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Circumcision reduces urinary tract infection in children with antenatal hydronephrosis: Systematic review and meta-analysis

  • Irfan Wahyudi
    Correspondence
    Correspondence to: I. Wahyudi, Department of Urology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jalan Diponegoro No. 71, Jakarta, 10430, Indonesia, Fax: +6221 3145592
    Affiliations
    Department of Urology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jalan Diponegoro No. 71, Jakarta 10430, Indonesia
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  • Putu Angga Risky Raharja
    Affiliations
    Department of Urology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jalan Diponegoro No. 71, Jakarta 10430, Indonesia
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  • Gerhard Reinaldi Situmorang
    Affiliations
    Department of Urology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jalan Diponegoro No. 71, Jakarta 10430, Indonesia
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  • Arry Rodjani
    Affiliations
    Department of Urology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jalan Diponegoro No. 71, Jakarta 10430, Indonesia
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Open AccessPublished:October 27, 2022DOI:https://doi.org/10.1016/j.jpurol.2022.10.029

      Summary

      Introduction

      Urinary tract infection (UTI) is more prevalent in boys with antenatal hydronephrosis (ANH). Circumcision is known to lessen the risk of UTI. This study was performed to examine the associations between circumcision and UTI among patients with ANH.

      Methods

      The Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed for conducting this systematic review and meta-analysis. PubMed, ScienceDirect, EMBASE, and Cochrane Library databases were searched through August 4th, 2022 to identify eligible studies. The risk of bias was measured using the Newcastle-Ottawa Scale (NOS). Review manager 5.4 was used for all analysis.

      Results

      A total of 21 studies involving 8,968 patients with ANH were included in the meta-analysis. The incidences of UTI were 18.1% in the uncircumcised group and 4.9% in the circumcised group. From analysis, circumcision had significant protective effect against UTI with pooled OR of 0.28 (95% CI 0.23–0.32). The significant protective effects were also found in subgroup analysis of hydronephrosis etiology, including vesicoureteral reflux (pooled OR of 0.24; 95% CI 0.17–0.32), obstructive hydronephrosis (pooled OR of 0.34; 95% CI 0.21–0.53), and posterior urethral valve (pooled OR of 0.28; 95% CI 0.16–0.52).

      Conclusion

      Our meta-analysis showed that circumcision was associated with a decreased incidence of UTI in children with ANH. This benefit was consistent irrespective of the underlying cause of hydronephrosis.

      Keywords:

      Introduction

      In 1%–2% of all pregnancies, antenatal hydronephrosis (ANH) is a frequently diagnosed condition [
      • Nguyen H.T.
      • Benson C.B.
      • Bromley B.
      • Campbell J.B.
      • Chow J.
      • Coleman B.
      • et al.
      Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system).
      ]. The rate of detection is rising due to the extensive use of prenatal ultrasonography [
      • Rianthavorn P.
      • Phithaklimnuwong S.
      The role of antibiotic prophylaxis in mild to moderate isolated hydronephrosis detected in antenatal screening.
      ]. ANH reflects a spectrum of potential etiologies, including transient or physiologic hydronephrosis, vesicoureteral reflux (VUR), ureteropelvic junction obstruction (UPJO), ureterovesical junction obstruction (UVJO), posterior urethral valve (PUV), and other conditions [
      • Nguyen H.T.
      • Benson C.B.
      • Bromley B.
      • Campbell J.B.
      • Chow J.
      • Coleman B.
      • et al.
      Multidisciplinary consensus on the classification of prenatal and postnatal urinary tract dilation (UTD classification system).
      ]. Early diagnosis during the antenatal period permits early postnatal monitoring for complications such as urinary tract infection (UTI), hypertension, growth failure, and even renal failure [
      • Rianthavorn P.
      • Phithaklimnuwong S.
      The role of antibiotic prophylaxis in mild to moderate isolated hydronephrosis detected in antenatal screening.
      ].
      Identifiable factors linked with UTI in ANH patients remain under investigation [
      • Zee R.S.
      • Herbst K.W.
      • Kim C.
      • McKenna P.H.
      • Bentley T.
      • Cooper C.S.
      • et al.
      Urinary tract infections in children with prenatal hydronephrosis: a risk assessment from the Society for Fetal Urology Hydronephrosis Registry.
      ]. Several studies found that hydronephrosis grade, VUR, gender, circumcision status, and prophylactic antibiotic use were linked with the incidence of UTI in hydronephrosis patients [
      • Braga L.H.
      • Farrokhyar F.
      • D'Cruz J.
      • Pemberton J.
      • Lorenzo A.J.
      Risk factors for febrile urinary tract infection in children with prenatal hydronephrosis: a prospective study.
      ,
      • Coelho G.M.
      • Bouzada M.C.F.
      • Pereira A.K.
      • Figueiredo B.F.
      • Leite M.R.S.
      • Oliveira D.S.
      • et al.
      Outcome of isolated antenatal hydronephrosis: a prospective cohort study.
      ,
      • Braga L.H.
      • Mijovic H.
      • Farrokhyar F.
      • Pemberton J.
      • DeMaria J.
      • Lorenzo A.J.
      Antibiotic prophylaxis for urinary tract infections in antenatal hydronephrosis.
      ,
      • Coelho G.M.
      • Bouzada M.C.F.
      • Lemos G.S.
      • Pereira A.K.
      • Lima B.P.
      • Oliveira E.A.
      Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation.
      ,
      • Zareba P.
      • Lorenzo A.J.
      • Braga L.H.
      Risk factors for febrile urinary tract infection in infants with prenatal hydronephrosis: comprehensive single center analysis.
      ,
      • Estrada C.R.
      • Peters C.A.
      • Retik A.B.
      • Nguyen H.T.
      Vesicoureteral reflux and urinary tract infection in children with a history of prenatal hydronephrosis—should voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis?.
      ,
      • Szymanski K.M.
      • Al-Said A.N.
      • Pippi Salle J.L.
      • Capolicchio J.-P.
      Do infants with mild prenatal hydronephrosis benefit from screening for vesicoureteral reflux?.
      ]. This is evidence that boys with hydronephrosis are more prone to getting UTI [
      • Silay M.S.
      • Undre S.
      • Nambiar A.K.
      • Dogan H.S.
      • Kocvara R.
      • Nijman R.J.M.
      • et al.
      Role of antibiotic prophylaxis in antenatal hydronephrosis: a systematic review from the European association of urology/European society for paediatric urology guidelines panel.
      ,
      • Ellison J.S.
      • Dy G.W.
      • Fu B.C.
      • Holt S.K.
      • Gore J.L.
      • Merguerian P.A.
      Neonatal circumcision and urinary tract infections in infants with hydronephrosis.
      ]. Ellison et al. stated that the incidence of UTI among boys with ANH (12%) was significantly higher compared to healthy boys (1%) [
      • Ellison J.S.
      • Dy G.W.
      • Fu B.C.
      • Holt S.K.
      • Gore J.L.
      • Merguerian P.A.
      Neonatal circumcision and urinary tract infections in infants with hydronephrosis.
      ].
      In boys with hydronephrosis, circumcision is known to minimize the risk of UTI [
      • Morris B.J.
      • Wiswell T.E.
      Circumcision and lifetime risk of urinary tract infection: a systematic review and meta-analysis.
      ]. The American Academy of Pediatrics’ (AAP) consensus statement on male circumcision also recommends circumcision for boys with urological anomalies to reduce UTI incidence [
      • Blank S.
      • Brady M.
      • Buerk E.
      • Carlo W.
      • Diekema D.
      • Freedman A.
      • et al.
      Male circumcision.
      ]. A meta-analysis investigating the correlations between circumcision and UTI in boys with ANH has not been published. Consequently, we performed a systematic review and meta-analysis to review the available evidence regarding potential associations between circumcision and UTI in children with ANH.

