5Hematology Laboratory Department Hospital Sant Pau Barcelona Spain

Address correspondence to M Pilar Vaquero MD PhD Department of Metabolism and Nutrition Institute of Food Science Technology and Nutrition (ICTAN) ConsejoSuperior de Investigaciones Cientıficas (CSIC) CJose Antonio Novais 10 Madrid 28040 Spain E-mail mpvaqueroictancsices

ordf Fernandez-Jimenez et al 2020 Published by Mary Ann Liebert Inc This Open Access article is distributed under the terms of the Creative CommonsLicense (httpcreativecommonsorglicensesby40) which permits unrestricted use distribution and reproduction in any medium provided theoriginal work is properly cited

Womenrsquos Health ReportsVolume 11 2020DOI 101089whr20190011

26

of anemia but the nonhematological symptoms of thistrace element deficiency have been often overlooked

Nonhematological manifestations of ID include fa-tigue reduced physical endurance defective structureor function of epithelial tissues pica restless legs syn-drome (RLS) decreased cognitive performance andbehavioral disturbances34 ID impairs the health andwell-being of women and increases the risk of ad-verse maternal and neonatal outcomes56 Our researchgroup has observed elevated bone remodeling in IDAyoung adult women that improved during iron recoverysuggesting that chronic ID may be a risk factor for futureosteoporosis in women7ndash9 According to the Global Bur-den of Disease Study 2016 IDA is the first cause of yearslived with disability burden in women10 Neverthelessthere remains a lack of awareness of the clinical conse-quences of IDA among this population

The aim of this study was to prospectively analyzethe characteristics analytical data and nonhematolog-ical signs and symptoms of IDA in a homogeneousgroup of women of reproductive age and their responseto iron therapy

Materials and MethodsSubjectsParticipants were required to be Caucasian women agedbetween 18 and 40 years with IDA Patients were in-cluded when they had hemoglobin pound110 gL mean cor-puscular volume lt98 fL transferrin saturation lt15and ferritin lt20 ngmL or if ferritin was 20ndash50 ngmLsoluble transferrin receptor (sTfR) was gt5 mgL

Exclusion criteria were as follows smoking amen-orrhea menopause current pregnancy or pregnancywithin the previous year breastfeeding thalassemiairon metabolism-related diseases such as hemochroma-tosis bleeding disorders autoimmune diseases chronicgastrointestinal diseases (inflammatory bowel diseasegastric ulcers coeliac disease and Crohnrsquos disease)neoplastic diseases renal disease or hormone-relateddiseases independent of IDA chronic inflammation(C-reactive protein gt5 mgL) creatinine levels gt10 mgdL (120 lmolL) abnormal liver tests (gt2 times nor-mal) blood donation in the past 3 months currentuse of iron supplements and excess alcohol consump-tion or use of recreational drugs prescription drugs orherbal preparations that could interfere with iron ab-sorption andor affect mental performance

Over 18 months 84 women who met the inclusioncriteria were interviewed by telephone to assess allexclusion criteria After the exclusion criteria were ap-

plied 36 women agreed to participate 1 subject aban-doned the study due to a change of residence

Study protocolThis prospective interventional study was conducted atthe Complejo Hospitalario de Toledo Spain in 2014 asa part of a larger long-term project The study followedguidelines stated in the Declaration of Helsinki and wasapproved by the Complejo Hospitalario de Toledo Clin-ical Research Ethics Committee and the Spanish NationalResearch Council Ethics Committee (Bioethics subcom-mittee) Written informed consent was obtained fromall participants before study commencement

At enrolment a full medical history was recordedand anthropometric measurements were carried outPatients underwent dietary physical activity menstrualblood loss and cognitive function assessment Bloodsamples were taken for complete blood count (CBC)coagulation tests and measures of iron status andother biochemical parameters

Patients were prescribed 8 weeks of oral iron ther-apy in the form of ferrous sulfate tablets (TardyferonPierre Fabre Medicament Boulogne France) one tab-let (80 mg Fe) daily if hemoglobin gt100 gL or twotablets a day (160 mg Fe) if hemoglobin lt100 gLPatients were instructed to take the tablets in fastingconditions with water or orange juice At the time thestudy was conducted this was the conventional treat-ment for ID but mounting evidence indicates thatlow doses and treatment on alternate days are moreeffective and better tolerated11ndash13

A follow-up visit was scheduled 9 weeks after thebaseline visit 1 week after completing the prescribedpharmacological treatment to allow iron levels to stabi-lize Blood samples were taken to repeat the CBC andbiochemical parameters measurement and cognitivefunction was assessed again Patients were asked to re-port possible side effects associated with the treatmentand any health problems from their last visit If patientshad not recovered from anemia andor ID after the first8-week cycle of treatment (hemoglobin gt120 gL andferritin Dagger15 ngmL) a further 8 weeks of treatmentwas prescribed with a second follow-up visit scheduled1 week after finishing the second cycle of treatmentFigure 1 shows the study flow chart

Complete response was defined by normalization ofHb (Hb gt120 gL) and serum ferritin Dagger15 ngmL theferritin cutoff value suggested by the World HealthOrganization to indicate depleted iron stores for individ-uals of 5 years of age or older14 A final Hb gt120 gL but

Fernandez-Jimenez et al Womenrsquos Health Report 2020 11httponlineliebertpubcomdoi101089whr20190011

