Risk of urinary tract infection in patients with hydroureter: An analysis from the Society of Fetal Urology Prenatal Hydronephrosis Registry

Open AccessPublished:September 07, 2021DOI:https://doi.org/10.1016/j.jpurol.2021.09.001

      Summary

      Background

      Prenatal hydronephrosis is one of the most common anomalies detected on prenatal ultrasonography. Patients with prenatal hydronephrosis and ureteral dilation are at increased risk of urinary tract infection (UTI) and continuous antibiotic prophylaxis (CAP) is recommended. However, current guidelines do not define the minimum ureteral diameter that would be considered a dilated ureter in these patients.

      Objective

      We evaluate the definition of clinically relevant hydroureter, its association with UTI, and the impact of CAP.

      Study design

      Patients with prenatal hydronephrosis from seven centers were enrolled into the Society for Fetal Urology Prenatal Hydronephrosis Registry from 2008 to 2020. Patients with ureteral measurement on ultrasound were included. Patients with ureterocele, ectopic ureter, neurogenic bladder, posterior urethral valves, horseshoe or solitary kidney, known ureteropelvic junction obstruction, or follow-up less than one month were excluded. Primary outcome was UTI. Analyses were performed using Cox regression.

      Results

      Of the 1406 patients enrolled in the registry, 237 were included. Seventy-six percent were male, ureteral diameter ranged from 1 to 34 mm, and median follow-up was 2.2 years. Patients with ureters 7 mm or greater had nearly three times the risk of UTI adjusting for sex, circumcision status, antibiotic prophylaxis and hydronephrosis grade (HR = 2.7, 95% CI: 1.1–6.5, p = 0.03; Figure). In patients who underwent voiding cystourethrogram (VCUG; 200/237), ureteral dilation of 7 mm or more identified patients at increased UTI risk controlling for sex, circumcision status, vesicoureteral reflux and hydronephrosis grade (HR = 2.3, 95% CI: 0.97–5.6, p = 0.06). CAP was significantly protective against UTI (HR = 0.50 (95% CI: 0.28–0.87), p = 0.01). Among patients who underwent VCUG and did not have vesicoureteral reflux, ureteral dilation 7 mm or greater corresponded with higher UTI risk compared to ureteral diameter less than 7 mm on multivariable analysis (HR = 4.6, 95% CI: 1.1–19.5, p = 0.04).

      Conclusions

      Figure
      Graphical AbstractUTI-free probability stratified by <7 mm and ≥7 mm ureteral dilation.

      Keywords

      Abbreviations:

      CAP (Continuous antibiotic prophylaxis), PNH (Prenatal Hydronephrosis), SFU (Society for Fetal Urology), UVJ (Ureterovesical junction), UPJO (Ureteropelvic junction obstruction), UTI (Urinary tract infection), VCUG (Voiding cystourethrogram), VUR (Vesicoureteral reflux)

