Recurrent abdominal and � ank pain in children with idiopathichypercalciuria

P Vachvanichsanong, M Malagon and ES Moore

Department of Pediatrics, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, USA

Vachvanichsanong P, Malagon, M, Moore ES. Recurrent abdominal and � ank pain in childrenwith idiopathic hypercalciuria. Acta Pædiatr 2001; 90: 643–648. Stockholm. ISSN 0803-5253

Objective: To evaluate the role of idiopathic hypercalciuria (IH) as a cause of recurrent abdominalpain (RAP) in children. Patients and methods: We retrospectively reviewed the medical records of124 children referred for various complaints who had 24-h urine calcium excretion greater than2 mg/kg/d or random urine calcium-creatinine ratio greater than 0.18 mg/mg. Results: Fifty-twochildren with various clinical complaints had RAP or � ank pain. These comprised of 22 males and30 females, 9 mo to 15.9 y of age, mean 6.7 § 3.5 y. A family history of urolithiasis was presentin 50% of all the children. Only 6 of the 52 children with abdominal pain had renal stones. Inaddition to abdominal pain, 27 children had hematuria and 10 had urinary incontinence. Mildmetabolic acidosis was present in three children, parathyroid hormone activity elevated in two andserum vitamin D activity was increased in nine. All children were treated with increased � uidintake and a reduction in dietary sodium and oxalate and some required treatment with thiazideand antispasmodics. Forty-� ve cases responded to treatment, 5 failed to improve from therapy, and2, which were not followed up as patients, were not available.

Conclusion: We describe 52 children with RAP or back pain due to IH and recommend that IH beconsidered in the differential diagnosis of RAP in childhood.

Key words: Flank pain, idiopathic hypercalciuria, recurrent abdominal pain

Prayong Vachvanichsanong, Department of Pediatrics, Faculty of Medicine, Prince of SongklaUniversity, Hat Yai, 90110, Thailand (Tel. ‡66 74 212070-9 (Ext. 1250), fax. ‡66 74 212900,212912, e-mail. vprayong@ratree.psu.ac.th)

Recurrent abdominal pain (RAP) is probably one of themost enigmatic complaints in pediatric medicine.Oberlander and Rappaport de� ned RAP during child-hood as a constellation of symptoms characterized by atleast one episode of abdominal pain per month for atleast three consecutive months (1). The reported causesof RAP are multiple, with Oberlander and Rappaportstating that more than 100 different conditions havebeen associated with RAP in childhood (1). However,Apley and Naish (2) estimated that approximately 90%of RAP in children is non-organic. Back pain is lesscommon in children and, when present, is oftendescribed by the child as a single complaint ofabdominal pain. We � rst reported that the syndromeof idiopathic hypercalciuria (IH) is more often a causeof non-stone clinical complaints in children rather thana cause of urolithiasis (3, 4). We termed this clinicalcomplex as non-calculous symptomatic IH. The non-calculous clinical signs and symptoms include hema-turia, both microscopic and gross, urinary tract infection(UTI), urinary frequency-urgency syndrome, urinaryincontinence, bladder “spasms”, dysuria, sterile pyuriaand mild proteinuria in addition to abdominal or � ank

pain (5). Although most published articles related toRAP list overt stone formation as a cause, few if anycurrently list non-calculous IH as a possible cause (6).Recently, Moir suggested that no more than 1 of 15school-age children with RAP has a serious conditionand laboratory studies are rarely indicated (7). How-ever, symptomatic IH is being shown with increasingfrequency to be a common clinical problem in children,and screening for this diagnosis is quite simple.

Patients and methodsWe evaluated 124 children referred to the Children’sKidney Center at Knoxville from the Knoxville area andbeyond for clinically signi� cant IH. Hypercalciuria inthis study was de� ned as either quantitative urinecalcium excretion exceeding 2 mg per kilogram bodyweight per day (mg/kg/d) or non-fasting random urinecalcium-creatinine concentration ratio (UCa/UCr) equalto or greater than 0.18 mg/mg (3, 5). When hyper-calciuria was found but secondary causes could not bedemonstrated, it was de� ned as idiopathic or genetic

