Journal of Perinatology (2014), 1–5 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Prevalence of upper urinary tract anomalies in hospitalized premature infants with urinary tract infection A Vachharajani1, GJ Vricella2, T Najaf1 and DE Coplen2 OBJECTIVE: The 2011 American Academy of Pediatrics (AAP) guidelines address imaging after initial febrile urinary tract infection (UTI) in infants 42 months of age. We sought to determine the frequency of upper urinary tract anomalies (hydronephrosis and vesicoureteral reflux (VUR)) in hospitalized premature infants with UTI. STUDY DESIGN: We retrospectively reviewed the electronic medical records of neonatal intensive care unit (NICU) admissions at a tertiary care children’s hospital between 1 January 2006 and 31 December 2010. We queried the records for UTI, renal ultrasound (US) and voiding cystourethrogram (VCUG). RESULT: We identified 3518 unique admissions. UTI occurred in 118 infants (3%). Sixty-nine (60%) had a normal US. Renal dilation was predominantly renal pelvic dilation (12%) and isolated caliectasis (22%). VUR was identified in 15 (14%) infants evaluated with a VCUG. VUR was identified in nine (12%) infants without and in seven (16%) with an abnormality on US. Reflux was identified in 7% of male and 38% of female infants with a UTI. CONCLUSION: Anatomic abnormalities of the upper urinary tract are uncommon in premature infants with a UTI that occurs during neonatal hospitalization. In concordance with the AAP guidelines, a VCUG may not be required in all NICU infants under age 2 months after a single UTI. Journal of Perinatology advance online publication, 4 December 2014; doi:10.1038/jp.2014.209
INTRODUCTION Urinary tract infections (UTIs) are a cause of bacterial infection in up to 7% of febrile infants and children.1 Up to 20% of these UTIs occur in children o 3 months of age.2 The incidence of UTI in neonates hospitalized in a neonatal intensive care unit (NICU) is as high as 12% and may be related to birth weight.3 UTI in the first 6 months of life occurs more commonly in male infants and this may be related to urinary tract obstruction and vesicoureteral reflux (VUR). In addition, uncircumcised male infants are known to have a higher incidence of UTI than those infants who have undergone circumcision.4,5 In 2011 the American Academy of Pediatrics (AAP) published revised guidelines for the management and evaluation of infants and young children (age 2 months to 2 years) with a UTI.6 A renal ultrasound (US) is recommended in all infants with a UTI but a voiding cystourethrogram (VCUG) is recommended after the first UTI only when the renal US is abnormal. This guideline recommends a VCUG in infants with recurrent UTIs. In the prior AAP guidelines iteration, investigations included an US during the acute infection and a VCUG once the infant had recovered.7 The change in recommendations regarding VCUG after the first UTI was based upon a meta-analysis of randomized controlled trials failing to support antimicrobial prophylaxis to prevent febrile UTI.6 However, the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial published in May 2014 demonstrated that trimethoprim–sulfamethoxazole prophylaxis was associated with a 50% reduction in symptomatic recurrences.8 Although there was no reduction in renal scarring in the study
population that was 42 months of age, detection of VUR and prevention of recurrent infections in neonates may be beneficial. Neither guideline specifically addresses the evaluation of UTI in infants o 2 months of age. Nowell et al.9 found very few urinary tract anomalies in 141 infants with a UTI prior to 2 months of age, but only 80% of the study population was evaluated with an US and 16% had neither an US or a VCUG performed. In an evaluation of low-birth-weight preterm infants the incidence of reflux was 14% in 42 infants o 1500 g at the time of UTI.3 In this study, we evaluate the incidence of UTI in premature infants hospitalized at a single tertiary care NICU between 2006 and 2010. Prior to 2011, we utilized the 1999 guidelines and recommended an US and VCUG in all infants with a UTI. We examined the frequency of upper urinary tract anomalies (hydronephrosis and VUR) in premature infants diagnosed with UTI.
METHODS We performed a retrospective review of all NICU admissions during a 5-year period (1 January 2006 to 31 December 2010) at a tertiary care children’s hospital. We queried the computerized hospital record for UTI, renal US and VCUG. All charts were reviewed individually for a discharge diagnosis of UTI, a urine culture (sent or not sent), blood cultures in conjunction with a urine culture and ordered radiologic tests including a renal US and VCUG. The indications for urine cultures were tabulated. Gender, race, birth weight, estimated gestational age (as determined by best obstetrical estimate) and congenital anomalies were recorded for each infant.
1 Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine and St Louis Children’s Hospital, Saint Louis, MO, USA and 2Division of Urology, Department of Surgery, Washington University School of Medicine and St Louis Children’s Hospital, Saint Louis, MO, USA. Correspondence: Dr DE Coplen, Division of Urology, Department of Surgery, Washington University School of Medicine and St. Louis Children's Hospital, 4990 Children's Place, Suite 1120, Saint Louis, MO 63110, USA. E-mail: [email protected] Received 14 August 2014; revised 20 September 2014; accepted 14 October 2014
Prevalence of upper urinary tract anomalies A Vachharajani et al
2 Urine samples were obtained by urethral catheterization in all cases. A dipstick and microscopic urinalysis was performed when sufficient volume was obtained via catheter. Leukocyte esterase and nitrite positivity was recorded. A positive urine microscopy was defined as 410 white blood cells per high power field. A UTI was defined as a growth of 4100K bacteria of a single colony type or growth of 10 to 50K bacteria in conjunction with a positive urinalysis. At our institution, whenever sepsis is suspected blood cultures are obtained at the time of urine cultures prior to initiating antibiotics. Results from blood cultures obtained within 72 h of the positive urine culture were recorded. Between 2006 and 2010, an US and VCUG were recommended in all infants treated for a UTI. All US images were reviewed by the attending radiologists at our institution and the senior author (DEC). Renal dilation was categorized using the Society for Fetal Urology classification.10 Renal parenchyma was assessed for echogenicity and ureteral dilation was tabulated. Bladder images are obtained in all US studies to assess for bladder distension, bladder wall thickening and distal ureteral dilation. VUR was graded using the International Reflux Classification.11 The hospital-based and outpatient electronic medical record for our practice plan was queried for infections and other urologic issues in all infants with a history of UTI after discharge from the NICU. We excluded from primary evaluation children with prenatally identified renal anomalies or postnatally identified conditions like posterior urethral valves or VACTERL (vertebral, anorectal, cardiac, trachea-esophageal fistula, renal and limbs), prune belly syndrome, spinal dysraphism and so on associated with UTIs that had been placed on antibiotic prophylaxis in the NICU. A two-tailed Fisher’s exact test was used to ascertain differences between study groups. A P-value o 0.05 was significant. Institutional review board approval for this study was obtained from the Human Research Protection Office (IRB # 201011824 BIO Utility of Contrast Studies).
