Role of antibiotic prophylaxis in antenatal hydronephrosis ... · In a previous systematic review by Braga et al. [4],no beneﬁt of CAP could be demonstrated in ANH. Infants with

+ MODEL

Journal of Pediatric Urology (2017) xx, 1e30

aDivision of Pediatric Urology,Department of Urology,Istanbul Medeniyet University,Istanbul, Turkey

bDepartment of Pediatric andAdult Urology, East and NorthHerts NHS Trust, Stevenage, UK

cDepartment of Urology,Freeman Hospital, Newcastleupon Tyne, UK

dDivision of Pediatric Urology,Department of Urology,Hacettepe University, Ankara,Turkey

eDepartment of Urology,General Teaching Hospital andCharles University, 1st Facultyof Medicine in Praha, Prague,Czechia

fDepartment of Urology andPediatric Urology, UniversityMedical Centre Groningen, TheNetherlands

gDepartment of Urology,University of Mainz, Germany

hDepartment of Urology, MedicalUniversity of Innsbruck, Austria

Correspondence to: M.S. Silay,Division of Pediatric Urology,Department of Urology, IstanbulMedeniyet University, DoktorErkin Caddesi, 34722, Kadikoy,Istanbul, Turkey, Tel.: þ90 505645 4005; fax: þ90 212 4530453

[email protected]

(M.S. Silay)

Keywords

Antenatal hydronephrosis;Antibiotic prophylaxis; Urinarytract infection; Children

Received 18 October 2016Accepted 5 February 2017Available online xxx

Please cite this article in prethe European Association ofhttp://dx.doi.org/10.1016/j.

http://dx.doi.org/10.1016/j.j1477-5131/ª 2017 Journal of P

Review Article

Role of antibiotic prophylaxis inantenatal hydronephrosis: A systematicreview from the European Association ofUrology/European Society for PaediatricUrology Guidelines Panel

Mesrur Selcuk Silay a, Shabnam Undre b, Arjun K. Nambiar c,Hasan Serkan Dogan d, Radim Kocvara e, Rien J.M. Nijman f,Raimund Stein g, Serdar Tekgul d, Christian Radmayr h

Summary

BackgroundThe benefits and harms of continuous antibioticprophylaxis (CAP) versus observation in patients withantenatal hydronephrosis (ANH) are controversial.

ObjectiveThe aim was to determine the effectiveness of CAPfor ANH, and if beneficial to determine the best typeand regimen of antibiotic and the most harmful toprovide guidance for clinical practice.

MethodsA systematic literature search was performed indatabases including Medline, Embase, and Cochranein June 2015. The protocol was prospectively regis-tered to PROSPERO (CRD42015024775). The searchstarted from 1980, when maternal ultrasound wasfirst introduced into clinical practice. Eligiblestudies were critically evaluated for risk of biasusing Revman software. The outcomes includedreduction in urinary tract infections (UTI), drug-related adverse events and kidney functions.

ss as: Silay MS, et al., Role of antibiotic prophylaxis in aUrology/European Society for Paediatric Urology Guidjpurol.2017.02.023

purol.2017.02.023ediatric Urology Company. Published by Elsevier Ltd. A

ResultsOf 797 articles identified, 57 full text articles and sixabstracts were eligible for inclusion (2 randomizedcontrolled trials, 11 non-randomized comparativestudies, and 50 case series). It remains unclearwhether CAP is superior to observation in decreasingUTIs. No conclusion could be drawn for drug-relatedadverse events and kidney function because of lackof data. Children who were not circumcised, withureteral dilatation, and high-grade hydronephrosismay be more likely to develop UTI, and CAP may bewarranted for these subgroups of patients. A ma-jority of the studies had low-to-moderate quality ofevidence and with high risk of bias.

ConclusionsThe benefits of CAP in a heterogeneous group ofchildren with ANH involving different etiologies re-mains unproven. However, the evidence in the formof prospective and retrospective observationalstudies has shown that it reduces febrile UTI inparticular subgroups.

Introduction

Antenatal hydronephrosis (ANH) is one of themost common birth abnormalities with anoverall incidence between 1% and 5% [1]. Thewidespread use of ultrasonography duringpregnancy has resulted in a higher detectionrate for ANH. Owing to the increased risk ofurinary tract infections (UTIs) and upper uri-nary tract (UUT) deterioration, the use ofcontinuous antibiotic prophylaxis (CAP) isrecommended [2,3]. However, the evidence-based data for this practice are lacking andthe use of CAP is generally based on expert

opinion. Prophylactic policies seem extremelyvariable, and UTI rates vary widely with com-parable rates reported between patients fol-lowed on and off antibiotics [4]. Nevertheless,infants who are potentially at increased risk ofUTI are recommended to receive CAP in manyreports.

Observation is another option in thosechildren which eliminates the side effects ofthe antibiotics and reduces the cost. However,the risk of developing UTI during observation isalso unclear. Therefore, the benefits andharms of CAP versus observation in patientswith ANH still remains controversial.

ntenatal hydronephrosis: A systematic review fromelines Panel, Journal of Pediatric Urology (2017),

ll rights reserved.

mailto:[email protected]

mailto:[email protected]

http://dx.doi.org/10.1016/j.jpurol.2017.02.023



2 M.S. Silay et al.

+ MODEL

In a previous systematic review by Braga et al. [4], nobenefit of CAP could be demonstrated in ANH. Infants withhigh-grade hydronephrosis (HN) were at increased risk ofdeveloping UTI. However, the other important variablessuch as ureteral dilatation, circumcision status, and ves-icoureteral reflux (VUR) could not be assessed.

The challenge in the management of ANH is to decidewhether CAP should be used or not, and if decided, inwhom, how, and when should it be started.

This systematic review was performed by the EuropeanAssociation of Urology (EAU) Pediatric Urology GuidelinePanel as part of its update for 2017 and aimed to determinethe effectiveness of CAP in infants with ANH, and, ifbeneficial, to determine the best type and regime of anti-biotic and the most harmful to provide guidance for clinicalpractice.

Methods

Search strategy

The protocol of this review was published in PROSPEROwebsite (www.crd.york.ac.uk) with the registration numberCRD42015024775. The search strategy is provided in theElectronic Supplement 1. In summary, databases, includingEmbase, Medline, and Cochrane, were systematicallysearched in June 2015. All abstracts and full texts of thearticles were evaluated by two independent reviewers(M.S.S., S.U.) for eligibility. Disagreements were resolvedby interactive discussion or by consulting an independentthird reviewer. Only studies published after 1980 wereincluded since maternal ultrasound was popularized after-wards. No language restrictions were applied. The searchwas supported by additional sources including pediatricurology congress abstracts and a panel of experts (EAU-ESPU Paediatric Urology Guideline Panel).

Types of study design

All study types, including randomized controlled trials(RCTs), non-randomized comparative studies (NRSs), andsingle-arm case series of no treatment or antibiotic pro-phylaxis for ANH. Systematic or narrative reviews wereexcluded but retained as a source for discussion.

Types of participants

Children (<18 years old) with HN diagnosed prenatally andconfirmed postnatally or diagnosed postnatally within thefirst year of life (for postnatal diagnosis, it has to be made 3days or more after delivery) were included. Only asymp-tomatic patients at diagnosis with bilateral or unilateral HNwere included in this review. The definition of HN includedall grades (1e4) of the Society for Foetal Urology (SFU),anteroposterior renal pelvis diameter, and severity (mild-moderate and severe) of HN. If grade or severity was notspecified, all types of descriptions and severity of HN wereincluded. The presence/absence of vesicoureteric reflux(VUR) was not an exclusion criterion, but data on this were

Please cite this article in press as: Silay MS, et al., Role of antibiotic pthe European Association of Urology/European Society for Paediatrihttp://dx.doi.org/10.1016/j.jpurol.2017.02.023

to be analyzed as a subgroup. The cause of HN was alsoconsidered as a subgroup (e.g., ureteropelvic junctionobstruction [UPJO], megaureter, VUR, duplicated systems,etc.). Children with solitary kidney, posterior urethralvalves, bladder exstrophy, and neurological abnormality(e.g., spina bifida) were excluded. The other subgroupsanalyzed were gender (girls versus boys), circumcisionversus non-circumcision for boys, grade of HN (low gradeversus high grade), and ureteral dilation (HNversus hydroureteronephrosis [HUN]).

Types of interventions

The experimental intervention was administration ofantibiotic prophylaxis in asymptomatic patients only,including (but not restricted to) trimethoprim, Macro-dantin, cephalosporin, amoxycillin, sulphometoxazole,with trimethoprim, and any others as specified by thetrialist and judged relevant by reviewer. The controlintervention was observation or no treatment in asymp-tomatic patients with ANH.

Types of outcome measures

The primary benefit outcome was the reduction in UTIs;there was no restriction on the definition of UTI (i.e., asdefined by trialists, including standardized or non-standardized definitions), measured within the first 2years of life. The primary harm outcomes were drug-related adverse effects (e.g., allergies, diarrhea, antimi-crobial resistance, constipation, etc.) and any otheradverse events as defined and reported by trialists.

The secondary outcomes were reduction in UTImeasured after 2 years of life, febrile and non-febrile in-fections, and function of kidney, defined in the followingways: (1) renography (i.e., split renal function; delayeddrainage from renal pelvis; etc.); (2) renal scarring (asdetermined by DMSA only); (3) anatomical or morphologicalchanges (as determined by ultrasound; e.g., changes to HN,anteroposterior diameter, etc.), measured at any timepoint. The other secondary outcomes were pain (as definedby trialist) and severity or grade of HN at the end of follow-up.

