Accepted Manuscript Urinary tract infection and vesicoureteral reflux in children with Mild antenatal hydronephrosis A. Sencan , MD F. Carvas , MD I. Cem Hekimoglu , N. Caf , A. Sencan , MD J. Chow , MD H.T. Nguyen , MD PII:
S1477-5131(14)00113-2
DOI:
10.1016/j.jpurol.2014.04.001
Reference:
JPUROL 1678
To appear in:
Journal of Pediatric Urology
Received Date: 4 February 2014 Accepted Date: 6 April 2014
Please cite this article as: Sencan A, Carvas F, Hekimoglu IC, Caf N, Sencan A, Chow J, Nguyen HT, Urinary tract infection and vesicoureteral reflux in children with Mild antenatal hydronephrosis, Journal of Pediatric Urology (2014), doi: 10.1016/j.jpurol.2014.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Urinary tract infection and vesicoureteral reflux in children with Mild antenatal hydronephrosis
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A. Sencan, MD1, F. Carvas, MD1, I. Cem Hekimoglu1, N. Caf1, A. Sencan, MD1, J. Chow, MD1, 2, H.T. Nguyen, MD1
Department of Urology, Boston Children’s Hospital, Boston, MA, USA
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Department of Radiology, Boston Children’s Hospital, Boston, MA, USA
[email protected] [email protected] drhekimoğ[email protected]
[email protected]
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[email protected]
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[email protected]
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[email protected]
CORRESPONDING AUTHOR:
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Hiep T. Nguyen, M.D. Department of Urology, Hunnewell-353 Children’s Hospital Boston 300 Longwood Avenue, Boston, MA 02115, USA [email protected] Phone: 617- 355-6842 Fax: 617-730-0474
ACCEPTED MANUSCRIPT Summary
Objective: The postnatal management of mild antenatal hydronephrosis (ANH) remains controversial. The purpose of this study was to evaluate the incidence of UTI and VUR in
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children with mild ANH in order to determine the necessity of antibiotic prophylaxis (ABP) and VCUG.
Method: The data of 1511 patients with various grades of ANH who were referred to
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Department of Urology, Boston Children’s Hospital between January 1998 and January 2010 were reviewed and 760 patients who had mild ANH were identified. The inclusion criteria
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were:
1) A confirmed report of ANH or actual prenatal ultrasound (US) images.
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2) Postnatal evaluation and management conducted at the institution.
3) Persistent mild hydronephrosis on the first US done between two weeks and three months of age.
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abnormalities.
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4) No other US findings such as ureteral dilatation, duplication anomalies or bladder
5) At least one three-month follow up.
Univariate statistical analysis was performed using a Student's t test.
Results: Of the 760 patients who were identified, 608 (80%) were males, and 225 (30%) had bilateral mild hydronephrosis. Of these, 475 patients (63%) underwent an initial screening VCUG. VUR was identified in 13 patients (1.7%) with grades varying from 1–5. At follow up, hydronephrosis resolved in 67% of the renal units and worsened in 3.3%. Among the 692 1
ACCEPTED MANUSCRIPT patients with available follow-up data, 23 (3.3%) had a documented UTI. Twelve of these children had an initial screening VCUG that was negative for VUR. Of these 12 patients, seven underwent a subsequent RNC with none having VUR; five of the 12 patients did not undergo a repeat evaluation for VUR (four had a UTI after the screening VCUG and one had
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an afebrile UTI). Eleven of the 23 children with mild ANH did not have an initial screening VCUG, and all underwent a subsequent VCUG/RNC. Only two children were then found to
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have VUR Grade 4–5.
Conclusion: The incidence of UTI and VUR in children with mild PNH is low. Consequently,
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routine VCUG screening for VUR and the use of long-term ABP is not necessary for all patients with asymptomatic mild AHN. Evaluation for VUR in children with mild ANH
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should be reserved for those who subsequently present with a UTI.
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Introduction
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Keywords: Hydronephrosis; Antenatal; Prenatal; Mild
Dilatation of the urinary collecting systems (i.e. antenatal hydronephrosis, ANH) is detected in 1% to 5% of fetuses during the second and third trimesters by ultrasonography (US) [1-3]. The clinical significance of ANH is dependent on its severity, with the more severe grades correlating with increasing incidence of clinically significant pathologies [4]. Mild, isolated ANH represents up to 80% of cases and is considered to be more benign than those of moderate or severe grades [5-6]. A review of the literature indicates the risk of urological pathology with mild ANH to be 11.9%, compared to 88.3% for the more severe cases [7].