Ó 2001 Taylor & Francis. ISSN 0803-5253

Acta Pñ diatr 90: 643± 648. 2001

(8). Abdominal or lumbar pain was de� ned as acomplaint that was accepted as genuine by the parent.All children ful� lled the de� nition of RAP (1). Noattempt was made to consistently quantitate the severityof the pain or the number of pain episodes per day.However, we considered the pain to be signi� cant if itcaused the child to interrupt an on-going activity tocomplain of pain or become inactive after verbalizing acomplaint of pain. Additionally, in some youngchildren, pictures of smiling faces (no pain) progressingto crying faces (severe pain) were used to roughlyestimate pain severity. When the available historyrevealed an estimate of the number of pain episodesper day or the parent or child offered a description ofapparent pain severity, these were recorded for com-parison after initiation of treatment. In addition to UCa/UCr and 24-h urine collection for quantitation of urinecalcium excretion, the children also had a renalultrasound (RUS), biochemical pro� le, serum assayfor 1,25(OH)2 vitamin D3 and immunoreactive para-thyroid hormone activity (iPTH), bone X-rays formetabolic bone disease, urinalysis and urine culture.Children found to have positive urine culture onrepeated studies also had a voiding cystourethrogram(VCUG). With the exception of routine measurement of1,25(OH)2 vitamin D3 and iPTH, no other attempt wasmade to distinguish a speci� c subtype of IH (9).

When the diagnosis of IH was con� rmed, treatmentwas started. If complaints of pain occurred 3 d eachweek or less, general treatment was initially givenwithout pharmacotherapy. If there was no detectableimprovement after 2–4 consecutive weeks, pharma-cotherapy was added. “treatment failure” was de� ned assymptoms persisting without determining patient com-pliance or the ineffective method. General treatment

consisted of a liberal � uid intake to decrease calciumsaturation in the urine. Since in most cases of IHcalcium in urine usually precipitates as the oxalate,nutritional counseling was obtained to reduce dietaryoxalate to that needed only for growth. Finally, studieshave shown a sodium-dependent subtype of IH, andexcess dietary salt, when present in our patients, wasreduced to the minimum daily requirement for growth(8). Speci� c pharmacotherapy consisted of thiazidediuretics to reduce urine calcium excretion and anti-spasmodics either oxybutynin chloride or hyoscyaminesulfate. Analgesics were not regularly prescribed. Wehave noted low serum HCO3 in some of our patientswith IH and, when present, alkali was initiated at aninitial dose of 2 mEq/kg/d (unpublished observations).Also, if signi� cant bactiuria was present, appropriateantimicrobial therapy was given, as we have observedrecurrent UTI associated with non-calculous IH (10).No child was treated with a reduction in dietary calciumintake. Evaluation of the ef� cacy of the treatment wasundertaken when improvement was � rst noted, or aftertreatment of at least 2 wk with no noticeable improve-ment. Response to therapy was de� ned as resolved withno further complaints of pain; improved if the patient orparent estimated a minimum decrease of 50% incomplaints or apparent severity of pain and as noresponse if there was no discernible change in thechild’s complaints. Statistical analysis was used ofunpaired t-test and a p value of 0.05 or less wasconsidered to be signi� cant.

Results and case reportsOne-hundred-and-twenty-four children referred for all

Table 1. Age, gender, calcium excretion, 1,25(OH)2 vitamin D3 and iPTH in 52 children with abdominal and/or lumbar pain and IH.

Total Males Females

n (%) 52 22 (42) 30 (58)Age (y)

Mean 6.7 § 3.5 7.2 § 3.2 6.3 § 3.7Range 0.9–15.7 2.5–15.7 0.9–14.5

Abdominal pain 39 15 24Lumbar pain 8 6 2

Both 5 1 4UCa/UCr, mg/mg

Mean (n) 0.27 § 0.15 (51) 0.29 § 0.17 (22) 0.26 § 0.13 (29)Range 0.04–0.87 0.04–0.87 0.05–0.58

Urine Ca mg/kg/dMean (n) 4.11 § 1.88 (45) 3.96 § 2.04 (20) 4.2 § 1.7 (25)Range 0.93–9.89 0.93–9.89 1.8–8.9

1,25(OH)2 vitamin D3, pg/dl (20–76)Mean (n) 56.9 § 25.2 (34) 47.8 § 12.5 (13) 62.5 § 28.6 (21)Range 28–144 28–70 29–144

