Iron Deficiency and Anaemia in Children with a High Prevalence of Haemoglobinopathies: Implications for Screening

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1 Internatinal Jurnal f Epidemilgy Internatinal Epidemilgical Assciatin 1996 Vl. 25, N. 6 Printed in Great Britain Irn Deficiency and Anaemia in Children with a High Prevalence f Haemglbinpathies: Implicatins fr Screening SUKANYA LINPISARN,* PRASNG TIENBN,*" NNGKRAN PRMTET,* PACHERN PUTSYAINUNT,* SAPPAPRN SANTAWANPAT* AND GERGE J FUCHS*"* Linpisam S (Research Institute fr Health Sciences, Chiang Mai University, Thailand), Tienbn P, Prmtet N, Putsyainunt P, Santawanpat and Fuchs G J. Irn deficiency and anaemia in children with a high prevalence f haemglbinpathies: Implicatins fr screening. Internatinal Jurnal f Epidemilgy 1996; 25: Backgrund. Haemglbin (Hb) cncentratin is used as a sle test fr irn deficiency anaemia (IDA) in mst develping cuntries since mst anaemia is believed t be due t irn deficiency and cnfirmatry testing is generally unavailable. Yet the validity f this apprach in regins where haemglbinpathies are endemic has nt been dcumented. Methds. Haemglbin and serum ferritin (SF) were measured in 559 Nrthern Thai children aged 6 mnths t 13 years f age. The sensitivity f SF t identify irn deficiency was als assessed in a subsample f children with lw r lwnrmal Hb and nrmal SF by testing the Hb respnse t a trial f ral irn. Results. While anaemia was cmmn (27%), IDA cnstituted 19% and nne f all anaemia in preschl and schl age children, respectively (P < 0.002). Irn depletin was similarly mre prevalent in yunger children (P < ). Children with IDA were yunger (P < 0.001) and the anaemia mre severe (P < ) cmpared t thse with nn-ida. f anaemic children with nrmal SF values wh received a therapeutic trial f irn, nly 6% respnded with an increase in Hb f s=1g/dl. Cnclusins. Fr ppulatins such as urs mst anaemia is nt due t irn deficiency and a single Hb determinatin is therefre nt acceptable fr a presumptive diagnsis f IDA. Keywrds: Irn deficiency, anaemia, ferritin, haemglbinpathy, children, Thailand, Sutheast Asia Anaemia is cmmn wrldwide affecting millins f peple, and the mst cmmn cause f anaemia is irn deficiency. 1 Pregnant wmen and yung children are at greatest risk. The cnsequences f irn deficiency anaemia (IDA) are particularly severe in children and include abnrmalities f immune functin, increased risk f infectins, pr grwth, and ptentially irreversible deficits f cgnitin and mtr functin in infants. 2 " 6 The identificatin and treatment f IDA is therefre ne f the highest health care pririties. In practice the use f the terms anaemia, nutritinal anaemia, and irn deficiency anaemia are used interchangeably in much f the wrld since it is suspected that irn deficiency is highly prevalent particularly * The Research Institute fr Health Sciences, Chiang Mai University, Thailand. ** Department f Pediatrics, Chiang Mai University, Thailand. * Department f Pediatrics, Luisiana State University Medical Schl, New rleans, LA. USA. Reprint requests: Dr Gerge J Fuchs, Internatinal Centre fr Diarrheal Disease Research, GP Bx 128, Dhaka 1000, Bangladesh. cmpared t the prevalence f anaemia due t ther nutritinal r genetic causes. 78 Fr this reasn, recmmendatin and practice in develping cuntries fr diagnstic, treatment, and screening purpses has ften been the sle use f haemglbin (Hb) r haematcrit as the principle methdlgy t identify IDA. 7 ' 9 Hwever, this apprach wuld be errneus in areas with a lw prevalence f irn deficiency r with a high prevalence f anaemia due t ther causes. 10 Unfrtunately, in many cuntries in which bth irn deficiency and haemglbinpathies are cnsidered t be particularly prevalent, precise characterizatin f anaemias is nt feasible because f the relatively high cst f mre definitive methdlgies, the need fr highly trained technical expertise, r the requirement f venipuncture t btain sufficient bld vlumes fr testing. 7 In Thailand, anaemia is cmmn in all age grups with a prevalence as defined by Wrld Health rganizatin (WH) criteria f apprximately 25% in males and 45% in wmen and children as determined in ne survey." Anaemia in pregnant wmen ranges frm Dwnladed frm by guest n 15 ctber

