Paediatrica Indonesiana VOLUME 49
September
NUMBER 5
Original Article
Behavior of elementary schoolchildren with iron deficiency anemia after iron therapy Rina A.C. Saragih, T. Mirda Zulaicha, Sri Sofyani, Bidasari Lubis, Iskandar Z. Lubis
Abstract Background Some studies had been performed to determine the association between iron status and children’s behavior yet it is still controversial. Objective To investigate whether iron therapy has an effect on WKHEHKDYLRURIFKLOGUHQZLWKLURQGHILFLHQF\DQHPLD ,'$ Method $ UDQGRPL]HG SODFHERFRQWUROOHG FOLQLFDO WULDO ZDV FRQGXFWHGLQ/DEXKDQ%DWXRQ1RYHPEHU²$SULO,'$ ZDVGHILQHGDV+E JGO0&+& 5':LQGH[! DQG0HQW]HULQGH[!(OHPHQWDU\VFKRROFKLOGUHQ ²\HDUV ROG ZLWK,'$ZHUHUDQGRPO\DVVLJQHGWRWKHWUHDWPHQWJURXS ZLWKDGDLO\WKHUDS\RIPJLURQNJGD\RUSODFHERJURXSIRUWKUHH PRQWKV7KHVXEMHFWV·EHKDYLRUZDVHYDOXDWHGZLWKFKLOGEHKDYLRU FKHFNOLVW &%&/ EHIRUHDQGVL[PRQWKVDIWHULQWHUYHQWLRQ Results$IWHUVL[PRQWKVVXEMHFWVFRPSOHWHGWKHWKHUDS\ 6FRUHVRI&%&/LQLURQJURXSDIWHULQWHUYHQWLRQZHUHLQWHUQDOL]LQJ 6' H[WHUQDOL]LQJ 6' WRWDOVFRUH 6' 7KHUHZDVVLJQLILFDQWGHFUHDVHGRQH[WHUQDOL]LQJDQG total problems score in the treatment group after intervention 3 +RZHYHUWKHUHZDVQRVLJQLILFDQWGLIIHUHQFHRQVFRUHV between groups. Conclusion ,URQWKHUDS\KDGVLJQLILFDQWO\GHFUHDVH&%&/VFRUH on externalizing and total problems in the treatment group, however there was no significant difference on scores if compared with placebo group. [Paediatr Indones. 2009;49:276-80]. Keywords: behavior, iron-deficiency anemia, child behavior check list
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URQGHILFLHQF\DQHPLD ,'$ LVDQHPLDUHVXOWLQJ IURP ODFN RI VXIILFLHQW LURQ XVHG WR V\QWKHVL]H hemoglobin and the most common hematologic disease in infancy and childhood. It is the most common form of anemia in worldwide, especially in developing countries. Family surveilance in ,QGRQHVLD VKRZHG WKDW RI WRGGOHUV DQG RI VFKRRODJH FKLOGUHQ VXIIHUHG IURP LURQGHILFLHQF\ DQHPLD $ VXUYH\ RI \HDUV ROG HOHPHQWDU\VFKRROFKLOGUHQVKRZHGWKDWRIDOO DQHPLDLVLURQGHILFLHQF\W\SH4 The consequence of iron deficiency can be characterized as hematologic DQHPLD DQGQRQKHPDWRORJLF EHKDYLRUDOHSLWKHOLDO and neurocognitive).5 Over the past three decades, there have been a considerable number of studies on the relationship between iron status and cognition, and behavior, but the topic remain controversial. Lozoff et al studied about the long term effects of iron deficiency in LQIDQF\DQGIRXQGWKDWRYHUWKHSDVW\HDUVSDUHQWV
Presented at National Symposium ‘New Trend in Management of Pediatric 3UREOHPV·0HGDQ-DQXDU\WK²WK )URP WKH 'HSDUWPHQW RI &KLOG +HDOWK 0HGLFDO 6FKRRO 8QLYHUVLW\ RI 1RUWK6XPDWHUD+$GDP0DOLN+RVSLWDO0HGDQ,QGRQHVLD 5HSULQW UHTXHVWV WR 5LQD $ & 6DUDJLK 0' 'HSDUWPHQW RI &KLOG +HDOWK0HGLFDO6FKRRO8QLYHUVLW\RI1RUWK6XPDWHUD+$GDP0DOLN +RVSLWDO-O%XQJD/DXQR0HGDQ,QGRQHVLD7HO )D[(PDLO
[email protected]
276Paediatr Indones, Vol. 49, No. 5, September 2009
Rina A.C. Saragih et al %HKDYLRURI,'$FKLOGUHQDIWHULURQWKHUDS\
