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Short-term outcome of mild isolated antenatal hydronephrosis conservatively managed
Journal of Pediatric Urology (2012) 8, 129e133
Short-term outcome of mild isolated antenatal hydronephrosis conservatively managed Marı´a Marcela Tombesi a,*, Laura Fernanda Alconcher b a
Radiology Department, Hospital Interzonal General de Agudos “Dr. Jose´ Penna”, Lainez y Necochea, Bahı´a Blanca,Provincia de Buenos Aires, Argentina b Pediatric Nephrology Unit, Hospital Interzonal General de Agudos “Dr. Jose´ Penna”, Lainez y Necochea, Bahı´a Blanca,Provincia de Buenos Aires, Argentina Received 21 January 2011; accepted 10 June 2011 Available online 28 July 2011
KEYWORDS Hidronephrosis prenatal; Mild; Outcome; Conservatively management
Abstract Objectives: To assess the outcome of newborns with mild isolated antenatal hydronephrosis (MIAHN) managed with neither antibiotic prophylaxis nor voiding cystourethrography (VCUG). Material and methods: Inclusion criteria: anterior-posterior pelvic diameter 5e15 mm at third trimester of gestation, confirmed by first postnatal ultrasound. Exclusion criteria: pelvic diameter > 15 mm, calyectasis, hydroureteronephrosis, renal or bladder abnormalities. Clinical and ultrasound follow-up was performed. Parents were familiarized with urinary tract infection (UTI) signs. If UTI was confirmed, VCUG was performed. Hydronephrosis outcome was assessed as intrauterine resolution, total or partial resolution, stability or progression. Results: MIAHN was detected in 193 newborns (109 unilateral, 84 bilateral; 277 renal units); 23 (12%) had UTI and 2 of them showed low-grade reflux. After a mean follow-up of 15 months, 91 renal units showed intrauterine resolution (33%), 111 (40%) total resolution, 20 (7%) partial resolution, 52 (19%) stability and 3 (1%) progression. Conclusion: Total resolution of hydronephrosis was observed in 73% of renal units during the first year. Routine antibiotic prophylaxis and VCUG might not be necessary in all infants with MIAHN, clinical and ultrasound follow-up being advisable during the first year of life. ª 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction Mild isolated antenatal hydronephrosis (MIAHN) represents not only the most frequent urinary tract abnormality detected by antenatal ultrasound (US) but also the most frequent fetal abnormality [1e3].
Different criteria have been used to define hydronephrosis (HN) and different cut-off limits to define mild HN [1,4,5e7]. Following Grignon et al. and Homsy et al. we consider HN to be mild when the anterior-posterior pelvic diameter (APPD) is 5e15 mm, without calyceal dilatation and with normal cortical thickness on prenatal and
* Corresponding author. Tel.: þ54 291 155067733. E-mail address: [email protected] (M.M. Tombesi). 1477-5131/$36 ª 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2011.06.009
130 postnatal US [5,6]. Isolated HN means HN not associated with other morphologic renal tract abnormalities. There is growing evidence that MIANH is a benign condition, but controversy still exists about the need to perform voiding cystourethrography (VCUG) and the prescription of antibiotic prophylactics (AP) to all newborns (NB) with MIAHN [8e21]. Systematic screening without differentiating populations at risk would imply overinvestigation and over-treatment in a significant number of asymptomatic NB. From 1989 to 1998, according to the bibliography recommendations of that time, we prescribed AP and performed VCUG in all NB with MIAHN. Worried about the real value of this systematic practice, in 1998 we decided to follow cases conservatively, and in 2003 we analyzed the data from these two periods. From 1989 to 1998, 23 NB were investigated using VCUG and AP was prescribed from birth. The incidence of vesicoureteral reflux (VUR) in this group was 13%. Only one patient had a UTI and his VCUG was normal. From 1998 to 2003, 47 NB who received neither AP nor VCUG were followed: 4 patients had a UTI and the VCUG performed post UTI showed in one of them grade I reflux and a vesical diverticulum in another. The difference in incidence of UTI was not statistically significant between the groups with and without AP (p Z 0.24) [14].Taking into account these results, our approach was changed and since then neither VCUG nor AP has been indicated systematically in NB with MIAHN. The aim of this study was to assess the outcome of NB with MIAHN who were conservatively managed since 1998.
M.M. Tombesi, L.F. Alconcher each visit, physical examination was done and weight and height were recorded. UTI was suspected when the infant had fever higher than 38 C or less than 38 C associated with failure to thrive, vomiting, irritability, lethargy and poor feeding. The diagnosis was confirmed by urinary sample. Collection by bag was not used; urine samples were obtained by midstream clean-catch technique. Transurethral catheterization or suprapubic aspirations were used only if sepsis was suspected [22,23]. Urinary microscopy for pyuria and dipstick for nitrites and leukocyte esterase were performed in all the urinary samples. Pyuria was considered as more than five white blood cells per high-power field. A positive urine culture was defined as more than 105 colonyforming units of a single pathogen. If UTI was confirmed, a cyclic VCUG (three voiding cycles, the third without catheter) was prescribed and 99mTc-dimercaptosuccinic acid scintigraphy was performed 6 months after the episode. VUR was graded according to the International Reflux Study Committee [24]. The outcome of HN was assessed as intrauterine resolution (NB with antenatal pelvic dilatation and without dilatation on first postnatal US), total resolution, partial resolution, stability and/or progression of the HN. The outcome of HN and the incidence of UTI in NB with APPD 5e10 mm and those with APPD 11e15 mm were compared. For statistical analysis, the Chi-square test was applied and p < 0.05 was considered significant. The study was approved by the local Ethics Committee.