RESULTS There were 3518 (1481 female and 2037 male infants) unique NICU admissions during the 5-year time period. UTI was identified in 118 infants (3%). The indications for urine culture are shown in Table 1. There were 27 female infants (1.8%) and 91 male infants (4.5%) with UTI during this time period. During the course of their NICU hospitalization, 28 patients (27 with 2 and one with 3) had multiple documented UTIs, with 24 (86%) of these being male infants. UTIs were more common in low gestational age and low birth-weight infants (Table 2). None of the male infants was circumcised at the time of UTI. Escherichia coli (19%), Klebsiella (19%) and Enterococcus (17%) were among the most commonly isolated organisms (Table 3). Only one infant with a Candida UTI was 428 weeks gestational age. Simultaneous blood cultures were obtained in 114/118 (97%) of infants. Seven infants (6%) had a blood culture that was ultimately positive for the same organism that was identified in their urine.
Table 1.
An US was obtained in 116 of 118 (98%) infants diagnosed with a UTI. The US showed no dilation in 75 (65%) infants. The renal parenchyma was echogenic in six infants without renal dilation. US showed grade 1 dilation in 14 infants, grade 2 dilation in 25 infants and grade 3 dilation in 2 infants. Hydroureteronephrosis was present in three infants (two grade 2 and one grade 3). One infant had a duplicated collecting system and one had a horseshoe kidney. A VCUG was obtained in 104 infants diagnosed with a UTI (87% male and 88% female infants). The renal US was normal in 12 of 14 with UTI in whom a VCUG was not obtained. VCUG showed reflux in 15 (14%) infants overall. This was identified in 7% (6/80) of male infants and 38% (9/24) of female infants with a UTI that was evaluated with a VCUG (P o0.0009 Fisher’s test). Reflux was grade I in one infant, grade II in seven infants, grade III in five infants and grade IV in two infants. Reflux was identified in 9 (12%) infants with no renal dilation versus 7 (16%) infants with an abnormal US. This included 3 (27%) infants with grade 1 dilation, 3 (12%) infants with grade 2 dilation and one of six with isolated renal echogenicity. There was no relationship found between the isolated organism, number of UTIs and either US abnormality or the presence of VUR (data not shown). All seven of the infants with a positive blood culture had a normal renal US. One of seven with bacteremia (Klebsiella) had reflux (Table 3). The clinical findings and outcomes in the infants with VUR are delineated in Table 4. None of the infants had surgery for reflux and recurrent UTIs. One child with severe cerebral palsy had two
Table 2. Proportion of urinary tract infections (UTIs) by gestational age and birth weight Number of infants
Number with UTI
Gestational age (weeks) o28 28–33 433
432 763 2327
48 (11%) 43 (5.6%) 27 (1.1%)
Birth weight (g) o1000 1000–1499 ⩾ 1500
441 463 2619
44 (9.9%) 35 (7.6%) 39 (1.5%)
Table 3.
Distribution of urine and blood culture findings and relationship to ultrasound (US) and voiding cystourethrogram (VCUG) findings
Indications for obtaining a urine culture
Hypertension Abdominal distension Instability Apnea/bradycardia Bradycardia Bradycardia/desaturation Desaturation Emesis/feeding intolerance Fevers Hypothermia Respiratory failure Seizures Sepsis evaluation Thrombocytopenia Metabolic acidosis Hypoglycemia
Journal of Perinatology (2014), 1 – 5
1 10 3 21 4 5 9 7 12 2 21 2 7 2 5 2
Candida Citrobacter Coag Neg staph E. Coli Enterobacter Enterococcus Group B Strep Klebsiella Proteus Pseudomonas Serratia
Number of infants
+ Blood culture
US normal
9a 3 9 25a 9 19 5 24 3 4 8
0/8 0/3 3/8 2/24 0/9 0/18 0/5 2/23 0/3 0/4 0/8
5 3 3 11 6 14 3 15 2 3 4
US Reflux abnormal 3 0 6 13 3 5 2 9 1 1 4
1/4 0/2 0/7 3/24 1/7 4/18 0/4 4/24 0/3 1/4 0/7
Abbreviations: Coag Neg Staph, coagulase negative staphylococcus; Group B Strep, group B Streptococcus. aUS was not obtained in one patient in this subset. Abnormal US includes echogenic kidneys and those with renal dilation. A VCUG was not obtained in 14 infants with urinary tract infection.
© 2014 Nature America, Inc.
Prevalence of upper urinary tract anomalies A Vachharajani et al
Negative Enterobacter 40 34 weeks/2200 g Male
© 2014 Nature America, Inc.
Abbreviations: Bil, bilateral; CP, cerebral palsy; EGA, estimated gestational age; LP, lower pole; LTFU, lost to follow-up; US, ultrasound; UTI, urinary tract infection.