2 IRN DEFICIENCY, ANAEMIA AND SCREENING % t 60% with the higher prevalences ccurring in rural areas While the prevalence f anaemia is well-described, the precise cause is prly defined althugh mst anaemia is believed t be due t irn deficiency. 7 ' 1415 Hwever, the prevalence f Haemglbin E and thalassaemias in many Sutheast Asian ppulatins is high which presents a ptential prblem in crrectly ascribing anaemia t irn deficiency. 16 " 20 Haemglbin E alne is estimated t ccur in apprximately peple in Sutheast Asia. 21 It is in this cntext that we reprt the results f a study t delineate further the prevalence f irn deficiency and IDA in Thai children. METHDS Haemglbin and serum ferritin (SF) were measured in 559 Nrthern Thai children age 6 mnths t 13 years frm urban and rural Chiang Mai (bth nn-malarial areas) after infrmed cnsent. Urban children were enrlled during visits fr rutine immunizatins frm the 'well-child' clinic f the Maharaj Nakrn Chiang Mai University Hspital, the main prvincial hspital f Chiang Mai Prvince. Rural children were recruited frm tw agrarian villages lcated within 60 km f Chiang Mai city. Children with any sign f infectin were excluded frm participatin. Apprximately 300 )il f capillary bld was btained by skin puncture f the palmar surface f a fingertip ('fingerstick'). Hb was measured by spectrphtmetry after cnversin f Hb t cyanmethaemglbin. 22 Standards prvided by WH were used as internal cntrls. SF was determined by slid phase enzyme immunassay. 23 Respnse t ral Irn T assess the sensitivity f SF t detect irn deficiency in preschl age children, 40 apparently healthy children with an SF > 12 (Xg/L were randmly selected after the initial determinatins t receive a trial dse f ral ferrus sulfate 3 mg/kg/day. Hb and SF estimatins were repeated after 1 mnth and values cmpared with pretreatment values. An increase in Hb f 3=1 g/dl was cnsidered t indicate irn deficiency. 24 Data Analysis The children were divided int tw grups n the basis f age; preschl age (6 mnths t 6 years) and schl age (6-14 years). Anaemia was defined accrding t the WH criteria, i.e. 6 mnths t 6 years, <11.0 g Hb/dl; 6-14 years <12.0 g Hb/dl. 25 Irn status f the children was characterized as lw irn stres in thse having a nrmal Hb and SF (ig/l, irn depletin was defined as a nrmal Hb and the SF <12 ig/l at any I Qgp_ < rfsqf, IV Ii n " M 358 W n ' TJ] 0 " Serum Ferritln ( jg/l) FIGURE 1 Irn and haemglbin status f 340 Thai preschl age children. I, irn depletin; II, nrmal; III, anaemia; IV, irn deficiency anaemia age, and IDA as anaemia and SF < 12 j.g/l. 26 Althugh anaemia and SF <10-12 (Ig/L is the cnventinal definitin f IDA, 8 we als examined thse children with anaemia and SF <20 J.g/L since a 'lw-nrmal' SF value (e.g Hg/L) might als represent a risk f irn deficiency. 