Restless legs syndrome, pica, and iron status in blood donors

B L O O D D O N O R S A N D B L O O D C O L L E C T I O N

Restless legs syndrome, pica, and iron status in blood donors

Bryan R. Spencer, Steven Kleinman, David J. Wright, Simone A. Glynn, David B. Rye, Joseph E. Kiss,

Alan E. Mast, and Ritchard G. Cable for the REDS-II RISE Analysis Group

BACKGROUND: The association of blood donation–related iron deficiency with pica or restless legs syn-drome (RLS) remains poorly elucidated. This studyevaluated the prevalence of RLS and pica in blooddonors completing the REDS-II Iron Status Evaluation(RISE) study.STUDY DESIGN AND METHODS: RISE enrolled 2425blood donors in a prospective cohort study; 1334donors provided blood samples to characterize ironstatus and answered a questionnaire inquiring intosymptoms of RLS and pica at a final visit after 15 to 24months of follow-up. Associations between both condi-tions and iron status were evaluated.RESULTS: There were 9 and 20% of donors reportingsymptoms of probable or probable/possible RLS,respectively. Iron depletion and donation intensity werenot predictive of RLS. Pica was reported by 65 donors(5.5%), half of whom reported daily cravings. Preva-lence of pica increased with degree of iron depletion inwomen (2% in iron-replete females, 13% in those withferritin < 12 ng/mL), but not in men. Probable RLS andpica coexpressed in eight individuals, but no more fre-quently than expected by chance.CONCLUSION: RLS and pica have been associatedwith iron deficiency in nondonor populations. This studyindicates a potentially high prevalence of RLS in fre-quent blood donors but shows no association with ironstatus or donation intensity. Low iron stores were asso-ciated with higher prevalence of pica, but only infemales. Furthermore, the results are incompatible withRLS and pica sharing a common pathophysiology.

Iron depletion as a consequence of repeated blooddonation is well documented.1 Only recently havecomprehensive, longitudinal data been collectedthat speak to the impact of demographic, behav-

ioral, and genetic factors along with donation intensityupon decrements in serum iron variables.2 While irondepletion is thought to contribute to fatigue and cognitiveimpairment, its clinical correlates are not firmly estab-lished. Both acute and chronic iron deficiency interferewith the function of the neurotransmitter dopamine,3

which is essential to motivation, reward, feeding, sleep,and vigilance.4 Two common clinical conditions in whichiron deficiency has been implicated as an intermediatetrait—accounting for the sensitivities of each trait todopaminergic medications—are restless legs syndrome(RLS)5,6 and pica.7,8

ABBREVIATIONS: AIS = absent iron stores; FT = first time

(donors with no prior donation history); FV = final visit;

IDE = iron-deficient erythropoiesis; RA = reactivated (donors

with no donations within the past 2 years); RISE = Retrovirus

Epidemiology Donor Study-II Iron Status Evaluation (study);

RLS = restless legs syndrome; RPT = repeat.

From the American Red Cross Blood Services, New England

Region, Dedham, Massachusetts; AABB, Bethesda, Maryland;

Westat, Inc., Rockville, Maryland; the National Heart, Lung, and

Blood Institute, Bethesda, Maryland; the Emory University

Program in Sleep, Atlanta, Georgia; the Institute for Transfusion

Medicine, Pittsburgh, Pennsylvania; BloodCenter of Wisconsin,

Milwaukee, Wisconsin; and the American Red Cross Blood

Services, Connecticut Region, Farmington, Connecticut.

Address reprint requests to: Bryan R. Spencer, MPH,

American Red Cross, New England Region, 180 Rustcraft

Road, Suite 115, Dedham, MA 02026; e-mail:

[email protected].

This study was supported by Contracts N01HB47168,

N01HB47169, N01HB47170, N01HB47171, N01HB47172,

N01HB47174, N01HB47175, and N01HB57181 from the

National Heart, Lung, and Blood Institute.

Received for publication November 4, 2012; revision

received April 14, 2013, and accepted April 14, 2013.

doi: 10.1111/trf.12260

TRANSFUSION 2013;53:1645-1652.