      Material and methods

      Literature search

      This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Through August 4th, 2022, systematic searches were performed using PubMed, ScienceDirect, EMBASE, and Cochrane Library databases to identify relevant literature evaluating associations between circumcision and the incidence of UTI in children with ANH. The subsequent subject terms and keywords were used: (“circumcision” or “circumcised” or “uncircumcised”) and (“UTI” or “urinary tract infection” or “urinary infection” or “bacteriuria” or “bacteremia” or “pyuria”) and (“hydronephrosis” or “renal dilatation” or “renal dilation” or “vesico-ureteral reflux” or “vesicoureteral reflux” or “VUR” or “ureteropelvic junction obstruction” or “UPJO” or “ureterovesical junction obstruction” or “UVJO” or “megaureter” or “dilated ureter” or “posterior urethral valve” or “PUV”. This study conducted a search using the most pertinent keywords for each database. In addition, manual searches using references from related papers were also undertaken. This study's protocol has been registered.

      Inclusion and exclusion criteria

      The population is comprised of male children with ANH history or subsequent postnatal diagnosis. This study included patients with reflux (VUR), obstructive hydronephrosis (UPJO and UVJO), PUV, and unspecified hydronephrosis. The outcome of the eligible studies must have included any UTI associated with circumcision status. The following inclusion criteria were necessary for studies to qualify: (1) a prospective, retrospective, or randomized trial evaluating the associations between circumcision status and UTI in ANH patients; (2) English language; and (3) comparability of UTI incidence between case and control groups in order to calculate odds ratios (OR). These were the exclusion criteria for the study: (1) qualitative studies, case reports, commentary, editorials, systematic reviews, and meta-analyses; and (2) unavailability of full text. The dates of publication were not restricted. When two studies of the same population were found, only the one with the bigger sample size was used.

      Quality assessment and data extraction

      Two independent investigators conducted data extraction and quality assessment. Disagreement was addressed by discussion and, if necessary, the assistance of other investigators. The risk of bias was evaluated using the Newcastle-Ottawa Scale (NOS) [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ]. We identified three domains for assessing bias, including: (1) selection, (2) comparability, and (3) outcome. Based on the scores in each domain, the total methodological quality was derived. Information on the author, publication year, population characteristics, UTI definition, circumcision classification, and circumcision incidence from eligible studies was collected.

      Statistical analysis

      Associations between circumcision status and the incidence of urinary tract infections were evaluated using OR and 95% confidence interval (CI). A chi-square-based Q test was conducted to examine the heterogeneity of the eligible studies. The presence of heterogeneity was established if the P value was less than 0.10. The fixed-effects model was employed for the calculation of pooled ORs for homogeneous studies (p value of Q test >0.10). In instances of heterogeneity, the random-effects model was utilized. If at least two studies were available, sub-analyses based on the etiology of hydronephrosis were conducted. The publication bias was assessed with Begg's funnel plot. Review manager 5.4. (Revman Cochrane, London, UK) was utilized to perform statistical analyses.