and teacher whose children had iron deficiency in infancy rated their behavior as more problematic in several areas, they also agreed that there has been an LQFUHDVHGFRQFHUQVDERXWDQ[LHW\GHSUHVVLRQVRFLDO problems, and attention problems. Preschool children with iron deficiency with or without anemia have been shown to have problems of inattention resulting in difficulties with higher cognitive function.9 Other studies have demonstrated lower scores on cognitive WHVWLQJ LQ DGROHVFHQWV ZLWK ,'$ $ VWXG\ RI FKLOGUHQ \HDUVROG LQ8QLWHG6WDWHVIRXQGWKDW RIWKHPZHUHLURQGHILFLHQWDQGFKLOGUHQZLWKLURQ GHILFLHQF\KDGJUHDWHUWKDQWZLFHWKHULVNRIVFRULQJ below average in math than did children with normal iron status.7KHPDMRULWLHVRIVWXGLHVRQFKLOGUHQ·V EHKDYLRU ZLWK ,'$ KDG D IRFXV RQ LURQ GHILFLHQW LQIDQWV RI ² PRQWKV ROG 7KHUH LV VWLOO OLPLWHG studies of older children. In this study we wanted to investigate whether iron therapy has an effect on EHKDYLRURIHOHPHQWDU\VFKRROFKLOGUHQZLWK,'$
Methods $ UDQGRPL]HG SODFHERFRQWUROOHG FOLQLFDO WULDO ZDV performed in five elementary schools at subdistrict RI%LODK+XOXLQGLVWULFWRI/DEXKDQ%DWX6XPDWHUD Utara Province for six months, from November XQWLO$SULO&DSLOODU\EORRGVDPSOHVZHUH WDNHQ IURP DOO \HDUV VWXGHQWV XVLQJ QHHGOH RQ PLGGOHILQJHUDQGH[DPLQDWLRQRIKHPRJORELQ +E KHPDWRFULW +W PHDQFRUSXVFXODUYROXPH 0&9 PHDQ FRUSXVFXODU KHPRJORELQH 0&+ PHDQ FRUSXVFXODU KHPRJORELQ FRQFHQWUDWH 0&+& UHG EORRGFHOO 5%& DQGUHGEORRGFHOOGLVWULEXWLRQZLGWK 5': ZHUH SHUIRUPHG &KLOGUHQ ZLWK ,'$ ZHUH recruited in the study. $QHPLDZDVGHILQHGDFFRUGLQJWR:+2FULWHULD IRU²\HDUROGFKLOGUHQDQHPLDGHILQHGDV KHPRJORELQ +E JGO:HLQFOXGHGFKLOGUHQ ZLWKDQHPLDDFFRUGLQJWR:+2GHILQLWLRQ0&+& 5':,QGH[!DQG0HQW]HULQGH[! and excluded children with other hematologic disease, severe malnutrition, renal disease and other chronic GLVHDVHV KHOPLQWKLDVLVQHIULWLVQHIURVLVHWF WKRVH who had neurologic impairment or severely anemic. $QWURSRPHWULF PHDVXUHPHQW ZDV SHUIRUPHG ERG\ ZHLJKW ZDV PHDVXUHG ZLWK ZHLJKWPHWHU &DPU\ ®
wearing minimal clothes and body height was measured with stadiometer by standing on the wall without shoes. 7KH SDUHQWV ZHUH DVNHG WR DQVZHU WKH TXHVWLRQQDLUHVRIFKLOGEHKDYLRUFKHFNOLVW &%&/ in Indonesian version after an explanation about how WRDQVZHULW6XEMHFWVZHUHUDQGRPL]HGDVWUHDWPHQW group with iron or placebo group with simple UDQGRPL]DWLRQPHWKRG7UHDWPHQWJURXSUHFHLYHG PJHOHPHQWDOLURQ.J%:GD\GLYLGHGLQWKUHHGRVHV Placebo was sacharum lactis in a capsule and given three times daily. The capsule of iron and placebo KDGWKHVDPHVL]HDQGFRORUWKHFKLOGWRRNWKHGUXJ every day infront of their teacher or parent for three PRQWKV7KHSDUHQWVZHUHDVNHGWRDQVZHU,QGRQHVLDQ YHUVLRQRI&%&/DJDLQVL[PRQWKVDIWHUWKHWKHUDS\ The illness was recorded by the teacher every day. The minimal sample size was calculated by using IRUPXOD WR GHWHFW D UHDO GLIIHUHQFH RI ZLWK SRZHURIDQGW\SH,HUURURIVXEMHFWVSHU JURXSZHUHQHHGHG'DWDZDVDQDO\]HGZLWK6366IRU :LQGRZ 6366 ,QF &KLFDJR 7KH GLIIHUHQFH of means between the two groups were analyzed XVLQJ LQGHSHQGHQW VDPSOH WWHVW RU 0DQQ:KLWQH\ U Test while proportion between the two groups ZHUHDQDO\]HGXVLQJ[7RFRPSDUHWKHVFRUHEHIRUH and after the intervention, we used Wilcoxon signed UDQNV WHVW 3 ZDV GHWHUPLQHG DV VWDWLVWLFDOO\ significant.