27

serum ferritin lt15 lgL or an increase in Hb Dagger20 gLwere regarded as incomplete response

The compliance of the study was assessed by ques-tionnaires and a personal interview in each visit Patientswere asked about the number of tablets that were takenthroughout treatment

Data collectionClinical data Medical history was taken by an hema-tologist at the time of initial evaluation through a pre-structured questionnaire that included medicationdietary supplements any past or present prestructuredquestionnaire medical conditions previous opera-tions and reproductive history Particular attentionwas given to a family history of anemia hypercholes-terolemia hypertension osteoporosis and kidney orthyroid disease Patients were questioned specificallyabout whether they had pica or other symptoms attrib-uted to ID such as fatigue epithelial manifestations

(hair loss angular cheilitis and brittle nails) and neu-romuscular symptoms (RLS) Pica was defined as thecompulsive eating of food or nonfood items singly orin combination not part of the patientrsquos habitual dietor preferences

Menstrual cycle duration period length and num-ber of days with intense menstrual blood loss (heavybleeding days) were monitored using a self-administeredpaper questionnaire as described previously1516 Ques-tions on the presence of blood clots bleeding lastinggt7 days and whether multiple pads or tampons weresaturated during the menstrual flow period were alsoincluded Patients with heavy blood loss were voluntar-ily referred to a gynecologist for further evaluation Theuse of oral contraceptives was also recorded

A short questionnaire was used to assess overallphysical activity Questions included duration and in-tensity of daily walking and moderate- and vigorous-intensity activities per week17

FIG 1 Flow chart


28

Anthropometric data Height and weight wereobtained at baseline and weight measurements wererepeated on next visits Weight was measured to thenearest 100 g using a medical weighing scale (Seca LtdHamburg Germany) and height was measured with astadiometer incorporated into the scale Body massindex (BMI) was worked out via the formula weight(kg)height (m2)

Hematological and biochemical assaysBlood samples were collected between 800 and 1000 byvenepuncture after a 12-hour fasting period Serum andplasma were obtained after centrifugation (for 5 minutesat 1000 g) The CBC was measured in whole blood fol-lowing standard laboratory techniques using the Beck-man Coulter LH780 Analyzer (Beckman Coulter BreaCA) Routine coagulation tests including prothrombintime activated partial thromboplastin time and fibrin-ogen were assayed on a blood coagulation analyzer ACLTOP 700 (Beckman Coulter) Serum iron serum ferri-tin total iron binding capacity serum vitamin B12serum folate sTfR and other biochemical variableswere determined by modular analyzers (Elecsys andModular DP Roche Diagnostics Mannheim Germany)

Dietary assessmentEach subjectrsquos dietary intake was evaluated at baselinewith a 72-hour detailed dietary intake report previ-ously validated and proved valuable to assess nutrientintake18 specifying the types of food consumed andserving weights The possible food intake changesthroughout the study were monitored using a foodfrequency questionnaire The options of frequency ofconsumption and their corresponding codes were asfollows never (0) less than once a week (05) once aweek (1) two to three times a week four to six timesa week (25) daily (7) and more than once a day (10)

Cognitive testingCognitive performance was assessed at baseline andfollow-up Two cognitive tasks were included in thisstudy Verbal version of the flanker task19 that tests ex-ecutive attention and 2-back task20 that is widely usedto measure working memory The computerized pro-grams of both tasks were taken from the COG-LAB-UAM Battery21 Verbal flanker task required decidingas fast as possible whether the letter in the center of aset of three letters was vowel or consonant The target(eg vowel) could be surrounded by compatible (egvowel) or incompatible letters (eg consonant) There

were a total of 22 practice trials and 80 test trials Halfof the trials were compatible and they were randomlypresented across the session Mean reaction time forcorrect responses and number of hits and errors wererecorded Given that speedndashaccuracy trade-off couldvary between experiments participants and conditionswe used the inverse efficiency score (IES)22 whichadjusts the reaction time by the proportion of correctanswers combining speed and accuracy into a singlemeasure High IES values indicate a less efficient perfor-mance that is greater difficulties in solving the task Inthe 2-back task upper and lower case letters were pre-sented in one of eight equidistant spatial locationsaround the center of the screen Stimuli were presentedfor 200 ms and 1300 ms were given for respondingThere were 75 test stimuli of which 24 were match stim-uli Participants pressed the space bar of the keyboard tomake a match response (a letter presented in the samespatial location two positions back in the sequence)

To assess potential confounding variables subjectsfilled out a short questionnaire aimed to determine pa-tientsrsquo latest education level profession urbanndashruralresidence and level of interaction with computersbefore completing the computerized cognitive testsAll sessions were monitored by trained research staffoverhead lighting was kept low the subject was askedto maintain a fixed distance from the screen and envi-ronmental distractions were minimized

Statistical analysisThe collected data were analyzed using the SPSS forWindows program (version 250 IBM Corp ArmonkNY) All continuous variables were analyzed for nor-mality and when required were log-transformed toachieve normality Pearson correlation coefficient wasused to analyze correlations between continuous vari-ables A stepwise-forward multiple linear regressionanalysis was used to determine which variables con-tribute significantly to the results of cognitive testsTo identify factors associated with nonhematologicalsymptomatology univariate and multivariate logisticregression analyses were applied Pretreatment andpost-treatment cognitive assessments were comparedusing paired t-tests The level of statistical significancewas considered as p lt 005