Results Material and methods This is a prospective observational study of a cohort of patients with MIAHN. From January 1998 to January 2009, 354 NB with antenatal renal abnormalities were prospectively studied in our institution. The inclusion criteria were NB with APPD of 5e15 mm at third trimester of gestation, confirmed by the first postnatal US performed at day 3e7 after birth. The exclusion criteria were: APPD greater than 15 mm, calyectasis, hydroureteronephrosis, renal abnormalities such as small kidney, irregular shape, poor corticomedullary differentiation, increased echogenicity, parenchymal thinning and/or bladder alterations. Clinical and US follow-up was performed at 1, 3, 6 and 12 months or until two consecutive normal US were obtained. An APPD equal to or less than 5 mm was considered normal. US were carried out with Toshiba Capasee and Sonosite Titan machines equipped with transducers of 3.5, 5 and 7.5 MHz, getting longitudinal and transverse plane images with the child in prone and supine position. Neither VCUG nor AP was indicated. Familiar history of urinary tract abnormalities was recorded. Parents were instructed about when UTI should be suspected, how to collect the urine sample for culture, to call immediately when pyuria appeared, and about the importance of starting an early treatment. Before giving consent, they were informed about the possibility of reflux, the possibility of progression of the HN and the importance of the followup. The clinical and US follow-up was performed by the same pediatric nephrologist and pediatric radiologist. At
Of 354 NB with urinary tract abnormalities detected by antenatal US, 208 had MIAHN, being unilateral in 119 and bilateral in 89. After the first postnatal US, 15 NB were excluded, 10 with unilateral and 5 with bilateral MIAHN. Of these, 10 were excluded because they showed hydroureteronephrosis, 2 because of small kidney, 2 with calyectasis, and the last one had an APPD greater than 15 mm. Therefore, 193 NB achieved the inclusion criteria, being unilateral in 109 (56%) and bilateral in 84 (44%), resulting in a total of 277 renal units. Thirty-three NB (34 renal units) had an APPD of 11e15 mm. In 76 NB (70%) with unilateral HN the left kidney was affected. One hundred and forty-eight NB were males (77%). Twenty-three patients had UTI (12%), all of whom had pyuria. UTI was more frequent in girls: 8 out of 45 females (18%) vs 15 out of 148 males (10%), but this difference was not statistically significant (p Z 0.26). The mean age at first UTI was 7 months (range: 1e24 months). No patient required hospitalization. The difference in incidence of UTI was not statistically significant between NB with APPD 5e10 mm and those with APPD 11e15 mm (Table 1). In all patient with UTI, a cyclic VCUG was performed: 2 patients (1 female) showed grade I reflux and 1 boy a small vesical diverticulum. Only 1 patient (female) with UTI and without VUR had slight abnormalities on DMSA scan. The outcome of HN was evaluated as renal units. Ninetyone showed intrauterine resolution (33%), 111 (40%) total resolution, 20 (7%) partial resolution, 52 (19%) stability and 3 (1%) progression of the HN, after a mean follow-up of 15
Mild isolated antenatal hydronephrosis
131
Table 1 UTI by APPD in newborns with mild isolated antenatal hydronephrosis. 23 NB with UTI
Yes
No
APPD 11e15 mm APPD 5e10 mm
1 22
32 138
P Z 0.15.
months (median 7.5 months, range 1e114 months). The patients with 1 month of follow-up were 17 NB that belonged to the subgroup with intrauterine resolution of HN. Two of the three patients who showed progression of the HN required surgery, and in one a polar artery was found. The third patient with moderate HN and normal renal function went on follow-up. The outcome of HN was similar between the patients with APPD of 5e10 mm and those with APPD of 11e15 mm (Table 2).
Discussion MIAHN represented in our hospital more than half of the antenatal renal abnormalities detected by antenatal US. A growing detection rate has been reported in the last years, being in the Ismaili series as high as 4.5% [25]. This could be related to the widespread use of US during pregnancy and the improvement in US techniques [2]. We have also noticed this tendency in our institution, where detection has been more than doubled in the last 6 years (23 NB with MIAHN from 1989 to 1998, 47 from 1998 to 2003 and 146 from 2003 to 2009). The main objective of postnatal images is to confirm the prenatal findings and to make an accurate diagnosis. In our cohort, 15 out of the 203 NB with antenatal diagnosis of MIAHN (7%) had another diagnosis on the initial postnatal US that required different management. In experienced hands, the first detailed postnatal US is the most important procedure to decide further investigation [15]. There are different cut-off points to define mild HN. For most of the authors the upper limit of the APPD is 10 mm [8,12,17e19,21]. To our knowledge, this is one of the largest cohorts of patients with an APPD up to 15 mm, managed with neither VCUG nor AP, and in whom outcome was assessed. Even nowadays a lack of agreement exists concerning the need for a postnatal VCUG in all NB with MIAHN. Some authors recommend to perform VCUG in all NB and others consider that this group of patients should not be studied or treated [2,8,10e12,14,16,17,21]. Tibballs and De Bruyn found that 25% of NB with normal postnatal US had VUR grade III or more, so they recommended performing VCUG in all NB with antenatal HN even if they showed Table 2 Hydronephrosis outcome based on APPD of 277 renal units.
APPD 11e15 mm APPD 5e10 mm
IURs and TR«
PR
SN
P
23 179
5 15
5 47
1 2
p Z 0.71. IURs intrauterine resolution, TR« total resolution, PR partial resolution, SN stability, P progression.