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ACCEPTED MANUSCRIPT These findings suggest that while the majority of the cases of mild ANH are benign, 10% may have significant urological pathologies and may develop complications such as febrile urinary tract infection and renal injury if left untreated.
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Consequently, recommendations regarding the evaluation and management of mild ANH are controversial. They vary from no follow up to extensive postnatal radiological evaluation including US, VCUG, RNC and medical therapies such as antibiotic prophylaxis (ABP). Of
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particular controversy in this patient population is the use of ABP and performing VCUG. In a recent survey of pediatric radiologists, pediatric urologists and maternal-fetal obstetricians
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on the management of mild ANH, there was lack of consensus about these issues [8]. The purpose of this study is to evaluate the incidence of UTI in children with mild antenatal and persistent postnatal hydronephrosis in order to determine the necessity of ABP and VCUG.
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Patients and Methods
Since 1986, children with ANH, who had been referred to the Department of Urology, Boston Children’s Hospital for evaluation and management, were prospectively enrolled onto an
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IRB-approved database. For this study, in order to evaluate a contemporary series of children with ANH, analysis was limited to patients seen from January 1998 to January 2010,. The
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inclusion criteria included:
1) A confirmed report of ANH or actual prenatal US images. 2) Postnatal evaluation and management conducted at the institution. 3) Persistent mild hydronephrosis on the first US done between two weeks and three months of age.
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ACCEPTED MANUSCRIPT 4) No other US findings such as ureteral dilatation, duplication anomalies or bladder abnormalities. 5) At least one three-month follow up.
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A total of 1511 patients with various grades of ANH met the inclusion criteria. Of these, 760 children had mild ANH, which was defined by an anterior-posterior pelvic diameter (APPD) of 7–10 mm diagnosed by fetal US in the third trimester of gestation and persistent postnatal
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mild hydronephrosis. Due to the ultrasonographers’ preference at the institution, postnatal hydronephrosis for this study was graded on a scale of mild, moderate and severe. Although
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this grading system is not standardized like the SFU system, this correlates generally to SFU Grade 1-2 for mild, SFU Grade 3 for moderate and SFU Grade 4 for severe and is based on the amount of pelvic and calyceal dilatation. This ‘mild-severe’ grading system is the most commonly used system among radiologists and, specifically, pediatric radiologists.
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The patients’ postnatal evaluation and management (such as performing a VCUG and the use of ABP) were based on the preferences of his/her pediatric urologist. The primary outcomes evaluated were the incidence of UTI and VUR, and the secondary outcomes were the rate of
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hydronephrosis resolution and the incidence of surgical intervention. The patients’ clinical
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course was assessed for the degree of hydronephrosis, the development of UTI and the need for surgical intervention. The outcome of hydronephrosis was categorized as: resolved, improving, worsening, or unchanged. A UTI was defined based on the presence of one or more signs (foul smelling urine, hematuria, fever or chills) and/or symptoms (dysuria, frequency, suprapubic discomfort, or flank pain in older children) and a positive urine culture based upon criteria suggested by 2011 AAP Guidelines [9]. UTI was further classified as febrile (temperature greater 38.5oC), nonfebrile (no associated fever) or nonspecific (no documentation of fever could be determined). The primary (the development of a UTI) and
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ACCEPTED MANUSCRIPT secondary (resolution of the ANH or need for surgical intervention) outcomes were correlated with the patient’s demographic and postnatal management. Univariate statistical analysis was performed using a Student’s t test and a P-value of < 0.05 was considered to be statistically
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significant.
Results:
General Demographics
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A total of 760 patients met this study’s inclusion criteria and had median follow-up time of 23
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months (range 3 months to 147 months). Of the 760 patients, 608 (80%) were males, and 225 (29.6%) had bilateral mild hydronephrosis. Twenty-one percent of the males were uncircumcised. Of the 535 patients with unilateral mild hydronephrosis, 356 (66.5%) occurred on the right side. Based on their pediatric urologist’s preference, 475 patients (62.5%) underwent a VCUG (70.2% of the bilateral and 59.3% of the unilateral mild hydronephrosis).