Assessment of risk of bias

The “risk of bias” (RoB) of each included study was assessedby two independent reviewers and any disagreement wasresolved by discussion or by consulting a third reviewauthor. RoB of the eligible RCTs were assessed by using therecommended tool in the Cochrane Handbook for System-atic Reviews of Interventions [5].

RoB in NRSs was assessed using all the domains used forRCTs plus assessing the risk of confounding. This was apragmatic approach informed by methodological literaturefor the assessment of RoB in NRSs. Four potential con-founders were identified and developed a priori by the EAUPaediatric Urology Guideline Panel: severity or grade of HN,cause of HN, gender, and circumcision status for boys. The

rophylaxis in antenatal hydronephrosis: A systematic review fromc Urology Guidelines Panel, Journal of Pediatric Urology (2017),

http://www.crd.york.ac.uk

Role of antibiotic prophylaxis in antenatal hydronephrosis 3

+ MODEL

judgment of each confounder depended on whether it wasmeasured, balanced between the groups, or if it was sta-tistically adjusted.

RoB in case series were assessed again with a pragmaticapproach informed by methodological literature. In thiscase, the judgment was based on whether the studyincluded consecutive patients, if there was a priori proto-col, attrition bias (patients lost to follow up accounted for)and if the outcome measurements were addressed.

Data analysis

The number of UTIs and other outcomes measured includingantibiotic type, dosage, and side effects were extractedfrom the eligible studies where available. The progress ofHN and renal function at the end of follow-up were alsoextracted where available. Meta-analyses was intended forthe data retrieved from RCTs, but because of the lack ofthis evidence data have been represented in Forest plotswithout meta-analysis (because of methodological hetero-geneity and the high RoB). For binary/dichotomous/cate-gorical benefit or harm outcomes, risk ratios (RR) or oddsratios (OR) were used where available. Mean difference(MD) or standardized mean difference (SMD) with corre-sponding 95% confidence intervals (CIs) were used to reportthe continuous outcomes.

If there were sufficient data, to elucidate the potentialimpact of clinical heterogeneity on outcomes, subgroupanalyses were planned for factors, including presence ofVUR, bladder pathology, distal ureteric dilatation, surgicalintervention, antibiotic regime, circumcision status,gender, and febrile UTIs (see protocol for the reviewhttp://www.crd.york.ac.uk/PROSPERO; registration num-ber CRD42015024775).

Figure 1 Prisma


Results

Quantity of evidence identified

The selection process of the studies is demonstrated inthe Preferred Reporting Items for Systematic Reviews andMeta-analysis (PRISMA) flow diagram (Fig. 1). A total of811 abstracts and titles were screened and 97 wereretrieved for full text screening. Finally, 63 studies werefound eligible for the systematic review, recruiting a totalof 10,019 children (RCTs, 85; NRSs, 4027; case series,5907). This included two RCTs [7,11] (1 as an abstractonly), 11 NRSs [6,8e10,12e18] (one as an abstract), and50 case series [19e68] with four of them published as anabstract.

Characteristics of the included studies

The baseline characteristics of the 13 comparative studiesand 50 case series are presented in Tables 1 and 2,respectively.

Characteristics of comparative studiesAlthough all patients recruited had ANH, the etiology wasvariable between the studies. Two studies included onlypatients with primary obstructive megaureter (POM) (1published as an abstract only) [6,16]. Three studiesexcluded children with VUR from their study cohort[6,7,16] while two studies included only patients with VUR[11,12].

The SFU grade or severity of HN was not stated in threestudies [11,14,16]. In one study, only patients with mild HNwere included [15], whereas in another only patients withSFU G2 HN were recruited [12].

flow diagram.


http://www.crd.york.ac.uk/PROSPERO

4 M.S. Silay et al.

+ MODEL

In six studies, the numbers of circumcised boys wereeither not stated or unclear [9,11,12,14,16,17]. In onestudy all boys were non-circumcised [10].

Development of UTI during follow-up was reported in allcomparative studies. However, the standardized definitionof UTI was made in six of them [7,8,13,15,17,18]. Antibioticside effects were not reported in any of the studies exceptone RCT [7].

Characteristics of case seriesA total of 50 case series were included in this review. Of the50 case series, 10 included patients with ANH plus VUR[31e33,37,42,43,49,58,61,63], three included ANH plusUPJO [20,47,66], five included ANH plus POM[21,23,34,50,67], and three included ANH plus ureterocele[27,28,30]. The rest of the case series included varioussubgroups.

The reported outcomes were variable in between theseries but mainly included UTI rates, prognostic factors forUTI, necessity for surgery, efficacy of surgery, and theprocess of HN. Antibiotic type and dosage, side effects,progress of HN, and renal functions at the end of follow-upwere rarely reported.

Risk of bias and confounding assessment of theincluded studies

Fig. 2A demonstrates the RoB summary and confoundingassessments for the two RCTs and 11 NRSs. NRSs had high riskof selection, performance, and detection biases. There wasalso a high risk of attrition bias (incomplete outcome data) inthe majority of the comparative studies. In addition,reporting bias was also either high risk or unclear in moststudies. Severity of HN, cause of HN, and gender as theconfounding factors weremeasured and corrected inmost ofthe studies. However, circumcision status for boys was notconsidered in five studies and was unclear in two of them.

Fig. 2B demonstrates the RoB summary for the 50 caseseries. In general, these studies were at high risk of se-lection bias and selective outcome reporting. More thanhalf of the studies had low RoB for loss to follow-up. Finally,21 out of 50 studies had an a priori protocol.

Comparisons of intervention results

Data from comparative studiesThe outcome results of two RCTs and 11 NRSs are summa-rized and demonstrated in Table 3.

Clinical effectiveness of CAP on UTI rates. UTI rates inpatients who received CAP (n Z 1307) and no CAP(n Z 2692) were reported in 12 comparative studies. It isunclear whether CAP makes any difference from the dataavailable as ORs varied from 0.17 (95% CI 0.01e3.82) to13.57 (95% CI 0.60e306.64), with a large variation in di-rection of effect between studies and wide confidence in-tervals throughout. This is demonstrated clearly in Fig. 3.

In the only RCT with full text available [7], 46 patientswere enrolled into the study but only 29 completed


the trial. In the end, the number of patients who receivedCAP was unclear and no conclusion could be drawn bythe investigators regarding the clinical effectiveness ofCAP.

In the prospective longitudinal study by Braga et al. [8],lack of CAP (p < 0.01) was found to be an independent riskfactor for fUTI.

Coelho and coworkers [10] prospectively followed 192children with ANH with a median period of 2 years. Anti-biotic prophylaxis was discontinued in children without VURand with renal pelvis diameter <10 mm. Twenty patientspresented with UTI while on CAP and seven after discon-tinuation of CAP.

Herz et al. [13] retrospectively compared the UTI ratesamong 401 children who received CAP versus no CAP. Theincidence of fUTI was significantly lower in children on CAP(7.9%) than no CAP (18.7%), (p Z 0.02).

Zareba et al. [18] found no benefit of CAP on decreasingthe risk of UTI (OR 0.93, CI 0.45e1.94, p Z 0.85). CAP wasalso not beneficial in any high-risk group including females,uncircumcised males and high grade HN.

Antibiotic regimen and adverse events of CAP. In themajority of the comparative trials, the type and dosage ofthe antibiotic was not provided. In the rest of them, themost common antibiotic used for CAP was trimethoprimwith 1 mg/kg dosage [7,10,14,18]. In one studytrimethoprim/sulfamethoxazole (TMP/SMX) combinationwith 2 mg/kg dosage was preferred by the trialists [11].

The only report for side effects was from the RCT byBraga et al. [7] found a total of six side effects (5 gastro-enteritis, 1 choking). The other comparative studies did notreport whether a side effect was observed or not in theirstudy population.

Circumcision status and rates of UTI. UTI rates in patientswho were circumcised (n Z 674) and non-circumcised CAP(nZ 484) were reported in FOUR comparative studies. Dataon this outcome seemed to be more consistent, withdirection and size of effect broadly similar across studies(Fig. 4). OR varied from 0.12 (95% CI 0.04e0.37) to 0.30(95% CI 0.10e0.91). Sencan et al. [15] found that 10 ofthe 15 males with UTI were non-circumcised and boyswho were uncircumcised were at a 7.8-fold increased riskof UTI (p < 0.01).

Gender and rates of UTI. UTI rates of females (n Z 639)versus males (1390) were reported and compared in sevencomparative studies. Again, direction and magnitude ofeffects were variable and no definite conclusions could bedrawn (Fig. 5).

In three comparative studies, female gender was re-ported as an independent predictor of developing UTI[8,10,18].

Low-grade versus high-grade HN and rates of UTI. Thecomparison of the UTI rates between patients with low-grade and high-grade HN was provided in five studies[6,8e10,18]. There appears to be a trend towards less UTI


Table 1 Summary of findings (sof), baseline characteristics of comparative studies.