intrauterine resolution [16]. Recently, Estrada et al. recommended that patients with a history of prenatal HN and postnatal persistent grade II HN should be screened with VCUG early in life and placed on AP [11]. On the other hand, Yerkes et al. concluded that VCUG is not mandatory in HN of grade II or less if close follow-up and AP is possible for at least 6 months [21]. Lidefelt and Herthelius concluded that infants with minor postnatal dilatation do not need AP if VCUG show no VUR [12]. We agree with De Kort et al., who affirmed that in infants with HN up to 15 mm non-invasive postnatal follow-up is justified and VCUG should not be performed except in cases of ureteral dilatation [10]. In a recent meta-analysis, Lee et al. stated that children with MIAHN that persists postnatally or children with resolved antenatal HN should be considered for further imaging studies case by case [20]. Similar recommendations were reported by the Society for Fetal Urology and, in a recent consensus, 25% of their members would institute AP and perform VCUG in NB with unilateral MIAHN that does not persist postnatally and 50% would do so if MIAHN persists [8]. It is true that no statistically significant relationship has been found between the degree of HN and the presence of VUR, confirming the poor predictive value of US for diagnosing VUR [16,20,26]. In series that performed VCUG for all NB with antenatal HN, the prevalence of VUR was between 12% and 33% [2,17,27]. We admit that when VCUG is omitted VUR may be missed. But what is the clinical significance of detecting VUR in an asymptomatic NB with MIAHN? VCUG is an invasive and distressing method for children and parents, is not without risks such as UTI, and involves a considerable gonadal radiation dose in this vulnerable population [28,29]. The relationship between VUR, UTI and renal damage is complex [30,31]. The importance of VUR has been questioned because acquired renal scarring is related more to infection than to the presence or absence of reflux [32]. The main way to prevent or minimize renal damage is the early diagnosis and treatment of UTI. The intensive search for VUR in the last 30 years has not changed the prevalence of chronic renal disease, probably because most of the cases of chronic renal failure are associated with renal dysplasia [33]. Congenital renal damage coexists frequently with highgrade VUR, especially in males, and constitutes the subgroup of NB with the highest risk of developing chronic renal failure. The most common US findings of congenital renal damage are small kidney, thinned or hyper-echoic cortex and cortical cysts with or without HN [27,34,35]. While the prevalence of VUR in children with UTI is nearly 30% [36], in our group the prevalence was very low. This difference is difficult to explain, but it could be due to the fact that we studied a very select group of NB who only had mild and isolated HN without ureteral dilatation, or renal or bladder abnormalities. The incidence of UTI reported in children is 8.4% in girls and 1.7% in boys before the age of 7 years [37]. In our group, the incidence was higher than in the general population (12%). This has been reported by other authors and is probably related to the intensive research on UTI, to the fact that in our country circumcision is not performed on boys with UTI, and to the possibility of overestimation if the urine sample was not collected in a proper manner [38]. Also, parent education improves the care of this group of children. A study which
132 focused on the effect of a nurse-led education program showed an increase in identification of children with UTI and improved referral of those at risk of renal damage [39]. AP from birth in babies with antenatal HN has been recommended to prevent UTI and further renal damage until VUR has been resolved [11,12,17]. Coelho et al. reported that, despite the use of AP, UTI occurred in 14% of 192 children with prenatal renal dilatation [38]. Few studies have followed infants with antenatal HN without AP. Kapadia et al. followed 51 infants with antenatal HN up to 10 mm with neither AP nor VCUG during 2 years, and none of them had UTI [40]. Recently, the role of AP has been increasingly questioned, even in patients in whom VUR has been confirmed [41e43]. Two randomized controlled trials about AP and VUR showed that AP does not significantly decrease the risk of recurrent UTI and may increase the risk of resistant organisms [42,43]. If we had performed VCUG in the 193 NB with MIAHN and if we had indicated AP to all the patients with VUR, we could have prevented, at best, the UTI of 2 patients. In our study, two thirds of cases showed resolution of the HN in the first year of life and progression was observed in 3 patients (1.5%). Similarly, Anderson et al followed prospectively 208 NB with MIAHN without reflux and they observed resolution of the renal dilatation in 70% and progression in 2.4% [17]. Our study has some important limitations. There was no control group. In a previous experience with a small cohort of patients we found that the incidence of UTI was the same in patients on or off AP [14]. In spite of the fact that the sample size of this experience was too small to give definite conclusions, from that moment on no routine AP or VCUG was indicated. Since sterile VUR is innocuous and MIAHN represented more than half of the abnormalities, we believe that the risks of performing VCUG in all such asymptomatic NB outweigh the benefits of recognizing cases of sterile VUR. Our intention is to evaluate this conservative approach for a longer period of time.
Conclusion MIAHN was the most frequent urinary tract abnormality (54%) detected by antenatal US, and predominantly in males. The incidence of UTI was 12% and the prevalence of VUR in patients with UTI was less than 10%. Total resolution of the HN was observed in 73% of renal units, and 1% progressed during the first year of life. Our results give information to be exchanged between pediatricians and parents, allowing parents the opportunity to be involved in decisions about their child’s care and treatment. We recommend clinical and US follow-up during at least the first year of life, and we believe that routine AP and VCUG might not be necessary in all asymptomatic infants with MIAHN.
Conflict of interest None declared.
M.M. Tombesi, L.F. Alconcher
References [1] Sidhu G, Beyene J, Rosenblum ND. Outcome of isolated antenatal hydronephrosis: a systematic review and metaanalysis. Pediatr Nephrol 2006;21:218e24. [2] Mallik M, Watson AR. Antenatally detected urinary tract abnormalities: more detection but less action. Pediatr Nephrol 2008;23:897e904. [3] Estrada Jr CR. Prenatal hydronephrosis: early evaluation. Curr Opin Urol 2008;18:401e3. [4] Corteville JE, Gray DL, Crane JP. Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome. Am J Obstet Gynecol 1991;165:384e8. [5] Grignon A, Filion R, Filiatrault D, Robitaille P, Homsy Y, Boutin H, et al. Urinary tract dilatation in utero: classification and clinical applications. Radiology 1986;160:645e7. [6] Homsy YL, Saad F, Laberge I, Williot P, Pison C. Transitional hydronephrosis of the newborn and infant. J Urol 1990;144: 579e83. [7] Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol 1993;23:478e80. [8] Nguyen HT, Herndon CD, Cooper C, Gatti J, Kirsch A, Kokorowski P, et al. The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis. J Pediatr Urol 2010;6:212e31. [9] Ismaili K, Avni F, Piepsz A, Wissing K, Cochat P, Aubert D, et al. Current management of infants with fetal renal pelvis dilation: a survey by French-speaking pediatric nephrologists and urologists. Pediatr Nephrol 2004;19:966e71. [10] de Kort EHM, Bambang Oetomo S, Zegers SHJ. The long-term outcome of antenatal hydronephrosis up 15 millimeters justifies a noninvasive postnatal follow-up. Acta Paediatr 2008;97:708e13. [11] Estrada CR, Peters CA, Retik AB, Nguyen HT. Vesicoureteral reflux and urinary tract infection in children with a history of prenatal hydronephrosiseshould voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis? J Urol 2009;181:801e6. [12] Lidefelt K, Herthelius M. Antenatal hydronephrosis: infants with minor postnatal dilatation do not need prophylaxis. Pediatr Nephrol 2008;23:2021e4. [13] Misra D, Kempley ST, Hird MF. Are patients with antenatally diagnosed hydronephrosis being over-investigated and overtreated? Eur J Pediatr Surg 1999;5:303e6. [14] Alconcher L, Tombesi M. Mild antenatal hydronephrosis: management controversies. Pediatr Nephrol 2004;19:819e20. [15] de Bruyn R, Marks SD. Postnatal investigation of fetal renal disease. Semin Fetal Neonatal Med 2008;3:133e41. [16] Tibballs JM, De Bruyn R. Primary vesicoureteric refluxdhow useful is postnatal ultrasound? Arch Dis Child 1996;75:444e7. [17] Anderson NG, Fischer J, Leighton D, Hector-Taylor J, McEwing RL. Management in children of mild postnatal renal dilatation but without vesicoureteral reflux. Pediatr Nephrol 2010;25:477e83. [18] Mamı` C, Paolata A, Palmara A, Marrone T, Berte LF, Marseglia L, et al. Outcome and management of isolated moderate renal pelvis dilatation detected at postnatal screening. Pediatr Nephrol 2009;10:2005e8. [19] Coelho GM, Bouzada MC, Pereira AK, Figueiredo BF, Leite MR, Oliveira DS, et al. Outcome of isolated antenatal hydronephrosis. A prospective cohort study. Pediatr Nephrol 2007; 22:1653e6. [20] Lee RS, Cendron M, Kinnamon DD, Nguyen HT. Antenatal hydronephrosis as a predictor of postnatal outcome: a metaanalysis. Pediatrics 2006;118:586e93.