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VUR was identified in 13 patients (2.7%) with grade varying from 1 to 5. PUV were identified in two (0.3%). Immediately after birth, 369 patients (48.55%) were placed on ABP
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(principally amoxicillin). In 90% of the patients, ABP was discontinued after they underwent a VCUG documenting the absence of VUR. In the 13 patients in whom VUR was identified,
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ABP was continued.
Incidence of urinary tract infection Of the 760 patients evaluated, detailed clinical follow up was not available in 68 patients. Of the remaining 692 patients, 23 (3.3%) had a documented UTI (Figure 1). Thirteen (eight male, five female) had associated fever, five (three male, two female) did not, and in the remaining five patients (four male, one female) the presence or absence of fever was not documented. Table 1 illustrates the association with gender, the degree of hydronephrosis in follow up, and 5
ACCEPTED MANUSCRIPT the presence of VUR in patients who developed a UTI. Ten of the 15 males who developed a UTI were uncircumcised; boys who were uncircumcised were at a 7.8 fold increased risk of developing a UTI (P < 0.001).
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Of the 23 patients who developed a UTI, 12 had a negative initial screening VCUG. A subsequent VCUG/RNC was performed in 18 of 23 patients (78.3%) who had a UTI; only two (8.7%) had VUR, of which both were of high grade. In the five patients who were not
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evaluated with a subsequent VCUG/RNC, four (17.4%) had developed a UTI after undergoing screening VCUG and were not on ABP; the remaining patient had a non-febrile
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UTI. It was determined by their primary pediatric urologist that further evaluation for VUR was not clinically indicated. Of the 23 patients, the median age at which the UTI developed was three months (mean = 7.4, range = 1 month to 4 years). Two (8.7%) of the 23 patients developed a UTI while on ABP. One of these two patients had a UPJ obstruction and
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subsequently underwent pyeloplasty for progressive hydronephrosis and prolonged T ½. The other had an ectopic ureter with a high-grade refluxing lower pole system and underwent a
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common sheath ureteral reimplantation for a breakthrough UTI while on ABP.
Resolution of hydronephrosis and need for surgical intervention
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In the 760 patients, mild hydronephrosis was documented on the first postnatal US in 985 renal units. During follow up, complete resolution (no hydronephrosis) was observed in 663 renal units (67.30%), improved (defined as only pelviectasis, SFU Grade 2 now down to Grade 1) in 131 (13.3%), worsened (SFU Grade 3 or more) in 32 (3.3%) and unchanged (remained SFU Grades 1 or 2) in 158 (16.0%). The median time to resolution was approximately 24 months. It should be noted that US was performed every six months to yearly at the discretion of the treating urologist. Consequently, the median time to resolution
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ACCEPTED MANUSCRIPT observed in this study may be somewhat arbitrary. However, it does provide a rough estimate to help with parental counseling.
Thirteen of 760 (1.7%) underwent surgical intervention. Four of the 13 patients with VUR
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underwent antireflux surgery for persistent (> three years) high-grade reflux or for breakthrough UTIs. Both patients with PUV underwent endoscopic valve ablation. Six patients underwent pyeloplasty for progressive hydronephrosis with t ½ > 30 minutes on
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MAG-3 imaging. One patient underwent ureteral tapering and reimplant for an obstructed
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megaureter.
Discussion
In this population of children with mild antenatal and persistent postnatal hydronephrosis, VUR was identified in only 1.7% of the 63% who underwent a VCUG. This suggests that
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VUR is uncommon in children with mild ANH and that screening VCUG can be avoided in the majority of cases. Although commonly performed, VCUG is an invasive imaging modality that exposes infants to ionizing radiation, risk of UTI and is a stressful procedure for
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both the patient and the parents [10].
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Several studies have suggested that VCUG screening is necessary in children with mild ANH. Similar incidences of VUR (ranging from 12–25%) among different grades of ANH have been previously reported in the literature, suggesting the importance of investigation of this pathology even in mild cases [7,11]. Tibbails et al. found that 25% of newborns with normal postnatal US had VUR Grade 3 or higher. This warranted the recommendation for VCUG evaluation in all newborns with ANH, even those in which the hydronephrosis resolved in utero [12]. In contrast, other studies suggested that VCUG is not mandatory in children with
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ACCEPTED MANUSCRIPT ANH of Grade 2 or less [1,13,14,15]. Ismaili et al. observed in their cohort of 264 infants with mild ANH and a normal postnatal US, that 6.7% had VUR. However, the complication rate associated with performing the VCUG was 3.4% [10].