Study ID, design,country,recruitmentperiod

N Age (months)mean (SD),median(range)

GenderM/F

Boyscirc(n)

Inclusioncriteria

Exclusion criteria SFU grade orseverityof HN n (%)

UPJO,n (%)

VUR,n (%)

Megaureter,n (%)

Non-obstructiveor isolated HN,n (%)

Outcomesmeasured

Braga L 2015,comparativestudy, Canada,2008e2014,abstract

72 3.4 64/8 22 POM VUR I, II: 9(12.5)III, IV: 63(87.5)

0 (0) 0 (0) 72 (100) 0 (0) Rates offUTI, surgeryand resolutionof POM

Braga LH 2014,RCT, Canada,2010e2013

44 Newborn 38/6 17 Isolated HNor HUN, 1e5months old andSFU grade III/IV

Infants with VURbased onmandatory VCUG,solitary kidney,PUV, renalinsufficiency,duplicationanomalies(ureterocele orectopic ureter)and neuropathicbladder

III, IV: 46(100)

26 (59.1) 0 (0) 18 (40.9) 0 (0) fUTI,improvementof HN

Braga LH 2015,comparativestudy, Canada,2010e2014

334 4.1 � 4.1 261/73 95 Prenatal HNconfirmedpostnatally

Ectopic ureter,ureterocele, PUV,neurogenicbladder, diagnosisafter 24 months

I, II: 142(42.5)III, IV: 192(57.5)

0 (0) 57 (17.1) 59 (17.6) 218 (65.3) fUTI

Brophy MM 2002,comparativestudy, US,1992e1998

234 Newborn 174/60 NS Prenatal HN Duplicationanomaly, MCDK,BOO

I, II: 141(60.3)III, IV: 80(34.2)

0 (0) 40 (17.1) 30 (12.8) 182 (77.7) UTI, resolutionof VUR

Coelho 2008,comparativestudy, Brazil,1999e2006

192 Newborn 140/52 0 Prenatal HN,RPD �5 mmon prenatalUS after28 weeks ofgestation andat least6 months off/u

Presence of aduplex systemwith ureterocele,hypoplastickidney, horseshoekidney and PUV

I, II: 139(72.4)III, IV: 53(27.6)

55 (28.6) 16 (8.3) 7 (3.6) 114 (59.3) UTI

Craig JC 2002,RCT, Australia,period NS,abstract

41 Newborn 29/17 NS ANH with VUR NS NS 0 (0) 41 (100) 0 (0) 0 (0) UTI

(continued on next page)

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Table 1 (continued )


N Age (months)mean (SD),median(range)

GenderM/F

Boyscirc(n)

Inclusioncriteria

Exclusion criteria SFU grade orseverityof HN n (%)

UPJO,n (%)

VUR,n (%)

Megaureter,n (%)

Non-obstructiveor isolated HN,n (%)

Outcomesmeasured

Estrada CR, 2009,comparativestudy, US,1998e2006

1514 Newborn NS NS SFU G2 onpostnatal US

h/o SeverebilateralPNH,oligohydramniosisand/or distendedfetal bladder

II: 1514(100)

NS 322 (21.2) NS NS fUTI

Herz D, 2014,comparativestudy, US, 2001e2011

405 Newborn 236/169 197 AsymptomaticANH

HN detected afterUTI, incompleterecords, <2 yearsf/u

I, II: 260(64.2)III, IV: 145(35.8)

41 (10.1) 84 (20.7) 43 (10.5) 239 (59) fUTI

Liedefelt KJ, 2008,comparativestudy, Sweden,2003e2005

50 Newborn NS NS ANH NS NS 6 (12) 6 (12) 1 (2) 34 (68) UTI

Sencan A, 2014,comparativestudy, US, 1998e2010

692 Newborn 608/225 481 ANH, persistentpostnatal HN,3 month f/u

Any otherabnormality

Mild: 692(100)

6 (0.8) 13 (1.7) 1 (0.1) 670 (96.8) UTI and incidenceof VUR

Shukla A, 2005,comparativestudy, US, 1986e1999

40 Newborn 32/8 NS ANH þ primarymegaureter

VUR, PUV, duplexkidneys,dysfunctionalvoiding

NS 0 (0) 0 (0) 40 (100) 0 (0) Resolutionrates ofmegaureter

Wollenberg A,2005,comparativestudy,Switzerland,1995e2000

78 Newborn NS NS ANH Fetuses presentingwith megacystis orantenatally knowngenetic disorderswere excluded

Mild: 20,moderate: 22,severe: 36

18 (23) 9 (11.5) 7 (8.9) Unclear Rates ofUTI andsurgery

Zareba, 2014,comparativestudy, Canada,2005e2011

376 Newborn 277/99 76 ANH Other urinary tractanomalies, such asPUV, ureterocelesor ectopic ureters,as well as thosewith neurogenicbladder

I, II: 248III, IV: 128

96 (25.5) 79 (21) 35 (9.3) Unclear UTI

ANH Z antenatal hydronephrosis; AP Z anteroposterior; APPD Z anteroposterior pelvic diameter; BOO Z bladder outlet obstruction; fUTI Z febrile UTI; G Z grade;HN Z hydronephrosis; HUN Z hydroureteronephrosis; LUTO Z lower urinary tract obstruction; MCDK Z multicystic dysplastic kidney; MGU Z megaureter; NB Z new born;POM Z primary obstructive megaureter; PUV Z posterior urethral valves; SFUZ Society of Fetal Urology; UPJ Z ureteropelvic junction; UPJO Z ureteropelvic junction obstruction;UTI Z urinary tract infection; VCUG Z voiding cystourethrography; VUR Z vesicoureteral reflux; US Z ultrasound.

6M.S.

Silayetal.

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SilayMS,

etal.,

Role

ofantib

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prophyla

xisin

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hyd

ronephrosis:

Asyste

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mtheEuropeanAsso

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nofUrology/E

uropeanSo

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forPaediatric

Urology

Guidelin

esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

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rg/10.1016/j.jpurol.2017.02.023

Table 2 Summary of findings (sof), baseline characteristics of case series.

Study ID, design,country, recruitmentperiod

N Age(months)mean (SD),median[range]

Gender M/F Boyscirc (n)

Inclusion criteria Exclusioncriteria

SFU grade

or severity

of HN or AP

diameter n (%)

UPJO,n (%)

VUR,

n (%)Megaureter,n (%)

Non-obstructive

or isolated HN,

n (%)

Outcomesmeasured

Alconcher LF 2012,case series,Argentina,1998e2010

236 Newborn 78/20

(bilateral),

unclear

(unilateral)

NS NBs with bilateral

mild isolated ANHAPPD of>15 mm,caliectasis,HUN, and renalabnormalities

Mild, 236 (100) 2 2 0 80% UTI rates,resolution ratesof HN

Arora S 2015, caseseries, India,2004e2012

109 Newborn 90/19 NS All cases of ANH

due to primary

UPJO

VUR, a solitarykidney, pelvicstones,ureteraldilatation,anatomical orneurogenicabnormality ofthe lowerurinary tract,or abnormalityother thanUPJO of thecontralateralnormal kidney

I: 11 (10)

II: 26 (23.8)

III: 26 (23.8)

IV: 46 (42.2)

109 0 0 Unclear Predictors ofsurgery forUPJO

Babut B 1987, caseseries, France,1981e1987

27 Newborn 24/5 NS POM MGUs due toVUR or withureterocele orwith ectopicimplantation

NS 0 0 29 0 Resolution andsurgery rates ofPOM

Bahat H 2014, caseseries, Israel,recruitmentperiod NS,abstract

285 Newborn NS NS Children who

underwent VCUGNS NS 0 285

(100%)0 0 UTI rates

Baskin LS 1994, caseseries, US,1981e1987

25 Newborn 19/6 NS POM who

were not

operated

AssociatedVUR,duplicationanomalies,ureteroceles,ureteralectopia, PUV,dysfunctionalvoiding, prunebelly syndrome

Mild: 4 (16)

Moderate:

8 (32)

Severe: 6 (24)

0 0 25 0 Renal function,pain, UTI rates


Role

ofantib

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prophyla

xisin

antenatalhyd

ronephrosis

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citethisarticle

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as:

SilayMS,

etal.,

Role

ofantib

iotic

prophylaxis

inantenatalhyd

ronephrosis:

Asyste

matic

revie

wfro

mtheEuropeanAsso

ciatio

nofUrology/E

uropeanSo

ciety

forPaediatric

Urology

Guidelin

esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

oi.o

rg/10.1016/j.jpurol.2017.02.023






SFU grade

or severity

of HN or AP

diameter n (%)

UPJO,n (%)

VUR,


Non-obstructive

or isolated HN,

n (%)

Outcomesmeasured

Beckers G 2008, caseseries,Netherlands andGermany,1999e2001

18 Unclear NS NS SFU G3e4 ANH VUR IIIeIV: 18 (100) 18 0 0 0 Electrophoresis

Blachar A 1994, caseseries, Israel,1987e1991

100 Newborn 77/23 NS Prenatal HN VUR 0: (13%)

Mild: (51.5%)

Moderate: (23%)

Severe: (12.5%)

95 U 24 U 0 34 U Surgery rates,renal function,UTI rates

Borobio V 2013, caseseries, Spain, 2011e2012, abstract

110 Newborn NS NS ANH NS Mild: (71%)

Moderate/

severe: (29%)