Volume 53, August 2013 TRANSFUSION 1645

mailto:[email protected]

RLS is a common disorder that manifests as anintense urge to move the legs that is uncomfortable,worsens at rest, is relieved by movement, and interfereswith sleep because of its diurnal preference for theevening and night.9 Insufficient brain iron has beenposited as a universal feature common to both theprimary or idiopathic and secondary forms of RLS,5,6 andgenetic variants conferring susceptibility to RLS associatewith lower measures of mobilizable iron in a dose-dependent fashion.10 Nonetheless, iron deficiency isneither necessary nor sufficient to cause RLS.9 Pica hasbeen described as a “devouring passion” or insatiable urgeto consume primarily nonnutritive items, including ice,dirt, clay, raw pasta, and starch.11,12 An association withiron decrements is extensively documented.11 Associa-tions of iron deficiency with RLS and pica, two conditionsthat share in common compulsive urges that are modifi-able by dopaminergic drugs, suggests a potential sharedetiology. Blood donors represent a population suitable forfurther delineating the potentially causative associationsof iron deficiency to both RLS and pica and to examine forthe first time the potential interrelationship betweenthese two clinical conditions. Previous studies, althoughreporting prevalence of RLS13,14 and pica14 that were muchhigher among blood donors, failed to find or examine for arelationship to donation intensity. We therefore examinedself-reported RLS-like symptoms and pica behaviorsamong repeat (RPT) blood donors at the conclusion of theRetrovirus Epidemiology Donor Study-II (REDS-II) IronStatus Evaluation Study (RISE) and probed for associa-tions between iron status and RLS and pica.

MATERIALS AND METHODS

Donor populationThe RISE study has been described elsewhere.2 Briefly, sixblood centers participating in the REDS-II program, spon-sored by the National Heart, Lung and Blood Institutes,recruited 2425 donors for multiple follow-up visits over 15to 24 months. Donors were recruited into four cohortsstratified by sex and recent donation history. Donors withno prior donation history (FT) or no donations within thelast 2 years (RA) entered the “first-time/reactivated”donor cohort (FT/RA), while those who had made two(females) or three (males) whole blood donations in theprior 12 months entered the frequent RPT cohorts. Infor-mation on behavioral, demographic, and other factorswas collected at enrollment. When possible, extra plasmasamples were collected from all donor visits for hemato-logic and iron assays. Of the 2425 donors enrolled at base-line, 1334 donors (187 FT/RA females, 149 FT/RA males,486 RPT females, 512 RPT males) completed a final visit(FV) at least 15 months postenrollment. The FV differedfrom other follow-up visits by the administration of aquestionnaire on use of mineral and vitamin supple-

ments, and symptoms indicative of RLS or pica. Thisarticle reports the prevalence of RLS and pica at the timeof the FV and characterizes their associations with demo-graphic factors and iron status observed at the sametime.

RLS in RISE donorsUnder the best of circumstance, the sensitivities andspecificities of subjective assessments for RLS do notexceed 0.80 to 0.9015 due to several clinical conditions thatclosely mimic RLS.16 We therefore employed two differentscreening questions, one with nearly 100% sensitivity and97% specificity in a sleep disorders population (Q9,Appendix S1, available as supporting information in theonline version of this paper)17 and another with approxi-mately 75% sensitivity and specificity in a general popu-lation (Q10, Appendix S1).10 Donor status was classified as“probable RLS” if a subject was affected by RLS-like symp-toms at least two to four times per month with the addi-tional requirements of worsening while at rest and beingrelieved by movement (Condition 2, Table in Appendix S1)and that predominated in the evening or at bedtime (Con-dition 3, Table in Appendix S1). “Possible RLS” applied toindividuals who reported symptoms less frequently orwho answered “don’t know” as to worsening at rest orrelief with movement, but still noted a preponderance ofsymptoms in the evening or at night (Appendix S1). Theclassifications of probable or possible RLS were mutuallyexclusive. Those who answered “no” to both screeningquestions were classified as not having RLS, as were thosewho answered affirmatively to one or both screeningquestions but whose symptoms did not conform to theconsensus definition of RLS. Those with informationmissing for any of the five questions or serum iron vari-ables at FV were excluded from analysis. Of the 1334donors with a FV, 1166 had complete information on RLSquestions and 1145 of these had information on ironstatus.

Pica in RISE donorsA capture question asking “Do you ever crave and regularlyeat or chew nonnutritional substances, such as ice, clay,dirt, starch, raw pastas, chalk, or coal?” was used toclassify donors as having pica (see Appendix S2).Follow-up questions asked about specific substances andinquired into the frequency and duration of these cravingsas well as their responsiveness to blood donation. Due tothe challenge of eliciting detail on socially unusual behav-iors, donor response to the capture question alone wasused to classify subjects as reporting the presenceor absence of pica, independent of their follow-upresponses. Of the 1334 donors with a FV, 1175 completed

SPENCER ET AL.

1646 TRANSFUSION Volume 53, August 2013

the capture question, and 1154 had information on theiriron status.

