Wht Drives Prescribing of Asthm Mediction to Children? A Multilevel Popultion-Bsed Study Mir G. P. Zuidgeest, PhrmD, PhD 1,3 Liset vn Dijk, PhD 2 Peter Spreeuwenberg, MA 2 Henriëtte A. Smit, MD, PhD 3 Bert Brunekreef, PhD 4,5 Hubertus G. M. Arets, MD, PhD 6 Mdelon Brcke, PhD 1 Hubert G. M. Leufkens, PhrmD, PhD 1 1 Division of Phrmcoepidemiology & Phrmcotherpy, Utrecht Institute for Phrmceuticl Sciences (UIPS), Fculty of Science, Utrecht University, Utrecht, The Netherlnds 2 NIVEL (Netherlnds Institute for Helth Services Reserch), Utrecht, The Netherlnds 3 Centre of Prevention nd Helth Services Reserch, Ntionl Institute for Public Helth nd the Environment (RIVM), Bilthoven, The Netherlnds 4 Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlnds 5 Julius Center for Helth Sciences nd Primry Cre, University Medicl Center, Utrecht, The Netherlnds 6 Deprtment of Peditric Pulmonology, Wilhelmin Children s Hospitl, University Medicl Centre, Utrecht, The Netherlnds Confl ict of interest: The deprtment employing uthors M.G.P.Z, M.B. nd H.G.M.L. hs received n eductionl grnt from GSK for the conduct of phrmcoepidemiologicl reserch. All other uthors declre tht they hve no confl ict of interest. CORRESPONDING AUTHOR Bert Leufkens, PhD Division of Phrmcoepidemiology & Phrmcotherpy Utrecht University PO Box 80082, 3508 TB Utrecht, The Netherlnds h.g.m.leufkens@uu.nl ABSTRACT PURPOSE Dignosing sthm in children with sthmtic symptoms remins chllenge, prticulrly in preschool children. This chllenge cretes n opportunity for vribility in prescribing. The im of our study ws to investigte how nd to wht degree ptient, fmily, nd physicin chrcteristics influence prescribing of sthm mediction in children. METHODS We undertook multilevel popultion-bsed study using the second Dutch ntionl survey of generl prctice (DNSGP-2), 2001. Prticipnts were 46,371 children ged 1 to 17 yers belonging to 25,537 fmilies registered with 109 generl prctitioners. Using multilevel multivrite logistic regression nlysis with 3 levels, our min outcome mesure ws the prescribing of sthm mediction, defined s t lest 1 prescription for β 2 -drenergic gonists, inhled corticosteroids, cromones, or montelukst during the 1-yer study period. RESULTS We identified chrcteristics significntly ssocited with prescribing sthm mediction on ll 3 levels (child, fmily, nd physicin). The vrince in prescribing mong physicins ws significntly higher with children who were younger thn 6 yers thn with children ged 6 yers nd older (95% CI, 3.5%- 25.2% vs 2.4%-13.4%). Severl dignoses other thn sthm nd sthmtic complints were strongly ssocited with prescribing sthm mediction, including bronchitis/bronchiolitis (OR = 9.04; 95% CI, 7.57-10.8) nd cough (OR = 6.51; 95% CI, 5.68-7.47). CONCLUSIONS Our study shows much higher vrince in prescribing ptterns mong generl prctitioners for children younger thn 6 yers compred with older children, which could be direct result of the dignostic complexities found in young children with sthmtic symptoms. Thus dignostic gps my led to more physicin-driven prescribing irrespective of the clinicl context. Ann Fm Med 2009;7:32-40. DOI: 10.1370/fm.910. INTRODUCTION Asthm in children hs been recognized s mjor clinicl nd public helth problem. 1,2 Reported dt on the prevlence of sthm symptoms in children vry signifi cntly, from 1% to more thn 30% in different popultions. 3 Despite ll scientifi c nd clinicl progress, dignosing sthm in children nd treting children with sthmtic symptoms remin chllenge. 4-6 First, children often receive mediction to reduce symptoms during wheezing episodes to prevent further excerbtions nd to serve more or less s dignostic tool. At young ge, however, vlid dignostic possibilities for sthm re still limited. Although most children will eventully turn out to be trnsient wheezers, there is lck of objective dignostic tools to distinguish these trnsient wheezers from the true sthmtics. 6 Second, the fmily of the child my ply role, for exmple, with its specifi c help-seek- 32