      Results

      Literature search and study characteristics

      There were 682 articles identified from the first literature search. There were 488 articles remaining after the removal of duplicates. After further title and abstract review, 411 articles were excluded. Then, the eligibility of the full texts of the remaining 77 articles was evaluated. Finally, we found 21 studies that met the criteria for inclusion in the meta-analysis [
      • Zee R.S.
      • Herbst K.W.
      • Kim C.
      • McKenna P.H.
      • Bentley T.
      • Cooper C.S.
      • et al.
      Urinary tract infections in children with prenatal hydronephrosis: a risk assessment from the Society for Fetal Urology Hydronephrosis Registry.
      ,
      • Braga L.H.
      • Farrokhyar F.
      • D'Cruz J.
      • Pemberton J.
      • Lorenzo A.J.
      Risk factors for febrile urinary tract infection in children with prenatal hydronephrosis: a prospective study.
      ,
      • Zareba P.
      • Lorenzo A.J.
      • Braga L.H.
      Risk factors for febrile urinary tract infection in infants with prenatal hydronephrosis: comprehensive single center analysis.
      ,
      • Ellison J.S.
      • Dy G.W.
      • Fu B.C.
      • Holt S.K.
      • Gore J.L.
      • Merguerian P.A.
      Neonatal circumcision and urinary tract infections in infants with hydronephrosis.
      ,
      • Herndon C.D.A.
      • McKenna P.H.
      • Kolon T.F.
      • Gonzales E.T.
      • Baker L.A.
      • Docimo S.G.
      A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis.
      ,
      • Farhat W.
      • McLorie G.
      • Geary D.
      • Capolicchio G.
      • Bägli D.
      • Merguerian P.
      • et al.
      The natural history of neonatal vesicoureteral reflux associated with antenatal hydronephrosis.
      ,
      • Kwak C.
      • Oh S.J.
      • Lee A.
      • Choi H.
      Effect of circumcision on urinary tract infection after successful antireflux surgery.
      ,
      • Mukherjee S.
      • Joshi A.
      • Carroll D.
      • Chandran H.
      • Parashar K.
      • McCarthy L.
      What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?.
      ,
      • Roth C.C.
      • Hubanks J.M.
      • Bright B.C.
      • Heinlen J.E.
      • Donovan B.O.
      • Kropp B.P.
      • et al.
      Occurrence of urinary tract infection in children with significant upper urinary tract obstruction.
      ,
      • Alsaywid B.S.
      • Saleh H.
      • Deshpande A.
      • Howman-Giles R.
      • Smith G.H.H.
      High grade primary vesicoureteral reflux in boys: long-term results of a prospective cohort study.
      ,
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ,
      • Sencan A.
      • Carvas F.
      • Hekimoglu I.C.
      • Caf N.
      • Sencan A.
      • Chow J.
      • et al.
      Urinary tract infection and vesicoureteral reflux in children with mild antenatal hydronephrosis.
      ,
      • Evans K.
      • Asimakadou M.
      • Nwankwo O.
      • Desai D.
      • Cherian A.
      • Mushtaq I.
      • et al.
      What is the risk of urinary tract infection in children with antenatally presenting dilating vesico-ureteric reflux?.
      ,
      • Hidas G.
      • Billimek J.
      • Nam A.
      • Soltani T.
      • Kelly M.S.
      • Selby B.
      • et al.
      Predicting the risk of breakthrough urinary tract infections: primary vesicoureteral reflux.
      ,
      • Braga L.H.
      • D'Cruz J.
      • Rickard M.
      • Jegatheeswaran K.
      • Lorenzo A.J.
      The fate of primary nonrefluxing megaureter: a prospective outcome analysis of the rate of urinary tract infections, surgical indications and time to resolution.
      ,
      • Varda B.K.
      • Finkelstein J.B.
      • Wang H.H.
      • Logvinenko T.
      • Nelson C.P.
      The association between continuous antibiotic prophylaxis and UTI from birth until initial postnatal imaging evaluation among newborns with antenatal hydronephrosis.
      ,
      • Chan Y.Y.
      • Rosoklija I.
      • Shannon R.
      • Singal A.
      • D'Oro A.
      • Meade P.
      • et al.
      Urinary tract infection after robot-assisted laparoscopic pyeloplasty: are urine cultures and antibiotics helpful?.
      ,
      • Holzman S.A.
      • Chamberlin J.D.
      • Davis-Dao C.A.
      • Le D.T.
      • Delgado V.A.
      • Macaraeg A.M.
      • et al.
      Retractable foreskin reduces urinary tract infections in infant boys with vesicoureteral reflux.
      ,
      • Holzman S.A.
      • Braga L.H.
      • Zee R.S.
      • Herndon C.D.A.
      • Davis-Dao C.A.
      • Kern N.G.
      • et al.
      Risk of urinary tract infection in patients with hydroureter: an analysis from the society of fetal urology prenatal hydronephrosis registry.
      ,
      • Chamberlin J.D.
      • Braga L.H.
      • Davis-Dao C.A.
      • Herndon C.D.A.
      • Holzman S.A.
      • Herbst K.W.
      • et al.
      Continuous antibiotic prophylaxis in isolated prenatal hydronephrosis.
      ,
      • Harper L.
      • Blanc T.
      • Peycelon M.
      • Michel J.L.
      • Leclair M.D.
      • Garnier S.
      • et al.
      Circumcision and risk of febrile urinary tract infection in boys with posterior urethral valves: result of the CIRCUP randomized trial.
      ]. Fig. 1 depicts the eligibility process in this meta-analysis. The characteristics of the studies considered in the quantitative synthesis are presented in Table 1. Table 2 shows that, based on the NOS scale, 9 studies (43%) were judged to be of high quality.
      Fig. 1
      Fig. 1Flow chart of eligible study selection.
      Table 1Characteristics of individual studies included in the meta-analysis.
      NoStudyCountryDesignsPopulationHydronephrosis DefinitionUTI DefinitionCircumcision ClassificationUTI/Total CircumcisedUTI/Total Uncircumcised
      1Herndon et al., 1999 [
      • Herndon C.D.A.
      • McKenna P.H.
      • Kolon T.F.
      • Gonzales E.T.
      • Baker L.A.
      • Docimo S.G.
      A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis.
      ]
      United StatesRetrospectiveChildrenVURNot statedMedical records7/3610/19
      2Farhat et al., 2000 [
      • Farhat W.
      • McLorie G.
      • Geary D.
      • Capolicchio G.
      • Bägli D.
      • Merguerian P.
      • et al.
      The natural history of neonatal vesicoureteral reflux associated with antenatal hydronephrosis.
      ]
      CanadaCohort,