26 Chi-square (x 2 ) tests f independence were used t examine the distributin f indices f irn status amng preschl age and schl age children. Grup cmparisns f cntinuus data were made by Student's t test and paired Hb data in respnse t ral irn treatment assessed by pairwise t test. Analysis f variance was used t determine differences in mean levels f age, Hb, and SF amng children stratified by anaemia and irn status. Pst analysis f variance cmparisns amng grups were examined using Duncan's multiple range test. Nn-nrmally distributed data (e.g. Hb distributin amng age grups) was analysed after lgarithmic transfrmatin and grup cmparisns f cntinuus data were assessed by Mann-Whitney U test and paired results cmpared by Wilcxn test. Significance levels apply t unaltered data since adjustments did nt substantially alter the statistical results. The data is presented as mean ± SD r mean (95% cnfidence intervals [CI]). RESULTS The distributin f anaemia and irn status amng the tw grups f children is shwn in Figures I and 2. While the prevalence f anaemia was equivalent in bth grups, nly 19% (16 f 84) f the anaemia in preschl age children was assciated with irn deficiency (SF <I2 Hg/L) cmpared t nne in the schl age children. If a mre inclusive cut-ff f SF f <20 ig/l is used instead f the cnventinal < 12 Hg/L, a ttal f 27 (11%) preschl age children had an SF <20 ig/l Dwnladed frm by guest n 15 ctber 2018

3 1264 INTERNATINAL JURNAL F EPIDEMILGY Serum Fenitin (pg/l) FIGURE 2 Irn and haemglbin status f 219 Thai schl age children. I, irn depletin; II, nrmal; III, anaemia; IV, irn deficiency anaemia tgether with anaemia which cmprised 32% f all anaemic preschl children. ne schl age child had lw irn stres and an Hb f 14.2 and tw had depleted irn stres with Hb f 12.5 and 13.0 g/dl, respectively. Nne f the schl age children with anaemia had an SF <20 ig/l. SF was similarly lwer in the yunger than the lder children (51 ng/l ± 32 versus 80 ng/l ± 44, respectively, P < ). verall, significant TABLE 1 Prevalence f anaemia and irn depletin in Nrthern Thai children Anaemia" Ferritin <12 ng/l Ferritin (ig/l Irn deficiency + anaemia 6 mnths t 6 years N = (25%) 26 (8%) 28 (8%) 16(5%) differences were evident between the tw grups in the number f children with lw irn stres (P < ), irn depletin (P < ), and IDA (P < 0.003) (Table 1). Twenty-ne per cent f all preschl age children had either IDA r lw r depleted irn stres cmpared t nly 1% f the schl age children (P< ). Additinal analysis f the preschl children revealed that the children with IDA were significantly yunger than either the nrmal children r the children with nn-ida (Table 2). The Hb f the IDA grup was mre prfundly depressed than the Hb f the children with anaemia frm ther causes (P ). There was n difference in SF between nrmal and nn-ida anaemic children but as expected the mean SF was lwer in the IDA grup. Nr were there significant differences between rural and urban sites in the numbers f children with IDA r irn depletin (data nt shwn). f the 40 preschl children with nrmal SF wh participated in the ral irn trial, the mean pretreatment Hb was 11.0 g/dl ± 6 (range, g/dl) and the mean SF was 62 u.g/l ± 30 (range, Hg/L). The mean Hb increased t 11.3 g/dl ± 7 and SF t 87 ig/l ± 33 (P = and P < , respectively) 1 mnth Age grup 6-13 years N = (29%) 1 (0.5%) 2 (0.5%) 0 Haemglbin f <11.0 g/dl and <12.0 g/dl in children age 6 mnths t 6 years, and 6-14 years respectively. TABLE 2 Characteristics f children with nrmal haemglbin, anaemia f irn deficiency and nn-irn deficiency anaemia Nrmal N = 256 Irn deficiency + anaemia N= 16 Nn-IDA anaemia N = 68 P value 0.28 < < <0.002 P value- Dwnladed frm by guest n 15 ctber 2018 Age (mnths) Haemglbin (g/dl) Serum ferritin (Hg/L) 35 (33-37) 12.0( ) 52 (49-55) 18(13-23)" 9.8 ( )" 6 (4.8) b 32 (27-37) 10.4( ) c 58(48-68) <0.001 C0.001 All values expressed as mean (95% CI). IDA = irn deficiency anaemia. "ANVA, pst lgarithmic transfrmatin when data nn-nrmally distributed. bc Values with different superscripts differ significantly frm each ther (Duncan's Multiple Range Test).