ing behvior 7 nd genetic infl uence on disese susceptibility. 8 Lst but not lest, it is the treting physicin who mkes the decision whether to prescribe sthm mediction. To id in this decision, guidelines re vilble with informtion on how sthmtic symptoms in children should be treted nd which kind of sthm mediction should be used. 9-11 There is generl consensus tht dignosis of sthm cnnot be mde with resonble certinty erlier thn the ge of 5 to 6 yers; therefore, different tretment recommendtions re mde for children who re younger thn 5 to 6 yers thn for children ged 6 yers nd older. 9-11 Prescribing sthm mediction to children is the result of complex interply mong the child, the cregivers or prents of the child, nd the treting physicin. Given the bsence of cler dignostic guidnce in children, prticulrly in preschool children, vribility in prescribing is to be expected. As result, drug utiliztion studies describing ctul use of sthm medicines in children show mple diversity in the pplied therpies. 12-14 Other studies hve reported mismtch between sthm mediction use nd dignosis of sthm. 15-17 A key question driven by these observtions is whether this diversity seen in peditric sthm therpy is minly determined by the ptient itself, the fmily, or the treting physicin. The ttitude of the physicin or preferences of the cregivers or prents could ply much lrger role in the decisionmking process t young ge, when the dignosis is uncertin, thn t n older ge, when the dignosis of sthm cn be more fi rmly estblished. The im of this study ws to investigte how nd to wht degree prescribing sthm mediction to children is infl uenced by ptient, fmily, nd physicin chrcteristics. We investigted to wht extent vrince in prescribing is ssocited with differences mong children, how much vrince cn be ttributed to the fmily or physicin or both, nd whether these vrinces differ for younger nd older children. METHODS Setting nd Study Popultion In the Netherlnds children with sthmtic symptoms nd morbidity re primrily seen by the physicins in generl prctice. This study ws therefore undertken within the frmework of the Second Dutch Ntionl Survey of Generl Prctice (DNSGP-2). This ntionwide survey ws crried out in 2001 by the NIVEL (Netherlnds Institute for Helth Services Reserch) in coopertion with the Ntionl Institute for Public Helth nd the Environment (RIVM). Prctices lredy prticipting in the Dutch Ntionl Informtion Network of Generl Prctice were invited to prticipte in this study becuse of their experience in the use of electronic medicl records. All prctices within the DNSGP-2 mde use of electronic medicl records. The prticipting generl prctitioners (GPs) were representtive of ll Dutch GPs. 18 A pilot study lso showed no differences in prctice style between GPs prticipting in registrtion network nd those who were not. 19 The DNSGP-2 survey hs been described in detil elsewhere. 18,20 In short, 195 GPs in 104 prctices serving pproximtely 400,000 ptients registered ll physicin-ptient contcts during 12 consecutive months. The DNSGP-2 provides dt on ll dignoses mde nd prescriptions written by the GP. Every single helth problem reported within consulttion ws coded by the GP using the Interntionl Clssifi ction for Primry Cre (ICPC). 21 Additionl informtion on ptient nd GP chrcteristics ws collected through questionnires. In the Netherlnds ll noninstitutionlized inhbitnts re registered in single generl prctice, with few chnges over time. The DNSGP-2 survey ws crried out ccording to Dutch legisltion on privcy. The privcy regultion of the study ws pproved by the Dutch Dt Protection Authority. For the present study we nlyzed dt from 72 GP prctices. The other prctices were excluded for vrious resons: 20 prctices were excluded becuse the informtion on which ptient belongs to which individul GP ws not vilble, 10 becuse of incomplete dt collection on morbidity items, nd 2 more becuse of lck of informtion on GP chrcteristics. The remining 109 GPs within the 72 prctices did not differ signifi cntly from the totl group of GPs prticipting in the DNSGP-2 except for higher percentge of solo prctices (becuse of our selection criterion of including only ptients tht could be linked to specifi c GP). A totl of 1,804 children (3.7%) who could not be linked to single fmily were lso excluded. The fi nl study popultion consisted of 46,371 children ged 1 to 17 yers within 25,537 fmilies, belonging to 109 GPs within 72 prctices. Children, fmilies, nd GPs seem to be representtive for the Dutch sitution on bsic chrcteristics. 18,20 Mesurements Outcome Vrible: Prescribing of Asthm Mediction Drug prescriptions were registered by the GP ccording to the Antomic Therpeutic Chemicl Clssifi ction system. 22 The following medictions were considered sthm mediction: inhled nd orl short-cting β 2 -gonists, inhled long-cting β 2 -gonists, inhled corticosteroids, inhled cromones, nd montelukst. We determined whether child from the study popultion received t lest 1 prescription for 1 of these med- 33