NS NS NS NS Resolutionrates of HN,surgery rates

Chertin 2001, Israel,case series,1990e1998

34 13 14/20 NS Pts treated with

endoscopic

puncture of

ureterocele

NS NS 0 20 0 0 Surgicalsuccess rates

Chertin 2003, Ireland,case series,1984e2001

52 Newborn 30/22 NS Pts treated with

endoscopic

puncture of

ureterocele

NS NS 0 51 0 0 Surgicalsuccess rates

Dacher 1992, US, caseseries, 1984e1991

13 Newborn 10/3 3 Prenatal HN plus

pts having UTI in

first 6 months of

life

PUV NS 6 6 1 0 UTI rates,antibioticcompliance

Direnna T 2006,Canada, caseseries, 1990e2001

10 Newborn 4/6 NS Prenatally

detected

ureteroceles

Ipsilaterallower polemoietyobstruction,high-grade (IVor V) VUR and/or BOO

I: 2 (20)

II: 5 (50)

III: 2 (20)

0 4 0 0 Resolutionrates of HN andVUR

Evans K, 2005, UK,case series, 1997e2013

54 Newborn 42/12 27 Asymptomatic

VUR diagnosed

after ANH <16

years old

Pts presentingwith UTI,secondary VURor duplexsystems

NS 0 54 0 0 UTI rates, renalfunction, riskfactors

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xisin

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Farhat W 2000,Canada, caseseries, 1993e1998

31 Newborn 24/7 Of thepatientswho hadUTI, 7 hadbeencircumcised

ANH plus primary

VUR detected

within first month

of life

Secondary VUR(PUV,duplication,ureterocele)

I: 10 U (25)

II: 21 U (52.5)

III: 5 U (12.5)

IV: 4 (10)

0 31 1 0 Resolutionrates of VUR,UTI rates

Farhat W, 2002,Canada, caseseries, 1993e1999

26 Newborn 19/7 NS ANH plus primary

VUR detected

within first month

of life

Secondary VUR(PUV,duplication,ureterocele)

I: 4 U

II: 12 U

III: 4 U

IV: 8 U

0 26 0 0 Correlationbetween renalmorphology,renal functionand VUR

Gimpel C, 2010,Germany, caseseries, 1994e2006

49 Newborn:20 pts,10 months:the rest ofthe cases

35/14 NS POM, followed for

at least 1 year

and had at least

one US and

isotope renal

scan

Secondarymegaureters(PUV, prunebelly,ureteroceles,VUR), non-obstructiveureters, duplexsystem

I: 10 U

II: 39 U

III: 5 U

IV: 1 U

2 2 49 0 UTI rates,resolution ofHN, renalfunction

Glover J 2015, UK,case series, 2003e2008, abstract

40 Newborn NS NS Severe unilateral

ANHNS Severe: 40 (100) 12 7 NS NS UTI rates and

surgery rates

Gokce I, 2012,Turkey, caseseries, 1999e2009

256 Newborn 187/69 NS Antenatally

detected urinary

tract

abnormalities

NS NS 94 U 63 U 20 U 0 UTI rates, renalfunction

Herndon CDA 1999,US, case series,1993e1998

71 Newborn 56/15 37 Neonatal VUR

presenting with

prenatal HN

PUV <10 mm: 88%

10e20 mm: 9%

>20 mm: 3%

3 71 NS NS UTI rates,resolution ratesof VUR

Islek A 2011, Turkey,case series, 2007e2009

84 Newborn 56/28 NS Unilateral or

bilateral AHNPUV, VUR,duplex kidneys,renalhypoplasia,complexurinaryanomalies, <1year follow-up

I: 23 (27.3)

II: 23 (27.3)

III: 20 (23.8)

IV: 18 (21.4))

84 0 0 0 Resolutionrates of HN, UTIrates

Lee JH, 2008, SouthKorea, case series,1989e2006

430 Newborn 351/79 0 Non-refluxing

neonatal HNVUR, PUV, NB I: 161 (37.4)

II: 94 (21.8)

III: 79 (18.3)

IV: 96 (22.3)

Unclear 0 Unclear Unclear Incidence ofUTI


Role

ofantib

iotic

prophyla

xisin

antenatalhyd

ronephrosis

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iotic

prophylaxis

inantenatalhyd

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ciatio

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uropeanSo

ciety

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Urology

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esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

oi.o

rg/10.1016/j.jpurol.2017.02.023






SFU grade

or severity

of HN or AP

diameter n (%)

UPJO,n (%)

VUR,


Non-obstructive

or isolated HN,

n (%)

Outcomesmeasured

Madden-Fuentes RJ,2014, US, caseseries, 2004e2009

416 1.2 292/124 Of thepatientswho hadUTI, 8had beencircumcised

Infants diagnosed

with isolated low

grade (I, II) HN

VUR, spinabifida,ureterocele,PUV, priorsurgery, noimaging

I: 398 U

II: 225 U1 0 1 414 Resolution

rates ofHN, UTIrates andneed forsurgicalintervention

Mandic V, 2015,Bosnia andHerzeginova, caseseries,recruitmentperiod NS

56 Unclear 32/24 NS NS NS NS 48 1 1 Unclear Rates ofUTI, incidenceof symptoms

Martin AD, 2014, US,case series,2004e2010

80 <6 mo 26/8 71 Infants (<6 mo)

with ANH or fUTI

and having

dilating VUR (�3)

Secondary VURor non-dilatingVUR (<3)

NS 0 34 (100) 0 0 Rates of febrileUTI, resolutionof VUR

McIlroy PJ, 2000, NewZealand, caseseries, 1989e1994

69 Newborn 32/37 NS Infants with

primary VUR,

detected

subsequent to

abnormal fetal US

Duplex system,ureterocele orPUV

NS 0 69 (100) 0 0 Rates of UTI,renal damage,

Mears AL, 2007, UK,case series,1999e2002

55 Newborn 39/16 NS ANH Referrals fromother hospitals

>10 mm 9 8 3 Unclear Rates of UTI,resolution ofHN, necessityof surgery

Miranda ML 2012,Brazil, case series,1997e1999

34 Newborn NS NS ANH NS NS 9 7 5 4 Necessity ofsurgery, finaldiagnosis

Misra D, 1999, UK,case series,1994e1996

42 Newborn 25/17 NS ANH NS 10e15 mm: 22

15e20 mm: 10

20e40 mm: 6

>40 mm: 2

21 5 Unclear Unclear Rates of UTI,necessity ofsurgery

Molina CAF, 2013,Brazil, case series,recruitmentperiod NS

45 Newborn 33/12 NS ANH due to UPJO NS NS 45 (100) 0 0 0 Necessity ofsurgery

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xisin

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uropeanSo

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JournalofPediatric

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Moorthy I, 2013, UK,case series,recruitmentperiod NS

425 Newborn 311/114 NS ANH NS NS 19(20.4)

38

(40.8)6 (6.4) Unclear Rates of UTI,

rates of urinarytractabnormalities

Oliveira EA, 1998,Brazil, case series,recruitmentperiod NS

28 Newborn 24/4 NS ANH with VUR NS NS 0 28 (100) 0 0 Ultrasound andscintigraphicfeatures offetal VUR

Oliveira EA, 2000,Brazil, case series,1985e1995

8 Newborn 5/3 NS ANH with POM Other causes ofANH

NS 0 0 8 (100) 0 Progress of HNand renalfunction

Onen A, 2006, Turkey,case series,2001e2005

162 Newborn 114/48 Primary UPJ-type

ANHVUR, duplexsystem, fusedkidney, solitarykidney,ureteraldilatation, oranatomical orneuropathicabnormality ofthe lowerurinary tract

IeII: 153 U

III: 48 U

IV: 27 U

162(100)

0 0 Unclear Resolutionrates of HN,necessity ofsurgery

Owen RJT, 1995, UK,case series,recruitmentperiod NS

31 Newborn NS NS ANH NS NS 6 (19.3) 4 (12.9) 0 14 (45.1) Postnatal USand otherimagingtechniqueswhereappropriate

Quirino IG, 2012,Brazil, case series,1989e2009

822 Newborn 557/265 NS Congenital

anomalies of the

kidney and

urinary tract

NS NS 641(77.9)

157

(19.1)59 (7.3) 308 (37.5) Rates of UTI,

development ofhypertension

Roth CC, 2009, US,case series,recruitmentperiod NS

92 Newborn 72/20 41 Grade 3e4 HN

secondary to

UPJO or

obstructive MGU

Any patientwith VUR orLUTO

IIIeIV: 92 (100) 56(60.8)

0 36 (39.2) 0 Rates of UTI,risk factors forUTI

Senaneyeke M, 1996,UK, case series,1991e1992

65 Newborn NS NS ANH NS NS 6 (9.2) 5 (7.6) 0 34 (52.3) Resolution ofHN, UTI rates

Shaul DB, 1994, caseseries, 1985e1992

63 Newborn NS NS Pts undergoing

pyeloplasty in

infancy

NS NS 63 (100) 4 (6.3) 0 0 Operativeoutcomes,rates of UTI

Signorelli M, 2005,Italy, case series,recruitmentperiod NS

375 Newborn 265/110 NS Mild ANH NS Mild: 375 (100) 13 9 Unclear Unclear Resolution ofHN, necessityof surgery


Role

ofantib

iotic

prophyla

xisin

antenatalhyd

ronephrosis

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SilayMS,

etal.,

Role

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iotic

prophylaxis

inantenatalhyd

ronephrosis:

Asyste

matic

revie

wfro

mtheEuropeanAsso

ciatio

nofUrology/E

uropeanSo

ciety

forPaediatric

Urology

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esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

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rg/10.1016/j.jpurol.2017.02.023






SFU grade

or severity

of HN or AP

diameter n (%)

UPJO,n (%)

VUR,


Non-obstructive

or isolated HN,

n (%)

Outcomesmeasured

Silva JMP, 2006,Brazil, 2006, caseseries, 1986e2004

53 Newborn 41/12 NS ANH and VUR NS NS 0 53

(100)0 0 Resolution of

VUR, rates ofUTI

Song SH, 2007, Korea,case series,1994e2004

105 Newborn 82/23 0 ANH, obstruction

and no abxPUV, VUR, NB III: 47 (45)

IV: 58 (55)75 0 30 0 Rates of UTI,

risk factors forUTI

St Aubin M, 2013, US,case series,2007e2010

87 Newborn 56/31 NS ANH MCDK, PUV,ureteroceles orPOM

NS 25 U 12 U 0 107 U Rates of UTI,necessity ofsurgery

Takvani A, 2015,India, case series,2002e2013,abstract

212 Group 1:newborn,group 2: NS

NS NS VUR NS NS 0 212 (100) 0 0 Resolutionrates of VUR,necessity ofsurgery

Tombesi MM, 2012,Argentina, caseseries, 1998e2009

193 Newborn 148/45 NS Mild isolated ANH APPD >15 mm,calycealdilatation,HUN, renalabnormalities,bladderabnormalities

Mild: 193 (100) 2 (1) 2 (1) 0 189 (98) Resolutionrates of HN

Upadhyay J, 2003,Canada, caseseries, 1993e1998

25 Newborn 24/7 NS ANH and VUR Secondary VUR NS 0 25 (100) 0 0 Rates of UTI,resolution ratesof VUR

Winters 1990, US,case series,1982e1989

40 Newborn 7/33 NS ANH of upper

pole with or

without

ureterocele

NS NS NS 20 NS NS Rates of UTI,necessity ofsurgery

Yerkes EB, 1999, US,case series,1992e1997

60 Newborn 43/17 NS ANH, SFU G0e1

e2Severe (G3-4)HN, HUN,duplication,small orechogenickidney, bladderabnormalities

0eII: 60 (100) NS 6 0 NS Rates of UTI,necessity ofsurgery

Ylinen E, 2004,Finland, caseseries, 1983e1998

68 Newborn 47/21 NS ANH with UPJO Other urinarytractabnormality

NS 68 (100) 0 0 0 Resolution ofHN, necessityof surgery

12M.S.

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SilayMS,

etal.,

Role

ofantib

iotic

prophyla

xisin

antenatal

hyd

ronephrosis:

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uropeanSo

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Zampieri

N,20

11,

Italy,ca

seseries,

2004

e20

06

20Newborn

12/8

NS

ANHandPOM

(G1

e3HN)in

Cauca

sianand

hadatleast

2US

andscintigraphy

VUR,

Neuropathic,

SFUIV

I:8(40)

II:7(35)

III:5(25)

00

20(100

)0

RatesofUTI,

nece

ssityof

surgery

ZerinJM

,19

93,US,

case

series,

1988

e19

92

130Newborn

91/3

9NS

Antenatalrenal

anomalies

Pts

whodid

not

have

VCUGby6

monthsofage

ornotatall

NS

3149

7NS

RatesofUTI,

nece

ssityof

surgery,

resolutionof

VUR

ANH

Zantenatalhyd

ronephrosis;

AP

Zanteroposterior;

APPD

Zanteroposterior

pelvic

diameter;

BOO

Zbladder

outlet

obstruction;

fUTIZ

febrile

UTI;

GZ

grad

e;

HN

Zhyd

ronephrosis;

HUN

Zhyd

roureteronephrosis;

LUTO

Zlowerurinary

tract

obstruction;MCDK

Zmulticystic

dysplastic

kidney;

MGU

Zmega

ureter;

NB

Znew

born;

POM

Zprimary

obstructivemega

ureter;

PUVZ

posteriorurethralva

lves;

SFUZ

Society

ofFetalUrology

;UPJZ

ureteropelvic

junction;UPJO

Zureteropelvic

junctionobstruction;

UTIZ

urinarytract

infection;VCUG

Zvo

idingcystourethrography;

VURZ

vesico

ureteralreflux;

USZ

ultrasound.


+ MODEL


occurring in low-grade HN, particularly in the studies withlarger sample sizes (Fig. 6).

Zareba et al. [18] reported that high-grade HN was anindependent predictor of UTI (OR 2.40; 95% CI 1.26e4.56).In this study the fUTI rates were 10.1% (25/248) and 19.5%(25/128) for low-grade and high-grade HN respectively.

Ureteral dilatation and rates of UTI. UTI rates betweenpatients with HN and HUN was compared and reported infour comparative studies. The studies seem to consistentlysuggest less UTI occurring with HN compared to HUN (Fig. 7).

Herz et al. demonstrated that in infants with ureteraldilatation >11 mm and not maintained on CAP had a 5.5-fold increased risk of developing fUTI (OR 5.54, 95% CI3.15e7.42, p Z 0.001). In a RCT by Braga et al. [7], a totalof six UTIs were reported in 44 patients. Five of the six UTIsdeveloped in children with HUN and one developed in achild with HN.

VUR and rates of UTI. The impact of VUR on UTI rates ininfants with ANH could not be estimated because of a lackof reporting studies and heterogeneity of the subgroups.

In an RCT which was published as a congress abstract byCraig et al. [11], 46 infants with ANH and VUR wererandomly assigned to 3 years of TMP/SMX 2 mg/kg dailydose treatment or matching placebo. At the end of follow-up, two children with placebo and no children with CAPdeveloped UTI (p Z 0.02). Moreover, none of the childrenin either group developed new scar on DMSA scintigraphy.

Estrada et al. [12] focused on follow up outcomes of1514 infants with G2 HN. The patients were divided intotwo groups, either screened or non-screened. In 322 pa-tients with VUR who were screened, 1.6% had a rate of UTIunder CAP. In the non-screened group who did not receiveCAP and with 101 estimated patients with VUR, 11.8%developed UTI. Those results suggested the benefit of CAPin decreasing UTI rates among patients with VUR and ANH.

Kidney status at the end of follow-up. The kidney func-tions assessed by scintigraphy (DMSA) at the end of thefollow-up was provided only in two studies [11,16]. In anRCT in children with VUR and ANH, none of the 41children developed new scarring on DMSA at the end of 3years [11]. Shukla et al. [16] reported a series of 40patients with POM, and four patients required surgerybecause diminished renal function on scintigraphy.

The changes in the status of HN was also provided in twodifferent studies [15,16]. The creatinine and glomerularfiltration rate (GFR) was not provided in any of the studies.

Data from case seriesThe outcome results of 50 case series are summarized anddemonstrated in Table 4 [19e68].

Clinical effectiveness of CAP on UTI rates. The effect ofCAP on UTI rates was demonstrated in some of the studiesand the results were highly variable. Islek et al. [38]reported a case series including 84 infants with UPJO.After a median follow-up of 18 months without CAP noneof the patients developed UTI, and CAP was notrecommended in UPJO. Madden-Fuentes et al. [40]reported similar results in a cohort of isolated low-grade


Figure 2 A. Risk of bias (RoB) summary and confounding assessments for comparative studies including the two RCTs and 11 NRSs.B. Risk of bias (RoB) summary and confounding assessments for case series.

14 M.S. Silay et al.

+ MODEL

Please cite this article in press as: Silay MS, et al., Role of antibiotic prophylaxis in antenatal hydronephrosis: A systematic review fromthe European Association of Urology/European Society for Paediatric Urology Guidelines Panel, Journal of Pediatric Urology (2017),http://dx.doi.org/10.1016/j.jpurol.2017.02.023

Table 3 Summary of findings (sof), outcomes of comparative studies.


CAP n (%) Ab type and dosage Ab sideeffects

Surgery n(%)

f/u(mo)

HN progress Renalfunctionprogress

UTI (n) fUTI (n) Summary

Braga L 2015,comparativestudy, Canada,2008e2014,abstract

31 (43) NS NS 17 (20) 24 NS NS 21 0 Circumcision and useof CAP significantlyreduced fUTI rates inpts with POM

Braga LH 2014, RCT,Canada, 2010e2013

Unclear TMP Total: 6Gastroenteritis(n: 5)Choking (n: 1)

9 (20.5) 8.4 NS NS 6 6 Due to low eligibilityrate for the RCT nocertain conclusioncould be made andmulticenter trial wassuggested

Braga LH 2015,comparativestudy, Canada,2010e2014

96 (28.7) NS NS NS 18 NS NS 65 65 Females anduncircumcised maleswith high grade HUNhad significantlyhigher fUTI rates.