Mild isolated antenatal hydronephrosis [21] Yerkes EB, Adams MC, Pope JC, Brock JW. Does every patient with prenatal hydronephrosis need voiding cystourethrography? J Urol 1999;162:1218e20. [22] Grimoldi I, Amore AI. Infeccio ´n urinaria. In: Comite ´ Nacional de Nefrologı´a Pedia ´trica, Sociedad Argentina de Pediatrı´a. Buenos Aires: Nefrologı´a Pedia ´trica; 2008. p. 407e23. [23] http://guidance.nice.org.uk/CG54/Guidance/pdf/English. [24] International Reflux Committee. Medical versus surgical treatment of primary vesicoureteral reflux. Pediatrics 1981; 67:392e400. [25] Ismaili K, Hall M, Donner C, Thomas D, Vermeylen D, Avni FE. Results of systematic screening for minor degrees of fetal renal pelvis dilatation in an unselected population. Am J Obstet Gynecol 2003;188:242e6. [26] Phan V, Traubici J, Hershenfield B, Stephens D, Rosenblum ND, Geary DF. Vesicoureteral reflux in infants with isolated antenatal hydronephrosis. Pediatr Nephrol 2003;18:1224e8. [27] Marra G, Barbieri G, Dell’Agnola CA, Caccamo ML, Castellani MR, Assael BM. Congenital renal damage associated with primary vesicoureteral reflux detected prenatally in male infants. J Pediatr 1994;124:726e30. [28] Agrawalla S, Pearce R, Goodman TR. How to perform the perfect voiding cystourethrogram. Pediatr Radiol 2004;34: 114e9. [29] Ismaili K, Avni FE, Hall M. Brussels Free University Perinatal Nephrology (BFUPN) Study Group. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr 2002;141:21e4. [30] Swerkersson S, Jodal U, Sixt R, Stokland E, Hansson S. Relationship among vesicoureteral reflux, urinary tract infection and renal damage in children. J Urol 2007;178:647e51. [31] Alconcher L, Tombesi M. Relacio ´n entre pielonefritis aguda, dan ˜o renal y reflujo vesicoureteral. Arch Argent Pediatr 2007; 105:211e5. [32] Gordon I, Barkovics M, Pindoria S, Cole TJ, Woolf AS. Primary vesicoureteral reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and a meta-analysis. J Am Soc Nephrol 2003;14: 739e44.
133 [33] Merguerian PA. Editorial comment. J Urol 2009;181(2):806e7. [34] Marra G, Oppezzo C, Ardissino G, Dacco ´ V, Testa S, Avolio L, et al. Severe vesicoureteral reflux and chronic renal failure: a condition peculiar to male gender? Data from the ItalKid Project. J Pediatr 2004;144:677e81. [35] Assael BM, Guez S, Marra G, Secco E, Manzoni G, Bosio M, et al. Congenital reflux nephropathy: a follow-up of 108 cases diagnosed perinatally. Br J Urol 1998;82:252e7. [36] Llera J, Caruso M, Ruiz E. Evaluacio ´n de las ecografı´as renales prenatalyposinfeccio ´n,ennin ˜ospequen ˜osconunprimerepisodio de infeccio ´n urinaria. Arch Argent Pediatr 2006;104:328e32. [37] Hellstro ¨m A, Hanson E, Hansson S, Hja ¨lmas K, Jodal U. Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 1991;66:232e4. [38] Coelho G, Bouzada M, Lemos G, Pereira A, Lima B, Oliveira E. Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation. J Urol 2008;179:284e9. [39] Coulthard MG, Vernon SJ, Lambert HJ, Matthews JNS, et al. A nurse led education and direct access service for the management of urinary tract infections in children: prospective controlled trial. BMJ 2003;327:656e61. [40] Kapadia H, Lidefelt K-J, Erasmie U, Pilo C. Antenatal renal pelvis dilatation emphasizing vesicoureteric reflux: two-year follow-up of minor postnatal dilatation. Acta Pediatr 2004; 93:336e9. [41] Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R. Recurrent urinary tract infection in children. Risk factors and association with prophylactic antimicrobials. Jama 2007;298:179e86. [42] Garin EH, Olavarria F, Garcı´a Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117:626e32. [43] Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008;121:1489e94.