icine groups in the yer under study (ie, 2001), clling them children prescribed sthm mediction. Child Chrcteristics At the level of the individul child, the following vribles were tken into ccount: ge (ctegorized into children younger thn 6 yers nd children ged 6 yers nd older to conform with the guidelines), sex, the number of prescriptions child received for ntibiotics in the yer under study, the number of prescriptions child received for orl glucocorticosteroids in the yer under study, the number of contcts child hd with the GP in the yer under study, nd whether child hd t lest 1 referrl for respirtory complints/diseses or to lung specilist in the yer under study. Every helth problem reported during consulttion ws coded by the GP using the ICPC. 21 We included the following ICPC dignoses of respirtory complints nd diseses s dichotomous vribles: R02 (shortness of breth/dyspne), R03 (wheezing), R05 (cough), R74 (cute upper respirtory trct infection), R78 (cute bronchitis/bronchiolitis), R81 (pneumoni), R96 (sthm), nd R97 (llergic rhinitis). If child hd t lest 1 consulttion coded with 1 of these ICPC codes, then the dichotomous vrible for tht specifi c code for tht child would be positive. Fmily Chrcteristics At the fmily level the following vribles were tken into ccount: ethnicity (whether 1 or both prents hd non-western culturl bckground bsed on the country of birth), the highest socil economic sttus of the prent(s) using the Interntionl Socio-Economic Index of Occuptionl Sttus, nd prentl sthm (t lest 1 prent with registered ICPC code R96 during the study period). GP Chrcteristics At the GP level the following vribles were tken into ccount: ge; sex; prctice type (solo vs group prctice); degree of urbniztion of prctice loction (s clssifi ed by Sttistics Netherlnds on 5-point scle); GP informtion system used to register contcts, prescriptions, etc; whether the GP is dispensing doctor ( doctor, uthorized or required by the Helth Authority to provide phrmceuticl services to his or her ptients); whether the GP is working full-time or prt-time by the number of full-time equivlents (FTEs); worklod of the GP (totl number of ptients divided by the number of FTEs per 1,000 ptients); prescribing volume of the GP (verge number of prescriptions issued per ptient during 1 yer); proportion of 0- to 17-yer-old ptients per GP; nd the proportion of children with sthm dignosis per GP. We divided the GPs into 2 groups: those who within their ptient popultion of children prescribed sthm mediction to 7.4% of children or less (the verge t the GP level is 7.4%), nd those who prescribed sthm mediction to more thn 7.4% of children. Sttisticl Anlyses We performed multilevel logistic regression nlysis with 3 levels, nmely, children within fmilies clustered within GPs, which enbled us to study not only the infl uence of the child, fmily, nd GP chrcteristics on sthm mediction use in children simultneously, but lso the vrince in prescribing t the 2 higher levels. The vrince t the level of the child ws not determined, s the outcome mesure is dichotomous: child either receives sthm mediction or not. The ssocition between prescribing sthm mediction nd the vribles described bove ws fi rst tested by univrite nlysis for ech vrible. Only vribles signifi cntly ssocited (P <.05) with prescribing sthm mediction were included in the multivrite nlysis. All vribles tht no longer showed signifi cnt ssocition in the multivrite nlysis were excluded. A sensitivity nlysis including ll child chrcteristics irrespective of signifi cnce showed tht including the nonsignifi cnt vribles did not lter the estimtes for the signifi cnt vribles. The child chrcteristics of sex nd ll dignoses of