      Introduction

      Prenatal hydronephrosis (PNH) is one of the most common anomalies detected on prenatal ultrasonography and is reported in up to five percent of pregnancies [
      • Nguyen H.T.
      • Herndon C.D.
      • Cooper C.
      • Gatti J.
      • Kirsch A.
      • Kokorowski P.
      • et al.
      The society for fetal urology consensus statement on the evaluation and management of antenatal hydronephrosis.
      ]. The etiology of PNH can include transient or physiologic hydronephrosis, ureteropelvic junction obstruction, and vesicoureteral reflux. Ureteral dilation occurs in 5–10% of antenatal hydronephrosis cases [
      • Nguyen H.T.
      • Herndon C.D.
      • Cooper C.
      • Gatti J.
      • Kirsch A.
      • Kokorowski P.
      • et al.
      The society for fetal urology consensus statement on the evaluation and management of antenatal hydronephrosis.
      ]. Currently, nearly 79% of patients with hydroureteronephrosis present on perinatal ultrasound while the minority of patients present after a febrile urinary tract infection (UTI) [
      • Rubenwolf P.
      • Herrmann-Nuber J.
      • Schreckenberger M.
      • Stein R.
      • Beetz R.
      Primary non-refluxive megaureter in children: single-center experience and follow-up of 212 patients.
      ]. Most patients with ureteral dilation will resolve spontaneously on postnatal follow-up and can be managed conservatively [
      • McLellan D.L.
      • Retik A.B.
      • Bauer S.B.
      • Diamond D.A.
      • Atala A.
      • Mandell J.
      • et al.
      Rate and predictors of spontaneous resolution of prenatally diagnosed primary nonrefluxing megaureter.
      ,
      • Dekirmendjian A.
      • Braga L.H.
      Primary non-refluxing megaureter: analysis of risk factors for spontaneous resolution and surgical intervention.
      ].
      Patients with ureteral dilation are at increased risk for UTI and thus continuous antibiotic prophylaxis (CAP) is recommended [
      • Farrugia M.K.
      • Hitchcock R.
      • Radford A.
      • Burki T.
      • Robb A.
      • Murphy F.
      • et al.
      British association of paediatric urologists consensus statement on the management of the primary obstructive megaureter.
      ,
      • Herz D.
      • Merguerian P.
      • McQuiston L.
      Continuous antibiotic prophylaxis reduces the risk of febrile UTI in children with asymptomatic antenatal hydronephrosis with either ureteral dilation, high-grade vesicoureteral reflux, or ureterovesical junction obstruction.
      ,
      • Castagnetti M.
      • Cimador M.
      • Esposito C.
      • Rigamonti W.
      Antibiotic prophylaxis in antenatal nonrefluxing hydronephrosis, megaureter and ureterocele.
      ,
      • 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.
      ,
      • Hodhod A.
      • Capolicchio J.P.
      • Jednak R.
      • El-Sherif E.
      • El-Doray A.E.
      • El-Sherbiny M.
      Influence of postnatal hydroureter in determining the need for voiding cystourethrogram in children with high-grade hydronephrosis.
      ]. However, the literature is inconsistent with regard to the ureteral diameter threshold that appears to be clinically relevant. The British Association of Paediatric Urologists consensus statement recommends a threshold of 7 mm as utilized previously for primary non-refluxing megaureter [
      • Farrugia M.K.
      • Hitchcock R.
      • Radford A.
      • Burki T.
      • Robb A.
      • Murphy F.
      • et al.
      British association of paediatric urologists consensus statement on the management of the primary obstructive megaureter.
      ,
      • 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.
      ]. A recent prospective study on patients with prenatal hydronephrosis found that patients with non-refluxing primary megaureter (defined as ureteral diameter 7 mm or greater) had almost an 11 times higher risk of UTI [
      • 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.
      ]. Conversely, Hodhod et al. (2018) demonstrated an increased UTI risk in prenatal hydronephrosis patients with hydroureter greater than 4 mm [
      • Hodhod A.
      • Capolicchio J.P.
      • Jednak R.
      • El-Sherif E.
      • El-Doray A.E.
      • El-Sherbiny M.
      Influence of postnatal hydroureter in determining the need for voiding cystourethrogram in children with high-grade hydronephrosis.
      ].
      Previously reported risk factors for UTI in patients with ureteral dilation include lack of CAP and intact prepuce [
      • 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.
      ,
      • Gimpel C.
      • Masioniene L.
      • Djakovic N.
      • Schenk J.P.
      • Haberkorn U.
      • Tonshoff B.
      • et al.
      Complications and long-term outcome of primary obstructive megaureter in childhood.
      ,
      • Song S.H.
      • Lee S.B.
      • Park Y.S.
      • Kim K.S.
      Is antibiotic prophylaxis necessary in infants with obstructive hydronephrosis?.
      ]. The purpose of this study is to analyze our prospective multi-institutional registry of PNH patients with ureteral dilation to determine a ureteral diameter threshold associated with increased UTI risk. We hypothesize that patients with ureteral dilation greater than 7 mm are at greater risk of developing a UTI.