ResultsPatient characteristics and evaluationA total of 35 anemic young women completed thestudy In total 743 of participants reported past


29

personal history of IDA and 571 had female familyhistory of IDA (first- andor second-grade relatives)Patient characteristics and hematological data at base-line are summarized in Table 1

Most participants (853) reported IDA-related non-hematological symptomatology 324 pica (ice orone particular food especially crunchy foods) 206cheilitis 206 RLS 559 diffuse hair loss 382 un-gual changes and 206 intense fatigue Four patientsreported headache one tinnitus and another one dys-

phagia (without esophageal webs) In total 588 ofwomen had two or more symptoms associated with IDA

Heavy menstrual bleeding according to the ques-tionnaire was reported by 24 patients (686) 9 outof them presented some physical condition affectingthe uterus such as fibroids and polyps after furtherevaluation Seven women refused gynecological exam-ination All patients showed normal coagulation testsOnly four women used oral contraceptives

No significant differences were found in nutrientintake between patients nor in womenrsquos diet among base-line and end of treatment except for lsquolsquofruit juices atbreakfastrsquorsquo that showed an increased consumption (me-dian increased from never to once a week) ( p = 0015)and lsquolsquoother dairy products at breakfastrsquorsquo that decreased(median values lower than once a week) ( p = 0022)

Most patients reported low physical activity andnone high-intensity exercise BMI was 261 ndash 46 kgm2

at baseline and did not significantly vary through-out study In total 50 of the patients were overweightand three out of the patients had grade 1 obesity (BMIgt30 kgm2)

Significant associations between parameters at base-line are presented in Tables 2 and 3 Interestingly picaRLS and ungual changes were related to age of men-arche In addition associations between cognitive func-tion measures and neurological symptoms specificallypica and reaction time in 2-back test were observed

Outcome after iron therapyThirty-four out of 35 patients showed response to oraliron treatment 24 showed complete response (16 at

Table 1 Patient Characteristics and Hematological Dataat Baseline

Mean SD

Age 350 55Body mass index 261 46Energy intake (kcalday) 2194 415Dietary iron intake (mgday) 165 57Hemoglobin (gdL) 999 097Hematocrit () 3114 246Mean corpuscular volume (fL) 7311 672Mean corpuscular hemoglobin

concentration (gdL)3203 097

Red blood cell distribution width () 1751 180Serum ferritin (ngmL) 423 196Transferrin (mgdL) 3811 469Serum iron (lgdL) 2483 787PTH (pgmL) 3929 1412

Median IQR

Age at menarche (years) 13 3Menstrual cycle length (days) 28 5Period length (days) 5 3Heavy bleeding (days) 2 1

Values of the women who completed the study (n = 35)IQR interquartile range PTH parathyroid hormone SD standard

deviation

Table 2 Univariate and Multivariate Logistic Regression Analyses of Several Clinical and BiochemicalVariables Associated with Nonhematological Symptomatology at Baseline

Symptom Variables

Univariate Multivariate

OR (95 CI) p OR (95 CI) p

Pica Menarche age 184 (105ndash322) 0034 mdash mdashReaction time (2-back) 16 (106ndash245) 0027 214 (119ndash387) 0012

RLS Menarche age 057 (032ndash099) 0045 mdash mdashSerum total protein 007 (0005ndash082) 0035 008 (006ndash092) 0043Platelet count 103 (103ndash104) 0023 mdash mdash

Cheilitis Mean corpuscular volume 064 (046ndash09) 001 mdash mdashMean corpuscular hemoglobin 037 (018ndash078) 0008 0388 (0189ndash0799) 001Mean corpuscular hemoglobin concentration 026 (009ndash079) 0017 mdash mdashRed blood cell distribution width 179 (102ndash313) 0041 mdash mdashSerum iron 07 (052ndash096) 0027 mdash mdashSoluble transferrin receptor 135 (102ndash178) 0038 mdash mdashTransferrin saturation 028 (008ndash09) 0033 mdash mdashSerum folate 051 (028ndash095) 0034 mdash mdash

Diffuse hair loss Procollagen type 1N-terminal propeptide 106 (101ndash113) 0045 NA mdashUngual changes Menarche age 062 (039ndash09) 0045 NA

CI confidence interval RLS restless leg syndrome NA nonapplicable OR odds ratio


30

8 weeks and 8 at 16 weeks follow-up) and 10 showedincomplete response The patient who did not respondto therapy (refractoriness) was excluded from thestudy This patient was further diagnosed with Helico-bacter pylori infection

Nineteen patients (543) notified side effectsthat were gastrointestinal symptoms including nau-sea constipation loose stools and epigastric painReported side effects were all mild transient andself-limited and did not require discontinuation oftreatment

All cases of pica cheilitis and RLS completely re-solved with iron therapy even when some patients didnot achieve complete response to treatment Ungual

changes and hair loss improved in 923 and 842of women respectively but were not totally resolvedFatigue headache tinnitus and dysphagia disappearedafter treatment The clinical data and response to irontreatment are summarized in Table 4

Regarding cognitive function assessment a betterperformance in executive attention and working mem-ory was observed after iron therapy measured byFlanker and 2-back tests as is shown in Table 5 Inthe Flanker task an improvement of the IES was seenin compatible and incompatible trials and in the 2-back task a decrease in response latencies and an in-crease in accuracy were observed