Resolved at 21 months
Well at 18 months off prophylaxis CP two infections in 6.5 years Resolved at 22 months No infections off prophylaxis 12 months No infections off prophylaxis 2 years LTFU No infections off prophylaxis 2 years Normal US age 6 years No infections off prophylaxis 5 years No infections off prophylaxis 28 months LTFU Resolved at 19 months LTFU Grade II at 2 years
Right grade I Left LP grade II Right grade II Left grade II Right grade II Bilateral grade II Left grade II Right grade II Bil. grade III Bil. grade III Bil. grade III Bil. grade III Bilateral grade III Right lower pole grade IV reflux Right grade IV, left grade II Normal Bilateral grade II Normal Left grade I Normal Normal Normal Left grade 1 Left grade I Normal Right grade II, left grade I Normal Normal Right duplication with LP grade II dilation Horseshoe kidney, no dilation Negative Negative Negative Negative Negative Negative Negative Negative Positive Negative Negative Negative Negative Negative Klebsiella Klebsiella Enterococcus Candida E. Coli Klebsiella Enterococcus E. Coli Klebsiella Enterococcus E. Coli Pseudomonas Klebsiella Enterococcus 23 weeks /690 g 26 weeks/810 g 26 weeks/820 g 27 weeks/935 g 30 weeks/1579 g 32 weeks/1200 g 34 weeks/2080 g 40 weeks/2955 g 26 weeks/815 g 25 weeks/905 g 25 weeks/840 g 34 weeks/2945 g 37 weeks/2413 g 26 weeks/990 g Male Female Male Male Male Female Female Female Female Female Male Female Female Female
35 30 63 32 20 45 124 30 63 18 63 142 38 36
US findings Blood culture Age at infection (days) Bacteria EGA/weight Gender
Table 4.
Demographics and clinical findings in 15 premature infants with UTI and vesicoureteral reflux
Reflux
Follow-up
3 recent UTIs and prophylaxis has been restarted. Reflux resolution has been documented in 20%. Based on changing practice patterns with respect to antibiotics and reflux, prophylaxis has been stopped in 40% and they are well without known recurrent UTI. A total of 92/118 (78%) infants with a UTI returned for postdischarge follow-up in the Newborn follow-up clinic. The mean follow-up interval was 25 months (range 4 to 96 months, median 23 months). DISCUSSION Although the incidence of UTIs was only 3% of our overall population, the incidence in infants with a birth rate of o 1500 g is 8.7%. The findings in this and Bauer’s study would suggest that lower birth weight and gestational age infants are at higher risk for UTI. However, the overall rate is lower than the 9 to 14% incidence reported in non-hospitalized febrile infants o 8 months of age.12,13 The majority of infants had blood cultures and only 7% of the infants had documented urosepsis. It is unlikely that the UTIs are secondary to hematogenous seeding of the urinary tract. The higher prevalence in male infants is likely related to the presence of foreskin.4 UTI in premature infants may be related to urinary tract obstruction or VUR. Published guidelines do not discuss imaging in premature or full-term infants o2 months of age. In full-term and older infants with a UTI, US shows an abnormality in ~ 15%. Obstruction (ureteropelvic junction obstruction, ureterovesical junction obstruction, ureterocele and ectopic ureter) is present in 1 to 2%. Renal dilation is identified in 6 to 7%, and duplication anomalies, fusion anomalies and renal cortical abnormalities (scarring) are present in the remainder.6 Reflux can be identified in up to 40% of infants but up to 80% is low grade.14 The risk of obtaining an US in a premature infant with presumed UTI is small. The majority of the premature babies do not have prenatal US imaging, so testing is more likely to demonstrate abnormalities that may have been identified in a term pregnancy (that is, hydronephrosis, ureteral dilation, posterior urethral valves and so on). In this study, the US was abnormal in 34% of infants. This dilation was predominantly renal pelvic dilation and minimal caliectasis that is not consistent with obstruction. A small percentage had echogenic parenchyma suspicious for renal dysplasia. It has consistently been shown that renal dilation is a poor predictor of VUR.15,16 The incidence of reflux was not statistically more likely to be found in infants with an abnormal US. Ureteral dilation may be a better predictor of reflux,16 but only three infants in our population had ureteral dilation on US and none of these had reflux. We did not obtain dimercaptosuccinic acid cortical imaging to evaluate for acute pyelonephritis or renal scarring in our population with a UTI. Dimercaptosuccinic acid more accurately predicts renal risk and has been used to select children who would benefit from identification of reflux.17 Because of technical and logistical concerns dimercaptosuccinic acid has not been routinely used in premature infants. In our population, longer-term followup is required to ascertain long-term sequelae (hypertension, renal insufficiency and so on) from the index UTI. The overwhelming majority of reflux detected in our cohort was low grade. Three (20%) children diagnosed with reflux in this study were lost to follow-up. Mean follow-up in the remainder was 34 months (median 24 months). Only one infant has had recurrent infections. Although reflux resolution has not been documented in all the infants, the remainder have not had documented clinical UTIs, regardless of whether or not they were maintained on continuous antibiotic prophylaxis. None of the patients in our cohort had surgical correction of reflux. Although the follow-up of Journal of Perinatology (2014), 1 – 5
Journal of Perinatology (2014), 1 – 5
290 (161 M/129 F)
Preda et al.18 o12 Months 52 (18%)
9/43 (21%)
21/44 (48%)
6/34 (18%)
1/33 (3%)
8/37 (22%)
6/82 (7%)
4/17 (23%)
2/26 (7.7%)
VUR/VCUG
210/670 (31%) 109/606 (18%)
120 (41%)
11/43 (26%)
12/45 (27%)
15/39 (38%)
13/35 (11%)
19/42 (45%)
10/114 (9%)
1 (3.5%)
9 (26%)
Abnormal US
VUR/abnormal US 52/203 (26%) VUR/normal US 51/315 (16%)
29/120 Abnormal 23/170 Normal
6/14 Abnormal 3/26 Normal
8/12 Abnormal 13/32 Normal
6/19 Abnormal 2/18 Normal 0/14 Abnormal 1/19 Normal 2/14 Abnormal 4/20 Normal
2/6 With VUR had abnormal US
1/9 Abnormal 1/17 Normal 0/1 Abnormal 4/13 Normal
VUR and US findings
Premature: 9/123 (7%) males; 12/68 (18%) females Term: 52/237 (22%) males; 30/140 (21%) females
25/161 (16%) Males; 27/129 (21%) females
6/32 (19%) Males; 3/11 (27%) females
All males (48%)
4/28 Males 4/9 Female 0/27 Males 1/6 Female 2/25 Males 4/9 Female
Unknown
3/43 (7%) Males; 3/23 (13%) females
6/80 (7.5%) Males; 9/45 (20%) females
Reflux by gender
8/10 With grade IV and V reflux had an abnl US
6 Grade I–III VUR; 3 grade IV–V had abnl US
All grade IV (4) and V (1) had an abnormal US PUV in one
1 Grade I; 7 grade II; 5 grade III; 2 grade IV
3 Grade I; 2 grade II; 1 grade III; PUV in one
2 Grade I; 3 grade II; 1 grade III
Comments
Abbreviations: abnl, abnormal; F, females; M, males; PUV, posterior urethral valves; US, ultrasound; UTI, urinary tract infection; VCUG, voiding cystourethrogram; VUR, vesicoureteral reflux.