      Materials and methods

       Setting and population

      Seven medical centers enrolled patients into the Society for Fetal Urology (SFU) Prenatal Hydronephrosis Registry between 2008 and 2020. Children were eligible for the registry if they were diagnosed with PNH based on in utero imaging and presented at a participating center with prenatal imaging records available. The patients were followed prospectively through the fifth year of life. Clinical variables collected included imaging results, CAP use, and the development of UTI based on urinalysis, urine culture and antibiotic treatment. Data on demographics, circumcision status, and other diagnoses were collected. All centers obtained individual Institutional Review Board (IRB) approval (coordinating center IRB # HM20007783).

       Inclusion and exclusion criteria

      Patients with PNH and a ureteral diameter measurement recorded on ultrasound at any visit were considered for inclusion in the study. For patients with ureteral diameters recorded at multiple visits, the largest ureteral diameter recorded was used for analysis. Children with the following were excluded: ureterocele, bladder diverticulum, posterior urethral valves, urethral atresia, neurogenic bladder, prune belly syndrome, nephrolithiasis, horseshoe kidney, multicystic dysplastic kidney, solitary kidney, suspected ureteropelvic junction obstruction and/or history of pyeloplasty (Supplemental Fig. 1). Patients with missing data and those with less than one month of follow-up were also excluded. Children who were diagnosed with hydronephrosis following a UTI in the postnatal setting were not eligible for enrollment in the registry.

       Primary outcome and covariates

      The primary outcome was development of the first UTI during follow-up. UTI was strictly defined as positive pyuria (urinalysis with positive leukocyte esterase and/or greater than five white blood cells per high-power field) with a urine culture containing a single-organism with greater than 50,000 CFU/mL collected on a mid-stream clean-catch or catheterized specimen depending on patient age and toilet training status [
      Subcommittee on urinary tract infection. Reaffirmation of AAP clinical practice guideline: the diagnosis and management of the initial urinary tract infection in febrile infants and young children 2-24 Months of age.
      ]. All UTIs were reviewed by a senior investigator to confirm that these criteria were met.
      The use of CAP was assessed in all children during follow-up. Patients placed on CAP at any time point after establishing urologic care were defined as receiving CAP. However, patients without prior CAP exposure who were only prescribed antibiotics in response to a UTI were not defined as receiving CAP. Hydronephrosis grade was defined using the SFU hydronephrosis grading system, based on the first postnatal ultrasound. High grade hydronephrosis was defined as SFU grades 3–4 and low grade hydronephrosis was defined as SFU grades 1–2. For patients with bilateral hydronephrosis, the highest SFU grade was reported. A voiding cystourethrogram (VCUG) was obtained at the discretion of the treating center and vesicoureteral reflux (VUR) status was determined based on the initial VCUG. Since this was an observational study, use of CAP and testing for suspected UTIs were also at clinician discretion. Study data were collected and managed using REDCap (Research Electronic Data Capture, Vanderbilt University, Nashville, TN) [
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.
      ].

       Statistical analysis

      Univariate analyses were conducted using Chi-square and Kruskal–Wallis tests. Multivariable Cox regression analysis estimated the UTI risk adjusting for key risk factors including sex, circumcision status, CAP, and hydronephrosis grade. Hazard ratios and 95% confidence intervals were estimated for each variable in the model. Kaplan–Meier curves were used to calculate the probability of developing a UTI, with follow-up defined as time from birth to most recent clinical encounter or UTI event. Number needed to treat for the effectiveness of CAP in preventing UTI was estimated from the multivariable Cox regression model [
      • Austin P.C.
      Absolute risk reductions and numbers needed to treat can be obtained from adjusted survival models for time-to-event outcomes.
      ]. All statistical tests were two-tailed with p value less than 0.05 considered to be significant. Analyses were performed using SAS Statistical Software (Version 9.4, Cary, NC).