Brophy MM 2002,comparativestudy, US, 1992e1998

All pts withVUR and highgrade HN

NS NS 13 (5.5) 23 NS NS 10 0 VCUG was suggestedin all cases of ANH.CAP is suggested inpts with VUR

Coelho 2008,comparativestudy, Brazil, 1999e2006

172 (100) TMP (1e2 mg/kg),Cephalexin(50 mg)

NS 27 (15.6) 24 NS NS 27 0 Girls with VUR orurinary tractobstruction had ahigher risk of UTI

Craig JC 2002, RCT,Australia, periodNS, abstract

21 (51.2) TMP/SMX (2 mg/kg) NS NS 36 NS Unchanged:41/41

2 0 CAP did not reducethe risk of UTI or newrenal damage inchildren withasymptomatic VURduring the first 3years of life

Estrada CR, 2009,comparativestudy, US, 1998e2006

322 (21.2) NS NS NS 9.3 NS NS 21 21 In patients with ahistory of ANH andpersistent grade IIhydronephrosis,identification of VURand use of CAPsignificantly reducethe risk of fUTIs.


Role

ofantib

iotic

prophyla

xisin

antenatalhyd

ronephrosis

15

+MODEL

Please

citethisarticle

inpress

as:

SilayMS,

etal.,

Role

ofantib

iotic

prophylaxis

inantenatalhyd

ronephrosis:

Asyste

matic

revie

wfro

mtheEuropeanAsso

ciatio

nofUrology/E

uropeanSo

ciety

forPaediatric

Urology

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esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

oi.o

rg/10.1016/j.jpurol.2017.02.023



CAP n (%) Ab type and dosage Ab sideeffects

Surgery n(%)

f/u(mo)

HN progress Renalfunctionprogress

UTI (n) fUTI (n) Summary

Herz D, 2014,comparativestudy, US, 2001e2011

378 (74.5) NS NS NS >24 NS NS 134 86 CAP decreases therisk of fUTIs inchildren withasymptomatic ANHwith either ureteraldilation, high gradeVUR, and UVJO

Liedefelt KJ, 2008,comparativestudy, Sweden,2003e2005

14 (28) TMP (1 mg/kg) NS 1 (0.9) >24 NS NS 7 0 CAP is notrecommended inchildren with minorANH

Sencan A, 2014,comparativestudy, US, 1998e2010

13 (1.8) Amoxycillin NS 13 (1.8) NS Completeresolution:663/985 RU,improved:131/985 RU,unchanged:158/985 RU,worsened:32/985 RU

NS 23 13 Routine VCUGscreening for VUR andthe use of CAP is notnecessary for allpatients withasymptomatic mildANH.

Shukla A, 2005,comparativestudy, US, 1986e1999

12 (30) NS NS 4 (10) >24 Resolution:21/40, improvedor stable: 19/40

Decreased:1/40

2 0 Long-term follow-upof children withprenatally diagnosedprimary megaureterwith mild tomoderate ANHconfirms a highincidence ofresolution andimprovement

Wollenberg A, 2005,comparativestudy,Switzerland, 1995e2000

41 (52.5) NS NS 20 (25.6) 12 NS NS 8 0 The need forpostnatal treatmente antibiotic therapyof a UTI and/orsurgery e wassignificantlyassociated with thegrade of antenatalRPD

16M.S.

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SilayMS,

etal.,

Role

ofantib

iotic

prophyla

xisin

antenatal

hyd

ronephrosis:

Asyste

matic

revie

wfro

mtheEuropeanAsso

ciatio

nofUrology/E

uropeanSo

ciety

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esPanel,

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Urology

(2017),http

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Zareba,20

14,

comparative

study,

Canada,

2005

e20

11

227(60.3)

TMP

NS

NS

24NS

NS

5050

HighgradeHN,

female

genderand

uncircumcisedstatus

inmalesare

independentrisk

factors

forfU

TIin

infants

withANH.CAP

did

notreduce

the

risk

ofUTI

ANH

Zantenatalhyd

ronephrosis;

AP

Zanteroposterior;

APPD

Zanteroposterior

pelvic

diameter;

BOO

Zbladder

outlet

obstruction;

fUTIZ

febrile

UTI;

GZ

grade;

HN

Zhyd

ronephrosis;

HUN

Zhyd

roureteronephrosis;

LUTO

Zlowerurinary

tract

obstruction;MCDK

Zmulticystic

dysplastic

kidney;

MGU

Zmega

ureter;

NB

Znew

born;

POM

Zprimary

obstructivemega

ureter;

PUVZ

posteriorurethralva

lves;

SFUZ

Society

ofFetalUrology

;UPJZ

ureteropelvic

junction;UPJO

Zureteropelvic


UTIZ

urinary

tract

infection;VCUG

Zvo

idingcy

stourethrography;

VURZ

vesico

ureteralreflux;

USZ

ultrasound;AbZ

antibiotics.


+ MODEL


HN within the first year of life. In contrast, Song et al. [59]reported high UTI rates in neonates with UPJO (30.7%) andUVJO (50%) who did not receive CAP and recommendedantibiotic prophylaxis in those subgroup of patients.

Antibiotic regimen and adverse events of CAP. CAP wasadministered in the majority of the case series. However, ingeneral, antibiotic type and dosage was rarely reported. Inaddition, the side effects of antibiotics was not reported inany of the eligible studies.

Other prognostic factors on UTI rates. Lee et al. [39]investigated a total of 430 patients with ANH and withoutVUR. UTI rates were increased in infants with high gradeHN, HUN, and with obstructive uropathy (p < 0.001 forall). Bahat et al. [22] reported a significant increased riskof developing UTI in female neonates with ANH (HR 3.3,p Z 0.04).

Evans et al. [31] found increased risk of UTI in ANH ne-onates with congenital reflux nephropathy, non-circumcision, and with bladder dysfunction.

Kidney status during follow-up. The vast majority of thecase series did not report long-term follow-up of kidneyfunction, changes in the status of HN, and creatinine andGFR levels.

Upadhyay et al. [63] reported a case series including 25neonates with ANH and VUR. In two patients the renalfunctions were decreased after 4 years of follow-up.

In the case series by Madden-Fuentes et al. [40]including neonates with low-grade HN, the HN resolved in373, improved in 69, remained stable in 165, and worsenedin 16 within the first year of life.

Discussion

Principal findings

Conflicting results regarding the effectiveness of CAP ininfants with ANH were found. This may be attributed to theheterogeneity of the patient populations and differentsubgroups of ANH in the eligible trials. Some studies re-ported beneficial effect of CAP on UTI rates, such as thestudy by Braga et al. [8]. In that prospective longitudinalstudy, independent risk factors for fUTI was investigated ina total of 334 patients with ANH. Female gender (pZ 0.02),uncircumcised males (p Z 0.02), lack of CAP (p < 0.01),HUN (p < 0.01), and VUR (p < 0.01) were found to be theindependent predictors. The subgroup analysis by excludingpatients with VUR revealed that high-grade HN (p Z 0.04)was also a significant predictor for fUTI.

Some other studies did not find any beneficial effect ofCAP on UTI rates including the RCT by Craig et al. [11]. Thisstudy was mainly focused on patients with ANH and VUR,and the lack of the full text of this trial was a pitfall interms of determining the details of the study population.However, there were some other reports clearly statingthat no benefit of CAP was achieved regarding the UTI rateseven in the high risk groups [18].

The results of the forest plot tables demonstrate fiveimportant findings. First, it is not possible to establish


Figure 3 Forest plot demonstrating the development of urinary tract infection (UTI) in children receiving continuous antibioticprophylaxis (CAP) versus no CAP.

Figure 4 Forest plot demonstrating the development of urinary tract infection (UTI) in male patients who were circumcisedversus non-circumcised.

Figure 5 Forest plot demonstrating the development of urinary tract infection (UTI) in males versus females.

Figure 6 Forest plot demonstrating the development of urinary tract infection (UTI) in children with low grade versus high-gradehydronephrosis (HN).

Figure 7 Forest plot demonstrating the development of urinary tract infection (UTI) in children with hydronephrosis (HN) versushydroureteronephrosis (HUN).


+ MODEL

whether CAP was superior to no CAP in terms of decreasingUTI (Fig. 3). Second, non-circumcised infants, high-gradeHN, and HUN may be at higher risk of developing UTI(Figs. 4, 6 and 7). Finally, there was no significant differencein UTI risk between males and females (Fig. 5). No


conclusion could be drawn for the impact of VUR and no VURand comparison of the different degrees of VUR because oflack of data in the available literature. It is indeed difficultto assess risk of UTI because different thresholds exist toscreen for VUR in the available literature.


Table 4 Summary of findings (sof), outcomes of case series.