Total
43 (32 M/11 F)
Ismaili et al.2 0–3 Months
45 Males
39 (30 M/9 F)
41500 g
Goldman et al.15 Males o8 weeks old
35 (28 M/7 F)
1001–1499 g
44 (33 M/11 F)
141 (92 M/50 F)
Nowell et al.9 65, o 1000 g; 43, 1000–1499 g
Current study o1000 g
28 (15 M/13 F)
34 (28 M/6 F)
1001–1500 g
Bauer et al. o1000 g
3
No. of infants
US and VCUG findings in clinical series of premature infants and term infants with UTI
Population (references)
Table 5.
Prevalence of upper urinary tract anomalies A Vachharajani et al
4
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Prevalence of upper urinary tract anomalies A Vachharajani et al
the patients in our study would not be considered by some to be optimal, the detected reflux does not seem to be associated with significant morbidity. A summary of findings in other studies evaluating anatomic abnormalities in neonates with UTI is shown in Table 5. Different criteria were used to define an US abnormality in each study. Despite these differences, the majority of infants had a normal study. US findings of discrepant renal size, echogenic parenchyma and Doppler segmental perfusion abnormalities are suspicious for renal parenchymal involvement. By using these criteria, up to 48% of dimercaptosuccinic acid scan abnormalities can be detected on US.16 Although a normal US does not exclude high-grade reflux, the majority of grades IV and V reflux is identified on US (Table 5). VUR is identified in up to 40% of children with a UTI although grade IV and V reflux are identified in 0 to 6%.3,6,14,18 Consequently, limiting or restricting cystograms in premature infants with UTI and a normal US will miss very few infants with highgrade VUR. In our study, 8/15 with reflux would be missed if a VCUG was not obtained in infants with a normal renal US. This subset includes one infant with grade IV and three infants with grade III reflux. Both the studies by Bauer et al. and ours would suggest a higher incidence of reflux in premature female infants with a UTI when compared to male infants. On this basis, the foreskin and perhaps not urinary tract anatomic abnormalities appear to be etiologic in premature male infants with UTI. This may not be the case in postterm infants. The diagnosis of UTI in premature infants is challenging because of the non-specific nature of the presenting symptoms and the baseline comorbidities. Since urine samples were not routinely obtained in all patients, it is possible that we underestimated the incidence of UTI in our population. Since the majority of UTIs were identified in male infants who were not circumcised and the samples were obtained via urethral catheterization contamination could possibly overestimate the incidence of UTI. This is a retrospective study using chart review. It is possible that some infants treated for UTI did not have this discharge diagnosis coded and were missed. However, we looked at all patient charts for positive urine cultures and also reviewed the charts of all infants with an US and/or VCUG to ascertain if a UTI was the indication for the imaging. On this basis it is unlikely that we missed infants who were treated for a UTI. A mean of nearly 2 years of follow-up was available in threefourths of the infants with a UTI. A recurrent UTI was documented in only one infant but it is possible that parents were not specifically queried for history of UTI at the time of the newborn follow-up visits. If parents sought follow-up care at another institution, the number of UTIs would be underestimated. Despite an institutional practice pattern recommending an US and VCUG in all infants with UTI prior to 2011, two infants (1.7%) did not get an US and a VCUG was not obtained in 14 (12%). Clinical follow-up is available in all but three of these infants and none of had an additional UTI. This would suggest that it is less likely that a clinically significant abnormality was missed by omitting urinary tract imaging.
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CONCLUSION As anticipated, UTIs are more common in male neonates. Although anatomic abnormalities are rare, a renal US should be obtained in premature infants with a UTI. The rate of urinary tract obstruction and/or high-grade VUR is exceedingly low. In concordance with recent AAP guidelines, a VCUG may not be required in all NICU patients under the age of 2 months with a history of UTI. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1 Freedman AL. Urologic Diseases in America Project. Urologic diseases in North America Project: trends in resource utilization for urinary tract infections in children. J Urol 2005; 173: 949–954. 2 Ismaili K, Lolin K, Damry N, Alexander M, Lepage P, Hall M. Febrile urinary tract infections in 0-3 month old infants: a prospective follow-up study. J Pediatr 2011; 158: 91–94. 3 Bauer S, Eliakim A, Pomearnz A, Regev R, Litmanovits I, Arnon S et al. Urinary tract infection in very low birth weight preterm infants. Pediatr Infect Dis J 2003; 22: 426–429. 4 Wiswell TE, Hachey WE. Urinary tract infections and the uncircumcised state: an update. Clin Pediatr (Phila) 1993; 32: 130–134. 5 Schoen EJ, Colby CJ, Ray GT. Newborn circumcision decreases incidence and costs of urinary tract infections during the first year of life. Pediatrics 2000; 105: 789–793. 6 Finnell SM, Carroll AE, Downs SM. Subcommittee on Urinary Tract Infection. Technical report—diagnosis and management of an initial UTI in febrile infants and young children. Pediatrics 2011; 128: e749–e770. 7 American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999; 103: 843–852. 8 RIVUR Trial Investigators, Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med 2014; 370: 2367–2376. 9 Nowell L, Moran C, Smith PB, Seed P, Alexander BD, Cotten CM et al. Prevalence of renal anomalies after urinary tract infections in hospitalized infants less than 2 months of age. J Perinatol 2010; 30(4): 281–285. 10 Fernbach SK, Maizels M, Consay JJ. Ultrasound grading of hydronephrosis: introduction of the system used by the Society for Fetal Urology. Pediatric Radiology 1993; 23: 478–480. 11 Lebowitz RL, Olbing H, Parkkulainen KV, Smellie JM, Tamminen-Mobius TE. International system of radiographic grading of vesicoureteric reflux. International Reflux Study in Children. Pediatr Radiol 1985; 15: 105–109. 12 Lin DS, Huang SH, Lin CC, Tung YC, Huang TT, Chiu NC et al. Urinary tract infection in febrile infants younger than eight weeks of age. Pediatrics 2000; 105(2): E20. 13 Zorc JJ, Levine DA, Platt SL, Dayan PS, Macias CG, Krief W et al. Clinical and demographic factors associated with urinary tract infections in you febrile infants. Pediatrics 2005; 116: 644–648. 14 Nelson CP, Johnson EK, Logvinenko T, Chow S. Ultrasound as a screening test for genitourinary anomalies in children with UTI. Pediatrics 2014; 133: e394–e403. 15 Goldman M, Lahat E, Strauss S, Reisler G, Livne A, Gordin L et al. Imaging after urinary tract infection in male neonates. Pediatrics 2000; 105: 1232–1235. 16 Leroy S, Vantalon S, Larakeb A, Ducou-Le-Pointe H, Bensman A. Vesicoureteral reflux in children with urinary tract infection: comparison of diagnostic accuracy of renal US criteria. Radiology 2010; 255: 890–898. 17 Zhang X, Xu H, Zhou L, Cao Q, Shen Q, Sun L et al. Accuracy of early DMSA scan for VUR in young children with febrile UTI. Pediatrics 2014; 133: e30. 18 Preda I, Jodal U, Sixt R, Stokland E, Hansson S. Value of ultrasound in evaluation of infants with first urinary tract infection. J Urol 2010; 183: 1984–1988.