Statistical analysisDonors participating in RISE were previously character-ized at enrollment (baseline visit) and study end (FV) forseveral variables, including demographic factors, dona-tion intensity, hemoglobin (Hb) and iron levels, andderived iron outcome measures of iron-deficient erythro-poiesis (IDE) and absent iron stores (AIS). IDE was definedas the upper 2.5% of the distribution of log(soluble trans-ferrin receptor/ferritin) in the FT male cohort at enroll-ment and this threshold was applied to both men andwomen in all four cohorts. AIS was defined as ferritin levelof less than 12 ng/mL. Summary measures were presentedas means � SD, median (ferritin), or prevalence (AIS,IDE), stratified by FT/RA or RPT and sex status. To deter-mine whether those who completed RISE were systemati-cally different from those who did not, baseline measureswere stratified according to whether donors completeda FV. In logistic regression analysis, unadjusted andadjusted odds ratios (ORs) for predictors of probable orpossible RLS, probable RLS only, and pica were developedusing computer software (PROC LOGISTIC in SAS, Version9.2, SAS Institute, Cary, NC). For adjusted ORs, indepen-dent variables were included if they had previously beenshown to relate to the outcomes of interest (such as higherreported prevalence of RLS in females) or if they werepredictive of an individual’s iron status (age, body mass,use of supplemental iron). Models were also evaluatedthat estimated the explanatory value of donation intensityand changes in iron status (across replete, IDE, or AIS)from enrollment to FV. Missing values for independentvariables were included (using missing as an additionalcategory), but were not reported in summary tables.

RESULTS

Donors completing RISEAs discussed in detail elsewhere,2 1334 of 2425 donors(55%) who enrolled in RISE returned for a FV (Table 1).While a large proportion of donors in both the FT/RA(70%-79%) and frequent (>95%) cohorts returned for atleast one visit after enrollment, the percentages who madea FV were considerably smaller, from 37% to 39% for theFT/RA male and female cohorts to 63%-67% for the RPTmale and female cohorts. Table 1, which characterizes thefour RISE cohorts at baseline—stratified on whether theycompleted the study with a FV—shows that on many mea-sures, including Hb and indicators of iron status, thosewho completed RISE were very similar at enrollment tothose who did not make a FV. On average, within each ofthe four cohorts, those completing the FV were older by 6to 7 years, more likely to be taking supplemental iron at

TAB

LE

1.C

har

acte

riza

tio

no

fR

ISE

do

no

rsat

bas

elin

e(n

=24

25)

and

FV

s(n

=13

34)

FT

/RA

Fre

quen

t

Fem

ale

Mal

eF

emal

eM

ale

Bas

elin

evi

sit

for

thos

ew

ithno

FV

(n=

294)

Bas

elin

evi

sit

for

thos

ew

ithF

V(n

=18

7)F

V(n

=18

7)

Bas

elin

evi

sit

for

thos

ew

ithno

FV

(n=

258)

Bas

elin

evi

sit

for

thos

ew

ithF

V(n

=14

9)F

V(n

=14

9)

Bas

elin

evi

sit

for

thos

ew

ithno

FV

(n=

283)

Bas

elin

evi

sit

for

thos

ew

ithF

V(n

=48

6)F

V(n

=48

6)

Bas

elin

evi

sit

for

thos

ew

ithno

FV

(n=

256)

Bas

elin

evi

sit

for

thos

ew

ithF

V(n

=51

2)F

V(n

=51

2)

Age

(yea

rs)*

36.8

�14

.844

.0�

15.2

45.5

�15

.335

.0�

14.5

41.6

�16

.243

.2�

16.3

45.2

�14

.651

.2�

12.3

52.8

�12

.247

.5�

14.8

53.2

�13

.354

.8�

13.2

Wei

ght

(lbs)

*15

9�

3616

2�

39N

A19

3�

3819

8�

39N

A16

5�

3715

9�

33N

A19

9�

3719

8�

35N

AF

esu

pple

men

tatio

n(%

)42

4434

2230

2147

5546

2934

25

RB

Cdo

natio

nspa

st24

mon

ths*

0�

00

�0

3.7

�1.

90

�0

0�

04.

6�

2.2

4.2

�2.

35.

7�

2.5

6.5

�2.

46.

1�

2.8

7.5

�2.

58.

4�

2.3

RB

Cdo

natio

nspa

st12

mon

ths*

0�

00

�0

1.6

�1.

40

�0

0�

02.

1�

1.6

2.4

�1.

23.

2�

1.2

2.7

�1.

53.

4�

1.4

3.9

�1.

13.

7�

1.5

Hb

(g/d

L)*

13.3

�0.

913

.4�

1.0

13.2

�1.