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In the present study, VUR was only identified in 1.7% of the children with mild ANH and mild hydronephrosis on the first postnatal US. In addition, four of the 23 children with mild ANH and a UTI developed the UTI after having a VCUG. Consequently, the authors’ propose
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that routine performance of VCUG for mild AHN is not necessary, but it should be performed for patients who have febrile or recurrent UTI during follow up. This recommendation would
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avoid unnecessary radiation exposure, discomfort and risk of UTI in children with mild ANH.
Moreover, it was observed that UTI occurred in 3.4% of children with mild ANH. Of the 37% who did not undergo a screening VCUG initially, only two (0.07%) patients presented with a
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subsequent UTI and were found to have VUR. Uncircumcised boys with mild ANH were at higher risk of developing a UTI compared to their circumcised counterparts. Twenty-two percent of the children who had a UTI (0.8% of those who underwent VCUG evaluation)
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developed it after undergoing routine VCUG. In a prior study, the incidence of UTI was reported to be 10% in children with mild ANH, 20% in those with moderate, and 40% in
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those with severe ANH [16]. In the present study, a low incidence of UTI in the mild group was similarly observed. This difference emphasizes that isolated mild AHN should be considered as a distinct entity from severe HN and HN associated with other renal abnormalities. Based on these findings and other prior studies [17,18], long-term ABP for children with mild ANH is not warranted.
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ACCEPTED MANUSCRIPT Furthermore, in the present study’s population of children with mild antenatal and persistent postnatal hydronephrosis, 79.9% had improvement or resolution of their hydronephrosis, and only 3.3% were worse. Approximately 2% of the children with mild ANH eventually required surgical intervention (e.g. ureteral reimplants, ablation of PUVs and pyeloplasty). This study’s
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findings indicate that mild ANH is likely to resolve in the majority of the cases; however, in a small number of patients, it may represent a sign of an underlying, significant urological problem (i.e. those that required surgical intervention). Children with any degree of ANH are
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at greater risk of having urological pathology, compared to the normal population. The grade of hydronephrosis is correlated with the increased risk of urologic pathologies and could be
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used for making decision about further diagnostic imaging and treatment [19, 20].
In a recent meta-analysis, Lee et al. demonstrated that the risk of any urological pathology correlated with the degree of ANH, being 11.9% in the mild group, 45.1% in the moderate
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group, and 88.3% in the severe group [7]. Moderate and severe cases seem to be more often associated with obstructive pathologies such as UPJ obstruction and PUV, while mild ANH is often transient, with spontaneous prenatal or postnatal resolution in the majority of cases
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[1,21,22]. However, there is much debate as to whether urological pathologies such as VUR and UPJ obstruction that resolve without any sequelae (e.g. UTI) should be considered
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clinically significant. In a study of 213 infants with mild to moderate ANH, Sidhu et al. observed that significant uropathies were seen in 39% of the infants, although intervention was not required in most patients [18]. Consequently, it may be of greater clinical utility to determine the incidence of children with mild ANH who required medical/surgical intervention. In the present study’s patients, 2% of children with mild ANH required surgical intervention. It can be suggested that this lower rate would be of more relevance when counseling patients/families. However, follow up with US and clinical evaluation is
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ACCEPTED MANUSCRIPT mandatory in order to identify those rare patients with significant uropathies such as PUV despite having mild ANH.
The postnatal evaluation of mild isolated ANH is currently controversial, with some
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practitioners recommending full postnatal radiological evaluation while others do not [17]. Postnatal evaluation is needed to identify the underlying pathology, but it is not without associated disadvantages: time, expense, discomfort and radiation exposure from radiologic
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evaluation, the unintended consequences of false positives and the stress on the family. For children with mild or SFU Grade 1-2 hydronephrosis on the one-month US examination,
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some practitioners suggest discharging them from further surveillance with the recommendation that the child be seen again for UTI or pain [23,24], while others recommend serial USG examinations and UTI surveillance every six or twelve months [25] or in two to three years [26]. Based on the low incidence of observed pathologies, it can be proposed that
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they be followed with US yearly or every two years, until they are mature enough to verbalize signs of flank pain or dysuria to identify the few patients who may have clinically significant
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urological pathologies.