Journal of Perinatology (2014), 1 – 5
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ORIGINAL ARTICLE
Prevalence of upper urinary tract anomalies in hospitalized premature infants with urinary tract infection A Vachharajani1, GJ Vricella2, T Najaf1 and DE Coplen2 OBJECTIVE: The 2011 American Academy of Pediatrics (AAP) guidelines address imaging after initial febrile urinary tract infection (UTI) in infants 42 months of age. We sought to determine the frequency of upper urinary tract anomalies (hydronephrosis and vesicoureteral reflux (VUR)) in hospitalized premature infants with UTI. STUDY DESIGN: We retrospectively reviewed the electronic medical records of neonatal intensive care unit (NICU) admissions at a tertiary care children’s hospital between 1 January 2006 and 31 December 2010. We queried the records for UTI, renal ultrasound (US) and voiding cystourethrogram (VCUG). RESULT: We identified 3518 unique admissions. UTI occurred in 118 infants (3%). Sixty-nine (60%) had a normal US. Renal dilation was predominantly renal pelvic dilation (12%) and isolated caliectasis (22%). VUR was identified in 15 (14%) infants evaluated with a VCUG. VUR was identified in nine (12%) infants without and in seven (16%) with an abnormality on US. Reflux was identified in 7% of male and 38% of female infants with a UTI. CONCLUSION: Anatomic abnormalities of the upper urinary tract are uncommon in premature infants with a UTI that occurs during neonatal hospitalization. In concordance with the AAP guidelines, a VCUG may not be required in all NICU infants under age 2 months after a single UTI. Journal of Perinatology advance online publication, 4 December 2014; doi:10.1038/jp.2014.209
INTRODUCTION Urinary tract infections (UTIs) are a cause of bacterial infection in up to 7% of febrile infants and children.1 Up to 20% of these UTIs occur in children o 3 months of age.2 The incidence of UTI in neonates hospitalized in a neonatal intensive care unit (NICU) is as high as 12% and may be related to birth weight.3 UTI in the first 6 months of life occurs more commonly in male infants and this may be related to urinary tract obstruction and vesicoureteral reflux (VUR). In addition, uncircumcised male infants are known to have a higher incidence of UTI than those infants who have undergone circumcision.4,5 In 2011 the American Academy of Pediatrics (AAP) published revised guidelines for the management and evaluation of infants and young children (age 2 months to 2 years) with a UTI.6 A renal ultrasound (US) is recommended in all infants with a UTI but a voiding cystourethrogram (VCUG) is recommended after the first UTI only when the renal US is abnormal. This guideline recommends a VCUG in infants with recurrent UTIs. In the prior AAP guidelines iteration, investigations included an US during the acute infection and a VCUG once the infant had recovered.7 The change in recommendations regarding VCUG after the first UTI was based upon a meta-analysis of randomized controlled trials failing to support antimicrobial prophylaxis to prevent febrile UTI.6 However, the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial published in May 2014 demonstrated that trimethoprim–sulfamethoxazole prophylaxis was associated with a 50% reduction in symptomatic recurrences.8 Although there was no reduction in renal scarring in the study
population that was 42 months of age, detection of VUR and prevention of recurrent infections in neonates may be beneficial. Neither guideline specifically addresses the evaluation of UTI in infants o 2 months of age. Nowell et al.9 found very few urinary tract anomalies in 141 infants with a UTI prior to 2 months of age, but only 80% of the study population was evaluated with an US and 16% had neither an US or a VCUG performed. In an evaluation of low-birth-weight preterm infants the incidence of reflux was 14% in 42 infants o 1500 g at the time of UTI.3 In this study, we evaluate the incidence of UTI in premature infants hospitalized at a single tertiary care NICU between 2006 and 2010. Prior to 2011, we utilized the 1999 guidelines and recommended an US and VCUG in all infants with a UTI. We examined the frequency of upper urinary tract anomalies (hydronephrosis and VUR) in premature infants diagnosed with UTI.
METHODS We performed a retrospective review of all NICU admissions during a 5-year period (1 January 2006 to 31 December 2010) at a tertiary care children’s hospital. We queried the computerized hospital record for UTI, renal US and VCUG. All charts were reviewed individually for a discharge diagnosis of UTI, a urine culture (sent or not sent), blood cultures in conjunction with a urine culture and ordered radiologic tests including a renal US and VCUG. The indications for urine cultures were tabulated. Gender, race, birth weight, estimated gestational age (as determined by best obstetrical estimate) and congenital anomalies were recorded for each infant.