respirtory complints nd diseses were tested for n ge interction. The multivrite nlysis ws computed in severl steps to differentite between the infl uence of child, fmily, nd GP chrcteristics on the vrious estimtes. Step 1, the empty model, gives the unexplined vrince t the upper 2 levels (fmily nd GP) without correcting for ny differences tht might exist in the popultion of children belonging to these fmilies nd these GPs. In step 2 we seprted the vrince in prescribing t the GP level nd t the fmily level for children younger thn 6 yers nd older children. At ech level this nlysis rendered unique vrince ccording to ge-group nd covrince. If the covrince turned out to be much higher thn the 2 unique vrinces t certin level, seprting the vrince for the 2 ge-groups t this level ws not meningful. In step 3 we dded the child chrcteristics (including the ge-interction terms) to the model. This step serves 2 purposes: (1) to mke the popultions seen by the GP nd belonging to fmily s similr s possible, nd (2) to determine which child chrcteristics re ssocited with prescribing sthm mediction. The vrince in this model is the vrince unexplined by the child chrcteristics introduced in the model. In step 4 we dded the fmily chrcteristics to the model. In step 5 we dded the GP chrcteristics to the model. 34
The vribles included in the models described here were rescled by subtrcting the men, so tht the intercepts represent prescribing sthm mediction to the verge child. The percentge of children receiving sthm mediction cn be clculted by tking the inverse logit of the intercept. The ssocition between chrcteristics on ll 3 levels nd prescribing sthm mediction is expressed using odds rtios) nd 95% confi dence intervls. The 95% confi dence intervl of prescribing sthm mediction t the GP level cn be clculted for ech ge-group using the sum of the unique vrince of tht ge-group nd the covrince. All models were estimted using multilevel logistic regression, with PQL (penlized qusi-likelihood), 1st order, nd constrined level-1 vrince (MLwinN 2.02; Centre for Multilevel Modeling, University of Briston, Bristol, Englnd). RESULTS Chrcteristics of the Study Popultion Tble 1 displys the chrcteristics of the study popultion t the child level nd the results for the univrite nlyses. During the yer under study 7.3% of ll children (n = 3,374) received sthm mediction. All child chrcteristics were signifi cntly ssocited with prescribing sthm mediction when tested univritely. An overview of the pplied therpies strtifi ed by ge-groups is displyed in Tble 2. We see tht prescribing sthm mediction declines with the rising ge of the child. Short-cting β 2 -gonists nd inhled corticosteroids were the medicine groups most prescribed t ll ges. The children within our study popultion belonged to 3,081 fmilies (Tble 3); therefore, in 12.1% of the fmilies, 1 or more children were prescribed sthm mediction. The chrcteristics of the GPs re displyed in Tble 4. The Multivrite Model Tble 5 shows the stepwise-built, multivrite, multilevel, logistic regression model. We found tht in the empty model the vrince t the fmily level (0.567) ws much higher thn the vrince t the GP level (0.119). Compring 2 Age-Groups When seprting the vrince in prescribing t the GP level for children younger thn 6 yers nd for older children (model 1) we found tht the vrince is signifi cntly higher (χ 2 = 7.3) in younger children thn in older children. This ge infl uence ws not found t the fmily level; t this level the covrince ws much higher thn the 2 unique vrinces (model Tble 1. Child Chrcteristics nd Results From the Univrite Anlyses Child Chrcteristics Children Without n Asthm Prescription (n = 42,997) Children Prescribed Asthm Mediction (n = 3,374) OR (95% CI) Men ge (SD; rnge), y 9.1 (4.8; 1-17) 7.7 (4.9; 1-17) 0.94 (0.93-0.95) Age <6 y, No. (%) 11,948 (25.8) 1,386 (41.1) 1.82 (1.69-1.96) Sex, mle, No. (%) 21,798 (50.7) 1,922 (57.0) 1.29 (1.20-1.39) Antibiotic prescriptions, No. (SD; rnge) b 0.2 (0.6; 0-13) 0.6 (1.0; 0-12) 1.85 (1.77-1.93) Orl corticosteroid prescriptions, No. (SD; rnge) b 0.003 (0.11 ;0-12) 0.046 (0.26;0-5) 4.69 (3.59-6.12) Contcts with GP, No. (SD; rnge) c 2.1 (2.6; 0-35) 5.2 (4.0; 0-34) 1.30 (1.29-1.31) Children with 0 contcts in