      1993–1998
      InfantsPrimary VURPositive urine culture collected with catheterNot stated1/76/17
      3Kwak et al., 2004 [
      • Kwak C.
      • Oh S.J.
      • Lee A.
      • Choi H.
      Effect of circumcision on urinary tract infection after successful antireflux surgery.
      ]
      KoreaCohort,

      1985–1993
      Boys after anti-reflux surgeryPrimary VURRecurrent UTI (positive culture in midstream urine specimen) after surgeryPerformed during study2/2711/50
      4Mukherjee et al., 2009 [
      • Mukherjee S.
      • Joshi A.
      • Carroll D.
      • Chandran H.
      • Parashar K.
      • McCarthy L.
      What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?.
      ]
      United KingdomRetrospectiveBoys (1–18 years)PUVPossible febrile UTI treated with antibiotics or proven from culture resultsPerformed during study8/2751/78
      5Roth et al., 2009 [
      • Roth C.C.
      • Hubanks J.M.
      • Bright B.C.
      • Heinlen J.E.
      • Donovan B.O.
      • Kropp B.P.
      • et al.
      Occurrence of urinary tract infection in children with significant upper urinary tract obstruction.
      ]
      United StatesRetrospectiveChildrenUPJO & obstructive megaureterSymptomatic infection with positive urine cultureMedical records0/412/24
      6Alsaywid et al., 2010 [
      • Alsaywid B.S.
      • Saleh H.
      • Deshpande A.
      • Howman-Giles R.
      • Smith G.H.H.
      High grade primary vesicoureteral reflux in boys: long-term results of a prospective cohort study.
      ]
      AustraliaCohort,

      1995–2006
      Boys (birth-8.8 years)High-grade primary VURNot statedPerformed during study5/7462/137
      7Gücük et al., 2013 [
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ]
      TurkeyRandomized trialBoys (<3 years)Low-grade VURSymptomatic UTI with positive urine culturePerformed during study0/459/46
      8Sencan et al., 2014 [
      • Sencan A.
      • Carvas F.
      • Hekimoglu I.C.
      • Caf N.
      • Sencan A.
      • Chow J.
      • et al.
      Urinary tract infection and vesicoureteral reflux in children with mild antenatal hydronephrosis.
      ]
      United StatesProspective,

      1998–2010
      ChildrenAntenatal hydronephrosisSigns and/or symptoms with positive urine cultureNot stated5/48010/128
      9Zareba et al., 2014 [
      • Zareba P.
      • Lorenzo A.J.
      • Braga L.H.
      Risk factors for febrile urinary tract infection in infants with prenatal hydronephrosis: comprehensive single center analysis.
      ]
      CanadaRetrospectiveInfantsAntenatal hydronephrosisSymptomatic with positive culture from a catheterized urine specimenMedical records4/7623/149
      10Braga et al., 2015 [
      • Braga L.H.
      • Farrokhyar F.
      • D'Cruz J.
      • Pemberton J.
      • Lorenzo A.J.
      Risk factors for febrile urinary tract infection in children with prenatal hydronephrosis: a prospective study.
      ]
      CanadaCohort,

      2010–2013
      Infants (birth-18 months)Antenatal hydronephrosisPositive urine culture from catheter specimen associated with feverNot stated5/9535/166
      11Evans et al., 2015 [
      • Evans K.
      • Asimakadou M.
      • Nwankwo O.
      • Desai D.
      • Cherian A.
      • Mushtaq I.
      • et al.
      What is the risk of urinary tract infection in children with antenatally presenting dilating vesico-ureteric reflux?.
      ]
      United KingdomRetrospectiveChildren (<16 years)Primary VURPositive urine culture accompanied with feverNot stated6/2717/25
      12Hidas et al., 2015 [
      • Hidas G.
      • Billimek J.
      • Nam A.
      • Soltani T.
      • Kelly M.S.
      • Selby B.
      • et al.
      Predicting the risk of breakthrough urinary tract infections: primary vesicoureteral reflux.
      ]
      United StatesRetrospectiveChildren (0–130 months)Primary VURInfection characterized by fever, positive urinalysis, and cultureMedical records1/236/42
      13Braga et al., 2016 [
      • Braga L.H.
      • D'Cruz J.
      • Rickard M.
      • Jegatheeswaran K.
      • Lorenzo A.J.
      The fate of primary nonrefluxing megaureter: a prospective outcome analysis of the rate of urinary tract infections, surgical indications and time to resolution.
      ]
      These studies will be identified with (2) in the forest plot since there was similar first author name.
      CanadaCohort,