215

.2�

1.2

14.9

�1.

014

.6�

1.3

13.1

�0.

913

.2�

1.0

13.1

�1.

214

.5�

1.2

14.5

�1.

114

.4�

1.5

Fer

ritin

(ng/

mL)

†36

4122

109

105

4520

1818

2625

25A

IS(%

)7.

54.

820

.40

07.

727

.227

.027

.317

.615

.818

.1ID

E(%

)27

2251

2.3

2.7

2064

6762

4948

47

*M

ean

�S

D.

†M

edia

n.

RLS AND PICA IN BLOOD DONORS


enrollment, and had higher donation intensity in the prior12- and 24-month period before enrollment (for the RPTcohorts). In addition, the FT donor cohorts showed a sig-nificant increase in the prevalence of IDE and AIS betweenenrollment and their FV, while this did not occur to a sub-stantial degree in the RPT cohorts.2

RLS in RISE donorsAcross 1166 donors completing the RLS questions at FV,9% were classified as reporting probable RLS and an addi-tional 11% were classified as possible RLS; hence, a total of20% had probable or possible RLS. Both probable andpossible RLS were nearly twice as prevalent in females asin males, and no association with iron status was evident(Table 2). Table 3 reports ORs for RLS for several demo-graphic factors and for iron status, with unadjusted ORspresented from univariate analysis and adjusted ORsfrom multivariable logistic regression models. Across allmodels, sex is the only predictor with a consistent andsignificant association with RLS, with risk in femalesroughly twice that of males for probable or possible RLS(OR, 2.19; 95% CI, 1.52-3.14) and for probable RLS(OR, 2.08; 95% CI, 1.26-3.46) in multivariable analysis.Younger age (<40 years) is associated with a risk that is atleast 50% lower compared to 40- to 49-year-olds, who arestatistically indistinguishable from those 50 years andolder. The apparent lower risk of younger donors is con-sistent for both probable or possible and probable RLS,although the association does not reach significance inthe latter case. Neither weight, use of supplemental iron,nor iron status is associated with either probable or pos-sible RLS categories in unadjusted or adjusted analyses.Alternate models that added measures for recent dona-tion intensity, which substituted donation intensity foriron status, or that evaluated changes in iron status acrossa spectrum of replete, IDE, or AIS did not improve modelfit or predictive power. Because RLS prevalence is highestin those with Northern European origins,9 genetic variantsconferring susceptibility for RLS are underrepresented insub-Saharan Africans.18 In addition, there are distinctracial differences in hematologic measures and ironvariables;19 therefore, we repeated these analyses on the86% of subjects comprising the total RISE population whoself-reported as Caucasian. Results were not affected byrestricting analyses to Caucasians. Associations of ironstatus with greater frequency of RLS symptoms (five ormore times per month) were also absent in both unad-justed and adjusted analyses.

Pica in RISE donorsPica was reported by 5.5% (65 of 1175) of RISE donors whoanswered the capture question (Table 2). A clear trend wasseen between iron status and pica in females, with

TAB

LE

2.P

reva

len

ce(%

)o

fR

LS

and

pic

ab

yir

on

stat

us

atR

ISE

FV

(%)

Out

com

e

All

dono

rs(n

=11

45of

1334

with

FV

)*

Fem

ales

Mal

es

Rep

lete

(n=

240

of27

1w

ithF

V)*

IDE

with

outA

IS(n

=19

8of

221

with

FV

)*

AIS

(n=

151

of16

8w

ithF

V)*

Rep

lete

(n=

332

of38

4w

ithF

V)*

IDE

with

outA

IS(n

=13

1of

163

with

FV

)*A

IS(n

=93

of10

3w

ithF

V)*

Pro

babl

eor

poss

ible

RLS

20.0

24.2

27.8

25.2

14.2

12.2

15.1

Pro

babl

eR

LS9.

012

.110

.612

.66.

06.

17.

5P

ica

5.5

2.0

6.0

13.3

5.8

0.8

6.4

*A

tota

lof

1334

dono

rsco

mpl

eted

aF

V;

data

show

nar

efo

r11

45w

hoco

mpl

eted

ques

tions

onbo

thR

LSan

dpi

caan

dha

diro

nva

lues

.T

he18

9do

nors

who

seda

taar

eno

tsh

own

here

had

mis

sing

data

for

one

orm

ore

ofR

LS(n

=16

8),

pica

(n=

159)

,or

iron

assa

ys(n

=24

).

SPENCER ET AL.