registrtion yer, No. (%) 13,786 (32.1) 129 (3.8) Referrls, No. (%) d 93 (0.3) 94 (3.6) 13.0 (12.2-13.9) Registered diseses nd complints, e No. (%) Asthm 227 (0.5) 1,739 (51.5) 260 (221-305) Shortness of breth/dyspne 92 (0.2) 144 (4.3) 21.1 (15.9-28.1) Wheezing 16 (0.0) 63 (1.9) 55.2 (30.7-99.2) Cough 2082 (4.8) 873 (25.9) 6.90 (6.26-7.59) Acute bronchitis/ bronchiolitis 769 (1.8) 622 (18.4) 13.5 (11.9-15.3) Acute URTI 3,267 (7.6) 674 (20.0) 3.06 (2.78-3.38) Pneumoni 241 (0.6) 133 (3.9) 7.24 (5.74-9.15) Allergic rhinitis 1,029 (2.4) 252 (7.5) 3.24 (2.78-3.77) CI = confidence intervl; GP = generl prctitioner; ICPC = Interntionl Clssifiction for Primry Cre; OR = odds rtio; URTI = upper respirtory trct infection. Significnt vlues P <.05. b Averge number of prescriptions issued per ptient during 1 yer. c Averge number of contcts with GP during 1 yer. d Referrls for respirtory complints/diseses or to lung specilist. e Dichotomous vribles of the ICPC codes R02 (shortness of breth/dyspne), R03 (wheezing), R05 (cough), R74 (cute upper respirtory trct infection), R78 (cute bronchitis/bronchiolitis), R81 (pneumoni), R96 (sthm), nd R97 (llergic rhinitis). 35
Tble 2. Prescription of Asthm Mediction by Age-Group nd Type of Mediction Age-Groups, Yers Mediction Type 1-2 n = 5,293 3-5 n = 8,041 6-8 n = 8,335 9-11 n = 8,350 12-14 n = 8,196 15-17 n = 8,156 Totl n = 46,371 All sthm mediction, % 10.9 10.1 7.0 6.1 5.7 5.2 7.3 Mediction groups, % SABA 8.0 7.0 4.9 4.5 4.5 3.6 5.3 ICS 5.9 7.0 4.8 4.0 3.2 3.0 4.5 LABA 0.1 0.3 0.5 0.7 0.6 0.6 0.5 Cromones 0.8 0.5 0.1 0.1 0.1 0.1 0.2 Montelukst 0.0 0.1 0.1 0.1 0.0 0.1 0.1 Therpy groups, % SABA 38.6 25.7 29.2 32.4 41.9 39.1 33.4 ICS 20.7 24.7 24.3 18.7 15.1 21.9 21.3 SABA + ICS 33.2 43.2 40.9 40.4 36.2 30.2 38.1 Other medicines 7.5 6.5 5.6 8.6 6.8 8.8 7.2 ICS = inhled corticosteroids; LABA = long-cting β2-gonists; SABA = short-cting β2-gonists. We clculted percentge of children using some sort of sthm mediction, not percentge of totl popultion; therpy groups therefore dd up to 100%. Therpy groups re defined s follows: SABA = monotherpy with short-cting β 2-gonists; ICS = monotherpy with inhled corticosteroids; SABA + ICS = combintion therpy of these 2 mediction groups (10.3% of children in this group lso received 1 or more other sthm medicines, of which 82% were LABA); other medicines = ll other therpies. Tble 3. Fmily Chrcteristics nd Results From the Univrite Anlyses Fmily Chrcteristics No Child With Asthm Mediction Within Fmily (n = 22,456) 1 Child Within Fmily With Asthm Prescription (n = 3,081) OR (95% CI) 1 or both prents non-western culturl 1,834 (10.6) 275 (11.1) 1.01 (0.87-1.17) bckground, No. (%) Men SES highest (SD; rnge) b 50.4 (15.5;16-87) 49.5 (15.4;16-87) 1.00 (0.99-1.00) Prentl sthm, No. (%) c 821 (3.7) 256 (8.3) 2.33 d (1.90-2.85) CI = confidence intervl; ICPC = Interntionl Clssifiction for Primry Cre; OR = odds rtio; SES = socioeconomic sttus. Ethnicity bsed on the country of birth. b The highest SES of prent(s) using the Interntionl Socio-Economic Index of Occuptionl Sttus. c At lest 1 prent with registered ICPC code for sthm during the study period. d Significnt vlues P <.05. not shown). In children younger thn 6 yers, GPs prescribed sthm mediction to 9.9% of children (95% CI, 3.5%-25.2%); in the older ge-group they prescribed sthm mediction to 5.8% of children (95% CI, 2.4%-13.4%). The correltion between the 2 ge-groups t the GP level ws 0.83, indicting tht GPs who tended to prescribe sthm mediction to young children more often lso tended to do so for older children. Assocition Between Child Chrcteristics nd Prescribing The next step ws to dd the child chrcteristics to the model (model 2). In this model the correltion between the vrinces for the 2 ge-groups t the GP level incresed to 0.89, but the unique vrinces were still signifi cntly different (χ 2 = 9.5). Model 2 lso shows tht the different complints nd disese dignoses were strongly relted to prescribing sthm mediction. Children with dignosed cute bronchitis/bronchiolitis were much more likely to receive sthm mediction thn ws the verge child (OR = 9.04; 95% CI, 7.57-10.8), s were children experiencing shortness of breth (OR = 20.7; 95% CI, 14.3-29.9), wheezing (OR = 51.5; 95% CI, 24.7-107), or cough (OR = 6.51; 95% CI, 5.68-7.47). The number of ntibiotic prescriptions, the number of orl corticosteroid prescriptions, nd referrls were no longer signifi cntly ssocited with prescribing sthm mediction in the multivrite nlyses. Although children younger thn 6 yers were more frequently prescribed sthm mediction, no significnt ge interctions were found for sex of the child or ny of the dignoses. From the intercept in model 2, we see tht when correcting for child chrcteristics, young children no longer hd higher chnce of receiving sthm mediction thn older children. 36