Different patterns of associations among cognitivefunction measures and biochemical and clinical datawere observed after treatment The only correlationsthat remained statistically significant were betweenIES for incompatible trials (Flanker task) and BMI(r = 042 p = 0020) and between correct responsesand omission errors (2-back test) and BMI (r = 043p = 0016 r = 043 p = 0015) In addition increase inferritin levels and reticulocyte count was associatedwith a reduction in omission errors (r =040 p =0034 r =049 p = 0026) and an increment in correctresponses (r = 042 p = 0027 r = 050 p = 0026)

Changes in biochemical parameters after iron treat-ment included significant increases in serum folatevitamin B12 glucose uric acid total cholesterol high-density lipoprotein cholesterol and bilirubin Ureadecreased significantly These results have been dis-cussed elsewhere23

Table 3 Associations Between Cognitive Function Measures and Other Parameters at Baseline

Test Variable Correlations Multiple regression analysis b coefficient (SE) p

Flanker task Inverse efficiency scorefor compatible trials

PTH r = 043 p = 0015Serum albumin level r =047 p = 0019Reticulocyte count r =044 p = 0019Fasting glucose r = 041 p = 0025

PTH b 036 (14) p = 0035Fasting glucose b 057 (35) p = 0002(R2 = 063 p lt 0001)

Inverse efficiency scorefor incompatible trials

PTH r = 04 p = 0041Serum iron levels r =042 p = 0016

PTH b 052 (14) p = 0003(R2 = 052 p = 0003)

2-Back test Reaction time Transferrin saturation r =037 p = 0041Fasting glucose r = 042 p = 0025

No variables were entered into the equation

Correct responses BMI r =037 p = 0043Transferrin saturation r = 04 p = 0027Serum iron levels r = 043 p = 0018

Serum iron levels b 044 (045) p = 001BMI b 037 (093) p = 0029(R2 = 032 p = 0006)

Omission errors BMI r = 037 p = 0043Serum protein level r =045 p = 0025Serum albumin level r =042 p = 0047Fasting glucose r = 04 p = 003Transferrin saturation r =034 p = 0027Serum iron levels r =043 p = 0018

Serum iron levels b 04 (039) p = 0018BMI b 037 (08) p = 0037Fasting glucose b 049 (058) p = 0007(R2 = 054 p lt 0001)

Commission errors Significant correlations not found

BMI body mass index SE standard error

Table 4 Characteristics of Nonhematological Symptomsin Patients with Iron Deficiency Anemia and Responseto Therapy

Nonhematological symptoms Patients () Oral iron response ()

Cheilitis 206 100Pica 324 100Restless leg syndrome 206 100Hair loss 559 842Ungual changes 382 923Headache 117 100Others 58 100

No of symptoms Patients ()

1 3532 2653 1764 35 3


31

DiscussionThis research has focused on emphasizing the impor-tance of the nonhematological manifestations ofIDA in women of reproductive age and on identifyingfactors associated with this condition Although sev-eral published studies have concentrated on one spe-cific aspect such as pica and cognitive functionimpairment we have tried to analyze all the datataken as a whole

Concerning medical history we found that morethan half of our patients reported family history ofIDA which is consistent with studies suggesting thatsusceptibility to ID is in part influenced by geneticsGenetic variants of iron genes especially TMPRSS6HFE transferrin and hepcidin may predispose indi-viduals to IDA or protect them from it16182425 Incontrast a personal history of IDA was present in al-most three quarters of the patients These findingssupport the convenience of screening for IDA inthose with either prior personal or family historiesof IDA

As regards etiology among women of reproductiveage menstrual blood loss is the most common causeof ID and IDA Women with heavy menstrual bleedingare at a higher risk151826 In line with these data686 of the patients in our study reported heavymenstrual bleeding and few women used oral contra-ceptives that are known to regulate menstruationRegarding the different factors for IDA high menstrualblood losses and no use of oral contraceptives but notdietary iron intake have been consistently associatedwith poor iron status in women15182728 emphasizingthe importance of recognition and diagnosis of ID inthis particularly vulnerable female population

Most of our patients (853) reported nonhemato-logical symptoms highlighting its high incidence andthe fact that this symptomatology is often overlookedif patients are not directly questioned about it Diffusehair loss was the most prevalent symptom we observed

(559 of patients) followed by brittle nails (382) Inthe literature both signs have been associated withchronic ID and could at least partly arise from alter-ation in epithelial cellular replication produced byID2 Telogen effluvium or the rapid shift of hairfrom anagen (growing period) to telogen (resting peri-od) phase has been described as the mechanism under-lying hair loss in women with ID29 The most typicallesion seen in nails associated with ID is koilonychiadefined as a concavity of the outer surface of the nailbut it seems that this finding is now encountered rarelypossible due to earlier detection of ID Thinning andflattening of the nail as well as brittle nails precedethe development of koilonychia30 The fact that our pa-tients reported improvement but not complete resolu-tion of hair loss or brittle nails after iron administrationcould indicate that there are other factors involved orthat a longer follow-up is necessary In line with thisit has been reported that even with therapy koilony-chia takes a long period of time to return to a normalappearance30 Regarding hair loss most authors recom-mend maintaining serum ferritin at levels gt40 ngmL29

which would need longer to be achieved Another ID-related alteration of epithelium angular cheilitis char-acterized by ulcerations or fissures at the corners of themouth was observed in 206 of patients and com-pletely resolved with iron treatment Angular stomatitisis not specific of ID and can also been seen in othernutritional deficiencies It has been reported that IDApredisposes to angular cheilitis and the lesions healedwith iron supplementation31