TAB

LE

3.U

nad

just

edan

dad

just

edO

Rs

(95%

CIs

)fo

rp

oss

ible

pre

dic

tors

of

RL

San

dp

ica

Pro

babl

eor

poss

ible

RLS

*P

roba

ble

RLS

*P

ica*

Una

djus

ted

OR

Adj

uste

dO

RU

nadj

uste

dO

RA

djus

ted

OR

Una

djus

ted

OR

Adj

uste

dO

R

Age

(yea

rs)

p=

0.00

1p

=0.

007

p=

0.09

p=

0.21

p=

0.00

03p

<0.

0001

<30

0.36

(0.1

9-0.

70)

0.40

(0.2

0-0.

78)

0.44

(0.1

8-1.

10)

0.51

(0.2

0-1.

28)

1.36

(0.6

6-2.

83)

1.74

(0.8

0-3.

78)

30-3

90.

42(0

.21-

0.82

)0.

42(0

.22-

0.83

)0.

33(0

.11-

0.98

)0.

34(0

.11-

1.00

)1.

17(0

.53-

2.59

)1.

23(0

.54-

2.80

)40

-49

Ref

Ref

Ref

Ref

Ref

Ref

50-5

90.

97(0

.66-

1.42

)1.

00(0

.68-

1.48

)0.

88(0

.52-

1.50

)0.

88(0

.51-

1.51

)0.

38(0

.18-

0.79

)0.

36(0

.17-

0.76

)60

+0.

76(0

.51-

1.13

)0.

80(0

.53-

1.20

)0.

92(0

.54-

1.56

)0.

97(0

.56-

1.67

)0.

29(0

.13-

0.64

)0.

30(0

.13-

0.69

)S

exp

<0.

0001

p<

0.00

01p

=0.

0009

p=

0.00

5p

=0.

17F

emal

e2.

09(1

.55-

2.82

)2.

19(1

.52-

3.14

)2.

01(1

.32-

3.07

)2.

08(1

.26-

3.46

)1.

42(0

.85-

2.37

)In

tera

ctio

nw

ithiro

nsh

own

belo

wM

ale

Ref

Ref

Ref

Ref

Ref

Wei

ght

(lbs)

p=

0.09

p=

0.70

p=

0.22

p=

0.54

p=

0.29

p=

0.00

6<1

501.

54(1

.03-

2.30

)1.

20(0

.79-

1.83

)1.

80(1

.01-

3.19

)1.

39(0

.77-

2.52

)0.

52(0

.23-

1.19

)0.

33(0

.14-

0.79

)15

0-17

4R

efR

efR

efR

efR

efR

ef17

5-19

90.

96(0

.63-

1.48

)1.

11(0

.71-

1.74

)1.

18(0

.64-

2.20

)1.

29(0

.68-

2.44

)1.

06(0

.53-

2.09

)1.

34(0

.63-

2.79

)20

0+1.

11(0

.74-

1.67

)1.

37(0

.88-

2.14

)1.

34(0

.75-

2.41

)1.

73(0

.92-

3.25

)1.

11(0

.58-

2.13

)2.

00(0

.95-

4.19

)S

uppl

emen

tali

ron

p=

0.30

p=

0.16

p=

0.09

p=

0.49

p=

0.75

p=

0.21

Yes

1.19

(0.8

6-1.

63)

1.04

(0.7

4-1.

45)

1.46

(0.9

5-2.

27)

1.32

(0.8

4-2.

07)

1.09

(0.6

4-1.

86)

1.49

(0.8

4-2.

64)

No

Ref

Ref

Ref

Ref

Ref

Ref

Iron

stat

usp

=0.

42p

=0.

81p

=0.

63p

=0.

78p

=0.

001

Rep

lete

Ref

Ref

Ref

Ref

Ref

Inte

ract

ion

with

sex

show

nbe

low

IDE

with

outA

IS1.

22(0

.87-

1.72

)1.

14(0

.80-

1.62

)1.

03(0

.64-

1.67

)0.

99(0

.61-

1.63

)0.

94(0

.47-

1.87

)A

IS1.

21(0

.83-

1.75

)1.

11(0

.76-

1.64

)1.

27(0

.77-

2.10

)1.

23(0

.73-

2.07

)2.

74(1

.54-

4.87

)

Gen

der-

by-ir

onst

atus

inte

ract

ion

p<

0.00

01p

=0.

0002

Mal

ere

plet

evs

.fe

mal

ere

plet

e2.

98(1

.10-

8.09

)†1.

92(0

.68-

5.4)

Mal

eID

Evs

.m

ale

repl

ete

0.12

(0.0

2-0.

94)†

0.12

(0.0

2-0.