Tble 4. GP Chrcteristics nd Results From the Univrite Anlyses GP Chrcteristics GPs Prescribing Asthm Mediction Averge nd Below Averge (n = 58) GPs Prescribing Asthm Mediction Above Averge (n = 51) OR (95% CI) Men ge (SD; rnge), y 47.6 (5.7; 36-59) 46.2 (6.2; 33-56) 1.00 (0.99-1.01) Sex, mle, No. (%) 50 (86.2) 37 (72.6) 0.83 (0.69-1.00) Prctice type, solo, No. (%) 27 (46.6) 20 (39.2) 0.88 (0.75-1.02) Urbn prctice loction, men (SD; rnge) b 2.8 (1.4;1-5) 3.1 (1.0;1-5) 1.03 (0.98-1.10) Men FTE (SD; rnge) c 0.91 (0.15; 0.5-1.0) 0.88 (0.17; 0.5-1.0) 0.79 (0.48-1.28) Dispensing doctor, No. (%) d 5 (8.6) 3 (5.9) 0.97 (0.73-1.29) Worklod, men (SD; rnge) e 2.8 (0.7;1.4-5.5) 2.6 (0.6;1.3-4.8) 0.89 (0.80-1.00) Prescribing volume, men (SD; rnge) f 1.5 (0.5; 0.05-2.7) 1.8 (0.5; 0.9-3.2) 1.55 g (1.38-1.75) 25% of ptients 0-17 y, No. (%) h 15 (25.9) 6 (11.8) 0.77 g (0.64-0.93) Children with n sthm dignosis, % (SD; rnge) 3.5 (1.4; 0.8-7.3) 5.4 (2.1; 1.9-11.6) 1.10 g (1.07-1.14) CI = confidence intervl GP = generl prctitioner; FTE = full-time equivlent; OR = odds rtio. To disply the GP chrcteristics, we divided the GPs into 2 groups: those who prescribed sthm medicton to the verge percentge of children or less, nd those who prescribed bove verge (which, on the GP level, is 7.4%) within their childhood ptient popultion. b As clssified by Sttistics Netherlnds on 5-point scle, in which 1 = high level of urbnizton nd 5 = low urbniztion. c Full-time or prt-time working in number of FTEs. d Authorized or required by the Helth Authority to provide phrmceuticl services to his/her ptients. e Totl number of ptients divided by the number of FTEs per 1,000 ptients. f Averge number of prescriptions issued per ptient during 1 yer. g Significnt vlues P <.05. h GPs with 25% or more of their totl ptient popultion of children ged 0-17 yers. Tking Into Account the Fmily nd GP Chrcteristics Model 3 is the fi nl model nd includes both the fmily nd the GP chrcteristics. On the fmily level prentl sthm ws the only vrible signifi cntly correlted with prescribing sthm mediction in the univrite nlyses (Tble 3), nd this ssocition ws sustined in the multivrite model, where we djusted for sthm dignosis of the child (OR = 1.74; 95% CI, 1.41-2.15). Adding fmily nd GP chrcteristics did not hve signifi cnt impct on the ssocitions of the child s chrcteristics. This fi nl model shows tht in older children bout one-hlf of the unexplined vrince t the 2 upper levels occurs t the GP level, nd the other one-hlf occurs t the fmily level (intrclss correltion = 0.51). In younger children, however, the intrclss correltion ws 0.64; thus, more of the unexplined vrince lies on the GP level in this ge-group. Further nlysis of the GP chrcteristics showed tht GPs who prescribe more mediction in generl (the verge number of prescriptions per ptient per GP) prescribe more sthm mediction s well (OR = 1.99; 95% CI, 1.60-2.47). GPs who serve reltively lrge childhood ptient popultion (GPs for whom more thn 25% of their totl ptient popultion consisted of children) were less likely to prescribe sthm mediction to the verge child (OR = 0.59; 95% CI, 0.44-0.78) s were GPs who hd higher percentge of children dignosed with sthm within their ptient popultion (OR = 0.88; 95% CI, 0.83-0.93). DISCUSSION Our results show tht substntil number of children received sthm mediction during the 1-yer study period (7.3%). Through studying the infl uence of the child, fmily, nd GP chrcteristics simultneously in multilevel fshion, we were identifi ed chrcteristics t ll 3 levels tht were signifi cntly ssocited with prescribing sthm mediction. Compring 2 Age-Groups Bsed on the