IDA and ID also have a well-known association withintense fatigue32 which was present in almost a quarterof the patients in our study All cases reversed with irontherapy It could be argued that anemia could be re-sponsible for fatigue but it has been observed in non-anemic individuals with ID in several reports A recentmeta-analysis of studies in iron-deficient non-anemicpatients found that iron therapy improved objective

Table 5 Changes in Cognitive Function Measures after Iron Therapy

Test Variable Baseline (mean ndash SD) End of treatment (mean ndash SD)

Paired t-test

t p

Flanker task Inverse efficiency score for compatible trials (ms) 3019 ndash 1325 2335 ndash 377 32 0004Inverse efficiency score for incompatible trials (ms) 3122 ndash 131 2536 ndash 414 26 0014

2-Back test Reaction time (ms) 1333 ndash 22 13324 ndash 18 29 0008Correct responses () 579 ndash 225 68 ndash 216 23 0029Omission errors () 421 ndash 225 32 ndash 216 23 0029Commission errors () 159 ndash 146 15 ndash 142 03 ns


32

and self-rated assessments of fatigue33 reinforcing thefact that ID is a broader condition with extensive healthconsequences in addition to the well-known feature ofanemia These data highlight that for women of child-bearing age with unexplained prolonged fatigue IDshould be considered

Iron is also recognized to play a crucial role in main-tenance of neuronal activity and networks2 Linked tothis function two neurological symptoms pica andRLS have been associated with ID Pica was reportedby 324 of our patients consistent with the preva-lence observed in other studies34 Careful inquiry wasnecessary because some patients were ashamed oftheir behavior or underrated its importance Variousforms of pica have been associated with ID pagophagia(pica for ice) being considered quite specific35 In ourstudy patients reported either pagophagia or foodpica a subtype of pica that consists of compulsively eat-ing one particular food especially if crunchy36 Exactpathophysiology of pica in association with ID isunknown but it is probably attributable to ID in thecentral nervous system The reasons why some patientswith ID manifest pica and others do not have yet to besatisfactorily explained but heritable traits could con-tribute to pica susceptibility in adults with ID Allcases of pica in this study resolved rapidly with irontherapy even before any increase was noted in the he-moglobin concentration in agreement with previousreports34

RLS is a common disorder that manifests as an in-tense urge to move the legs that is uncomfortable andinterferes with sleep Although the exact pathophysiol-ogy remains unclear brain ID and altered dopaminer-gic function appear to play an important role in thepathogenesis of this condition37 In our patients theprevalence of clinically significant RLS was 206higher than that seen in the general population (5ndash15)38 and all cases resolved with iron administrationDespite its significant sleep morbidity RLS with IDA isoften overlooked In addition we found that patientswith RLS showed lower serum protein level than therest of IDA women which is according to a recentstudy reporting lower serum albumin levels in RLSpatients than in a control group39

A considerable body of evidence has established thatappropriate levels of brain iron are necessary for opti-mal brain development and functioning40 Nonethe-less despite the high prevalence of ID in women ofreproductive age relatively few studies41ndash45 have exam-ined the relationship between iron status and cognition

in this group focusing instead on infants and childrenOur study found a correlation between iron serumlevel and working memory measured by 2-back taskat baseline After iron treatment we detected an im-provement in attention and working memory testsmeasured by Flanker and 2-back tasks corroboratingothersrsquo previous findings that show that cognitive al-terations are responsive to iron administration46ndash48

Of note there was a significant decrease in omissionbut not commission errors in 2-back This is in linewith studies reporting that these two types of errorshave different correlates and thus may represent dif-ferent processes49

In addition to correlations related to iron metabo-lism we observed an intriguing association betweenparathyroid hormone (PTH) levels and IES (in com-patible as well as in incompatible trials) in Flankertask at baseline This finding could be related to thelink between higher serum PTH levels and increasedodds of poor cognition suggested by some reports al-though it is not yet well established50 Despite thefact our study initially seemed to corroborate this pos-sible link the association between PTH levels andFlanker test was not significant after iron therapyOne possible explanation could be that IDA patientspresented higher PTH levels at the beginning of thetrial Linked to this higher levels of PTH have beenreported in patients with low hemoglobin and low fer-ritin51 Nevertheless we could not detect statisticallysignificant differences in PTH levels before and aftertherapy although the small size of our sample limitsthe results of our study We also found an associationbetween BMI and accuracy in 2-back task both at thebaseline and after treatment which agrees with the im-paired working memory performance reported in over-weight and obese young adults compared with healthyweight controls52

ConclusionsDespite the high prevalence of ID and IDA amongwomen there is insufficient awareness of its unfavor-able consequences beyond anemia Iron plays an inte-gral role in a wide range of physiological functionstherefore the health consequences of ID and IDA areextensive and affect all aspects of the physical healthand well-being of women

AcknowledgmentsWe thank all the women who voluntarily participatedin the study


33

Author Disclosure StatementNo competing financial interests exist

Funding InformationThis study was supported by project ref 201170E15from Consejo Superior de Investigaciones CientıficasSpain