Results $PRQJVXEMHFWVWKHUHZHUHVXEMHFWVVXIIHUHG IURP ,'$ 7KH\ ZHUH UDQGRPO\ GLYLGHG LQWR WZR JURXSV VXEMHFWVLQWKHWUHDWPHQWJURXSZLWKLURQ DQGVXEMHFWVLQSODFHERJURXS$IWHUVL[PRQWKVRI VWXG\RQO\VXEMHFWVFRPSOHWHGWKHVWXG\ LQWKH iro ggroup and 3 of the placebo group dropped out. 7KHFKDUDFWHULVWLFVRIWKHVWXG\VXEMHFWVDUHGHSLFWHG in Table 1. $IWHUPRQWKVZHGLGQRWVHHDQ\GLIIHUHQFH EHWZHHQ WKH &%&/ 7 VFRUHV DQG SURSRUWLRQ RI FKLOGUHQZLWKVFRUH!EHWZHHQWKHWZRJURXSV See Table 2. 7KHUHZDVVLJQLILFDQWGHFUHPHQWRI&%&/VFRUHV RQH[WHUQDOL]LQJZLWKPHDQ 6' YHUVXV 6' DQGWRWDOSUREOHPV PHDQ 6'
Paediatr Indones, Vol. 49, No. 5, September 2009277
Rina A.C. Saragih et al %HKDYLRURI,'$FKLOGUHQDIWHULURQWKHUDS\ Table 1. Baseline characteristics of the subjects Parameter (n)
Iron group
Placebo gorup
N Age; mean ( SD ) yr Sex (%) - Male - Female Body weight, mean (SD) kg Hemoglobin;mean (SD) g/dl MCHC; mean (SD) % Mentzer Index; mean (SD) RDW Index; mean (SD) CBCL T Scores; mean (SD): CBCL Summary Measures - Internalizing problems - Externalizing problems - Skor T Total Individual CBCL Scales - Withdrawn - Somatic Complaints - Anxious/Depressed - Social Problems - Thought Problems - Attention Problems - Delinquent Behavior - Agressive Behavior CBCL T scores > 60 (%) - Internalizing problems - Externalizing problems - Total problems
57 10 (1.31)
58 10 (1.29)
33 (58) 24 (42) 26.91 (6.26) 10.14 (SD 1.29) 29.90(SD 0.67) 17.43(SD 4.19) 254.13(SD 104.47)
31(53) 27(47) 25.64 (5.55) 10.17(SD 1.39) 29.9(SD 0.56) 17.16(SD 4.47) 269.62(SD 125.70)
43.70 (SD 9.69) 38.53 (SD 9.90) 39.67 (SD 10.16)
44.33 (SD 10.97) 38.02 (SD 8.59) 38.83(SD 11.27)
52.09 (SD 3.33) 54.56 (SD 10.14) 51.05 (SD 3.57) 52.46 (SD 6.53) 51.02 (SD 3.50) 52.44 (SD 6.14) 52.07 (SD 5.02) 50.95 (SD 3.39)
53.10 (SD 5.58) 55.97 (SD 6.49) 51.72 (SD 4.37) 53.60 (SD 7.53) 51.48 (SD 3.99) 52.50 (SD 5.58) 52.38 (SD 5.32) 50.34 (SD 1.53)
5 (9) 3 (5) 6 (11)
7 (12) 2 (3) 8 (14)
Discussion
Table 2. Comparison of hemoglobin concentration before and after intervention Group Iron Plasebo
Hb1 g/dl
Hb2 g/dl
P
10,12±1,30 10,10±1,40
12,34±1,33 11,80±1,35
0,00* 0,00*
*P< 0,05 Value in Mean (SD) Note: Hb1: Hemoglobin concentration before intervention; Hb2: Hemoglobin concentration after intervention
YHUVXV 6' RIWUHDWPHQWJURXSZLWK LURQDIWHULQWHUYHQWLRQ 3 ZKLOHLQWKHSODFHER group there was no significant difference between &%&/VFRUHEHIRUHDQGDIWHULQWHUYHQWLRQ Table 3).