Short-term outcome of mild isolated antenatal hydronephrosis conservatively managed Marı´a Marcela Tombesi a,*, Laura Fernanda Alconcher b a
Radiology Department, Hospital Interzonal General de Agudos “Dr. Jose´ Penna”, Lainez y Necochea, Bahı´a Blanca,Provincia de Buenos Aires, Argentina b Pediatric Nephrology Unit, Hospital Interzonal General de Agudos “Dr. Jose´ Penna”, Lainez y Necochea, Bahı´a Blanca,Provincia de Buenos Aires, Argentina Received 21 January 2011; accepted 10 June 2011 Available online 28 July 2011
KEYWORDS Hidronephrosis prenatal; Mild; Outcome; Conservatively management
Abstract Objectives: To assess the outcome of newborns with mild isolated antenatal hydronephrosis (MIAHN) managed with neither antibiotic prophylaxis nor voiding cystourethrography (VCUG). Material and methods: Inclusion criteria: anterior-posterior pelvic diameter 5e15 mm at third trimester of gestation, confirmed by first postnatal ultrasound. Exclusion criteria: pelvic diameter > 15 mm, calyectasis, hydroureteronephrosis, renal or bladder abnormalities. Clinical and ultrasound follow-up was performed. Parents were familiarized with urinary tract infection (UTI) signs. If UTI was confirmed, VCUG was performed. Hydronephrosis outcome was assessed as intrauterine resolution, total or partial resolution, stability or progression. Results: MIAHN was detected in 193 newborns (109 unilateral, 84 bilateral; 277 renal units); 23 (12%) had UTI and 2 of them showed low-grade reflux. After a mean follow-up of 15 months, 91 renal units showed intrauterine resolution (33%), 111 (40%) total resolution, 20 (7%) partial resolution, 52 (19%) stability and 3 (1%) progression. Conclusion: Total resolution of hydronephrosis was observed in 73% of renal units during the first year. Routine antibiotic prophylaxis and VCUG might not be necessary in all infants with MIAHN, clinical and ultrasound follow-up being advisable during the first year of life. ª 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Introduction Mild isolated antenatal hydronephrosis (MIAHN) represents not only the most frequent urinary tract abnormality detected by antenatal ultrasound (US) but also the most frequent fetal abnormality [1e3].
Different criteria have been used to define hydronephrosis (HN) and different cut-off limits to define mild HN [1,4,5e7]. Following Grignon et al. and Homsy et al. we consider HN to be mild when the anterior-posterior pelvic diameter (APPD) is 5e15 mm, without calyceal dilatation and with normal cortical thickness on prenatal and
* Corresponding author. Tel.: þ54 291 155067733. E-mail address: [email protected] (M.M. Tombesi). 1477-5131/$36 ª 2011 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2011.06.009
130 postnatal US [5,6]. Isolated HN means HN not associated with other morphologic renal tract abnormalities. There is growing evidence that MIANH is a benign condition, but controversy still exists about the need to perform voiding cystourethrography (VCUG) and the prescription of antibiotic prophylactics (AP) to all newborns (NB) with MIAHN [8e21]. Systematic screening without differentiating populations at risk would imply overinvestigation and over-treatment in a significant number of asymptomatic NB. From 1989 to 1998, according to the bibliography recommendations of that time, we prescribed AP and performed VCUG in all NB with MIAHN. Worried about the real value of this systematic practice, in 1998 we decided to follow cases conservatively, and in 2003 we analyzed the data from these two periods. From 1989 to 1998, 23 NB were investigated using VCUG and AP was prescribed from birth. The incidence of vesicoureteral reflux (VUR) in this group was 13%. Only one patient had a UTI and his VCUG was normal. From 1998 to 2003, 47 NB who received neither AP nor VCUG were followed: 4 patients had a UTI and the VCUG performed post UTI showed in one of them grade I reflux and a vesical diverticulum in another. The difference in incidence of UTI was not statistically significant between the groups with and without AP (p Z 0.24) [14].Taking into account these results, our approach was changed and since then neither VCUG nor AP has been indicated systematically in NB with MIAHN. The aim of this study was to assess the outcome of NB with MIAHN who were conservatively managed since 1998.
M.M. Tombesi, L.F. Alconcher each visit, physical examination was done and weight and height were recorded. UTI was suspected when the infant had fever higher than 38 C or less than 38 C associated with failure to thrive, vomiting, irritability, lethargy and poor feeding. The diagnosis was confirmed by urinary sample. Collection by bag was not used; urine samples were obtained by midstream clean-catch technique. Transurethral catheterization or suprapubic aspirations were used only if sepsis was suspected [22,23]. Urinary microscopy for pyuria and dipstick for nitrites and leukocyte esterase were performed in all the urinary samples. Pyuria was considered as more than five white blood cells per high-power field. A positive urine culture was defined as more than 105 colonyforming units of a single pathogen. If UTI was confirmed, a cyclic VCUG (three voiding cycles, the third without catheter) was prescribed and 99mTc-dimercaptosuccinic acid scintigraphy was performed 6 months after the episode. VUR was graded according to the International Reflux Study Committee [24]. The outcome of HN was assessed as intrauterine resolution (NB with antenatal pelvic dilatation and without dilatation on first postnatal US), total resolution, partial resolution, stability and/or progression of the HN. The outcome of HN and the incidence of UTI in NB with APPD 5e10 mm and those with APPD 11e15 mm were compared. For statistical analysis, the Chi-square test was applied and p < 0.05 was considered significant. The study was approved by the local Ethics Committee.