      Results

       Patient characteristics

      Of the 1406 enrollees in the SFU registry, 237 were included in the study. Seventy-six percent (180/237) were male and 50% (90/180) of male patients were circumcised. Patients were enrolled at a median age of 1.1 months (IQR 0.43–3.2). Patients were followed for a median of 2.2 years (IQR 0.95–4.0). Median ureteral diameter was 8.5 mm (range 1.0–34). A large proportion of patients had high grade hydronephrosis (grades 3 and 4) (62%, 145/237). In addition, the majority of patients (84%, 200/237) had a VCUG and among those 41% (81/200) had VUR. Most patients with VUR were high grade (grades IV and V) (80%, 65/81). CAP was prescribed for 65% of patients (155/237) during urology follow-up. Twenty two percent (53/237) had a UTI during the study period (Table 1) and 91% (48/53) had a febrile UTI; the remaining five patients with UTI did not have fever but were symptomatic with pyuria and a positive culture.
      Table 1Characteristics of prenatal hydronephrosis patients with dilated ureter
      Patient Characteristics N (%)n = 237
      Sex
       Males circumcised89 (38)
       Males uncircumcised90 (38)
       Females57 (24)
      Missing circumcision status1
      Median follow-up time (in years, IQR)2.1 (0.83–3.9)
      Median age at first visit (in months, IQR)1.1 (0.42–3.2)
      Median ureter width (in mm, IQR)8.5 (5.9–11)
      High Grade Hydronephrosis (Grades 3–4)145 (61)
      VCUG200 (84)
      VUR (Grades I–V)81 (41)
      High grade VUR (Grades IV–V)65 (80)
      CAP155 (65)
      UTI53 (22)
      Median time to UTI (in months, IQR)4.4 (2.3–11)

       Hydroureter analysis

      Ureteral dilation of 7 mm was a significant threshold to distinguish patients at higher risk of UTI (Fig. 1). Fifty-eight patients had ureteral diameter measurements between 1 and 6 mm, and 179 patients had ureteral dilation of 7 mm or larger. In patients with dilation less than 7 mm, 0/28 circumcised males, 2/15 (13%) uncircumcised males and 4/15 (27%) females developed a UTI. Comparing different thresholds for ureteral dilation in the multivariable Cox regression model (4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm and 10 mm), the results for less than 7 mm compared with 7 mm or greater ureteral dilation produced the most highly significant and largest effect estimate for UTI risk. Patients with ureteral dilation 7 mm or greater had almost three times the risk of UTI adjusting for sex, circumcision status, CAP, and hydronephrosis grade (HR = 2.7, 95% CI: 1.13–6.45, p = 0.03). We also found that threshold diameters of 8, 9 and 10 mm were also significant predictors of UTI on Cox regression analysis (HR 2.2, 2.3 and 1.9 respectively), however the highest hazard ratio of 2.7 was found with 7 mm threshold ureteral diameter. In the cohort who underwent VCUG (200/237), ureteral diameter of 7 mm or greater identified patients at increased UTI risk controlling for sex, circumcision status, VUR, and hydronephrosis grade (HR = 2.3, 95% CI:0.97–5.6, p = 0.058) although this was just outside the level of statistical significance.
      Fig. 1
      Fig. 1Kaplan–Meier curves displaying UTI-free probability for all 237 patients stratified by <7mm and ≥7 mm ureter dilation.