Studies have shown an association between iron deficiency anemia and adverse effects on behavioral and psychomotor development in infants and children. The exact mechanisms behind these associations are not fully understood. The role of intraneuronal iron in metabolism is varied DQG LQYROYHV WKH IROORZLQJ LQFRUSRUDWLRQ RI LURQ LQWR HQ]\PHV RI R[LGDWLRQUHGXFWLRQ UHDFWLRQ RU HOHFWURQ WUDQVSRUW V\QWKHVLV DQG SDFNDJLQJ QHXURWUDQVPLWWHUV DQG XSWDNH DQG GHJUDGDWLRQ RI WKH QHXURWUDQVPLWWHUV LQWR RWKHU LURQFRQWDLQLQJ proteins that may directly or indirectly alter brain
Table 3. Comparison of CBCL T scores between before and after intervension Group Iron
CBCL T Scores - Internalizing problems - Externalizing problems - Total problems
Score 1 43.82 (SD 9.84) 38.58 (SD 10.03) 39.75 (SD 10.34)
Score 2 42.64 (SD 9.95) 37.13 (SD 9.04) 38.24 (SD 10.20)
P 0.23 0.01 0.002
Placebo
- Internalizing problems - Externalizing problems - Total problems
43.82 (SD 10.62) 37.76 (SD 8.67) 38.36 (SD 11.07)
43.49 (SD 10.60) 37.62 (SD 8.69) 38.15 (SD 11.10)
0.72 0.49 0.13
Note: Score 1: CBCL T scores before intervention; Score 2: CBCL T scores after intervention
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Rina A.C. Saragih et al %HKDYLRURI,'$FKLOGUHQDIWHULURQWKHUDS\
function through peroxide reduction, amino acid metabolism and fat desaturation, thus altering membrane functioning.13 Iron is essential for enzymes involved in neurotransmitter synthesis including WU\SWRSKDQ K\GUR[\ODVH VHURWRQLQ DQG W\URVLQH K\GUR[\ODVH QRUHSLQHSKULQH DQG GRSDPLQH ,URQ is also related to the activity of monoamine oxidase, an enzyme critical for proper rates of degradation of neurotransmitters. The effects of iron deficiency on brain dopamine are not due to anemia, per se, because hemolytic anemia without iron deficiency does not produce these abnormalities in dopamine neurobiology.14 0F&DQQ DQG $PHV LQ D UHYLHZ RI evidence for a causal relation between iron deficiency during development and deficits in cognitive or behavioral function concluded that a causal connection has not been clearly established.15 The brain is at its most vulnerable during critical periods of development, including the last trimester RIIHWDOOLIHDQGWKHILUVW\HDURIFKLOGKRRG³DSHULRG of rapid brain growth termed the “brain growth spurt”. Longitudinal studies consistently indicate that children who were anemic in infancy continue to have poorer cognition, school achievement, and more behavioral problems to middle childhood. In anemic FKLOGUHQOHVVWKDQ\HDUVROGVKRUWWHUPWULDOVRILURQ treatment have generally failed to produce benefits. Lozoff et alZKRVWXGLHGDERXWWKHORQJWHUPHIIHFWVRI iron deficiency in infancy found that after more than \HDUVFKLOGUHQZKRKDGLURQGHILFLHQF\LQLQIDQF\ had more problematic in several areas, and there had EHHQDQLQFUHDVHGFRQFHUQVDERXWDQ[LHW\GHSUHVVLRQ social problems, and attention problems. The study IRXQG WKDW IRUPHUO\ LURQGHILFLHQW FKLOGUHQ KDG significantly higher T scores for internalizing problems, externalizing problems, and total problems.9 In this study, we could not determine whether the anemia had already occured since early age. We found significant GHFUHDVH RI &%&/ VFRUH RQ H[WHUQDOL]LQJ DQG WRWDO score, and no significant decrease on internalizing after intervention. 7KHYDVWPDMRULW\RIVWXGLHVLQKXPDQVKDYHKDGD IRFXVRQLURQGHILFLHQWLQIDQWVRI²PRQWKVRIDJH A limited number of studies have been conducted to GHWHUPLQHLILURQGHILFLHQF\GXULQJQRQGHYHORSPHQWDO periods of life are associated with changes in behavior, cognition and brain function.14 A study of preschool DJHFKLOGUHQUHSRUWHGWKDWFRPSDUHGZLWKQRQDQHPLF