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of global anemia burden from 1990 to 2010 Blood 2014123615ndash6242 Musallam KM Taher AT Iron deficiency beyond erythropoiesis Should

we be concerned Curr Med Res Opin 20183481ndash933 Lopez A Cacoub P Macdougall IC Peyrin-Biroulet L Iron deficiency

anaemia Lancet (London) 2016387907ndash9164 Pompano LM Haas JD Increasing iron status through dietary

supplementation in iron-depleted sedentary women increasesendurance performance at both near-maximal and submaximal exerciseintensities J Nutr 2019149231ndash239

5 Janbek J Sarki M Specht IO Heitmann BL A systematic literature reviewof the relation between iron statusanemia in pregnancy and offspringneurodevelopment Eur JClin Nutr 2019731561ndash1578

6 Friedman AJ Chen Z Ford P et al Iron deficiency anemia inwomen across the life span J Womens Health (Larchmt) 2012211282ndash1289

7 Wright I Blanco-Rojo R Fernandez MC et al Bone remodelling is reducedby recovery from iron-deficiency anaemia in premenopausal womenJ Physiol Biochem 201369889ndash896

8 Toxqui L Vaquero MP Chronic iron deficiency as an emerging risk factorfor osteoporosis A hypothesis Nutrients 201572324ndash2344

9 Toxqui L Perez-Granados AM Blanco-Rojo R Wright I de la Piedra CVaquero MP Low iron status as a factor of increased bone resorptionand effects of an iron and vitamin D-fortified skimmed milk onbone remodelling in young Spanish women Eur J Nutr 201453441ndash448

10 GBD 2016 Disease and Injury Incidence and Prevalence CollaboratorsGlobal regional and national incidence prevalence and years lived withdisability for 328 diseases and injuries for 195 countries 1990ndash2016A systematic analysis for the Global Burden of Disease Study 2016 Lancet(London) 20173901211ndash1259

11 Stoffel NU Zeder C Brittenham GM Moretti D Zimmermann MB Ironabsorption from supplements is greater with alternate day than withconsecutive day dosing in iron-deficient anemic women Haematologica2019 Aug 14 doi 103324haematol2019220830 [Epub ahead of print]

12 Stoffel NU Cercamondi CI Brittenham G et al Iron absorption from oraliron supplements given on consecutive versus alternate days and assingle morning doses versus twice-daily split dosing in iron-depletedwomen Two open-label randomised controlled trials Haematology20174e524ndashe533

13 Moretti D Goede JS Zeder C et al Oral iron supplements increasehepcidin and decrease iron absorption from daily or twice-daily dosesin iron-depleted young women Blood 20151261981ndash1989

14 World Health Organization Serum ferritin concentrations forthe assessment of iron status and iron deficiency in populationsGeneva Switzerland Vitamin and Mineral Nutrition InformationSystem 2011

15 Toxqui L Perez-Granados AM Blanco-Rojo R Wright I Vaquero MPA simple and feasible questionnaire to estimate menstrual blood lossRelationship with hematological and gynecological parametersin young women BMC Womenrsquos Health 20141471

16 Blanco-Rojo R Baeza-Richer C Lopez-Parra AM et al Four variants intransferrin and HFE genes as potential markers of iron deficiency anaemiarisk An association study in menstruating women Nutr Metab (Lond)2011869

17 Blanco-Rojo R Perez-Granados AM Toxqui L Gonzalez-Vizcayno CDelgado MA Vaquero MP Efficacy of a microencapsulated ironpyrophosphate-fortified fruit juice A randomised double-blind

placebo-controlled study in Spanish iron-deficient women Br J Nutr20111051652ndash1659

18 Blanco-Rojo R Toxqui L Lopez-Parra AM et al Influence of dietmenstruation and genetic factors on iron status A cross-sectionalstudy in Spanish women of childbearing age Int J Mol Sci 2014154077ndash4087

19 Eriksen BA Eriksen CW Effects of noise letters upon identification ofa target letter in a non-search task Percept Psychophysics 197416143ndash149

20 Kirchner WK Age differences in short-term retention of rapidlychanging information J Exp Psychol 195855352ndash358

21 Shih PC Privado J Colom R Cog-Lab-UAM Poster presented at the Xmeeting of the Spanish Society for the Study of Individual Differences(SEIDI) Salamanca September 26 2008

22 Townsend JT Ashby FG Methods of modeling capacity in simpleprocessing systems In J Castellan F Restle (Eds) Cognitive theory Vol 3(pp 200ndash239) Hillsdale NJ Erlbaum 1978

23 Remacha AF Wright I Fernandez-Jimenez MC et al Vitamin B12 andfolate levels increase during treatment of iron deficiency anaemia inyoung adult woman Int J Lab Hematol 201537641ndash648

24 Camaschella C Iron deficiency Blood 201913330ndash3925 Sarria B Navas-Carretero S Lopez-Parra AM et al The G277S

transferrin mutation does not affect iron absorption in iron deficientwomen Eur J Nutr 20074657ndash60

26 Mirza FG Abdul-Kadir R Breymann C Fraser IS Taher A Impact andmanagement of iron deficiency and iron deficiency anemia in womenrsquoshealth Expert Rev Hematol 201811727ndash736

27 Gallego-Narbon A Zapatera B Vaquero MP Physiological and dietarydeterminants of iron status in Spanish vegetarians Nutrients 201911pii E1734