There are several limitations to the present study. First, this is a retrospective study. Not all
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patients underwent the same postnatal evaluation, and there was a potential for a UTI being missed during follow up. Second, while the median follow-up time was 23 months, longer follow-up time may provide more comprehensive information on the resolution, surgery and the incidence of UTI. Third, at the institution, the pediatric radiologists use a descriptive grading system in delineating the severity of the hydronephrosis. While, it is a more subjective system compared to the SFU grading system, it has good reliability when used to compare serial US. Finally, only patients who were referred to a tertiary care institution were
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ACCEPTED MANUSCRIPT evaluated and this would not account for those managed by their primary care physicians or at other referral institutions. There could be an inherent bias based on which patients were referred for specialized urology consultation and care. Despite these limitations, the authors’ believe that the findings provide further insights in the natural history of children with mild
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antenatal hydronephrosis.
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Conclusion
Given the low incidence of VUR in children with asymptomatic mild antenatal and postnatal
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hydronephrosis, screening VCUG is not routinely required. In addition, long-term ABP is similarly not required in this patient population due to the low rate of UTI. VCUG and longterm ABP should be reserved for those who present with recurrent UTIs. In the vast majority of cases, the mild hydronephrosis resolves or improves with time and less than 2% of children
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with mild ANH require surgical intervention. Together, these findings suggest that mild ANH
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is a relatively benign finding requiring specific but limited postnatal evaluation and follow up.
Source of funding: None declared
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Conflicts of interest: None declared The Ethics Committee of this Institution has approved the study.
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ACCEPTED MANUSCRIPT References [1] Malik M, Watson AR. Antenatally detected urinary tract abnormalities: more detection but less action. Pediatr Nephrol 2008; 23(6):897-904. [2] Cohen HL, Cooper J, Eisenberg P, Mandel FS, Gross BR, Goldman MA, et al.
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Normal length of fetal kidneys: sonographic study in 397 obstetric patients. Am J Roentgenol 1991; 157(3):545-8.
[3] Passerotti CC, Kalish LA, Chow J, Passerotti AM, Recabal P, Cendron M, et al.
hydronephrosis. J Pediatr Urol 2011; 7(2):128-36.
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The predictive value of the first postnatal ultrasound in children with antenatal
Hum Dev 2006; 82(1):3-8.
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[4] Pates JA, Dashe JS. Prenatal diagnosis and management of hydronephrosis. Early
[5] Ahmad G, Green P. Outcome of fetal pyelectasis diagnosed antenatally. J Obstet Gynaecol 2005; 25(2):119-22.
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[6] Nguyen HT, Herndon CD, Campbell JB et al. The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis. J Pediatr
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Urol 2010; 6:212-31.
[7] Lee RS, Cendron M, Kinnamon DD, Nguyen HT. Antenatal hydronephrosis as a
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predictor of postnatal outcome: a meta analysis. Pediatrics 2006; 118(2):586-93. [8] Zanetta VC, Rosman BM, Bromley B, Shipp TD, Chow JS, Campbell JB, et al.
Variations in management of mild prenatal hydronephrosis among Maternal-Fetal Medicine Obstetricians, and Pediatric Urologists and Radiologist. J Urol 2012; 188(5):1935-9. [9] Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management, K.B. Roberts. Urinary Tract Infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2-24 months. Pediatrics 2011; 128:595-610. 12
ACCEPTED MANUSCRIPT [10] Ismaili K, Avni FE, Hall M. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr 2002; 141(1):21-4. [11] Estrada CR, Peters CA, Retik AB, Nguyen HT. Vesicoureteral reflux and urinary tract
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infection in children with a history of prenatal hydronephrosis: should voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis? J Urol 2009; 181(2):801-6.
ultrasound? Arch Dis Child 1996; 75(5):444-7.