SUHVFKRROHUV SUHVFKRROHUV ZLWK ,'$ GLVSOD\HG OHVV VRFLDODELOLWLHVDQGORRNLQJIRUWKHLUPRWKHUVRUPRYHG FORVHO\WRWKHLUPRWKHUVTXLFNO\DQGVORZHUWRGLVSOD\ positive affect and touch novel toys for the first time. 7KHVH UHVXOWV LQGLFDWH WKDW ,'$ LQ WKH SUHVFKRRO age has affective and behavioral effects similar to WKRVH UHSRUWHG DERXW ,'$ LQ LQIDQF\ A study of LURQ VXSSOHPHQWDWLRQ LQ QRQDQHPLF LURQGHILFLHQW adolescent girls showed that girls who received the supplementation performed better on a test of verbal learning and memory than girls in the control group. In this study there was significant decrease on externalizing and total problems score in iron group after intervention, but there was no significant difference compared to placebo. There were some limitations in this study such DV WKHUHZHUHPDQ\IDFWRUVWKDWLQIOXHQFHEHKDYLRU OLNHRWKHUXQLGHQWLILHGQXWULHQWGHILFLHQFLHVSDUHQWDO intellectual disability and emotional limitations, or enviromental disadvantages. More over, many informant characteristics may be associated with VFRUHV RQ DOO NLQGV RI TXHVWLRQQDLUHV LQFOXGLQJ &%&/19 Parents, including those with less than a high school education or limited parenting experience, derive their concerns by comparing their children to others, an effective way of recognizing most SUREOHPV LQ FKLOGKRRG +RZHYHU SDUHQWV DUH QRW DOZD\VDFFXUDWH²GRQRWUDLVHFRQFHUQVZKHQ they should, and many parents are concerned when they need not to be. 0XOWLLQIRUPDQWV SURYLGH the possibility to assess the child from various DQJOHV&RPSDULVRQVRISDUHQWV·UHSRUWVZLWKUHSRUWV by others, such as teachers and adolescents, are HVSHFLDOO\KHOSIXOIRUDVVHVVLQJWKHFURVVLQIRUPDQW consistency of problems. The other limitation was that we did not H[DPLQHLURQSURILOH VHUXPLURQWRWDOLURQELQGLQJ FDSDFLW\7,%&VHUXPIHUULWLQWUDQVIHUULQVDWXUDWLRQ DQG IUHH HU\WKURF\WH SRUSK\ULQ)(3 LQ WKLV VWXG\ EHFDXVHRIWKHH[SHQVLYHFRVW&HUWDLQIRUPXODVWKDW are based in red cells can differentiate iron deficiency from thalassemia trait with reasonable certainty. An 0&95%& UDWLR 0HQW]HU ,QGH[ RI DW OHDVW LV LQGLFDWLYHRI,'$ZKHUHDVDUDWLRRIOHVVWKDQLV LQGLFDWLYHRIWKDODVVHPLDWUDLWZLWKVSHFLILFLW\ $Q 5': LQGH[ 0&95%& [ 5': RI DW OHDVW LVLQGLFDWLYHRI,'$ZKHUHDVDQLQGH[RIOHVV
Paediatr Indones, Vol. 49, No. 5, September 2009279
Rina A.C. Saragih et al %HKDYLRURI,'$FKLOGUHQDIWHULURQWKHUDS\
WKDQ LV LQGLFDWLYH RI WKDODVVHPLD WUDLW ZLWK D VSHFLILFLW\RI 5 We conclude that in children with iron deficiency anemia, iron therapy for six months does not alter VLJQLILFDQWO\&%&/FRPSDUHGZLWKSODFHER
Acknowledgments 7KLVVWXG\ZDVVXSSRUWHGE\373HUNHEXQDQ1XVDQWDUD,,, 3731 ,,, *UDWLWXGHVWR3731,,,GLUHFWRUVDQGGU+HQGL6XKHQGUR 06F PDQDJHURI$HN1DEDUD+RVSLWDO :HDOVRZRXOGOLNHWR WKDQNWKH+HDG2IILFHRI'LQDV3HQGLGLNDQ 3HQJDMDUDQ$HN Nabara, school headmasters, teachers, parents and all children who had participated in this study.
References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