28 Sekhar DL Murray-Kolb LE Kunselman AR Weisman CS Paul IM Differ-ences in risk factors for anemia between adolescent and adult womenJ Womens Health (Larchmt) 201625505ndash513

29 Almohanna HM Ahmed AA Tsatalis JP Tosti A The role ofvitamins and minerals in hair loss A review Dermatol Ther 2019951ndash70

30 Sato S Iron deficiency Structural and microchemical changes in hairnails and skin Sem Dermatol 199110313ndash319

31 Murphy NC Bissada NF Iron deficiency An overlookedpredisposing factor in angular cheilitis J Am Dietec Assoc (1939)197999640ndash641

32 DeLoughery TG Iron deficiency anemia Med Clin North Am 2017101319ndash332

33 Yokoi K Konomi A Iron deficiency without anaemia is a potentialcause of fatigue Meta-analyses of randomised controlled trials andcross-sectional studies Br J Nutr 20171171422ndash1431

34 Borgna-Pignatti C Zanella S Pica as a manifestation of iron deficiencyExpert Rev Hematol 201691075ndash1080

35 Brown WD Dyment PG Pagophagia and iron deficiency anemia inadolescent girls Pediatrics 197249766ndash767

36 Crosby WH Food pica and iron deficiency Arch Int Med 1971127960ndash961

37 Bollu PC Yelam A Thakkar MM Sleep medicine Restless legs syndromeMo Med 2018115380ndash387

38 Yeh P Walters AS Tsuang JW Restless legs syndrome A comprehensiveoverview on its epidemiology risk factors and treatment Sleep Breath201216987ndash1007

39 Olgun Yazar H Yazar T Ozdemir S Kasko Arici Y Serum C-reactiveproteinalbumin ratio and restless legs syndrome Sleep Med 20195861ndash65

40 Murray-Kolb LE Iron and brain functions Curr Opp Clin Nutr Met Care201316703ndash707

41 Greig AJ Patterson AJ Collins CE Chalmers KA Iron deficiency cognitionmental health and fatigue in women of childbearing age A systematicreview J Nutr Sci 20132e14

42 Lomagno KA Hu F Riddell LJ et al Increasing iron and zinc in pre-menopausal women and its effects on mood and cognition A systematicreview Nutrients 201465117ndash5141

43 Scott SP Murray-Kolb LE Iron status is associated with performance onexecutive functioning tasks in nonanemic young women J Nutr 201614630ndash37


34

44 Blanton CA Green MW Kretsch MJ Body iron is associated withcognitive executive planning function in college women Br J Nutr2013109906ndash913

45 Wenger MJ Rhoten SE Murray-Kolb LE et al Changes in iron statusare related to changes in brain activity and behavior in rwandanfemale university students Results from a randomized controlledefficacy trial involving iron-biofortified beans J Nutr 2019149687ndash697

46 Falkingham M Abdelhamid A Curtis P Fairweather-Tait S Dye LHooper L The effects of oral iron supplementation on cognition inolder children and adults A systematic review and meta-analysisNutr J 201094

47 Scott SP Murray-Kolb LE Wenger MJ et al Cognitive performance inindian school-going adolescents is positively affected by consumptionof iron-biofortified pearl millet A 6-month randomized controlledefficacy trial J Nutr 20181481462ndash1471

48 Wenger MJ Murray-Kolb LE Nevins JE et al Consumption of a double-fortified salt affects perceptual attentional and mnemonic functioningin women in a randomized controlled trial in India J Nutr 20171472297ndash2308

49 Meule A Reporting and interpreting working memory performance inn-back tasks Front Psychol 20178352

50 Lourida I Thompson-Coon J Dickens CM et al Parathyroid hormonecognitive function and dementia A systematic review PLoS One 201510e0127574

51 Atmaca M OM Tasdemir E Ozbay M Correlation of parathyroidhormone and hemoglobin levels in normal renal function Acta Endo(Buc) 20117317ndash323

52 Dye L Boyle NB Champ C Lawton C The relationship between obesityand cognitive health and decline Proc Nutr Soc 201776443ndash454

Cite this article as Fernandez-Jimenez MC Moreno G Wright IShih P-C Vaquero MP Remacha AF (2020) Iron deficiency inmenstruating adult women much more than anemia WomenrsquosHealth Report 11 26ndash35 DOI 101089whr20190011

Abbreviations UsedBMI frac14 body mass index

CI frac14 confidence intervalCBC frac14 complete blood count

IES frac14 inverse efficiency scoreIQR frac14 interquartile range

ID frac14 iron deficiencyIDA frac14 iron deficiency anemiaOR frac14 odds ratio

PTH frac14 parathyroid hormoneRLS frac14 restless legs syndromeSD frac14 standard deviationSE frac14 standard error

Publish in Womenrsquos Health Reports

- Immediate unrestricted online access- Rigorous peer review- Compliance with open access mandates- Authors retain copyright- Highly indexed- Targeted email marketing

liebertpubcomwhr


35

of anemia but the nonhematological symptoms of thistrace element deficiency have been often overlooked