      2008–2015
      Infants (birth-21 months)Primary non-refluxing megaureterFever, pyuria, and positive urine cultureNot stated4/2121/51
      14Zee et al., 2016 [
      • Zee R.S.
      • Herbst K.W.
      • Kim C.
      • McKenna P.H.
      • Bentley T.
      • Cooper C.S.
      • et al.
      Urinary tract infections in children with prenatal hydronephrosis: a risk assessment from the Society for Fetal Urology Hydronephrosis Registry.
      ]
      United StatesRetrospectiveInfants (<2 years)Antenatal hydronephrosisPositive urine culture based on laboratory testingMedical records1/1164/31
      15Ellison et al., 2018 [
      • Ellison J.S.
      • Dy G.W.
      • Fu B.C.
      • Holt S.K.
      • Gore J.L.
      • Merguerian P.A.
      Neonatal circumcision and urinary tract infections in infants with hydronephrosis.
      ]
      United StatesRetrospective, claims databaseBoysAntenatal hydronephrosisDatabase records of UTI diagnosisDatabase records146/2386514/3174
      16Varda et al., 2018 [
      • Varda B.K.
      • Finkelstein J.B.
      • Wang H.H.
      • Logvinenko T.
      • Nelson C.P.
      The association between continuous antibiotic prophylaxis and UTI from birth until initial postnatal imaging evaluation among newborns with antenatal hydronephrosis.
      ]
      United StatesRetrospectiveInfants (<3 months)Antenatal hydronephrosisSymptoms and microbiology resultsMedical records0/1852/77
      17Chan et al., 2021 [
      • Chan Y.Y.
      • Rosoklija I.
      • Shannon R.
      • Singal A.
      • D'Oro A.
      • Meade P.
      • et al.
      Urinary tract infection after robot-assisted laparoscopic pyeloplasty: are urine cultures and antibiotics helpful?.
      ]
      United StatesRetrospectiveChildren (<18 years)UPJO undergoing robot-assisted laparoscopic pyeloplastySymptoms with positive urine culture and positive urinalysisMedical records2/804/25
      18Holzman et al., 2021 [
      • Holzman S.A.
      • Chamberlin J.D.
      • Davis-Dao C.A.
      • Le D.T.
      • Delgado V.A.
      • Macaraeg A.M.
      • et al.
      Retractable foreskin reduces urinary tract infections in infant boys with vesicoureteral reflux.
      ]
      United StatesCohort,

      2014–2020
      Infants (<1 year)Primary VURSymptomatic/febrile infection with pyuria and positive cultureExaminations1/2417/81
      19Holzman et al., 2021 [
      • Holzman S.A.
      • Braga L.H.
      • Zee R.S.
      • Herndon C.D.A.
      • Davis-Dao C.A.
      • Kern N.G.
      • et al.
      Risk of urinary tract infection in patients with hydroureter: an analysis from the society of fetal urology prenatal hydronephrosis registry.
      ]
      These studies will be identified with (2) in the forest plot since there was similar first author name.
      United StatesCohort,