95)†

Mal

eA

ISvs

.m

ale

repl

ete

1.11

(0.4

3-2.

87)

1.28

(0.4

8-3.

38)

Fem

ale

IDE

vs.

fem

ale

repl

ete

3.10

(1.0

7-8.

96)†

3.18

(1.0

8-9.

39)†

Fem

ale

AIS

vs.

fem

ale

repl

ete

7.42

(2.7

2-20

.22)

‡8.

16(2

.90-

22.9

6)‡

*A

djus

ted

mod

els

for

RLS

incl

ude

1166

dono

rsan

dth

atfo

rpi

cain

clud

es11

75do

nors

.†

p<

0.05

.‡

p<

0.00

01.



reported prevalence increasing from 2% in iron repletefemales to 6% in those with IDE to 13% of those with AIS.No such trend was seen in males, with higher prevalenceof pica (6%) reported from iron-replete males and thosewith AIS and the lowest (1%) from those with IDE. In mul-tivariable models (Table 3), those age 50 years or olderwere associated with 65% to 70% lower risk, with those lessthan 40 years old statistically equivalent to those who were40 to 49 years old. Despite losing a proportionally largershare of blood with each donation, those whose weightwas less than 150 pounds had a significant lower risk forpica compared to those 150 to 174 pounds (OR, 0.33; 95%CI, 0.14-0.79). A sex-by-iron status interaction term wassignificant, with no clear trend by iron status in males butwith the estimated risk for pica being three times greaterfor females with IDE and eight times greater for those withAIS compared to females who were iron replete(p = 0.0002). As with the RLS models, donation intensitydid not improve the model’s discriminative power. Ofthose reporting pica, half claimed that their cravingsoccurred daily. Eleven donors reported the actual item(s)they consumed, with raw pasta (n = 5) and starch (5) beingmost frequently reported, followed by clay, ice, and rawoats (one each; two donors reported consumption of twoitems).

Coincidence of RLS and picaRLS and pica were both reported at relatively high levelscompared to population norms, but did not cooccur inRISE donors in a statistically significant manner. This wasequally true for probable or possible RLS (17 donors;p = 0.17), probable RLS (eight donors; p = 0.31), and RLSwith high frequency of symptoms (five donors, p = 0.25).

DISCUSSION

Despite the causal association between repeated blooddonation and low iron stores, little documentation existsof the attendant clinical consequences. It might be thecase that iron depletion in blood donors is of limited clini-cal significance, if those whose iron stores becomedepleted through repeated phlebotomy do not perceiveany adverse outcomes. Alternately, the impact might beself-limiting since donors who do experience symptomsmight take action to avoid adverse consequences.Symptom abrogation could occur through a variety ofmeans including supplemental iron ingestion, lengthen-ing intervals between donations, or discontinuing blooddonation altogether. What cannot be disputed is thatintermediate (IDE) and advanced (AIS) iron depletion arecommon outcomes in RPT blood donors in the RISE studyand that the strongest predictor of IDE and AIS is fre-quency of donation.

Although the primary intent of RISE was to character-ize the prevalence, incidence, and predictors of iron defi-

ciency in blood donors, the study also collected clinicalinformation to assess for the potential consequences ofthe resultant iron deficiency. Assessed only at the FV,symptoms compatible with probable RLS were reportedby 9% and with probable or possible RLS by 20% of RISEdonors, respectively. As detailed elsewhere2 and shown inTable 1, these results occurred in donor cohorts with ahigh prevalence of iron depletion (near or surpassing 50%prevalence of IDE in three of the four cohorts) and recentdonation intensity that is considerably higher than the“average” donor. Although several-fold higher thanreported figures for weekly (5%) or “medically significant”(2.7%) RLS symptoms in a recent report drawn from thegeneral population,20 RLS prevalence between 9 and 20%is consistent with other studies in blood donor popula-tions.13,14 In RISE, as in these earlier studies, RLS preva-lence nearly twice that of the general population in acohort enriched for iron deficiency (e.g., blood donors)does not require that such an association holds at theindividual level or that it is necessarily causative. The mostparsimonious explanation for our observing that irondeficiency is insufficient by itself to associate with RLS isthat RLS is a complex trait influenced by a number offactors including sex and age, as demonstrated here andelsewhere, as well as many environmental and genetic fac-tors.9 Iron status appears to be only one element of one ormore causal pathways that can lead to a RLS phenotype,since iron deficiency as manifest in serum variables is alsonot necessary for RLS symptom expression (e.g., weobserved probable RLS in 49 subjects classified as ironreplete).6 Ongoing and future research should help eluci-date the nature and magnitude of the association betweeniron and RLS, in blood donor populations and moregenerally.