1 Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine and St Louis Children’s Hospital, Saint Louis, MO, USA and 2Division of Urology, Department of Surgery, Washington University School of Medicine and St Louis Children’s Hospital, Saint Louis, MO, USA. Correspondence: Dr DE Coplen, Division of Urology, Department of Surgery, Washington University School of Medicine and St. Louis Children's Hospital, 4990 Children's Place, Suite 1120, Saint Louis, MO 63110, USA. E-mail: [email protected] Received 14 August 2014; revised 20 September 2014; accepted 14 October 2014
Prevalence of upper urinary tract anomalies A Vachharajani et al
2 Urine samples were obtained by urethral catheterization in all cases. A dipstick and microscopic urinalysis was performed when sufficient volume was obtained via catheter. Leukocyte esterase and nitrite positivity was recorded. A positive urine microscopy was defined as 410 white blood cells per high power field. A UTI was defined as a growth of 4100K bacteria of a single colony type or growth of 10 to 50K bacteria in conjunction with a positive urinalysis. At our institution, whenever sepsis is suspected blood cultures are obtained at the time of urine cultures prior to initiating antibiotics. Results from blood cultures obtained within 72 h of the positive urine culture were recorded. Between 2006 and 2010, an US and VCUG were recommended in all infants treated for a UTI. All US images were reviewed by the attending radiologists at our institution and the senior author (DEC). Renal dilation was categorized using the Society for Fetal Urology classification.10 Renal parenchyma was assessed for echogenicity and ureteral dilation was tabulated. Bladder images are obtained in all US studies to assess for bladder distension, bladder wall thickening and distal ureteral dilation. VUR was graded using the International Reflux Classification.11 The hospital-based and outpatient electronic medical record for our practice plan was queried for infections and other urologic issues in all infants with a history of UTI after discharge from the NICU. We excluded from primary evaluation children with prenatally identified renal anomalies or postnatally identified conditions like posterior urethral valves or VACTERL (vertebral, anorectal, cardiac, trachea-esophageal fistula, renal and limbs), prune belly syndrome, spinal dysraphism and so on associated with UTIs that had been placed on antibiotic prophylaxis in the NICU. A two-tailed Fisher’s exact test was used to ascertain differences between study groups. A P-value o 0.05 was significant. Institutional review board approval for this study was obtained from the Human Research Protection Office (IRB # 201011824 BIO Utility of Contrast Studies).
RESULTS There were 3518 (1481 female and 2037 male infants) unique NICU admissions during the 5-year time period. UTI was identified in 118 infants (3%). The indications for urine culture are shown in Table 1. There were 27 female infants (1.8%) and 91 male infants (4.5%) with UTI during this time period. During the course of their NICU hospitalization, 28 patients (27 with 2 and one with 3) had multiple documented UTIs, with 24 (86%) of these being male infants. UTIs were more common in low gestational age and low birth-weight infants (Table 2). None of the male infants was circumcised at the time of UTI. Escherichia coli (19%), Klebsiella (19%) and Enterococcus (17%) were among the most commonly isolated organisms (Table 3). Only one infant with a Candida UTI was 428 weeks gestational age. Simultaneous blood cultures were obtained in 114/118 (97%) of infants. Seven infants (6%) had a blood culture that was ultimately positive for the same organism that was identified in their urine.
Table 1.
An US was obtained in 116 of 118 (98%) infants diagnosed with a UTI. The US showed no dilation in 75 (65%) infants. The renal parenchyma was echogenic in six infants without renal dilation. US showed grade 1 dilation in 14 infants, grade 2 dilation in 25 infants and grade 3 dilation in 2 infants. Hydroureteronephrosis was present in three infants (two grade 2 and one grade 3). One infant had a duplicated collecting system and one had a horseshoe kidney. A VCUG was obtained in 104 infants diagnosed with a UTI (87% male and 88% female infants). The renal US was normal in 12 of 14 with UTI in whom a VCUG was not obtained. VCUG showed reflux in 15 (14%) infants overall. This was identified in 7% (6/80) of male infants and 38% (9/24) of female infants with a UTI that was evaluated with a VCUG (P o0.0009 Fisher’s test). Reflux was grade I in one infant, grade II in seven infants, grade III in five infants and grade IV in two infants. Reflux was identified in 9 (12%) infants with no renal dilation versus 7 (16%) infants with an abnormal US. This included 3 (27%) infants with grade 1 dilation, 3 (12%) infants with grade 2 dilation and one of six with isolated renal echogenicity. There was no relationship found between the isolated organism, number of UTIs and either US abnormality or the presence of VUR (data not shown). All seven of the infants with a positive blood culture had a normal renal US. One of seven with bacteremia (Klebsiella) had reflux (Table 3). The clinical findings and outcomes in the infants with VUR are delineated in Table 4. None of the infants had surgery for reflux and recurrent UTIs. One child with severe cerebral palsy had two
Table 2. Proportion of urinary tract infections (UTIs) by gestational age and birth weight Number of infants
Number with UTI
Gestational age (weeks) o28 28–33 433
432 763 2327
48 (11%) 43 (5.6%) 27 (1.1%)
Birth weight (g) o1000 1000–1499 ⩾ 1500
441 463 2619
44 (9.9%) 35 (7.6%) 39 (1.5%)
Table 3.
Distribution of urine and blood culture findings and relationship to ultrasound (US) and voiding cystourethrogram (VCUG) findings
Indications for obtaining a urine culture
Hypertension Abdominal distension Instability Apnea/bradycardia Bradycardia Bradycardia/desaturation Desaturation Emesis/feeding intolerance Fevers Hypothermia Respiratory failure Seizures Sepsis evaluation Thrombocytopenia Metabolic acidosis Hypoglycemia
Journal of Perinatology (2014), 1 – 5
1 10 3 21 4 5 9 7 12 2 21 2 7 2 5 2
Candida Citrobacter Coag Neg staph E. Coli Enterobacter Enterococcus Group B Strep Klebsiella Proteus Pseudomonas Serratia
Number of infants
+ Blood culture
US normal
9a 3 9 25a 9 19 5 24 3 4 8
0/8 0/3 3/8 2/24 0/9 0/18 0/5 2/23 0/3 0/4 0/8
5 3 3 11 6 14 3 15 2 3 4
US Reflux abnormal 3 0 6 13 3 5 2 9 1 1 4
1/4 0/2 0/7 3/24 1/7 4/18 0/4 4/24 0/3 1/4 0/7
Abbreviations: Coag Neg Staph, coagulase negative staphylococcus; Group B Strep, group B Streptococcus. aUS was not obtained in one patient in this subset. Abnormal US includes echogenic kidneys and those with renal dilation. A VCUG was not obtained in 14 infants with urinary tract infection.