       UTI analysis

      On multivariable analysis the following were identified as independent risk factors for UTI development: ureteral dilation 7 mm or greater, intact prepuce, female sex, and lack of CAP (Table 2). CAP was found to be protective against UTI in patients with ureteral diameter 7 mm or greater (HR = 0.50, 95% CI:0.28–0.87, p = 0.01; Table 2) and extremely protective when controlling for VUR in the 200 patients who underwent VCUG (HR = 0.30, 95% CI: 0.16–0.55, p < 0.0001). However, CAP was not associated with reduced UTI risk in the subset of patients with ureteral diameter less than 7 mm (58/237) (HR = 1.1, 95% CI: 0.20–6.0).
      Table 2Univariable and multivariable analysis of UTI risk among children with dilated ureters and prenatal hydronephrosis.
      No. UTI (%)Univariable p valueMultivariable model
      HR (95% CI)p value
      Overall53 (22)
      Ureter dilation
       ≥1 and < 7 mm6 (10)1.0 (Ref)
       ≥7 mm47 (26)0.012.7 (1.1–6.5)0.03
       Males circumcised7 (8.0)1.0 (Ref)
       Males uncircumcised27 (30)0.00014.0 (1.7–9.2)0.001
       Females19 (33)0.025.1 (2.1–12)0.0003
       Missing circumcision status1
      Hydronephrosis Grade
       Low grade18 (20)1.0 (Ref)
       High grade35 (24)0.411.1 (0.63–2.0)0.67
       Missing grade
      CAP
       No23 (28)1.0 (Ref)
       Yes30 (19)0.130.50 (0.28–0.87)0.01
      Based on the full cohort of all 237 patients with dilated ureter, we estimate that 9 patients need to be treated with CAP to prevent one UTI at one year of follow-up. Among the subset of patients with dilated ureter 7 mm or greater (179/237), the corresponding number needed to treat was 7.

       VUR analysis

      Among patients with ureteral diameter 7 mm or greater who underwent VCUG, there was no difference in UTI development for refluxing versus non-refluxing patients (HR = 1.4, 95% CI: 0.76–2.7, p = 0.27; Fig. 2). In patients who underwent VCUG and did not have VUR (119 patients), those with ureteral dilation 7 mm or greater had a significantly higher UTI risk compared to patients with ureteral dilation less than 7 mm (HR = 4.6, 95% CI: 1.1–19.5, p = 0.04). Conversely, in patients with VUR, ureteral diameter greater than 7 mm did not predict increased UTI risk on multivariable analysis (HR = 1.1, 95% CI: 0.31–3.6, p = 0.93). The presence of high grade hydronephrosis did not predict patients at higher UTI risk (HR = 1.1, 95% CI: 0.62–2.1, p = 0.69).
      Fig. 2
      Fig. 2Kaplan–Meier curves for subset of patients with only ≥7 mm dilated ureter showing no difference between patients with and without VUR (among those with VCUG performed, n = 157).