The results for pica in RISE donors are more sugges-tive, but nonetheless inconclusive. A dose–response rela-tionship between iron status and prevalence of pica wasobserved in female RISE donors, with those who are ironreplete being eight times less likely to report pica thanthose who have AIS at FV. In male donors, no such asso-ciation was found. This apparent sex difference may bereal (albeit unexplained) or may derive from the presenceof relatively sparse outcomes in a multivariable logisticmodel or potentially represent a differential in accuracy ofinformation elicited from male and female RISE donors.In any case, this mixed result, while unexplained, is con-sistent with the only other report of which we are awarethat has measured iron status and assessed pica in blooddonors, which also found an association between pica andiron status in females but not in male donors.14 Neitherour study nor the earlier one on pica in blood donorsreports a higher cooccurrence of pica and RLS than wouldbe expected by chance.

While intriguing given the paucity of clinical dataassociated with iron stores in blood donors, these results

SPENCER ET AL.


need to be interpreted cautiously. There are several limi-tations to our study. The RISE study was not designed, orpowered, to test hypotheses relating to clinical outcomes.With both RLS and pica having been assessed only at theFV, prevalence is the only measure of association avail-able. Estimates of incidence, if available, would add valu-able detail to these findings, as would finer temporalresolution regarding putative associations, including ageof onset, whether initial onset of symptoms precededblood donation, symptom duration, and whether symp-toms fluctuate as a function of donation activity andserum iron parameters. Furthermore, accuracy of RLS andpica diagnoses were not validated in RISE, which can beproblematic due to several mimics of RLS not easily dis-cernible by self-report.15,16 That being said, the tools usedto assign RLS affliction status here demonstrate discrimi-native power sufficient to discern genetic susceptibilityfactors of modest effect sizes (i.e., ORs of >1.5 per riskallele).10 Diagnosis of pica is also challenging given thestigma attached to socially unusual behaviors,11 albeitperhaps less so if ice is the primary nonnutritive sub-stance ingested. Only approximately 20% of RISE donorswho reported pica specified what item(s) they cravedand consumed, despite the questionnaires being self-administered rather than performed by oral interview.Almost half of those admitting to this behavior acknowl-edged that the cravings were intense as reflected in theirdaily occurrence. This suggests that the phenomenonis genuine, even if more detailed disclosures mightrequire additional investigator follow-up not available forRISE.

The findings reported here increase our appreciationfor the fact that RLS and pica are experienced by a signifi-cant number of frequent blood donors. This is particularlytrue of older women and RLS, and younger females in thecase of pica. Further research on these and other out-comes associated with low iron stores could provide sig-nificant value in terms of characterizing the problem ofiron depletion of blood donors and developing appropri-ate responses to protect donor health and quality of life.Moreover, such studies may yield important insights intothe interactions between measures of peripheral ironstatus, brain dopamine network “tone,” and the patho-physiologies underlying behaviors that share potent“urge” components.

ACKNOWLEDGMENTS

The authors thank the staff at all six participating blood centers.

Without their help, this study would not have been possible.

The Retrovirus Epidemiology Donor Study (REDS)-II was the

responsibility of the following persons:

Blood centers:

American Red Cross Blood Services, New England Region: R.

Cable, J. Rios, R.J. Benjamin

American Red Cross Blood Services, Southern Region/Emory

University: J.D. Roback

BloodCenter of Wisconsin: J. Gottschall, A.E. Mast

Hoxworth Blood Center, University of Cincinnati Academic

Health Center: R.A. Sacher, S.L. Wilkinson, P.M. Carey

Regents of the University of California/Blood Centers of the

Pacific/BSRI: E.L. Murphy, B. Custer, N. Hirschler

The Institute for Transfusion Medicine (ITxM)/LifeSource Blood

Services: D. Triulzi, R. Kakaiya, J. Kiss

Central laboratory:

Blood Systems Research Institute: M.P. Busch, P. Norris

Coordinating center:

Westat, Inc.: J Shulman, M. King

National Heart, Lung, and Blood Institute, NIH:

G.J. Nemo

Steering committee chairman:

R.Y. Dodd

CONFLICT OF INTEREST

The authors state that they have no conflicts of interest.

REFERENCES

1. Simon TL, Garry PJ, Hooper EM. Iron stores in blood

donors. JAMA 1981;245:2038-43.

2. Cable RG, Glynn SA, Kiss JE, Mast AE, Steele WR, Murphy

EL, Wright DJ, Sacher RA, Gottschall JL, Tobler LH, Simon

TL. Iron deficiency in blood donors: the REDS-II Donor

Iron Status Evaluation (RISE) study. Transfusion 2012;52:

702-11.