© 2014 Nature America, Inc.
Prevalence of upper urinary tract anomalies A Vachharajani et al
Negative Enterobacter 40 34 weeks/2200 g Male
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Abbreviations: Bil, bilateral; CP, cerebral palsy; EGA, estimated gestational age; LP, lower pole; LTFU, lost to follow-up; US, ultrasound; UTI, urinary tract infection.
Resolved at 21 months
Well at 18 months off prophylaxis CP two infections in 6.5 years Resolved at 22 months No infections off prophylaxis 12 months No infections off prophylaxis 2 years LTFU No infections off prophylaxis 2 years Normal US age 6 years No infections off prophylaxis 5 years No infections off prophylaxis 28 months LTFU Resolved at 19 months LTFU Grade II at 2 years
Right grade I Left LP grade II Right grade II Left grade II Right grade II Bilateral grade II Left grade II Right grade II Bil. grade III Bil. grade III Bil. grade III Bil. grade III Bilateral grade III Right lower pole grade IV reflux Right grade IV, left grade II Normal Bilateral grade II Normal Left grade I Normal Normal Normal Left grade 1 Left grade I Normal Right grade II, left grade I Normal Normal Right duplication with LP grade II dilation Horseshoe kidney, no dilation Negative Negative Negative Negative Negative Negative Negative Negative Positive Negative Negative Negative Negative Negative Klebsiella Klebsiella Enterococcus Candida E. Coli Klebsiella Enterococcus E. Coli Klebsiella Enterococcus E. Coli Pseudomonas Klebsiella Enterococcus 23 weeks /690 g 26 weeks/810 g 26 weeks/820 g 27 weeks/935 g 30 weeks/1579 g 32 weeks/1200 g 34 weeks/2080 g 40 weeks/2955 g 26 weeks/815 g 25 weeks/905 g 25 weeks/840 g 34 weeks/2945 g 37 weeks/2413 g 26 weeks/990 g Male Female Male Male Male Female Female Female Female Female Male Female Female Female
35 30 63 32 20 45 124 30 63 18 63 142 38 36
US findings Blood culture Age at infection (days) Bacteria EGA/weight Gender
Table 4.
Demographics and clinical findings in 15 premature infants with UTI and vesicoureteral reflux
Reflux
Follow-up
3 recent UTIs and prophylaxis has been restarted. Reflux resolution has been documented in 20%. Based on changing practice patterns with respect to antibiotics and reflux, prophylaxis has been stopped in 40% and they are well without known recurrent UTI. A total of 92/118 (78%) infants with a UTI returned for postdischarge follow-up in the Newborn follow-up clinic. The mean follow-up interval was 25 months (range 4 to 96 months, median 23 months). DISCUSSION Although the incidence of UTIs was only 3% of our overall population, the incidence in infants with a birth rate of o 1500 g is 8.7%. The findings in this and Bauer’s study would suggest that lower birth weight and gestational age infants are at higher risk for UTI. However, the overall rate is lower than the 9 to 14% incidence reported in non-hospitalized febrile infants o 8 months of age.12,13 The majority of infants had blood cultures and only 7% of the infants had documented urosepsis. It is unlikely that the UTIs are secondary to hematogenous seeding of the urinary tract. The higher prevalence in male infants is likely related to the presence of foreskin.4 UTI in premature infants may be related to urinary tract obstruction or VUR. Published guidelines do not discuss imaging in premature or full-term infants o2 months of age. In full-term and older infants with a UTI, US shows an abnormality in ~ 15%. Obstruction (ureteropelvic junction obstruction, ureterovesical junction obstruction, ureterocele and ectopic ureter) is present in 1 to 2%. Renal dilation is identified in 6 to 7%, and duplication anomalies, fusion anomalies and renal cortical abnormalities (scarring) are present in the remainder.6 Reflux can be identified in up to 40% of infants but up to 80% is low grade.14 The risk of obtaining an US in a premature infant with presumed UTI is small. The majority of the premature babies do not have prenatal US imaging, so testing is more likely to demonstrate abnormalities that may have been identified in a term pregnancy (that is, hydronephrosis, ureteral dilation, posterior urethral valves and so on). In this study, the US was abnormal in 34% of infants. This dilation was predominantly renal pelvic dilation and minimal caliectasis that is not consistent with obstruction. A small percentage had echogenic parenchyma suspicious for renal dysplasia. It has consistently been shown that renal dilation is a poor predictor of VUR.15,16 The incidence of reflux was not statistically more likely to be found in infants with an abnormal US. Ureteral dilation may be a better predictor of reflux,16 but only three infants in our population had ureteral dilation on US and none of these had reflux. We did not obtain dimercaptosuccinic acid cortical imaging to evaluate for acute pyelonephritis or renal scarring in our population with a UTI. Dimercaptosuccinic acid more accurately predicts renal risk and has been used to select children who would benefit from identification of reflux.17 Because of technical and logistical concerns dimercaptosuccinic acid has not been routinely used in premature infants. In our population, longer-term followup is required to ascertain long-term sequelae (hypertension, renal insufficiency and so on) from the index UTI. The overwhelming majority of reflux detected in our cohort was low grade. Three (20%) children diagnosed with reflux in this study were lost to follow-up. Mean follow-up in the remainder was 34 months (median 24 months). Only one infant has had recurrent infections. Although reflux resolution has not been documented in all the infants, the remainder have not had documented clinical UTIs, regardless of whether or not they were maintained on continuous antibiotic prophylaxis. None of the patients in our cohort had surgical correction of reflux. Although the follow-up of Journal of Perinatology (2014), 1 – 5
Journal of Perinatology (2014), 1 – 5