ssumption tht dignosis of sthm cn be mde with more certinty from the ge of 6 yers nd onwrd, we expected to fi nd more differences mong GPs when prescribing sthm medictions to children younger thn 6 yers thn when prescribing to older children. Indeed, we found tht the vrince in prescribing mong GPs ws much higher with young children thn with children ged 6 yers nd older. Only smll prt of the difference in prescribing between these 2 ge ctegories could be ttributed to differences in the chrcteristics of the child. Our fi ndings re in line with the current gp in the dignosis of sthm prticulrly in preschool children, 6,23,24 despite the ongoing serch for better dignostics. Such gp provides mple opportunity for interphysicin vri- 37
nce in prescribing sthm medictions bsed on personl preferences nd prescribing ttitudes in generl. Relted to this spect ws the fi nding tht the overll mediction prescribing volume of the GP ws positively ssocited with prescribing sthm medictions irrespective of complints nd illnesses of the child. Fmily Influence We lso found tht fmily infl uence on prescribing sthm mediction to children ws substntil. These fi ndings re in line with reports of genetic infl uence on disese susceptibility, 8 helth-seeking behvior, 7,25 nd the ttitude of the cregivers or prents regrding mediction use. 26 In our study, we found tht prentl sthm ws positively ssocited with prescribing sthm medictions. Since guidelines concerning sthm tretment stte tht prentl sthm sttus should be tken into ccount when evluting sthmtic symptoms in children, 9-11 this fi nding is not unexpected. Moreover, we found tht every dditionl contct with the GP renders 10% incresed chnce of receiving sthm mediction, indicting tht helthseeking behvior of the fmily hs relevnt impct on the tretment of the child. Tble 5. Multilevel Logistic Regression Anlyses With 3 Levels: Child, Fmily, nd Generl Prctitioner (GP) Explntory Vribles Empty Model Intercept (SE) Model 1 Intercept (SE) Model 2,b Intercept (SE) Model 3,b Intercept (SE) Age 1-17 y 2.580 (0.039) Age 1-5 y 2.210 (0.054) 3.629 (0.100) 3.645 (0.091) Age 6-17 y 2.779 (0.039) 3.573 (0.071) 3.605 (0.060) OR (95% CI) OR (95% CI) Sex, mle 1.25 (1.13-1.39) 1.25 (1.13-1.39) Shortness of breth/dyspne 20.7 (14.3-29.9) 20.2 (13.9-29.2) Wheezing 51.5 (24.7-107) 49.7 (23.8-104) Cough 6.51 (5.68-7.47) 6.46 (5.64-7.40) Acute bronchitis/bronchiolitis 9.04 (7.57-10.8) 8.91 (7.45-10.6) Acute upper respirtory trct infection 1.47 (1.26-1.72) 1.47 (1.26-1.72) Pneumoni 2.10 (1.44-3.07) 2.11 (1.44-3.09) Allergic rhinitis 2.12 (1.68-2.69) 2.10 (1.66-2.67) No. of contcts with GP 1.10 (1.08-1.12) 1.10 (1.08-1.12) Presence of prentl sthm 1.74 (1.41-2.15) Prescribing volume of GP 1.99 (1.60-2.47) Ptients 0-17 y 25% per GP 0.59 (0.44-0.78) Percentge of children with sthm dignosis per GP 0.88 (0.83-0.93) Vrince (SE) c Vrince (SE) Vrince (SE) Vrince (SE) Between-fmily vrince 0.567 (0.071) 0.535 (0.071) 0.474 (0.112) 0.471 (0.111) Between-GP vrince Age 1-17 y 0.119 (0.022) Age 1-5 y 0.209 (0.042) 0.751 (0.134) 0.547 (0.106) Age 6-17 y 0.097 (0.022) 0.384 (0.071) 0.214 (0.047) Covrince 0.118 (0.025) 0.479 (0.083) 0.284 (0.058) Correltions Correltions Correltions Correltions Correltion of GP vrince between 0.83 0.89 0.83 ge-groups d Intrclss correltion e Age 1-17 y 0.17 Age 1-5 y 0.38 0.72 0.64 Age 6-17 y 0.29 0.65 0.51 CI = confidence intervl; GP = generl prctitioner; OR = odds rtio; SE = stndrd error. Model 1 (ge-groups), model 2 (ge-groups, child chrcteristics), model 3 (ge-groups, child chrcteristics, fmily chrcteristics, GP chrcteristics). b In these models we corrected for the presence of n sthm dignosis in the child (model 2: OR = 262; 95% CI, 219-312; model 3: OR = 264; 95% CI, 221-315). c The vrince t the lowest level (children) is not determined becuse the outcome is dichotomous. d Correltion between the vrinces of the 2 defined ge-groups on the GP level. e ICC between the 2 upper levels (fmilies nd GPs). ICC is the reltive contribution of GP to sum of fmily nd GP vrince. 38