Results Material and methods This is a prospective observational study of a cohort of patients with MIAHN. From January 1998 to January 2009, 354 NB with antenatal renal abnormalities were prospectively studied in our institution. The inclusion criteria were NB with APPD of 5e15 mm at third trimester of gestation, confirmed by the first postnatal US performed at day 3e7 after birth. The exclusion criteria were: APPD greater than 15 mm, calyectasis, hydroureteronephrosis, renal abnormalities such as small kidney, irregular shape, poor corticomedullary differentiation, increased echogenicity, parenchymal thinning and/or bladder alterations. Clinical and US follow-up was performed at 1, 3, 6 and 12 months or until two consecutive normal US were obtained. An APPD equal to or less than 5 mm was considered normal. US were carried out with Toshiba Capasee and Sonosite Titan machines equipped with transducers of 3.5, 5 and 7.5 MHz, getting longitudinal and transverse plane images with the child in prone and supine position. Neither VCUG nor AP was indicated. Familiar history of urinary tract abnormalities was recorded. Parents were instructed about when UTI should be suspected, how to collect the urine sample for culture, to call immediately when pyuria appeared, and about the importance of starting an early treatment. Before giving consent, they were informed about the possibility of reflux, the possibility of progression of the HN and the importance of the followup. The clinical and US follow-up was performed by the same pediatric nephrologist and pediatric radiologist. At
Of 354 NB with urinary tract abnormalities detected by antenatal US, 208 had MIAHN, being unilateral in 119 and bilateral in 89. After the first postnatal US, 15 NB were excluded, 10 with unilateral and 5 with bilateral MIAHN. Of these, 10 were excluded because they showed hydroureteronephrosis, 2 because of small kidney, 2 with calyectasis, and the last one had an APPD greater than 15 mm. Therefore, 193 NB achieved the inclusion criteria, being unilateral in 109 (56%) and bilateral in 84 (44%), resulting in a total of 277 renal units. Thirty-three NB (34 renal units) had an APPD of 11e15 mm. In 76 NB (70%) with unilateral HN the left kidney was affected. One hundred and forty-eight NB were males (77%). Twenty-three patients had UTI (12%), all of whom had pyuria. UTI was more frequent in girls: 8 out of 45 females (18%) vs 15 out of 148 males (10%), but this difference was not statistically significant (p Z 0.26). The mean age at first UTI was 7 months (range: 1e24 months). No patient required hospitalization. The difference in incidence of UTI was not statistically significant between NB with APPD 5e10 mm and those with APPD 11e15 mm (Table 1). In all patient with UTI, a cyclic VCUG was performed: 2 patients (1 female) showed grade I reflux and 1 boy a small vesical diverticulum. Only 1 patient (female) with UTI and without VUR had slight abnormalities on DMSA scan. The outcome of HN was evaluated as renal units. Ninetyone showed intrauterine resolution (33%), 111 (40%) total resolution, 20 (7%) partial resolution, 52 (19%) stability and 3 (1%) progression of the HN, after a mean follow-up of 15
Mild isolated antenatal hydronephrosis
131
Table 1 UTI by APPD in newborns with mild isolated antenatal hydronephrosis. 23 NB with UTI
Yes
No
APPD 11e15 mm APPD 5e10 mm
1 22
32 138
P Z 0.15.
months (median 7.5 months, range 1e114 months). The patients with 1 month of follow-up were 17 NB that belonged to the subgroup with intrauterine resolution of HN. Two of the three patients who showed progression of the HN required surgery, and in one a polar artery was found. The third patient with moderate HN and normal renal function went on follow-up. The outcome of HN was similar between the patients with APPD of 5e10 mm and those with APPD of 11e15 mm (Table 2).
Discussion MIAHN represented in our hospital more than half of the antenatal renal abnormalities detected by antenatal US. A growing detection rate has been reported in the last years, being in the Ismaili series as high as 4.5% [25]. This could be related to the widespread use of US during pregnancy and the improvement in US techniques [2]. We have also noticed this tendency in our institution, where detection has been more than doubled in the last 6 years (23 NB with MIAHN from 1989 to 1998, 47 from 1998 to 2003 and 146 from 2003 to 2009). The main objective of postnatal images is to confirm the prenatal findings and to make an accurate diagnosis. In our cohort, 15 out of the 203 NB with antenatal diagnosis of MIAHN (7%) had another diagnosis on the initial postnatal US that required different management. In experienced hands, the first detailed postnatal US is the most important procedure to decide further investigation [15]. There are different cut-off points to define mild HN. For most of the authors the upper limit of the APPD is 10 mm [8,12,17e19,21]. To our knowledge, this is one of the largest cohorts of patients with an APPD up to 15 mm, managed with neither VCUG nor AP, and in whom outcome was assessed. Even nowadays a lack of agreement exists concerning the need for a postnatal VCUG in all NB with MIAHN. Some authors recommend to perform VCUG in all NB and others consider that this group of patients should not be studied or treated [2,8,10e12,14,16,17,21]. Tibballs and De Bruyn found that 25% of NB with normal postnatal US had VUR grade III or more, so they recommended performing VCUG in all NB with antenatal HN even if they showed Table 2 Hydronephrosis outcome based on APPD of 277 renal units.
APPD 11e15 mm APPD 5e10 mm
IURs and TR«
PR
SN
P
23 179
5 15
5 47
1 2
p Z 0.71. IURs intrauterine resolution, TR« total resolution, PR partial resolution, SN stability, P progression.