4 IRN DEFICIENCY, ANAEMIA AND SCREENING 1265 after receiving irn. Hwever, a ttal f just five children, and nly ne f the 16 (6%) with anaemia, demnstrated an increase in Hb f >1 g/dl. DISCUSSIN While several tests exist t determine irn nutritinal status, there is n single cmplete test t cnfirm irn deficiency. As a result, the diagnsis f irn deficiency and IDA in the clinical and public health envirnment is mre cmplex than usually appreciated. 27 This is particularly true in many less r newly develped cuntries where multiple tests f irn deficiency might nt be feasible fr ecnmic and/r technical reasns, an bstacle further cmpunded by the relatively high backgrund prevalence f haemglbinpathies in many ppulatins. Using a cmbinatin f Hb and SF, the results f ur study reveal that irn deficiency is a public health prblem in preschl age children f Nrthern Thailand, but unexpectedly cnstituted nly a minrity f all anaemias in ur grup f children. In ur sample f schl age children, the prevalence f irn deficiency and IDA is less even than that reprted 5 years earlier in which 7% and 4% f a grup f 9-12 year ld children in suth central Thailand had IDA and irn depletin, respectively. 28 Even s, ur data and thse f the afrementined study are cmparable in the suggestin that the prevalence f irn deficiency is cnsiderably less than reference estimates. In this respect, ur findings are als cnsistent with bservatins f the causes f micrcytsis and hypchrmia in Sutheast Asian refugees in the US. 16 ' 21 In these surveys mre than 25% f this ppulatin had frms f a-thalassaemia and apprximately 10% had haemglbin E trait which are als characterized by mild micrcytsis and hypchrmia and may be mistaken fr irn deficiency. It is likely that the prevalence f IDA in Sutheast Asia has been histrically verestimated. It is imprtant t emphasize that Hb, but nt SF, measurements are mre precise with bld specimens btained by venipuncture cmpared t thse btained by skin puncture. 29 The prevalence f anaemia in ur subjects therefre is pssibly a slight verestimate. Hwever, many cultures that cnsider venipuncture unacceptable are nne the less amenable t fingerstick. Venipuncture is als mre technically difficult in infants cmpared t skin puncture and has the added disadvantage f requiring anther persn t immbilize the extremity. It is amng these reasns that fingerstick methdlgy is preferentially used utside the hspital r research settings and in less ecnmically r technically develped regins, settings in which anaemia is ften mst prevalent. SF accurately reflects ttal bdy irn stres after 6 mnths f age and is nly depressed in irn deficiency. 28 As demnstrated by the respnse t ral irn, SF as the nly cnfirmatry test was quite accurate in ur ppulatin. That fur children respnded with an increase in Hb despite having a nrmal SF and Hb reflects the variability f this and ther labratry tests f irn status in individual children in envirnments f mild irn deficiency. 30 And althugh the children in ur trial were apparently healthy, SF cncentratins can be in the nrmal range independent f irn deficiency in cnditins f inflammatin, infectin, r significant liver disease A failure t respnd t treatment by anaemic children indicates the existence f a haemglbinpathy such as thalassaemia r that the medicatin has nt been administered. The frmer is bviusly f particular imprtance in areas in which the prevalence f haemglbinpathy is high including many cuntries f Asia, Africa, and the Mediterranean. nly rarely is there a failure t absrb irn. In ppulatins (e.g. pregnant wmen) in which irn deficiency is highly prevalent and is the primary cause f anaemia, mst anaemia will be IDA and the use f Hb r haematcrit (Hct) as the sle diagnstic test is prbably warranted. Hwever, in relatively irn replete ppulatins cmparable t ur study subjects, Hb r Hct is insufficiently discriminative. Clearly, the use f nly a Hb r Hct measurement in ur ppulatin f children wuld misdiagnse many children as having IDA rather than anaemia due t a cause ther than irn deficiency. We believe these results emphasize the need t recnsider the use f anaemia as the sle criteria t identify, treat and fllw IDA. We cnclude therefre, that althugh irn deficiency is a substantial prblem in yunger Thai children it is nt the primary cause f anaemia at least in certain ppulatins. It is apparent that in this and similar settings the term anaemia shuld n lnger be cnsidered synnymus with nutritinal anaemia r IDA. REFERENCES ' Wrld Health rganizatin. 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