      2008–2020
      InfantsAntenatal hydronephrosis with concomitant dilated ureterPyuria with positive urine cultureRegistry data7/8927/90
      20Chamberlin et al., 2022 [
      • Chamberlin J.D.
      • Braga L.H.
      • Davis-Dao C.A.
      • Herndon C.D.A.
      • Holzman S.A.
      • Herbst K.W.
      • et al.
      Continuous antibiotic prophylaxis in isolated prenatal hydronephrosis.
      ]
      United StatesRetrospectiveInfants (<2 years)Antenatal hydronephrosisSymptoms with positive urine cultureRegistry data3/36412/244
      21Harper et al., 2022 [
      • Harper L.
      • Blanc T.
      • Peycelon M.
      • Michel J.L.
      • Leclair M.D.
      • Garnier S.
      • et al.
      Circumcision and risk of febrile urinary tract infection in boys with posterior urethral valves: result of the CIRCUP randomized trial.
      ]
      FranceRandomized trialBoysPUVFever with evidence of pyuria and culture-proven infection from catheterization or suprapubic aspirationPerformed during study1/498/42
      a These studies will be identified with (2) in the forest plot since there was similar first author name.
      Table 2Summary of quality assessment scores using Newcastle Ottawa Scale.
      NoStudySelection (max. 4 stars)Comparability (max. 2 stars)Outcome (max. 3 stars)Methodological quality (high ≥7 stars)
      1Herndon et al., 1999 [
      • Herndon C.D.A.
      • McKenna P.H.
      • Kolon T.F.
      • Gonzales E.T.
      • Baker L.A.
      • Docimo S.G.
      A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis.
      ]
      ∗∗∗∗Low
      2Farhat et al., 2000 [
      • Farhat W.
      • McLorie G.
      • Geary D.
      • Capolicchio G.
      • Bägli D.
      • Merguerian P.
      • et al.
      The natural history of neonatal vesicoureteral reflux associated with antenatal hydronephrosis.
      ]
      ∗∗∗∗∗Low
      3Kwak et al., 2004 [
      • Kwak C.
      • Oh S.J.
      • Lee A.
      • Choi H.
      Effect of circumcision on urinary tract infection after successful antireflux surgery.
      ]
      ∗∗∗∗∗∗∗High
      4Mukherjee et al., 2009 [
      • Mukherjee S.
      • Joshi A.
      • Carroll D.
      • Chandran H.
      • Parashar K.
      • McCarthy L.
      What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?.
      ]
      ∗∗∗∗Low
      5Roth et al., 2009 [
      • Roth C.C.
      • Hubanks J.M.
      • Bright B.C.
      • Heinlen J.E.
      • Donovan B.O.
      • Kropp B.P.
      • et al.
      Occurrence of urinary tract infection in children with significant upper urinary tract obstruction.
      ]
      ∗∗∗∗∗Low
      6Alsaywid et al., 2010 [
      • Alsaywid B.S.
      • Saleh H.
      • Deshpande A.
      • Howman-Giles R.
      • Smith G.H.H.
      High grade primary vesicoureteral reflux in boys: long-term results of a prospective cohort study.
      ]
      ∗∗∗∗∗∗∗∗High
      7Gücük et al., 2013 [
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ]
      ∗∗∗∗∗Low
      8Sencan et al., 2014 [
      • Sencan A.
      • Carvas F.
      • Hekimoglu I.C.
      • Caf N.
      • Sencan A.
      • Chow J.
      • et al.
      Urinary tract infection and vesicoureteral reflux in children with mild antenatal hydronephrosis.
      ]
      ∗∗∗∗∗Low
      9Zareba et al., 2014 [
      • Zareba P.
      • Lorenzo A.J.
      • Braga L.H.
      Risk factors for febrile urinary tract infection in infants with prenatal hydronephrosis: comprehensive single center analysis.
      ]
      ∗∗∗∗∗∗∗∗∗High
      10Braga et al., 2015 [
      • Braga L.H.
      • Farrokhyar F.
      • D'Cruz J.
      • Pemberton J.
      • Lorenzo A.J.
      Risk factors for febrile urinary tract infection in children with prenatal hydronephrosis: a prospective study.
      ]
      ∗∗∗∗∗∗∗∗High
      11Evans et al., 2015 [
      • Evans K.
      • Asimakadou M.
      • Nwankwo O.
      • Desai D.
      • Cherian A.
      • Mushtaq I.
      • et al.
      What is the risk of urinary tract infection in children with antenatally presenting dilating vesico-ureteric reflux?.
      ]
      ∗∗∗∗∗Low
      12Hidas et al., 2015 [
      • Hidas G.
      • Billimek J.
      • Nam A.
      • Soltani T.
      • Kelly M.S.
      • Selby B.
      • et al.
      Predicting the risk of breakthrough urinary tract infections: primary vesicoureteral reflux.
      ]
      ∗∗∗∗∗Low
      13Braga et al., 2016 [
      • Braga L.H.
      • D'Cruz J.
      • Rickard M.
      • Jegatheeswaran K.
      • Lorenzo A.J.
      The fate of primary nonrefluxing megaureter: a prospective outcome analysis of the rate of urinary tract infections, surgical indications and time to resolution.
      ]
      These studies will be identified with (2) in the forest plot since there was similar first author name.
      ∗∗∗∗∗∗∗High
      14Zee et al., 2016 [
      • Zee R.S.
      • Herbst K.W.
      • Kim C.
      • McKenna P.H.
      • Bentley T.
      • Cooper C.S.
      • et al.
      Urinary tract infections in children with prenatal hydronephrosis: a risk assessment from the Society for Fetal Urology Hydronephrosis Registry.
      ]
      ∗∗∗∗∗∗∗∗High
      15Ellison et al., 2018 [
      • Ellison J.S.
      • Dy G.W.
      • Fu B.C.
      • Holt S.K.
      • Gore J.L.
      • Merguerian P.A.
      Neonatal circumcision and urinary tract infections in infants with hydronephrosis.
      ]
      ∗∗∗∗∗Low
      16Varda et al., 2018 [
      • Varda B.K.
      • Finkelstein J.B.
      • Wang H.H.
      • Logvinenko T.
      • Nelson C.P.
      The association between continuous antibiotic prophylaxis and UTI from birth until initial postnatal imaging evaluation among newborns with antenatal hydronephrosis.
      ]
      ∗∗∗∗∗∗High
      17Chan et al., 2021 [
      • Chan Y.Y.
      • Rosoklija I.
      • Shannon R.
      • Singal A.
      • D'Oro A.
      • Meade P.
      • et al.
      Urinary tract infection after robot-assisted laparoscopic pyeloplasty: are urine cultures and antibiotics helpful?.
      ]
      ∗∗∗∗∗Low
      18Holzman et al., 2021 [
      • Holzman S.A.
      • Chamberlin J.D.
      • Davis-Dao C.A.
      • Le D.T.
      • Delgado V.A.
      • Macaraeg A.M.
      • et al.
      Retractable foreskin reduces urinary tract infections in infant boys with vesicoureteral reflux.
      ]
      ∗∗∗∗∗∗∗∗High
      19Holzman et al., 2021 [
      • Holzman S.A.
      • Braga L.H.
      • Zee R.S.
      • Herndon C.D.A.
      • Davis-Dao C.A.
      • Kern N.G.
      • et al.
      Risk of urinary tract infection in patients with hydroureter: an analysis from the society of fetal urology prenatal hydronephrosis registry.
      ]
      These studies will be identified with (2) in the forest plot since there was similar first author name.
      ∗∗∗∗∗Low
      20Chamberlin et al., 2022 [
      • Chamberlin J.D.
      • Braga L.H.
      • Davis-Dao C.A.
      • Herndon C.D.A.
      • Holzman S.A.
      • Herbst K.W.
      • et al.
      Continuous antibiotic prophylaxis in isolated prenatal hydronephrosis.
      ]
      ∗∗∗∗∗Low
      21Harper et al., 2022 [
      • Harper L.
      • Blanc T.
      • Peycelon M.
      • Michel J.L.
      • Leclair M.D.
      • Garnier S.
      • et al.
      Circumcision and risk of febrile urinary tract infection in boys with posterior urethral valves: result of the CIRCUP randomized trial.
      ]
      ∗∗∗∗∗∗High
      ∗, ∗∗, ∗∗∗ corresponds to number of stars of each scale.
      a These studies will be identified with (2) in the forest plot since there was similar first author name.