intrauterine resolution [16]. Recently, Estrada et al. recommended that patients with a history of prenatal HN and postnatal persistent grade II HN should be screened with VCUG early in life and placed on AP [11]. On the other hand, Yerkes et al. concluded that VCUG is not mandatory in HN of grade II or less if close follow-up and AP is possible for at least 6 months [21]. Lidefelt and Herthelius concluded that infants with minor postnatal dilatation do not need AP if VCUG show no VUR [12]. We agree with De Kort et al., who affirmed that in infants with HN up to 15 mm non-invasive postnatal follow-up is justified and VCUG should not be performed except in cases of ureteral dilatation [10]. In a recent meta-analysis, Lee et al. stated that children with MIAHN that persists postnatally or children with resolved antenatal HN should be considered for further imaging studies case by case [20]. Similar recommendations were reported by the Society for Fetal Urology and, in a recent consensus, 25% of their members would institute AP and perform VCUG in NB with unilateral MIAHN that does not persist postnatally and 50% would do so if MIAHN persists [8]. It is true that no statistically significant relationship has been found between the degree of HN and the presence of VUR, confirming the poor predictive value of US for diagnosing VUR [16,20,26]. In series that performed VCUG for all NB with antenatal HN, the prevalence of VUR was between 12% and 33% [2,17,27]. We admit that when VCUG is omitted VUR may be missed. But what is the clinical significance of detecting VUR in an asymptomatic NB with MIAHN? VCUG is an invasive and distressing method for children and parents, is not without risks such as UTI, and involves a considerable gonadal radiation dose in this vulnerable population [28,29]. The relationship between VUR, UTI and renal damage is complex [30,31]. The importance of VUR has been questioned because acquired renal scarring is related more to infection than to the presence or absence of reflux [32]. The main way to prevent or minimize renal damage is the early diagnosis and treatment of UTI. The intensive search for VUR in the last 30 years has not changed the prevalence of chronic renal disease, probably because most of the cases of chronic renal failure are associated with renal dysplasia [33]. Congenital renal damage coexists frequently with highgrade VUR, especially in males, and constitutes the subgroup of NB with the highest risk of developing chronic renal failure. The most common US findings of congenital renal damage are small kidney, thinned or hyper-echoic cortex and cortical cysts with or without HN [27,34,35]. While the prevalence of VUR in children with UTI is nearly 30% [36], in our group the prevalence was very low. This difference is difficult to explain, but it could be due to the fact that we studied a very select group of NB who only had mild and isolated HN without ureteral dilatation, or renal or bladder abnormalities. The incidence of UTI reported in children is 8.4% in girls and 1.7% in boys before the age of 7 years [37]. In our group, the incidence was higher than in the general population (12%). This has been reported by other authors and is probably related to the intensive research on UTI, to the fact that in our country circumcision is not performed on boys with UTI, and to the possibility of overestimation if the urine sample was not collected in a proper manner [38]. Also, parent education improves the care of this group of children. A study which
132 focused on the effect of a nurse-led education program showed an increase in identification of children with UTI and improved referral of those at risk of renal damage [39]. AP from birth in babies with antenatal HN has been recommended to prevent UTI and further renal damage until VUR has been resolved [11,12,17]. Coelho et al. reported that, despite the use of AP, UTI occurred in 14% of 192 children with prenatal renal dilatation [38]. Few studies have followed infants with antenatal HN without AP. Kapadia et al. followed 51 infants with antenatal HN up to 10 mm with neither AP nor VCUG during 2 years, and none of them had UTI [40]. Recently, the role of AP has been increasingly questioned, even in patients in whom VUR has been confirmed [41e43]. Two randomized controlled trials about AP and VUR showed that AP does not significantly decrease the risk of recurrent UTI and may increase the risk of resistant organisms [42,43]. If we had performed VCUG in the 193 NB with MIAHN and if we had indicated AP to all the patients with VUR, we could have prevented, at best, the UTI of 2 patients. In our study, two thirds of cases showed resolution of the HN in the first year of life and progression was observed in 3 patients (1.5%). Similarly, Anderson et al followed prospectively 208 NB with MIAHN without reflux and they observed resolution of the renal dilatation in 70% and progression in 2.4% [17]. Our study has some important limitations. There was no control group. In a previous experience with a small cohort of patients we found that the incidence of UTI was the same in patients on or off AP [14]. In spite of the fact that the sample size of this experience was too small to give definite conclusions, from that moment on no routine AP or VCUG was indicated. Since sterile VUR is innocuous and MIAHN represented more than half of the abnormalities, we believe that the risks of performing VCUG in all such asymptomatic NB outweigh the benefits of recognizing cases of sterile VUR. Our intention is to evaluate this conservative approach for a longer period of time.
Conclusion MIAHN was the most frequent urinary tract abnormality (54%) detected by antenatal US, and predominantly in males. The incidence of UTI was 12% and the prevalence of VUR in patients with UTI was less than 10%. Total resolution of the HN was observed in 73% of renal units, and 1% progressed during the first year of life. Our results give information to be exchanged between pediatricians and parents, allowing parents the opportunity to be involved in decisions about their child’s care and treatment. We recommend clinical and US follow-up during at least the first year of life, and we believe that routine AP and VCUG might not be necessary in all asymptomatic infants with MIAHN.
Conflict of interest None declared.
M.M. Tombesi, L.F. Alconcher
References [1] Sidhu G, Beyene J, Rosenblum ND. Outcome of isolated antenatal hydronephrosis: a systematic review and metaanalysis. Pediatr Nephrol 2006;21:218e24. [2] Mallik M, Watson AR. Antenatally detected urinary tract abnormalities: more detection but less action. Pediatr Nephrol 2008;23:897e904. [3] Estrada Jr CR. Prenatal hydronephrosis: early evaluation. Curr Opin Urol 2008;18:401e3. [4] Corteville JE, Gray DL, Crane JP. Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome. Am J Obstet Gynecol 1991;165:384e8. [5] Grignon A, Filion R, Filiatrault D, Robitaille P, Homsy Y, Boutin H, et al. Urinary tract dilatation in utero: classification and clinical applications. Radiology 1986;160:645e7. [6] Homsy YL, Saad F, Laberge I, Williot P, Pison C. Transitional hydronephrosis of the newborn and infant. J Urol 1990;144: 579e83. [7] Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol 1993;23:478e80. [8] Nguyen HT, Herndon CD, Cooper C, Gatti J, Kirsch A, Kokorowski P, et al. The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis. J Pediatr Urol 2010;6:212e31. [9] Ismaili K, Avni F, Piepsz A, Wissing K, Cochat P, Aubert D, et al. Current management of infants with fetal renal pelvis dilation: a survey by French-speaking pediatric nephrologists and urologists. Pediatr Nephrol 2004;19:966e71. [10] de Kort EHM, Bambang Oetomo S, Zegers SHJ. The long-term outcome of antenatal hydronephrosis up 15 millimeters justifies a noninvasive postnatal follow-up. Acta Paediatr 2008;97:708e13. [11] Estrada CR, Peters CA, Retik AB, Nguyen HT. Vesicoureteral reflux and urinary tract infection in children with a history of prenatal hydronephrosiseshould voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis? J Urol 2009;181:801e6. [12] Lidefelt K, Herthelius M. Antenatal hydronephrosis: infants with minor postnatal dilatation do not need prophylaxis. Pediatr Nephrol 2008;23:2021e4. [13] Misra D, Kempley ST, Hird MF. Are patients with antenatally diagnosed hydronephrosis being over-investigated and overtreated? Eur J Pediatr Surg 1999;5:303e6. [14] Alconcher L, Tombesi M. Mild antenatal hydronephrosis: management controversies. Pediatr Nephrol 2004;19:819e20. [15] de Bruyn R, Marks SD. Postnatal investigation of fetal renal disease. Semin Fetal Neonatal Med 2008;3:133e41. [16] Tibballs JM, De Bruyn R. Primary vesicoureteric refluxdhow useful is postnatal ultrasound? Arch Dis Child 1996;75:444e7. [17] Anderson NG, Fischer J, Leighton D, Hector-Taylor J, McEwing RL. Management in children of mild postnatal renal dilatation but without vesicoureteral reflux. Pediatr Nephrol 2010;25:477e83. [18] Mamı` C, Paolata A, Palmara A, Marrone T, Berte LF, Marseglia L, et al. Outcome and management of isolated moderate renal pelvis dilatation detected at postnatal screening. Pediatr Nephrol 2009;10:2005e8. [19] Coelho GM, Bouzada MC, Pereira AK, Figueiredo BF, Leite MR, Oliveira DS, et al. Outcome of isolated antenatal hydronephrosis. A prospective cohort study. Pediatr Nephrol 2007; 22:1653e6. [20] Lee RS, Cendron M, Kinnamon DD, Nguyen HT. Antenatal hydronephrosis as a predictor of postnatal outcome: a metaanalysis. Pediatrics 2006;118:586e93.