      Discussion

      Herein, we present the results of over 1400 patients prospectively enrolled in the SFU prenatal hydronephrosis registry focusing on 237 patients with concomitant dilated ureter. Our study confirmed that a ureteral diameter of 7 mm or greater identified patients who were at higher risk of UTI development during follow-up on multivariable analysis controlling for multiple known risk factors. Interestingly, we found that patients with dilation 7 mm or greater were at increased risk of UTI regardless of the presence of VUR. Furthermore, among non-refluxing patients, ureteral diameter of 7 mm or larger identified patients at higher UTI risk likely secondary to increased urinary stasis in the more dilated ureters. We found that CAP was strongly protective for patients with hydroureter over 7 mm, providing a fourfold decrease in UTI risk (Table 2). Antibiotic prophylaxis was also extremely protective in patients with non-refluxing megaureter 7 mm or greater.
      While prenatal hydronephrosis with hydroureter has been established as risk factor for UTI development previously [
      • Herz D.
      • Merguerian P.
      • McQuiston L.
      Continuous antibiotic prophylaxis reduces the risk of febrile UTI in children with asymptomatic antenatal hydronephrosis with either ureteral dilation, high-grade vesicoureteral reflux, or ureterovesical junction obstruction.
      ], there was not a clear-cut definition of the minimum ureteral diameter to define hydroureter. In our study we found that 7 mm was a highly significant threshold to define patients at risk of developing a UTI. Similarly, ureteral diameters greater than 8 and 9 mm were also significant predictors of UTI risk but 7 mm was the minimum significant threshold with the highest hazard ratio. In our series, lower thresholds under 7 mm were not found to be significant to define patients at increased UTI risk. We found that patients with ureteral dilation less than 7 mm and confirmed VUR had a higher UTI rate (21%) compared to patients with dilation under 7 mm and no VUR (8%). We also found a relatively low number needed to treat of seven patients to prevent one UTI in patients with PNH and ureteral dilation 7 mm or greater. In this case, prescribing CAP is especially important as many patients presented under two months of age when a fever would prompt a neonatal sepsis admission. However, our study only had a small subset of patients with ureteral dilation under 7 mm with confirmed VUR (n = 19). Numerous prior studies identified patients with ureteral diameters greater than 10 mm as at risk for non-spontaneous resolution but were not focused on UTI risk [
      • Gimpel C.
      • Masioniene L.
      • Djakovic N.
      • Schenk J.P.
      • Haberkorn U.
      • Tonshoff B.
      • et al.
      Complications and long-term outcome of primary obstructive megaureter in childhood.
      ,
      • Ranawaka R.
      • Hennayake S.
      Resolution of primary non-refluxing megaureter: an observational study.
      ]. Furthermore, ureteral diameter 13 mm or greater has been established previously as having a significantly higher probability of requiring surgical intervention [
      • 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.
      ,
      • Chertin B.
      • Pollack A.
      • Koulikov D.
      • Rabinowitz R.
      • Shen O.
      • Hain D.
      • et al.
      Long-term follow up of antenatally diagnosed megaureters.
      ].
      The increased UTI rate noted in our patients with hydroureteronephrosis is consistent with prior studies on congenital dilated ureter with published UTI rates between 19 and 50% [
      • 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.
      ,
      • 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.
      ,
      • Song S.H.
      • Lee S.B.
      • Park Y.S.
      • Kim K.S.
      Is antibiotic prophylaxis necessary in infants with obstructive hydronephrosis?.
      ]. PNH with ureteral dilation has been identified previously as an independent risk factor for UTI [
      • Herz D.
      • Merguerian P.
      • McQuiston L.
      Continuous antibiotic prophylaxis reduces the risk of febrile UTI in children with asymptomatic antenatal hydronephrosis with either ureteral dilation, high-grade vesicoureteral reflux, or ureterovesical junction obstruction.
      ,
      • 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.
      ,
      • Hodhod A.
      • Capolicchio J.P.
      • Jednak R.
      • El-Sherif E.
      • El-Doray A.E.
      • El-Sherbiny M.
      Influence of postnatal hydroureter in determining the need for voiding cystourethrogram in children with high-grade hydronephrosis.
      ,
      • Lee J.H.
      • Choi H.S.
      • Kim J.K.
      • Won H.S.
      • Kim K.S.
      • Moon D.H.
      • et al.
      Nonrefluxing neonatal hydronephrosis and the risk of urinary tract infection.
      ,
      • 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.
      ]. Similarly, CAP has been shown to be highly protective for patients with PNH and ureteral dilation >11 mm [
      • Herz D.
      • Merguerian P.
      • McQuiston L.
      Continuous antibiotic prophylaxis reduces the risk of febrile UTI in children with asymptomatic antenatal hydronephrosis with either ureteral dilation, high-grade vesicoureteral reflux, or ureterovesical junction obstruction.