      Circumcision status and UTI in patients with ANH

      All studies were included in the quantitative synthesis. This resulted in 21 studies, with a total of 8,968 patients with ANH, and 4,272 (47.6%) were circumcised. The overall incidence of UTI in this population was 11.8% (1,060/8,968). The incidence of UTI was 3.7 times higher in the uncircumcised group (18.1%; 851/4,696) compared to the circumcised group (4.9%; 209/4,272). From the meta-analysis, circumcision had a significant protective effect against UTI in patients with ANH with a pooled OR of 0.28 (95% CI 0.23–0.32) as shown in Fig. 2. This dataset exhibited no substantial heterogeneity, as evidenced by the I2 of 6% and p value of the Q test of 0.38. Fig. 2 shows that there was no publication bias because there was no asymmetry in the funnel plot.
      Fig. 2
      Fig. 2Forest and funnel plots for showing pooled estimates of UTI rates according to circumcision status in patients with ANH.

      Circumcision status and UTI in patients with VUR

      There were nine studies involving 1,408 patients with VUR. The overall incidence of UTI in this population was 28% (395/1,408) and 12.9% (67/521) of circumcised males developed UTI compared to 37% (328/887) of uncircumcised males. Circumcision also had a significant protective effect against UTI in patients with VUR with a pooled OR of 0.24 (95% CI 0.17–0.32) as shown in Fig. 3. Sub-analysis of VUR grade showed that patients with high grade VUR (grade 4–5) also benefited from circumcision (pooled OR of 0.10; 95% CI 0.05–0.21). Sub-analysis for low grade VUR (grade 1–3) was not possible since there was only one study included [
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ]. However, a protective effect was also observed in low grade VUR based on that study. The dataset was homogenous with an I2 of 16% and p value of Q test of 0.30. There was no publication bias among eligible studies based on the funnel plot.
      Fig. 3
      Fig. 3Forest and funnel plots for showing pooled estimates of UTI rates according to circumcision status in patients with VUR.

      Circumcision status and UTI in patients with obstructive ANH

      We also performed sub-analysis in patients with obstructive ANH, including UPJO and primary non-refluxing megaureter. In the four studies with obstructive ANH, there were 823 patients, and 402 (48.8%) were circumcised. The overall incidence of UTI in this population was 14% (115/823) and 6.7% (27/402) of circumcised males developed UTI compared to 20.9% (88/421) of uncircumcised males. As shown in Fig. 4, circumcision was significantly protective against developing UTI in obstructive hydronephrosis patients with a pooled OR of 0.34 (95% CI 0.21–0.53). Eligible studies showed no heterogeneity (I2 = 0%; p value of Q test = 0.63). The funnel plot revealed no significant publication bias.
      Fig. 4
      Fig. 4Forest and funnel plots for showing pooled estimates of UTI rates according to circumcision status in patients with obstructive ANH.

      Circumcision status and UTI in patients with PUV

      In the three studies with UTI rates in patients with PUV, there were 316 males, and 115 (36.4%) were circumcised. The overall incidence of UTI in this population was 34.5% (109/316) and 15.7% (18/115) of circumcised males developed UTI compared to 45.3% (91/201) of uncircumcised males. Circumcision was significantly protective against developing UTI in PUV males with a pooled OR of 0.28 (95% CI 0.16–0.52), as shown in Fig. 5. Due to a lack of data, further sub-analysis of VUR status among PUV populations was not feasible. Harper et al. discovered that 55.2% of PUV patients had high-grade VUR (grades III-V) [
      • Harper L.
      • Blanc T.
      • Peycelon M.
      • Michel J.L.
      • Leclair M.D.
      • Garnier S.
      • et al.
      Circumcision and risk of febrile urinary tract infection in boys with posterior urethral valves: result of the CIRCUP randomized trial.
      ]. There was no significant variability between eligible studies (I2 = 23%; p value of Q test = 0.27). In addition, no asymmetry was observed in the resulting funnel plot.
      Fig. 5
      Fig. 5Forest and funnel plots for showing pooled estimates of UTI rates according to circumcision status in patients with PUV.