Mild isolated antenatal hydronephrosis [21] Yerkes EB, Adams MC, Pope JC, Brock JW. Does every patient with prenatal hydronephrosis need voiding cystourethrography? J Urol 1999;162:1218e20. [22] Grimoldi I, Amore AI. Infeccio ´n urinaria. In: Comite ´ Nacional de Nefrologı´a Pedia ´trica, Sociedad Argentina de Pediatrı´a. Buenos Aires: Nefrologı´a Pedia ´trica; 2008. p. 407e23. [23] http://guidance.nice.org.uk/CG54/Guidance/pdf/English. [24] International Reflux Committee. Medical versus surgical treatment of primary vesicoureteral reflux. Pediatrics 1981; 67:392e400. [25] Ismaili K, Hall M, Donner C, Thomas D, Vermeylen D, Avni FE. Results of systematic screening for minor degrees of fetal renal pelvis dilatation in an unselected population. Am J Obstet Gynecol 2003;188:242e6. [26] Phan V, Traubici J, Hershenfield B, Stephens D, Rosenblum ND, Geary DF. Vesicoureteral reflux in infants with isolated antenatal hydronephrosis. Pediatr Nephrol 2003;18:1224e8. [27] Marra G, Barbieri G, Dell’Agnola CA, Caccamo ML, Castellani MR, Assael BM. Congenital renal damage associated with primary vesicoureteral reflux detected prenatally in male infants. J Pediatr 1994;124:726e30. [28] Agrawalla S, Pearce R, Goodman TR. How to perform the perfect voiding cystourethrogram. Pediatr Radiol 2004;34: 114e9. [29] Ismaili K, Avni FE, Hall M. Brussels Free University Perinatal Nephrology (BFUPN) Study Group. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr 2002;141:21e4. [30] Swerkersson S, Jodal U, Sixt R, Stokland E, Hansson S. Relationship among vesicoureteral reflux, urinary tract infection and renal damage in children. J Urol 2007;178:647e51. [31] Alconcher L, Tombesi M. Relacio ´n entre pielonefritis aguda, dan ˜o renal y reflujo vesicoureteral. Arch Argent Pediatr 2007; 105:211e5. [32] Gordon I, Barkovics M, Pindoria S, Cole TJ, Woolf AS. Primary vesicoureteral reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and a meta-analysis. J Am Soc Nephrol 2003;14: 739e44.
133 [33] Merguerian PA. Editorial comment. J Urol 2009;181(2):806e7. [34] Marra G, Oppezzo C, Ardissino G, Dacco ´ V, Testa S, Avolio L, et al. Severe vesicoureteral reflux and chronic renal failure: a condition peculiar to male gender? Data from the ItalKid Project. J Pediatr 2004;144:677e81. [35] Assael BM, Guez S, Marra G, Secco E, Manzoni G, Bosio M, et al. Congenital reflux nephropathy: a follow-up of 108 cases diagnosed perinatally. Br J Urol 1998;82:252e7. [36] Llera J, Caruso M, Ruiz E. Evaluacio ´n de las ecografı´as renales prenatalyposinfeccio ´n,ennin ˜ospequen ˜osconunprimerepisodio de infeccio ´n urinaria. Arch Argent Pediatr 2006;104:328e32. [37] Hellstro ¨m A, Hanson E, Hansson S, Hja ¨lmas K, Jodal U. Association between urinary symptoms at 7 years old and previous urinary tract infection. Arch Dis Child 1991;66:232e4. [38] Coelho G, Bouzada M, Lemos G, Pereira A, Lima B, Oliveira E. Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation. J Urol 2008;179:284e9. [39] Coulthard MG, Vernon SJ, Lambert HJ, Matthews JNS, et al. A nurse led education and direct access service for the management of urinary tract infections in children: prospective controlled trial. BMJ 2003;327:656e61. [40] Kapadia H, Lidefelt K-J, Erasmie U, Pilo C. Antenatal renal pelvis dilatation emphasizing vesicoureteric reflux: two-year follow-up of minor postnatal dilatation. Acta Pediatr 2004; 93:336e9. [41] Conway PH, Cnaan A, Zaoutis T, Henry BV, Grundmeier RW, Keren R. Recurrent urinary tract infection in children. Risk factors and association with prophylactic antimicrobials. Jama 2007;298:179e86. [42] Garin EH, Olavarria F, Garcı´a Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006; 117:626e32. [43] Pennesi M, Travan L, Peratoner L, Bordugo A, Cattaneo A, Ronfani L, et al. Is antibiotic prophylaxis in children with vesicoureteral reflux effective in preventing pyelonephritis and renal scars? A randomized, controlled trial. Pediatrics 2008;121:1489e94.