C-PTH, pg/dl (50–330)Mean (n) 119.7 § 40.4 (22) 99.3 § 24.8 (10) 136.8 § 42.9 (12)Range 62–208 62–154 78–208

N-PTH, pg/dl (8–24)Mean (n) 19.0 § 7.4 (28) 19.5 § 6.7 (11) 18.8 § 7.8 (17)Range 10–46 13–39 10–46

644 P Vachvanichsanon g et al. ACTA PÆDIATR 90 (2001)

forms of symptomatic IH, such as hematuria, abdominalpain, enuresis, UTI and diagnosed IH, comprised 52males and 72 females 0.1–15.9 y of age. Fifty-twochildren (42%) had RAP or lumbar pain due to IH. Themean age for children with abdominal or lumbar painwas not different from the children without such pain(6.7 § 3.5 y versus 6.6 § 3.7 y). One girl was less than1 y of age and one girl was less than 2 y of age. In the11-mo-old infant, the mother sought medical help forwhat she described as a “colicky infant”. This infant hada dramatic response to therapy with resolution of colic.The mean age of boys with RAP or � ank pain due to IHwas not different from that for girls with the sameproblem. A family history of urolithiasis was present in9 boys (41%), which was in one parent in 4 boys and inboth parents in 5 boys. Similarly, a family history ofurolithiasis was found in 17 girls (57%), which was inone parent in 14 and in both parents in 3 girls.

Random UCa/UCr in the 52 children with abdominalor � ank pain was lower than that for children withsymptomatic IH without abdominal or � ank pain(0.27 § 0.15 mg/mg versus 0.36 § 0.31 mg/mg, p 50.05). However, quantitative urine calcium excretionwas not different for the two groups (4.11 § 1.88mg/kg/d versus 4.60 § 2.56 mg/kg/d). Additionally,serum 1,25(OH)2 vitamin D3 and iPTH were notdifferent.

Table 1 gives correlation of age, sex, type of pain,UCa/UCr, quantitative urine calcium excretion,1,25(OH)2 vitamin D3 and iPTH in boys and girls withRAP and � ank pain due to IH. Four boys had UCa/UCr50.18 mg/mg; however, they each had quantitativeurine calcium excretion greater than 2 mg/kg/d. Mean24-h quantitative urine calcium excretion was measuredin 20 boys (91%), and exceeded 2 mg/kg/d in all but 2boys. However, in these boys, UCa/UCr was abnormal.Serum iPTH activity was not elevated in any of theboys. Bone � lms were performed in 11 males and oneboy showed a delay in bone age. In all 22 males,biochemical studies showed normal serum electrolytes,normal blood urea nitrogen (BUN), serum creatinine,alkaline phosphatase as well as normal serum totalcalcium and inorganic phosphorus. Urine culture was

positive in only one male. RUS and VCUG were bothnormal in this child. RUS, performed on 11 males(50%), showed one with functional grade 1 hydrone-phrosis.

Table 1 also gives non-fasting UCa/UCr in 29females (97%). Five girls had UCa/UCr less than0.18 mg/mg, but they each had quantitative urinecalcium excretion greater than 2 mg/kg/d. Mean UCa/UCr in females did not differ from that for males.Quantitative urine calcium excretion was measured in25 females (83%), and exceeded 2 mg/kg/d in all butone girl in whom the UCa/UCr was abnormal. Meanurine calcium excretion in females did not differ fromthat for the males. Serum 1,25(OH)2 vitamin D3 wasmeasured in 21 females (70%), and was not differentfrom that for males. Serum 1,25(OH)2 vitamin D3 waselevated in 9 girls (43%). Serum iPTH activity in girlswas also measured. C-terminal PTH was not elevated inany of the girls. N-terminal PTH was elevated in 2 girls(12%). Bone � lms were performed in 16 girls and allwere normal. Biochemical studies were also normal inall of the girls; however, serum HCO3 was low in threeof them. Studies in these girls did not demonstrate aurinary acidi� cation defect; however, a de� nite inves-tigation had not been performed. RUS in 23 femalesshowed one with a calyceal stone, two with grade 1functional hydronephrosis and the remaining 20 werenegative.

Table 2 gives associated � ndings in these patients.Three children who had renal stones had familyhistories of renal stones, two from one parental side,another from both parental sides. However, the labora-tory investigation was not signi� cantly different fromthat of children who did not have stones. Thirteen girls(43%) had at least one episode of UTI compared to onlyone boy. None of these children had structural urinarytract abnormalities. Finally, 2 males and 6 females hadevidence for apparent bladder spasms.