      ]. Our study also identified uncircumcised males and female sex as independent risk factors for UTI development, which has been demonstrated previously within the SFU registry database and in the literature [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • 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 et al. (2016) found that CAP was also highly protective in primary non refluxing megaureter patients with a number needed to treat of three patients [
      • 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.
      ]. However, their study was limited to patients with non-refluxing megaureter while our study included both non refluxing and refluxing dilated ureters and included ureteral diameters under 7 mm. Indeed, CAP is recommended for any patient with prenatal hydroureteronephrosis in the Canadian guidelines of antenatally detected hydronephrosis [
      • Capolicchio J.P.
      • Braga L.H.
      • Szymanski K.M.
      Canadian urological association/pediatric urologists of Canada guideline on the investigation and management of antenatally detected hydronephrosis.
      ].
      Our results were interesting with regard to the effect of reflux in this population with dilated ureter. Contrary to prior studies, in examining only those who had VCUG, neither high grade hydronephrosis nor the presence of VUR were significant predictors of UTI risk in patients with ureteral diameter 7 mm or greater (HR 1.2, p = 0.64 for high grade hydronephrosis and HR 1.4, p = 0.27 for reflux). We found that in dilated ureter patients with VUR, 7 mm was not a significant threshold to determine UTI risk. Dilating VUR has been demonstrated previously to be a risk factor for UTI and this may explain why we did not see an increased risk in patients with ureteral dilation greater than 7 mm who also had underlying reflux [
      • Nordenstrom J.
      • Sjostrom S.
      • Sillen U.
      • Sixt R.
      • Brandstrom P.
      The swedish infant high-grade reflux trial: UTI and renal damage.
      ,
      • de Bessa Jr., J.
      • de Carvalho Mrad F.C.
      • Mendes E.F.
      • Bessa M.C.
      • Paschoalin V.P.
      • Tiraboschi R.B.
      • et al.
      Antibiotic prophylaxis for prevention of febrile urinary tract infections in children with vesicoureteral reflux: a meta-analysis of randomized, controlled trials comparing dilated to nondilated vesicoureteral reflux.
      ]. Conversely, in patients without reflux, ureteral dilation 7 mm or greater was a strong predictor of UTI risk (HR 4.6, p = 0.04).
      Strengths of our study include the prospective and multicenter design with seven included pediatric urology centers. We also present the largest cohort to date on prenatal hydronephrosis with concomitant dilated ureter. Our study examined children with lower diameter dilated ureters that have not been included in most prior studies [
      • 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.
      ]. However, our study is not without limitations. CAP use was analyzed as having ever versus never been prescribed during urology follow-up. Due to the multicenter nature of data collection, the precise length of time on CAP was not known for all patients and we were unable to assess CAP compliance. Given the young age of our included patients, we were not able to evaluate the effect of bladder and bowel dysfunction, which is a well-established UTI risk factor [
      • Dias C.S.
      • Silva J.M.
      • Diniz J.S.
      • Lima E.M.
      • Marciano R.C.
      • Lana L.G.
      • et al.
      Risk factors for recurrent urinary tract infections in a cohort of patients with primary vesicoureteral reflux.
      ]. Finally, two of the more common etiologies of dilated ureter, primary obstructive megaureter and VUR, are known to resolve spontaneously as children age and patients with dilated ureters less than 7 mm may have been more likely to resolve and not develop a UTI during the study period [
      • 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.
      ]. Given our study design of including patients with any dilated ureter measurement following enrollment, patients with resolved dilation would be followed when they no longer had increased UTI risk. Furthermore, the majority of patients did not undergo diuretic renography therefore we cannot evaluate primary obstructive megaureter and its effects on UTI risk in this study.

      Conclusions

      This is the first prospectively collected, multi-center study to demonstrate that ureteral diameter 7 mm or greater identifies patients at higher risk of UTI who appear to benefit from CAP administration. Additionally, ureteral diameter 7 mm or greater predicted higher UTI risk regardless of the status of VUR. In contrast, patients with non-refluxing hydroureter less than 7 mm were not at increased risk of UTI and thus may be managed more conservatively. Based on our study results, we recommend that patients with dilated ureter should be followed closely. When the ureteral dilation is 7 mm or greater, CAP is warranted, particularly when the patient has other risk factors for UTI, including female sex and intact prepuce.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflict of Interest

      The authors have no conflicts of interest to report.

      Acknowledgements

      The authors would like to thank Mr. John Irby for management and coordination of the registry database. We would also like to thank all of the personnel involved at each participating center.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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