CAP n (%) Ab typeand dosage

Ab side

effectsSurgeryn (%)

f/u (mo) HN progress Renal function

progressUTI (n) fUTI (n) Summary

Alconcher LF 2012,case series,Argentina, 1998e2010

0 (0) NS NS 2 15 n: 4 renal units NS 23 NS Bilateral mildisolated antenatalhydronephrosiscan be conservativelymanaged, butclinical andultrasoundfollow-up arerecommendedduring the firstyear of life

Arora S 2015, caseseries, India,2004e2012

0 (0) NS NS 26 54 NS NS NS NS APD and DRFare the predictivefactors for surgeryin patients withANH due to UPJO

Babut B 1987, caseseries, France,1981e1987

29 (100) NS NS 17 20 3 pts in theoperatedgroup

NS NS NS Surgery should bedeferred untildeterioration isnoted in pts withANH due to primarymegaureter

Bahat H 2014, caseseries, Israel,recruitmentperiod NS,abstract

109 (100) NS NS NS >6 mo

>12 mo in

80% of pts

NS NS 6 NS Females are at greaterrisk of recurrent UTIs,regardless of thepresence of VUR, VURdegree, ANH or aprevious UTI

Baskin LS 1994,case series, US,1981e1987

25 (100) NS NS 0 87.6 None Unchanged 0 0 Primary non-refluxingmegaureters can beconservatively managed

Beckers G 2008,case series,Netherlands &Germany,1999e2001

0 NS NS 10 32.4 Unclear Increased:

n Z 6

Decreased:

n Z 4

Unchanged:

n Z 8

4 NS Sodium dodecyl sulfatepolyacrylamide gelelectrophoresis withsilver staining seems tobe a good predictive testfor clinically relevantureteropelvic junctionobstruction(continued on next page)

Role

ofantib

iotic

prophyla

xisin

antenatalhyd

ronephrosis

19

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inantenatalhyd

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uropeanSo

ciety

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esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

oi.o

rg/10.1016/j.jpurol.2017.02.023




Ab side

effectsSurgeryn (%)



Blachar A 1994,case series,Israel,1987e1991

0 NS NS 11 15 30 kidneys Increased:

n Z 2

Decreased:

n Z 2

Unchanged:

n Z 130

7 NS In most cases withprenatal hydronephrosis,there is no need forimmediate surgery andconservativemanagement issuggested

Borobio V 2013,case series,Spain,2011e2012,abstract

46 (40) NS NS NS Unclear 17 resolution NS NS NS In cases of mildpyelectasis detected inthird trimester, it isnecessary a postnatal a 6e12 months follow-up.

Chertin 2001,Israel, caseseries,1990e1998

34 (100) NS NS 42 72 NS Improved:

n: 2,

unchanged

n: 32

NS NS Endoscopic puncture ofthe ureterocele is safeand effective in the longterm

Chertin 2003,Ireland, caseseries,1984e2001

52 (100) NS NS 87 108 NS NS 0 NS Endoscopic puncture ofthe ureterocele is safeand effective in the longterm

Dacher 1992, US,case series,1984e1991

5/13 of

the UTIsNS NS NS 6 NS NS 13 NS Infants with UTI in spite

of the prenatal diagnosisof hydronephrosisdemonstrate the manypotential pitfalls asregards diagnosis andtreatment

Direnna T 2006,Canada, caseseries, 1990e2001

10 (100) NS NS 0 60 Resolved, n: 6,Unchanged ordecreased, n: 4

NS NS NS There may be a role forwatchful waiting inselect cases ofprenatally detectedureteroceles

Evans K, 2005, UK,case series, 1997e2013

54 (100) NS NS 24 72 NS New renal

defects

(n Z 8)

28 NS Reflux nephropathy andbladder dysfunction wererisk factors for developinga UTI in pts with ANH dueto primary VURCircumcision appears tosignificantly reduce therisk of infection.

20M.S.

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xisin

antenatal

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uropeanSo

ciety

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esPanel,

JournalofPediatric

Urology

(2017),http

://dx.d

oi.o

rg/10.1016/j.jpurol.2017.02.023

Farhat W 2000,Canada, caseseries, 1993e1998

31 (100) TMP 2mg/kg 1 � 1

NS 5 Total unclear

(17 pts 12e32 mo)NS NS 8 (F:1, M:7),

1/7 of UTI’swerecircumcised

NS With an observationaltherapy protocol and inthe absence of recurrenturinary tract infectionsthe majority of neonatalVUR improves and mayresolve with time

Farhat W, 2002,Canada, caseseries, 1993e1999

26 (100) TMP 2mg/kg 1 � 1

NS NS NS NS NS NS NS Postnatal US is reliableand correlates well withrenal scans in pts withANH due to primary VUR

Gimpel C, 2010,Germany, caseseries, 1994e2006

30/44 TMP,Nitrofurantoin,Cephalosporin

NS 15 84 HN improvedin all

6/38 worsened 66 46/66 The long-term outcomeof POM appearsfavorable with mainlyconservative treatment.UTI as the most commoncomplication was 55%lower with antibioticprophylaxis in infants.

Glover J 2015, UK,case series, 2003e2008, abstract

40 (100) NS NS 21 NS NS NS 15 NS Unilateral severeantenatalhydronephrosis of morethan 14 mm with orwithout hydroureter isassociated withcongenital anomaliesand significant pathologyleading to surgery, UTI ornon-functioning kidney

Gokce I, 2012,Turkey, caseseries, 1999e2009

In pts with ANH TMP 1e2mg/kg 1 � 1Amoxycillin10 mg/kg 1 � 1

NS 61 35 NS 71 Renal

parenchymal

defects/162 HN

78/162 HN NS Renal parenchymaldefects and UTI rates arehigher in children withANH compare to otherabnormalities.

Herndon CDA 1999,US, case series,1993e1998

71 (100) NS NS 17 20 NS NS 18 NS In a significant number ofrenal units high-gradereflux resolvesspontaneously. Earlycircumcision maydecrease the incidenceof breakthrough urinarytract infection in thissubpopulation(continued on next page)

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antenatalhyd

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rg/10.1016/j.jpurol.2017.02.023




Ab side

effectsSurgeryn (%)



Islek A 2011, Turkey,case series, 2007e2009

0 NS NS 7 18 32 pts HNcompletelyresolved, 18 ptsregressed, 26 nochange, 1progressed

No scar

development0 0 UPJO do not require

antibiotic prophylaxis

Lee JH, 2008, SouthKorea, case series,1989e2006

0 NS NS NS 12 NS NS 83 NS Neonates withobstructive uropathy,severe HN or HUN haveincreased risk of UTIeven without VUR, andCAP may berecommended

MaddeneFuentes RJ,2014, US, caseseries, 2004e2009

36 (8.6) NS NS 2 14 Resolved: n:373 U,Stable: n: 165 U,Improved: n: 69 U,Worse: n: 16 U

NS 43 4 Low-grade HN diagnosedwithin the first year oflife remains stable orimproves in 97.4% ofrenal units. Given thelow rate of recurrent UTIin the ambulatorysetting, CAP has alimited role

Mandic V, 2015,Bosnia andHerzeginova, caseseries,recruitmentperiod NS

0 NS NS 56 NS NS NS 28 NS The experience of aninstitution on follow upof pts with ANH waspresented

Martin AD, 2014, US,case series,2004e2010

80 (100) Nitrofurantoin,TMP/SMX

NS 10 22 Unclear Unclear n: 28/80(35%)

Unclear Multivariate analysisrevealed initial DMSAscan status, occurrenceof breakthrough UTIs,circumcision status, andinitial VUR grade to bepredictors of VURresolution/improvement

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rg/10.1016/j.jpurol.2017.02.023

McIlroy PJ, 2000, NewZealand, caseseries, 1989e1994

34/57 NS NS 6 24 (4e84) NS No progression

in 19 pts who

had repeated

DMSA scan

8/69 Unclear The presence of high-grade VUR appears to bethe only importantfactor in predicting thepresence of renaldamage

Mears AL, 2007, UK,case series, 1999e2002

In pts with

APD >10 mmTMP NS 16 36 18/26 who did

not have MCUGhad spontaneousresolution of HN,5/26 increased HN

Unclear 0 0 MCUGs are superfluous inthe investigation ofsimple unilateral ANH,supporting the selectiveuse of MCUGs.

Miranda ML 2012,Brazil, case series,1997e1999

31 (100) NS NS 14 16.8 NS 17 remained

stableNS NS Prenatal diagnosis of

hydronephrosis allowsperinatal follow-upwhich results in anappropriate postnatalmanagement

Misra D, 1999, UK,case series,1994e1996

12 NS NS 2 10 monthse3

yearsNS NS 0 NS The vast majority of ANH

have a benign course.MCUG is not necessary inmost cases. Routine CAPis not required in allunilateral cases and inbilateral ones after VURhas been excluded.

Molina CAF, 2013,Brazil, case series,recruitmentperiod NS

All pts

before VCUG

(first month)

NS NS 25 72 NS 4 decreased

renal functionNS NS Fetal hydronephrosis due

to UPJ obstructiondeserves carefulpostnatal evaluation.UPJ obstruction is themost frequent anomalyand its surgicaltreatment has veryprecise indications.

Moorthy I, 2013, UK,case series,recruitmentperiod NS

All pts with

postnatal HNNS NS NS NS NS NS 230 NS Careful antenatal and

postnatal ultrasoundwith strict protocols iseffective in detectingcongenital renal tractabnormalities

Oliveira EA, 1998,Brazil, case series,recruitmentperiod NS

28 (100) Cephalexin100e200 mg1 � 1

NS NS NS NS 19 pts renal

damage on

DMSA

NS NS VUR should beinvestigated in cases offetal HN and renaldamage is frequentlycongenital and notsecondary to UTI(continued on next page)

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Ab side

effectsSurgeryn (%)



Oliveira EA, 2000,Brazil, case series,1985e1995

All patients either

for 5 years or until

resolution of HN

NS NS NS 75 9/11 uretersimproved

Stable in all NS NS Conservativemanagement is safe forprimary megaureterdetected inasymptomatic neonates,with most cases showingspontaneous regressionduring a prolongedfollow-up

Onen A, 2006, Turkey,case series,2001e2005

All NS NS 27 46 201 resolved, 18increased

13 decreased NS NS A new grading systemwas recommendedinstead of SFU

Owen RJT, 1995, UK,case series,recruitmentperiod NS

All TMP NS NS NS 23 pts withprenatal HNresolved at1 week of age

NS NS NS Early management ofcongenital HN within theradiology department ispractical, avoidsunnecessary referralsand has significant costbenefits

Quirino IG, 2012,Brazil, case series,1989e2009

All NS NS NS 43 NS NS 245(29.8%)

NS Clinical course ofprenatally detectedCAKUT washeterogeneous, andthose infants withassociated HN atbaseline were identifiedas a high-risk subgroup

Roth CC, 2009, US,case series,recruitmentperiod NS

Only while

waiting

investigation and

withdrawn if no

VUR found

NS NS NS 26.8 NS NS 4 (4.3%) 4 CAP is unlikely to benefitmost children with grade3 or 4 hydronephrosissecondary to upper tractobstruction

Senaneyeke M, 1996,UK, case series,1991e1992

6 NS NS 4 12 Spontaneousresolution in 32patients

4 deterioration 1 NS Majority of ANH is selflimited and benign andhalf of them improvespontaneously within 1year

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rg/10.1016/j.jpurol.2017.02.023

Shaul DB, 1994, caseseries, 1985e1992

NS NS NS NS 23 (gp 1)

12 (gp 2)30 RU improved inyounger group,29 in older group3 stable, 2unchanged

NS 5 NS Good results ofpyeloplasties performedin the infants in thisseries support earlycorrection ofureteropelvic junctionobstruction in infants.