Table 3 gives response to treatment. All childrenreceived general treatment with liberal � uid intake andreduced dietary salt and dietary oxalate. Thirty-eightchildren (73%) also required pharmacotherapy (25F and13M). Signi� cantly, 14 of the 33 children (42%) withcomplete relief from pain received general treatmentalone. Twelve children were signi� cantly improved; allof whom also received pharmacotherapy. Thus, acombined total of 45 children (87%) responded totreatment for hypercalciuria. Five children failedtherapy and two were lost to follow-up. Three females

Table 2. Additional clinical manifestation s associated with abdom-inal and/or lumbar pain due to IH.

n (%) Males Females

Total patients (%) 52 22 (42) 30 (58)Hematuria 27 (52) 14 13

Microscopic 24 12 12Gross 3 2 1

Urinary infection 14 (27) 1 13Incontinence 10 (19) 4 6

Night 7 4 3Day 2 – 2Mixed 1 – 1

Bladder spasm 8 (15) 2 6Urolithiasis 6 (12) 3 3

Table 3. Response to treatment for recurrent abdominal or lumbarpain.

Response n (%) Males Females

Resolved 33 (63) 16 (48) 17 (52)Improved 12 (23) 4 (33) 8 (67)No response 5 (10) 1 (20) 4 (80)Unknown 2 (4) 1 (50) 1 (50)

ACTA PÆDIATR 90 (2001) Idiopathic hypercalciuri a and abdominal pain 645

had borderline low serum HCO3 concentration and alsoreceived alkali treatment. There was no correlation inUCa/UCr or 24-h urine calcium excretion and require-ment for pharmacotherapy and response to treatmentdid not statistically correlate with reduction in urinecalcium excretion. Finally, the � ve children who failedtreatment did not differ from those who did respond.

Case reportM.D. is a 5 y old white male with a history of RAP since2 y of age and which had worsened in the 8 mo prior toreferral. Family history of kidney stones was positivefor both parents. Abdominal ultrasound and an upper GIseries performed before referral was negative. At ourCenter, physical examination was non-contributory.Serum electrolyte, urea nitrogen, creatinine, calcium,phosphate and alkaline phosphatase were normal forage. Urinalysis and urine culture were negative. Ran-dom UCa/UCr was 0.44 mg/mg and 24-h urine calciumexcretion was 179 mg/d or 9.89 mg/kg/d. N-terminalPTH was normal. 1,25(OH)2 vitamin D3 was elevated to64 pg/ml. Bone � lms were normal. A diagnosis ofsymptomatic IH was made and he was started on liberal� uid intake, reduced dietary salt and oxalate andhydrochlorothiazide 1 mg/kg/d. The patient improveddramatically and random UCa/UCr decreased to0.31 mg/mg. Since he still had some pain, the hydro-chlorothiazide was increased to 2 mg/kg/d and potas-sium chloride was given as a supplement. He no longerhad pain after a 6-mo follow-up and had a normalrandom UCa/UCr of 0.06 mg/mg.

DiscussionGiven the myriad possible causes of RAP or lumbarpain in childhood, the diagnostic approach is dif� cult atbest. Stevenson and Ziegler suggested that in thesechildren the best clinician is an outstanding history takercombined with excellence in diagnostic acumen andcareful decision-making (11). Because the clinicalpicture is often vague, it may not be easy for theclinician to resist the temptation to assume a non-organic etiology and that the child is well with apossible “attention-getting” emotional disturbance.Recently, Balistreri suggested “what not to do for achild with RAP” and listed several indications that maysuggest an organic cause for the pain (12). Aspreviously mentioned, Moir suggested that laboratorystudies are rarely indicated in these children (7). Thus,the signi� cance of our study is that IH is shown to be anadditional important organic cause of RAP in children.If the possibility of IH is considered in the evaluationthis may well reduce the need for endoscopy or otherunnecessary tests or avoid an unwarranted diagnosis ofa behavioral problem.