3. Lozoff B. Early iron deficiency has brain and behavior

effects consistent with dopaminergic dysfunction. J Nutr

2011;141:740S-6S.

4. Freeman A, Rye D. Dopamine in behavioral state control.

In: Sinton C, Perumal P, Monti J, editors. The neurochem-

istry of sleep and wakefulness. Cambridge: Cambridge

University Press; 2008. p. 179-223.

5. Allen R. Dopamine and iron in the pathophysiology of rest-

less legs syndrome (RLS). Sleep Med 2004;5:385-91.

6. Connor J. Pathophysiology of restless legs syndrome: evi-

dence for iron involvement. Curr Neurol Neurosci Rep

2008;8:162-66.

7. Singh N, Ellis C, Crews D Jr, Singh Y. Does diminished

dopaminergic neurotransmission increase pica? J Child

Adolescent Psychopharmacol 1994;4:93-9.

8. Takeda N, Hasegawa S, Morita M, Matsunaga T. Pica in rats

is analogous to emesis: an animal model in emesis

research. Pharmacol Biochem Behav 1993;45:817-21.

9. Rye D, Trotti LM. Restless legs syndrome and periodic leg

movements of sleep. In: Watts RL, Standaert DG, Obeso JA,

editors. Movement disorders. New York: McGraw-Hill;

2012. p. 909-33.

10. Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A,

Thorgeirsson TE, Palsson S, Sigmundsson T, Sigurdsson



AP, Eiriksdottir I, Soebech E, Bliwise D, Beck JM, Rosen A,

Waddy S, Trotti LM, Iranzo A, Thambisetty M, Hardarson

GA, Kristjansson K, Gudmundsson LJ, Thorsteinsdottir U,

Kong A, Stefansson K, et al. A genetic risk factor for peri-

odic limb movements in sleep. N Engl J Med 2007;357:639-

47.

11. Young S. Craving earth. New York: Columbia University

Press; 2011.

12. Starn AL, Udall JN Jr. Iron deficiency anemia, pica, and

restless legs syndrome in a teenage girl. Clin Pediatr (Phila)

2008;47:83-5.

13. Burchell BJ, Allen RP, Miller JK, Hening WA, Earley CJ. RLS

and blood donation. Sleep Med 2009;10:844-49.

14. Bryant BJ, Yau YY, Arceo SM, Hopkins JA, Leitman SF.

Ascertainment of iron deficiency and depletion in blood

donors through screening questions for pica and restless

legs syndrome. Transfusion 2013. doi: 10.1111/trf.12061.

15. Hening WA. Subjective and objective criteria in the diagno-

sis of the restless legs syndrome. Sleep Med 2004;5:285-92.

16. Hening WA, Allen RP, Washburn M, Lesage SR, Earley CJ.

The four diagnostic criteria for restless legs syndrome are

unable to exclude confounding conditions (“mimics”).

Sleep Med 2009;10:976-81.

17. Ferri R, Lanuzza B, Cosentino FI, Iero I, Tripodi M, Spada

RS, Toscano G, Marelli S, Aricò D, Bella R, Hening WA,

Zucconi M. A single question for the rapid screening of

restless legs syndrome in the neurological clinical practice.

Eur J Neurol 2007;14:1016-21.

18. Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L,

Jalilzadeh S, Fulda S, Pütz B, Eckstein G, Hauk S, Trenk-

walder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bach-

mann CG, Paulus W, Peglau I, Eisensehr I, Montplaisir J,

Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE,

Meitinger T, et al. Genome-wide association study of rest-

less legs syndrome identifies common variants in three

genomic regions. Nat Genet 2007;39:1000-6.

19. Hollowell JG, van Assendelft OW, Gunter EW, Lewis BG,

Najjar M, Pfeiffer C; Centers for Disease Control and Pre-

vention, National Center for Health Statistics. Hematologi-

cal and iron-related analytes—reference data for persons

aged 1 year and over: United States, 1988-94. Vital Health

Stat 11 2005;(247):1-156.

20. Allen RP, Walters AS, Montplaisir J, Hening W, Myers A,

Bell TJ, Ferini-Strambi L. Restless legs syndrome preva-

lence and impact: REST general population study. Arch

Intern Med 2005;165:1286-92.

SUPPORTING INFORMATION

Additional Supporting Information may be found in theonline version of this article at the publisher’s web-site:

Appendix S1. Classification of possible and probable RLSAppendix S2. Classification of pica

SPENCER ET AL.


Documents

Restless legs syndrome, pica, and iron status in blood donors