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[12] Tibballs JM, De Bruyn R. Primary vesicoureteric reflux: how useful is postnatal
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[13] Yerkes EB, Adams MC, Pope JC, Brock JW. Does every patient with prenatal hydronephrosis need voiding cystourethrography? J Urol 1999; 162(3 Pt 2):1218-20. [14] Tombesi MM, Alconcher LF. Short-term outcome of mild isolated antenatal
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hydronephrosis conservatively managed. J Pediatr Urol 2012; 8(2):129-33. [15] de Kort EHM, Bambang Oetomo S, Zegers SHJ. The long-term outcome of antenatal hydronephrosis up 15 millimeters justifies a noninvasive postnatal follow-up. Acta Paediatr
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2008; 97(6):708-13.
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[16] Coelho GM, Bouzada MC, Pereira AK, Figueiredo BF, Leite MR, Oliveira DS, Oliveira EA. Outcome of isolated antenatal hydronephrosis: a prospective cohort study. Pediatr Nephrol 2007; 22(10):1727-34. [17] Koff SA. Postnatal management of antenatal hydronephrosis using an observational approach. Urology 2000; 55(5):609-11. [18] Sidhu G, Beyene J, Rosenblum ND. Outcome of isolated antenatal hydronephrosis: a systematic review and meta-analysis. Pediatr Nephrol 2006; 21(2):218-24.
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ACCEPTED MANUSCRIPT [19] Valent-Moric B, Zigman T, Cuk M, Zaja-Franulovic O, Malenica. Postnatal evaluation and outcome of infants with antenatal hydronephrosis. M.Acta Clin Creat 2011; 50(4):451-5. [20] Gökaslan F, Yalçınkaya F, Fitöz S, Özçeker ZB. Evaluation and outcome of antenatal
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hydronephrosis: a prospective study. Ren Fail 2012; 34(6):718-21. [21] Koff SA. Postnatal management of antenatal hydronephrosis using anobservational approach. Urology 2000; 55(5):609-11.
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[22] Odibo AO, Raab E, Elovitz M, Merrill JD, Macones GA. Prenatal mild pyelectasis: evaluating the thresholds of renal pelvic diameter associated with normal postnatal renal
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function. J Ultrasound Med 2004; 23(4):513-7.
[23] Wollenberg A, Neuhaus TJ, Willi UV, Wisser J. Outcome of fetal renal pelvic dilatation diagnosed during the third trimester. Ultrasound Obstet Gynecol 2005; 25(5):483-8.
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[24] Riccabona M, Avni FE, Blickman JG, Dacher JN, Darge K, Lobo ML, et al. Imaging recommendations in paediatric uroradiology. Minutes of the ESPR uroradiology task force session on childhood obstructive uropathy, high-grade fetal hydronephrosis, childhood
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haematuria, and urolithiasis in childhood. Pediatr Radiol. 2009; 39(8):891-8.
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[25] Coelho GM, Bouzada MC, Lemos GS, Pereira AK, Lima BP, Oliveira EA. Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation. J Urol 2008; 179 (1):284-9.
[26] van Eerde AM, Meutgeert MH, de Jong TP, Giltay JC. Vesico-ureteral reflux in children with prenatally detected hydronephrosis: a systematic review. Ultrasound Obstet Gynecol 2007; 29(4):463-9.
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Figure Legend
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Figure 1: Clinical outcomes of the 760 children with mild antenatal hydronephrosis.