We suggest that IH be considered in the evaluation of

the child with RAP or � ank pain as avoidance ofunnecessary or invasive tests and, in the majority ofcases, affording the child relief, must be the � rstobjective. Studies of children with hematuria due toIH demonstrated that hematuria preceded the develop-ment of urolithiasis by a few months or up to 15 y (13).Additionally, it is estimated that as many as 72% ofchildren with hematuria due to IH ultimately developstones (13). Thus, although only six children in ourstudy were found to have stones, the remaining childrenmust be considered at risk of developing renal stonediathesis in the future. Finally, it has been suggestedthat certain clinical manifestations of IH are correlatedwith various subtypes; however, our study provides noinsight as to which IH subtype might be more commonin children with RAP (14).

In this study, a family history of urolithiasis wasfound in 41% of boys and 57% of girls, and in 30% ofthe cases it was present in both parents’ families. Wereported that IH is familial and that kindreds oftenshowed urolithiasis as well as symptomatic andasymptomatic IH (4). Thus, a family history of uro-lithiasis is very suggestive for IH, but a negative familyhistory does not lessen the probability. A history ofassociated � ndings such as hematuria, urine incon-tinence, bladder spasms or UTI should also suggest thepossibility of underlying IH. Collectively, these � ndingswere present in more than one-half of our patients. IH isnow thought to be the most common cause of hematuriain childhood and we reported that urine incontinenceand UTI were also frequent � ndings in children with IH(15, 16).

The physical examination in the child with RAP orlumbar pain due to IH is frequently not very helpful.Interestingly, we have observed some patients who hadtenderness to palpation or percussion over the kidneyswhose complaint was limited to abdominal rather than� ank pain. We have not observed intra-abdominalorganomegaly by either physical examination or byultrasound in any child with abdominal colic or lumbarpain due to IH. With the exception of low serum CO2 inthree patients, the metabolic work-up was not con-tributory in our patients. This � nding is of considerableinterest, since a form of renal tubular acidosis ormetabolic acidosis associated with IH has been reported(17).

The de� nition of normal urine calcium excretion inchildren is controversial and both random UCa/UCr and24-h urine quantitative calcium excretion are used.Infants and younger children have a higher than normalUCa/UCr. Of the eight children under 3 y of age fourcases had urine calcium 44 mg/kg/d. Three cases hadurine calcium at 2.37, 3.19 and 3.39 mg/kg/d, respec-tively, and one case had UCa/UCr 0.42 mg/mg. Variousauthors have de� ned quantitative hypercalciuria inchildhood as from greater than 2.0 to a high of greaterthan 8.0 mg/kg/d (5, 18–20). Additionally, studiessuggest that age, sex and race may in� uence urine

646 P Vachvanichsanon g et al. ACTA PÆDIATR 90 (2001)

calcium excretion in children (18–22). Because of thedif� culty in collecting 24-h urine samples in younginfants, we also recommend that a persistently (at leasttwice) elevated random non-fasting UCa/UCr can beused to de� ne hypercalciuria in very young children ashas been reported by other investigators (23). The lowerUCa/UCr in IH children with IH and RAP or � ank paincompared to other children with symptomatic IH mayrelate mainly to the known irregularity of urine calciumexcretion at any given time. Thus, if the child’s age isappropriate, we urge at least two 24-h urine calciumdeterminations if the � rst study is normal but IH isstrongly suspected or the etiology of pain remainsunclear.

In patients whom N-PTH were measured, apparentsecondary hyperparathyroidism was present which maybe related, at least in part, to overall negative calciumbalance as a result of the hypercalciuria. Although wehave previously reported elevated PTH values inchildren with symptomatic IH, not all investigatorsreport this abnormality in children with IH (5, 23). It isinteresting that serum 1,25(OH)2 vitamin D3 waselevated in a total of 12 children, suggesting a role incausation of the IH. These children were not takingvitamins and elevated serum 1,25(OH)2 vitamin D3 isreported as a subtype of IH (24).