      Discussion

      Our analysis indicates that UTI incidence in ANH patients was higher among uncircumcised boys (18.1%) compared to circumcised boys (4.9%). Circumcision is found to have a significant protective effect in such a population. Further sub-analysis found that the significant protective effect of circumcision was consistent regardless of the etiology of hydronephrosis (VUR, obstructive ANH, and PUV).
      Circumcision appears to be a successful, very straightforward, and inexpensive treatment for patients with ANH. The mechanism by which circumcision reduces UTI is most likely due to a reduction in bacterial contamination [
      • Mukherjee S.
      • Joshi A.
      • Carroll D.
      • Chandran H.
      • Parashar K.
      • McCarthy L.
      What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?.
      ]. Uropathogens can adhere to the preputial mucosal surface in uncircumcised males, enhancing colonization around the meatus [
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ,
      • Fussell E.N.
      • Kaack M.B.
      • Cherry R.
      • Roberts J.A.
      Adherence of bacteria to human foreskins.
      ]. After circumcision, pathogenic periurethral bacterial flora will be replaced by non-uropathogenic species [
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ]. In the first few months of infancy, boys with ANH have the highest risk of developing UTI [
      • Evans K.
      • Asimakadou M.
      • Nwankwo O.
      • Desai D.
      • Cherian A.
      • Mushtaq I.
      • et al.
      What is the risk of urinary tract infection in children with antenatally presenting dilating vesico-ureteric reflux?.
      ]. Circumcision should be considered as soon as possible. However, the decision to perform circumcision must be individualized for each patient since not all UTI result in renal scarring. In addition to possible unneeded complications, circumcision may also cause discomfort and affect the appearance of the genitalia.
      Most VUR patients who required reimplantation had a breakthrough UTI [
      • Herndon C.D.A.
      • McKenna P.H.
      • Kolon T.F.
      • Gonzales E.T.
      • Baker L.A.
      • Docimo S.G.
      A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis.
      ]. In addition, antibiotic prophylaxis does not appear to prevent UTI in many children [
      • Alsaywid B.S.
      • Saleh H.
      • Deshpande A.
      • Howman-Giles R.
      • Smith G.H.H.
      High grade primary vesicoureteral reflux in boys: long-term results of a prospective cohort study.
      ]. Our data revealed that circumcision reduces UTI in children with VUR, especially those with high-grade VUR. It seems logical that circumcision could lessen the necessity for surgical intervention and assist the resolution of reflux by extending observation time [
      • Herndon C.D.A.
      • McKenna P.H.
      • Kolon T.F.
      • Gonzales E.T.
      • Baker L.A.
      • Docimo S.G.
      A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis.
      ]. However, the impact of circumcision performed during anti-reflux surgery on the subsequent incidence of UTI is still inconclusive [
      • Kwak C.
      • Oh S.J.
      • Lee A.
      • Choi H.
      Effect of circumcision on urinary tract infection after successful antireflux surgery.
      ,
      • Gücük A.
      • Burgu B.
      • Gökçe I.
      • Mermerkaya M.
      • Soygür T.
      Do antibiotic prophylaxis and/or circumcision change periurethral uropathogen colonization and urinary tract infection rates in boys with VUR?.
      ].
      Our analysis showed a lower incidence of UTI among patients with obstructive ANH compared to VUR and PUV. Several studies also discovered similar findings [
      • Ellison J.S.
      • Dy G.W.
      • Fu B.C.
      • Holt S.K.
      • Gore J.L.
      • Merguerian P.A.
      Neonatal circumcision and urinary tract infections in infants with hydronephrosis.
      ,
      • Roth C.C.
      • Hubanks J.M.
      • Bright B.C.
      • Heinlen J.E.
      • Donovan B.O.
      • Kropp B.P.
      • et al.
      Occurrence of urinary tract infection in children with significant upper urinary tract obstruction.
      ]. However, circumcision also significantly reduced the risk of UTI in such population. Chan et al. found that boys with UPJO who had robot-assisted laparoscopic pyeloplasty had a significantly fewer UTI after the surgery if they had been circumcised [
      • Chan Y.Y.
      • Rosoklija I.
      • Shannon R.
      • Singal A.
      • D'Oro A.
      • Meade P.
      • et al.
      Urinary tract infection after robot-assisted laparoscopic pyeloplasty: are urine cultures and antibiotics helpful?.
      ]. Braga et al. also discovered that circumcisedmales with a primary non-refluxing megaureter had a substantially lower febrile UTI rate [
      • Braga L.H.
      • D'Cruz J.
      • Rickard M.
      • Jegatheeswaran K.
      • Lorenzo A.J.
      The fate of primary nonrefluxing megaureter: a prospective outcome analysis of the rate of urinary tract infections, surgical indications and time to resolution.
      ].
      In PUV patients, our study demonstrated that circumcision also reduces UTI considerably. Mukherjee et al. discovered that although circumcision reduced the incidence of UTI, it did not improve renal outcome [
      • Mukherjee S.
      • Joshi A.
      • Carroll D.
      • Chandran H.
      • Parashar K.
      • McCarthy L.
      What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?.
      ]. Only after circumcision is performed does it provide protection. If the procedure is delayed, the preventive impact is diminished, and pyelonephritis and subsequent kidney scarring may have already occurred [
      • Mukherjee S.
      • Joshi A.
      • Carroll D.
      • Chandran H.
      • Parashar K.
      • McCarthy L.
      What is the effect of circumcision on risk of urinary tract infection in boys with posterior urethral valves?.
      ]. Therefore, early circumcision in PUV is advantageous because it leads to improvement in renal outcome over the long term.
      Our analysis contained various potential biases. We decided to include all prenatal hydronephrosis patients, including those with VUR, UPJO, isolated hydronephrosis, non-refluxing megaureter, and PUV. Some of the individuals, however, were diagnosed postnatally. Several studies also failed to identify or discuss the cause of hydronephrosis. In addition, there were studies that did not specify how they defined UTI and circumcision status. There was heterogeneity in the definition of UTI between studies, with the possibility of phimosis and inadequate urine collection methods. In addition, we did not differentiate between febrile and non-febrile UTI, which may have affected the outcomes. Most of the studies also did not mention the hydronephrosis severity and timing of circumcision. There is a need for further study to define the relationship between circumcision and UTI, stratified by the severity of hydronephrosis and circumcision timing.
      This meta-analysis is, to our knowledge, the only study to evaluate the relationship between circumcision and UTI among children with ANH. Our findings may improve counseling regarding the risks and advantages of circumcision from the patient's perspective. Nevertheless, this meta-analysis had a number of limitations. The majority of studies were retrospective studies with poor quality. There was a possibility of inclusion bias among included studies. More high-quality RCTs are needed for future meta-analysis. In addition, there was limited number of studies that were eligible for subgroup analyses of hydronephrosis etiology. Other UTI risk factors, such as the severity of hydronephrosis and the use of prophylactic antibiotics, were not controlled. In this meta-analysis, only English-language studies were assessed for inclusion. This may have excluded studies conducted in languages other than English.

      Conclusions

      Our meta-analysis revealed that circumcision was associated with a lower incidence of UTI in children with ANH. This associated advantage was consistent with several etiologies of hydronephrosis, including VUR, obstructive ANH, and PUV. These findings will assist in counseling the risks and advantages of circumcision from the patient's perspective.

      Funding

      This study was supported by Universitas Indonesia with Publikasi Terindeks Internasional (PUTI) Q2 Grant [Grant Number NKB-1235/UN2.RST/HKP.05.00/2022].

      Conflict of interest

      None.

      Acknowledgements

      None.

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