Respirtory Morbidities Other Thn Asthm As expected, we found tht dignosis of sthm nd typicl sthmtic complints, such s wheezing, were strongly ssocited with prescribing sthm mediction. Our dt, however, showed tht sthm mediction ws used to tret not only sthm nd sthmtic complints but lso other respirtory morbidities, such s cute bronchitis nd cute upper respirtory trct infections. These fi ndings re similr to fi ndings from other studies showing discrepncy between sthm mediction use nd sthm dignosis, 15,16 nd they could indicte off-lbel use nd overtretment. Studies evluting the effectiveness of sthm mediction for indictions other thn sthm re inconclusive. 27-30 The ssocition between the child being mle nd receiving prescription for sthm mediction is in line with previous fi ndings. 14,31 Becuse none of the disese nd complints dignoses showed signifi cnt interction with ge, we cn conclude tht GPs do not regrd certin complints or illnesses s more or less importnt t young ge thn t n older ge when it comes to prescribing sthm mediction. Limittions of the Study The current study hs some limittions. First, the time reltionship between the event of prescribing nd the mesurement of the independent vribles ws not evluted. Also, we did not determine whether nd for how long use of sthm mediction ws continued. Second, the complints nd disese dignoses re not bsolute chrcteristics of the child; they re registered by the GP nd re the result of n interply between the child with certin complints nd the interprettion of the GP. Further, possible differences in disese severity re not expressed in these dichotomized vribles. Third, vribles vilble to chrcterize GPs nd fmilies were limited. Model 3 shows how much of the vrince is still unexplined fter introducing the vribles included in this model. Especilly t the two higher levels, but lso t the ptient level, one could think of chrcteristics not vilble in our study tht might be ssocited with prescribing sthm mediction to children, including culturl nd environmentl fctors (eg, prticulte mtter ir pollution, indoor climte). Strengths of the Study The strengths of this study re the gret number of children in our study popultion, the representtiveness of the smple, nd the dt bout dignosing nd prescribing derived directly from the GP s clinicl records. Furthermore, the wide rry of vribles tht might be ssocited with prescribing sthm mediction, which we hd vilble for multilevel nlysis, surpssed by fr tht of most vilble studies to dte. As result, we were ble to identify importnt fctors ssocited with prescribing sthm mediction to children nd their independent contribution to the vrince in prescribing. The reltively lrge vrinces found t the GP nd fmily level indicte substntil infl uence of both GP nd fmily on prescribing sthm mediction. As consequence, substntil smple size of GPs nd fmilies will be required to cross-vlidte these fi ndings elsewhere. In conclusion, our study showed tht ll 3 evluted prties (ptient, fmily, nd GP) hve signifi cnt infl uence on whether children re given prescription for sthm mediction. At the level of the child we found tht prescribing sthm mediction ws strongly relted not only to sthm nd sthmtic symptoms but lso to mny other respirtory diseses. Furthermore, helth-seeking behvior, prentl sthm, nd the ttitude nd experience of the GP seemed to be ssocited with prescribing sthm medictions to children. We found much higher vrince mong GPs when prescribing to children younger thn 6 yers compred with older children, which we consider to be result of the dignostic complexities especilly present in preschool children with sthmtic symptoms. Dignostics uncertinties my result in more physicin- nd fmilydriven prescribing irrespective of the clinicl context, feture not lwys in the interest of the child. To red or post commentries in response to this rticle, see it online t http://www.nnfmmed.org/cgi/content/full/7/1/32. Key words: Asthm/child; sthm/child, preschool; fmily prctice; professionl prctice; multilevel; phrmcoepidemiology; prescribing Submitted Februry 27, 2008; submitted, revised, June 11, 2008; ccepted June 24, 2008. Funding support: This study ws prtly funded by the Ntionl Institute for Public Helth nd the Environment (RIVM) nd the Division of Phrmcoepidemiology & Phrmcotherpy, Utrecht University, Utrecht, Amsterdm. References 1. Msoli M, Fbin D, Holt S, Besley R. 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