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VCUG performed
2/1
Female=2 Male =4
1/1 3/1
2 2
Female=1
1/0
2 resolved 2 resolved 1 unchanged 1 progressed (pyeloplasty) 1 progressed (pyeloplasty)
2
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5
Male =3
4 resolved 1 unchanged 3 resolved
1
VUR 1 (Grade 3-4) underwent reimplant 0
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4/1
6
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Unspecified UTI
Female= 5
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Non-febrile UTI
Male=8
Hydronephrosis during follow-up 7 resolved 1 unchanged
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Febrile UTI
Unilateral/ Bilateral 4/4
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Gender
0 0 1 (Grade 5) underwent reimplant 0
S1477-5131(14)00113-2
DOI:
10.1016/j.jpurol.2014.04.001
Reference:
JPUROL 1678
To appear in:
Journal of Pediatric Urology
Received Date: 4 February 2014 Accepted Date: 6 April 2014
Please cite this article as: Sencan A, Carvas F, Hekimoglu IC, Caf N, Sencan A, Chow J, Nguyen HT, Urinary tract infection and vesicoureteral reflux in children with Mild antenatal hydronephrosis, Journal of Pediatric Urology (2014), doi: 10.1016/j.jpurol.2014.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Urinary tract infection and vesicoureteral reflux in children with Mild antenatal hydronephrosis
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A. Sencan, MD1, F. Carvas, MD1, I. Cem Hekimoglu1, N. Caf1, A. Sencan, MD1, J. Chow, MD1, 2, H.T. Nguyen, MD1
Department of Urology, Boston Children’s Hospital, Boston, MA, USA
2
Department of Radiology, Boston Children’s Hospital, Boston, MA, USA
[email protected] [email protected] drhekimoğ[email protected]
[email protected]
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[email protected]
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1
[email protected]
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[email protected]
CORRESPONDING AUTHOR:
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Hiep T. Nguyen, M.D. Department of Urology, Hunnewell-353 Children’s Hospital Boston 300 Longwood Avenue, Boston, MA 02115, USA [email protected] Phone: 617- 355-6842 Fax: 617-730-0474
ACCEPTED MANUSCRIPT Summary
Objective: The postnatal management of mild antenatal hydronephrosis (ANH) remains controversial. The purpose of this study was to evaluate the incidence of UTI and VUR in
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children with mild ANH in order to determine the necessity of antibiotic prophylaxis (ABP) and VCUG.
Method: The data of 1511 patients with various grades of ANH who were referred to
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Department of Urology, Boston Children’s Hospital between January 1998 and January 2010 were reviewed and 760 patients who had mild ANH were identified. The inclusion criteria
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were:
1) A confirmed report of ANH or actual prenatal ultrasound (US) images.
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2) Postnatal evaluation and management conducted at the institution.
3) Persistent mild hydronephrosis on the first US done between two weeks and three months of age.
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abnormalities.
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4) No other US findings such as ureteral dilatation, duplication anomalies or bladder
5) At least one three-month follow up.
Univariate statistical analysis was performed using a Student's t test.
Results: Of the 760 patients who were identified, 608 (80%) were males, and 225 (30%) had bilateral mild hydronephrosis. Of these, 475 patients (63%) underwent an initial screening VCUG. VUR was identified in 13 patients (1.7%) with grades varying from 1–5. At follow up, hydronephrosis resolved in 67% of the renal units and worsened in 3.3%. Among the 692 1
ACCEPTED MANUSCRIPT patients with available follow-up data, 23 (3.3%) had a documented UTI. Twelve of these children had an initial screening VCUG that was negative for VUR. Of these 12 patients, seven underwent a subsequent RNC with none having VUR; five of the 12 patients did not undergo a repeat evaluation for VUR (four had a UTI after the screening VCUG and one had
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an afebrile UTI). Eleven of the 23 children with mild ANH did not have an initial screening VCUG, and all underwent a subsequent VCUG/RNC. Only two children were then found to
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have VUR Grade 4–5.
Conclusion: The incidence of UTI and VUR in children with mild PNH is low. Consequently,
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routine VCUG screening for VUR and the use of long-term ABP is not necessary for all patients with asymptomatic mild AHN. Evaluation for VUR in children with mild ANH
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should be reserved for those who subsequently present with a UTI.
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Introduction
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Keywords: Hydronephrosis; Antenatal; Prenatal; Mild
Dilatation of the urinary collecting systems (i.e. antenatal hydronephrosis, ANH) is detected in 1% to 5% of fetuses during the second and third trimesters by ultrasonography (US) [1-3]. The clinical significance of ANH is dependent on its severity, with the more severe grades correlating with increasing incidence of clinically significant pathologies [4]. Mild, isolated ANH represents up to 80% of cases and is considered to be more benign than those of moderate or severe grades [5-6]. A review of the literature indicates the risk of urological pathology with mild ANH to be 11.9%, compared to 88.3% for the more severe cases [7].
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ACCEPTED MANUSCRIPT These findings suggest that while the majority of the cases of mild ANH are benign, 10% may have significant urological pathologies and may develop complications such as febrile urinary tract infection and renal injury if left untreated.