Nonhematological manifestations of ID include fa-tigue reduced physical endurance defective structureor function of epithelial tissues pica restless legs syn-drome (RLS) decreased cognitive performance andbehavioral disturbances34 ID impairs the health andwell-being of women and increases the risk of ad-verse maternal and neonatal outcomes56 Our researchgroup has observed elevated bone remodeling in IDAyoung adult women that improved during iron recoverysuggesting that chronic ID may be a risk factor for futureosteoporosis in women7ndash9 According to the Global Bur-den of Disease Study 2016 IDA is the first cause of yearslived with disability burden in women10 Neverthelessthere remains a lack of awareness of the clinical conse-quences of IDA among this population

The aim of this study was to prospectively analyzethe characteristics analytical data and nonhematolog-ical signs and symptoms of IDA in a homogeneousgroup of women of reproductive age and their responseto iron therapy

Materials and MethodsSubjectsParticipants were required to be Caucasian women agedbetween 18 and 40 years with IDA Patients were in-cluded when they had hemoglobin pound110 gL mean cor-puscular volume lt98 fL transferrin saturation lt15and ferritin lt20 ngmL or if ferritin was 20ndash50 ngmLsoluble transferrin receptor (sTfR) was gt5 mgL

Exclusion criteria were as follows smoking amen-orrhea menopause current pregnancy or pregnancywithin the previous year breastfeeding thalassemiairon metabolism-related diseases such as hemochroma-tosis bleeding disorders autoimmune diseases chronicgastrointestinal diseases (inflammatory bowel diseasegastric ulcers coeliac disease and Crohnrsquos disease)neoplastic diseases renal disease or hormone-relateddiseases independent of IDA chronic inflammation(C-reactive protein gt5 mgL) creatinine levels gt10 mgdL (120 lmolL) abnormal liver tests (gt2 times nor-mal) blood donation in the past 3 months currentuse of iron supplements and excess alcohol consump-tion or use of recreational drugs prescription drugs orherbal preparations that could interfere with iron ab-sorption andor affect mental performance

Over 18 months 84 women who met the inclusioncriteria were interviewed by telephone to assess allexclusion criteria After the exclusion criteria were ap-

plied 36 women agreed to participate 1 subject aban-doned the study due to a change of residence

Study protocolThis prospective interventional study was conducted atthe Complejo Hospitalario de Toledo Spain in 2014 asa part of a larger long-term project The study followedguidelines stated in the Declaration of Helsinki and wasapproved by the Complejo Hospitalario de Toledo Clin-ical Research Ethics Committee and the Spanish NationalResearch Council Ethics Committee (Bioethics subcom-mittee) Written informed consent was obtained fromall participants before study commencement

At enrolment a full medical history was recordedand anthropometric measurements were carried outPatients underwent dietary physical activity menstrualblood loss and cognitive function assessment Bloodsamples were taken for complete blood count (CBC)coagulation tests and measures of iron status andother biochemical parameters

Patients were prescribed 8 weeks of oral iron ther-apy in the form of ferrous sulfate tablets (TardyferonPierre Fabre Medicament Boulogne France) one tab-let (80 mg Fe) daily if hemoglobin gt100 gL or twotablets a day (160 mg Fe) if hemoglobin lt100 gLPatients were instructed to take the tablets in fastingconditions with water or orange juice At the time thestudy was conducted this was the conventional treat-ment for ID but mounting evidence indicates thatlow doses and treatment on alternate days are moreeffective and better tolerated11ndash13

A follow-up visit was scheduled 9 weeks after thebaseline visit 1 week after completing the prescribedpharmacological treatment to allow iron levels to stabi-lize Blood samples were taken to repeat the CBC andbiochemical parameters measurement and cognitivefunction was assessed again Patients were asked to re-port possible side effects associated with the treatmentand any health problems from their last visit If patientshad not recovered from anemia andor ID after the first8-week cycle of treatment (hemoglobin gt120 gL andferritin Dagger15 ngmL) a further 8 weeks of treatmentwas prescribed with a second follow-up visit scheduled1 week after finishing the second cycle of treatmentFigure 1 shows the study flow chart

Complete response was defined by normalization ofHb (Hb gt120 gL) and serum ferritin Dagger15 ngmL theferritin cutoff value suggested by the World HealthOrganization to indicate depleted iron stores for individ-uals of 5 years of age or older14 A final Hb gt120 gL but


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FIG 1 Flow chart


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Mean SD




Median IQR



deviation


Symptom Variables









30















PTH b 052 (14) p = 0003(R2 = 052 p = 0003)













1 3532 2653 1764 35 3


31










Paired t-test

t p




32











33

















































34


















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FIG 1 Flow chart


28










29











Mean SD




Median IQR



deviation


Symptom Variables









30















PTH b 052 (14) p = 0003(R2 = 052 p = 0003)













1 3532 2653 1764 35 3


31










Paired t-test

t p




32











33

















































34


















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29











Mean SD




Median IQR



deviation


Symptom Variables









30















PTH b 052 (14) p = 0003(R2 = 052 p = 0003)













1 3532 2653 1764 35 3


31










Paired t-test

t p




32











33

















































34


















liebertpubcomwhr


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Mean SD




Median IQR



deviation


Symptom Variables









30















PTH b 052 (14) p = 0003(R2 = 052 p = 0003)













1 3532 2653 1764 35 3


31










Paired t-test

t p




32











33

















































34


















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PTH b 052 (14) p = 0003(R2 = 052 p = 0003)













1 3532 2653 1764 35 3


31










Paired t-test

t p




32











33

















































34


















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Paired t-test

t p




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33

















































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Iron Deficiency in Menstruating Adult Women - Digital CSIC

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