290 (161 M/129 F)
Preda et al.18 o12 Months 52 (18%)
9/43 (21%)
21/44 (48%)
6/34 (18%)
1/33 (3%)
8/37 (22%)
6/82 (7%)
4/17 (23%)
2/26 (7.7%)
VUR/VCUG
210/670 (31%) 109/606 (18%)
120 (41%)
11/43 (26%)
12/45 (27%)
15/39 (38%)
13/35 (11%)
19/42 (45%)
10/114 (9%)
1 (3.5%)
9 (26%)
Abnormal US
VUR/abnormal US 52/203 (26%) VUR/normal US 51/315 (16%)
29/120 Abnormal 23/170 Normal
6/14 Abnormal 3/26 Normal
8/12 Abnormal 13/32 Normal
6/19 Abnormal 2/18 Normal 0/14 Abnormal 1/19 Normal 2/14 Abnormal 4/20 Normal
2/6 With VUR had abnormal US
1/9 Abnormal 1/17 Normal 0/1 Abnormal 4/13 Normal
VUR and US findings
Premature: 9/123 (7%) males; 12/68 (18%) females Term: 52/237 (22%) males; 30/140 (21%) females
25/161 (16%) Males; 27/129 (21%) females
6/32 (19%) Males; 3/11 (27%) females
All males (48%)
4/28 Males 4/9 Female 0/27 Males 1/6 Female 2/25 Males 4/9 Female
Unknown
3/43 (7%) Males; 3/23 (13%) females
6/80 (7.5%) Males; 9/45 (20%) females
Reflux by gender
8/10 With grade IV and V reflux had an abnl US
6 Grade I–III VUR; 3 grade IV–V had abnl US
All grade IV (4) and V (1) had an abnormal US PUV in one
1 Grade I; 7 grade II; 5 grade III; 2 grade IV
3 Grade I; 2 grade II; 1 grade III; PUV in one
2 Grade I; 3 grade II; 1 grade III
Comments
Abbreviations: abnl, abnormal; F, females; M, males; PUV, posterior urethral valves; US, ultrasound; UTI, urinary tract infection; VCUG, voiding cystourethrogram; VUR, vesicoureteral reflux.
Total
43 (32 M/11 F)
Ismaili et al.2 0–3 Months
45 Males
39 (30 M/9 F)
41500 g
Goldman et al.15 Males o8 weeks old
35 (28 M/7 F)
1001–1499 g
44 (33 M/11 F)
141 (92 M/50 F)
Nowell et al.9 65, o 1000 g; 43, 1000–1499 g
Current study o1000 g
28 (15 M/13 F)
34 (28 M/6 F)
1001–1500 g
Bauer et al. o1000 g
3
No. of infants
US and VCUG findings in clinical series of premature infants and term infants with UTI
Population (references)
Table 5.
Prevalence of upper urinary tract anomalies A Vachharajani et al
4
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Prevalence of upper urinary tract anomalies A Vachharajani et al
the patients in our study would not be considered by some to be optimal, the detected reflux does not seem to be associated with significant morbidity. A summary of findings in other studies evaluating anatomic abnormalities in neonates with UTI is shown in Table 5. Different criteria were used to define an US abnormality in each study. Despite these differences, the majority of infants had a normal study. US findings of discrepant renal size, echogenic parenchyma and Doppler segmental perfusion abnormalities are suspicious for renal parenchymal involvement. By using these criteria, up to 48% of dimercaptosuccinic acid scan abnormalities can be detected on US.16 Although a normal US does not exclude high-grade reflux, the majority of grades IV and V reflux is identified on US (Table 5). VUR is identified in up to 40% of children with a UTI although grade IV and V reflux are identified in 0 to 6%.3,6,14,18 Consequently, limiting or restricting cystograms in premature infants with UTI and a normal US will miss very few infants with highgrade VUR. In our study, 8/15 with reflux would be missed if a VCUG was not obtained in infants with a normal renal US. This subset includes one infant with grade IV and three infants with grade III reflux. Both the studies by Bauer et al. and ours would suggest a higher incidence of reflux in premature female infants with a UTI when compared to male infants. On this basis, the foreskin and perhaps not urinary tract anatomic abnormalities appear to be etiologic in premature male infants with UTI. This may not be the case in postterm infants. The diagnosis of UTI in premature infants is challenging because of the non-specific nature of the presenting symptoms and the baseline comorbidities. Since urine samples were not routinely obtained in all patients, it is possible that we underestimated the incidence of UTI in our population. Since the majority of UTIs were identified in male infants who were not circumcised and the samples were obtained via urethral catheterization contamination could possibly overestimate the incidence of UTI. This is a retrospective study using chart review. It is possible that some infants treated for UTI did not have this discharge diagnosis coded and were missed. However, we looked at all patient charts for positive urine cultures and also reviewed the charts of all infants with an US and/or VCUG to ascertain if a UTI was the indication for the imaging. On this basis it is unlikely that we missed infants who were treated for a UTI. A mean of nearly 2 years of follow-up was available in threefourths of the infants with a UTI. A recurrent UTI was documented in only one infant but it is possible that parents were not specifically queried for history of UTI at the time of the newborn follow-up visits. If parents sought follow-up care at another institution, the number of UTIs would be underestimated. Despite an institutional practice pattern recommending an US and VCUG in all infants with UTI prior to 2011, two infants (1.7%) did not get an US and a VCUG was not obtained in 14 (12%). Clinical follow-up is available in all but three of these infants and none of had an additional UTI. This would suggest that it is less likely that a clinically significant abnormality was missed by omitting urinary tract imaging.
© 2014 Nature America, Inc.
CONCLUSION As anticipated, UTIs are more common in male neonates. Although anatomic abnormalities are rare, a renal US should be obtained in premature infants with a UTI. The rate of urinary tract obstruction and/or high-grade VUR is exceedingly low. In concordance with recent AAP guidelines, a VCUG may not be required in all NICU patients under the age of 2 months with a history of UTI. CONFLICT OF INTEREST The authors declare no conflict of interest.
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