Given that only 6 children with IH in our study haddocumented urolithiasis, how might non-calculous IHhave caused the complaint of RAP or lumbar pain in theremaining 46 children? Since this study was a retro-spective review, some data were limited and we hadonly 34 patients who had RUS performed. Both patientswho had negative � nding of RUS and who did not haveRUS performed should be followed as at risk of stoneformation (25). We previously speculated that calciumcrystals in these children causes irritation to urinarytract epithelium producing non-calculous clinical man-ifestations (3). The actual pain may well be more relatedto pelvoureteral and bladder spasm as a result of crystalinjury, since antispasmodics often afford relief withoutthiazide therapy. Similar pelvoureteral spasm is alsothought to play a major role in renal stone pain (26). Thefrequent � nding of hematuria and UTI in these childrenis supportive evidence for crystal injury since these arealso common in overt urolithiasis (26). Alternatively,calcium crystals may exist as aggregates of calciumoxalate as an early form of stone formation but are toosmall to be detected by present ultrasonographic tech-niques.

The majority of children with abdominal or � ank paindue to IH had either signi� cant improvement orcomplete resolution of all pain following initiation ofgeneral therapy, pharmacotherapy or both. Althoughnot shown here, the time required for response variedfrom a few weeks to as much as 11 mo. Thus far, thereare no clinical or biochemical side effects observed.Once thiazide was stopped, UCa/UCr increased. How-ever, abdominal pain recurred in some children while in

others it did not. The � ve cases which did not respond totreatment could be RAP, thus not affected by IHtreatment; individuals non-responsive to the IH treat-ment; or RAP of psychosomatic origin, which isdif� cult to prove at any time, and much more so in aretrospective study such as this. There is no associationbetween recurrence of abdominal pain and UCa/UCrlevels. We tried to stop the medication after a symptom-free period of at least 3 mo. Of considerable interest isour observation that there may be dissociation betweenimprovement or cessation of pain and change in urinecalcium excretion (data not shown). In several of ourpatients, hypercalciuria persisted despite improvementor complete resolution of pain. We interpret thepersistence of hypercalciuria with resolution of the painin some children as further evidence for the importantrole of pelvoureteral or bladder spasm as the etiology ofthe pain in these children. Since the pain could be due toeither direct crystal injury or urinary tract spasm andsince each of the medications is speci� c for each painmechanism, we used both medications to relieve pain.

Our demonstration of symptomatic IH as an im-portant cause of RAP or � ank pain due to urine calciumcrystallization without overt stone formation may beunderstandably viewed with some skepticism. Wepostulate that calcium crystals or micro-aggregates ofcalcium irritate the epithelium of the urinary tract,resulting in pelvoureteral muscle spasm and RAP inthese children with non-calculous idiopathic hypercal-ciuria. However, non-calculous clinical disorders due toIH in children is now well documented. This studysuggests that in some children previously thought tohave unexplained pain or pain due to dif� cult-to-provenon-organic causes such as emotional disorders, maywell have symptomatic IH. Thus, although there may beinitial skeptics, the signi� cance of our study is that werecommend the simple procedure of a non-fastingrandom UCa/UCr ratio be part of the routine evaluationof children with RAP or � ank pain. We recommenddoing it at least twice when clinical data are suggestive.Furthermore, if random UCa/UCr is normal but there isa family history of urolithiasis, quantitative urinecalcium determination may help to establish thediagnosis. For particularly dif� cult children in whomall studies are negative but continue to suffer from pain,we agree with the suggestion by Weir of a therapeutictrial with thiazide (27). Although Weir reported on asingle adolescent, we agree in clinical settings to try it inchildren with RAP of unknown etiology and in whomthiazide is not contraindicated. If thiazide therapy doesnot provoke a serious side effect, a therapeutic trial maybe more cost effective than further investigations andpain relief. However, because of our experience, westrongly urge use of general treatment measures of aliberal � uid intake combined with reduction in dietarysalt and oxalate be used either before thiazides or inaddition to a therapeutic trial of thiazide. Finally, if atherapeutic trial of thiazide is considered, we further

ACTA PÆDIATR 90 (2001) Idiopathic hypercalciuri a and abdominal pain 647

suggest combining it with an antispasmodic. Unfortu-nately, the clinical decision to continue drug therapyafter resolution of pain is unanswered by our study. Thereports of the long-term possibility of renal stones inchildren with hematuria due to IH suggest thatcontinuation of thiazide therapy must be seriouslyconsidered in those children with persistent hypercal-ciuria despite resolution of pain (13). More insight intothis problem must await further follow-up of childrenwith RAP due to IH.

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Received Aug. 1, 2000; revision received Nov. 13, 2000; acceptedNov. 20, 2000

648 P Vachvanichsanon g et al. ACTA PÆDIATR 90 (2001)