Signorelli M, 2005,Italy, case series,recruitmentperiod NS

39 NS NS 22 6e42 Resolution 156,unchanged: 89,worsened: 35

NS NS NS Prenatal diagnosis ofpyelectasis improves theoutcome of thesechildren due to a surgicalapproach that avoidsrenal damage.

Silva JMP, 2006,Brazil, 2006, caseseries, 1986e2004

47 TMP,Nitrofurantoin

NS 6 66 NS 31% renal

damagen: 12(25%)

NS There was no associationbetween urinary tractinfection and gender,grade of VUR andpresence of renaldamage at admission.There was no differencein occurrence of UTIbetween childrenreferred before or after6 months of age,

Song SH, 2007, Korea,case series, 1994e2004

0 (0) NS NS 77 12 NS NS 38 NS Infants with severe HNdue to obstruction of theupper urinary tractshould receive antibioticprophylaxis.

St Aubin M, 2013, US,case series, 2007e2010

Unclear TMP 2 mg/kg1 � 1Amox:20 mg/kg1 � 1

NS 19 33.5 ANH resolved in 60patients

NS 9 6 VCUG could be safelyreserved for high-gradeANH cases withoutincreasing the risk of UTIor pyelonephritis,validating current SFUrecommendations

Takvani A, 2015,India, case series,2002e2013,abstract

78 Gp 1 and all

(110) gp 2NS NS 52 NS NS NS NS 4/110

with

ANH þVUR

Outcomes of VUR due toANH and febrile UTI werepresented


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iotic

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Ab side

effectsSurgeryn (%)



Tombesi MM, 2012,Argentina, caseseries, 1998e2009

0 NS NS 1 15 Intrauterineresolution: 91, totalresolution: 111,partial resolution: 20,unchanged: 52,progression: 2

NS 23 NS Routine CAP and VCUGmight not be necessaryin all infants with mildANH, clinical andultrasound follow-upbeing advisable duringthe first year of life.

Upadhyay J, 2003,Canada, caseseries, 1993e1998

25 (100) TMP 2 mg/kg1 � 1

NS 6 48 NS 2 decreased 4 NS Expectant managementis safe and should be theprimary mode ofmanagement forprenatally diagnosedvesicoureteral reflux.

Winters 1990, US,case series, 1982e1989

17 NS NS 36 Unclear NS NS 10 (7 not onprophylaxis)

NS Prenatal diagnosis canprevent the UTIs ofpatients with HN of theupper pole, if CAPstarted.

Yerkes EB, 1999, US,case series,1992e1997

Unclear NS NS 1 6e54 mo Resolution: 14patients, stable ordecreased: 8,progressed: NS

NS 0 0 With careful counselingand follow-up mostpatients with less thangrade 2 HN can beobserved withouturological sequelae

Ylinen E, 2004,Finland, caseseries, 1983e1998

NS NS NS 42 86 Increased: 3, stable:32, Improved: 33,resolved: 13

Decreased in 3 NS NS In most patients theoutcome of antenatallydetected unilateral PUJobstruction with initiallygood renal function,whether treatedconservatively orsurgically, seemsfavorable.

26M.S.

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Zampieri

N,20

11,

Italy,ca

seseries,

2004

e20

06

20(100

)Amoxy

cillin

1/3dose,

1�

1

NS

3>36

Resolution:5,

decreased:30

%reductionin

AP

diameterin

9

Noneim

paired

88

Conservative

manage

mentis

succ

essfulin

POM

detectedasANH

ZerinJM

,19

93,US,

case

series,

1988

e19

92

49(pts

withVUR)

NS

NS

1019

NS

NS

00

Neonateswith

antenatallydetectedHN

should

beroutinely

screenedforVURwith

VCUG.

ANH

Zantenatalhyd

ronephrosis;

AP

Zanteroposterior;

APPD

Zanteroposterior

pelvic

diameter;

BOO

Zbladder

outlet

obstruction;

fUTIZ

febrile

UTI;

GZ

grad

e;

HN

Zhyd

ronephrosis;

HUN

Zhyd

roureteronephrosis;

LUTO

Zlowerurinary

tract

obstruction;MCDK

Zmulticystic

dysplastic

kidney;

MGU

Zmega

ureter;

NB

Znew

born;

POM

Zprimary

obstructivemega

ureter;

PUVZ

posteriorurethralva

lves;

SFUZ

Society

ofFetalUrology

;UPJZ

ureteropelvic

junction;UPJO

Zureteropelvic


UTIZ

urinarytract

infection;VCUG

Zvo

idingcystourethrography;

VURZ

vesico

ureteralreflux;

USZ

ultrasound.


+ MODEL


The best type of the antibiotic regimen and the adverseeffects of the antibiotics could not be assessed either. Theonly thing that can be said is the most commonly chosenantibiotic in infants with ANH is trimethoprim, and, exceptin one pilot RCT [7], no side effect was reported in any ofthe eligible comparative studies or case series. Therecently published paper which is a completion of the pilotRCT confirmed the same outcomes [69].

Implications for clinical practice

The benefit of CAP in infants with ANH is not proven. Basedon the lack of clinical effectiveness and unreported sideeffects, we are not able to recommend routine use of CAPin neonates with ANH. However, infants with ANH consti-tute a highly heterogeneous group of patients. Individualrisk stratification is warranted taking patient factors (ure-teral dilatation, circumcision status, high-grade HN) intoaccount during decision-making. If CAP is favored by theclinician, no recommendations can be made on the typeand optimal dose of antibiotic regimen.

Further research

Undoubtedly, RCTs are required to elucidate whether in-fants with ANH might benefit from CAP. There were onlytwo RCTs included in this systematic review, and both ofthem had significant drawbacks [7,11]. One of them is apilot study and no recommendation was provided by theauthors, but multicenter collaborative trials were encour-aged [7]. The other is a congress abstract lacking significantinformation in terms of methods and findings [11].

Another important area for future research is the sub-group of ANH, which carries different risks for developingUTI. Separate subgroup analyses should be conducted withthe subgroups (HUN, VUR, high-grade HN, POM, etc.).

Finally, there is a need for optimization of the antibioticregime and meticulous work to demonstrate the side ef-fects in the future studies.

Limitations and strengths

The main limitation was the heterogeneity of the patientpopulations in the available literature which made meta-analysis inappropriate for this particular review. Overall, thedata obtained from the eligible studies represent moderatequality of evidence. Another limitation was the varied def-initions of different clinical entities. The severity of HN wasreported in different ways including SFU grade, AP diameter,and other descriptions such as mild, moderate, and severeand needs to be standardized. In patients with HN withoutureteral dilatation, the definitions including UPJO, isolatedHN, and UPJO-like HN are used by the investigators and needstandardization as well. The standardization in the defini-tion of UTI and fUTI is another point that needs to beconsidered. Unfortunately, only a small number of thestudies discriminated UTIs as febrile or non-febrile.

In the end, although we could not demonstrate thebenefits and harms of CAP in ANH, we were able to identifysome potential risk factors for developing UTI which mayaffect the treatment strategy of the clinicians. This



+ MODEL

systematic review was performed by a group of expertsincluding clinicians and methodologists (EAU PediatricUrology Guideline Panel) according to PRISMA guidelines,and the results will be incorporated into the 2017 practiceguidelines.

Conclusions

The benefits of CAP in a heterogeneous group of childrenwith ANH involving different etiologies remains unproven.However, the evidence in the form of prospective andretrospective observational studies has shown that it re-duces fUTI in particular subgroups. Uncircumcised infants,HUN, and high-grade HN may be more likely to develop UTI.CAP may be reserved for this subgroup of patients who areproven to be at high risk. No conclusion could be drawn forpatients with VUR and ANH.

Conflict of interest

None.

Funding

None.

Appendix A. Supplementary data

Supplementary data related to this article can be found athttp://dx.doi.org/10.1016/j.jpurol.2017.02.023.

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Role of antibiotic prophylaxis in antenatal hydronephrosis ... · In a previous systematic review by Braga et al. [4],no beneﬁt of CAP could be demonstrated in ANH. Infants with