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Consequently, recommendations regarding the evaluation and management of mild ANH are controversial. They vary from no follow up to extensive postnatal radiological evaluation including US, VCUG, RNC and medical therapies such as antibiotic prophylaxis (ABP). Of
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particular controversy in this patient population is the use of ABP and performing VCUG. In a recent survey of pediatric radiologists, pediatric urologists and maternal-fetal obstetricians
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on the management of mild ANH, there was lack of consensus about these issues [8]. The purpose of this study is to evaluate the incidence of UTI in children with mild antenatal and persistent postnatal hydronephrosis in order to determine the necessity of ABP and VCUG.
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Patients and Methods
Since 1986, children with ANH, who had been referred to the Department of Urology, Boston Children’s Hospital for evaluation and management, were prospectively enrolled onto an
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IRB-approved database. For this study, in order to evaluate a contemporary series of children with ANH, analysis was limited to patients seen from January 1998 to January 2010,. The
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inclusion criteria included:
1) A confirmed report of ANH or actual prenatal US images. 2) Postnatal evaluation and management conducted at the institution. 3) Persistent mild hydronephrosis on the first US done between two weeks and three months of age.
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ACCEPTED MANUSCRIPT 4) No other US findings such as ureteral dilatation, duplication anomalies or bladder abnormalities. 5) At least one three-month follow up.
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A total of 1511 patients with various grades of ANH met the inclusion criteria. Of these, 760 children had mild ANH, which was defined by an anterior-posterior pelvic diameter (APPD) of 7–10 mm diagnosed by fetal US in the third trimester of gestation and persistent postnatal
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mild hydronephrosis. Due to the ultrasonographers’ preference at the institution, postnatal hydronephrosis for this study was graded on a scale of mild, moderate and severe. Although
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this grading system is not standardized like the SFU system, this correlates generally to SFU Grade 1-2 for mild, SFU Grade 3 for moderate and SFU Grade 4 for severe and is based on the amount of pelvic and calyceal dilatation. This ‘mild-severe’ grading system is the most commonly used system among radiologists and, specifically, pediatric radiologists.
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The patients’ postnatal evaluation and management (such as performing a VCUG and the use of ABP) were based on the preferences of his/her pediatric urologist. The primary outcomes evaluated were the incidence of UTI and VUR, and the secondary outcomes were the rate of
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hydronephrosis resolution and the incidence of surgical intervention. The patients’ clinical
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course was assessed for the degree of hydronephrosis, the development of UTI and the need for surgical intervention. The outcome of hydronephrosis was categorized as: resolved, improving, worsening, or unchanged. A UTI was defined based on the presence of one or more signs (foul smelling urine, hematuria, fever or chills) and/or symptoms (dysuria, frequency, suprapubic discomfort, or flank pain in older children) and a positive urine culture based upon criteria suggested by 2011 AAP Guidelines [9]. UTI was further classified as febrile (temperature greater 38.5oC), nonfebrile (no associated fever) or nonspecific (no documentation of fever could be determined). The primary (the development of a UTI) and
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ACCEPTED MANUSCRIPT secondary (resolution of the ANH or need for surgical intervention) outcomes were correlated with the patient’s demographic and postnatal management. Univariate statistical analysis was performed using a Student’s t test and a P-value of < 0.05 was considered to be statistically
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significant.
Results:
General Demographics
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A total of 760 patients met this study’s inclusion criteria and had median follow-up time of 23
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months (range 3 months to 147 months). Of the 760 patients, 608 (80%) were males, and 225 (29.6%) had bilateral mild hydronephrosis. Twenty-one percent of the males were uncircumcised. Of the 535 patients with unilateral mild hydronephrosis, 356 (66.5%) occurred on the right side. Based on their pediatric urologist’s preference, 475 patients (62.5%) underwent a VCUG (70.2% of the bilateral and 59.3% of the unilateral mild hydronephrosis).
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VUR was identified in 13 patients (2.7%) with grade varying from 1 to 5. PUV were identified in two (0.3%). Immediately after birth, 369 patients (48.55%) were placed on ABP
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(principally amoxicillin). In 90% of the patients, ABP was discontinued after they underwent a VCUG documenting the absence of VUR. In the 13 patients in whom VUR was identified,
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ABP was continued.
Incidence of urinary tract infection Of the 760 patients evaluated, detailed clinical follow up was not available in 68 patients. Of the remaining 692 patients, 23 (3.3%) had a documented UTI (Figure 1). Thirteen (eight male, five female) had associated fever, five (three male, two female) did not, and in the remaining five patients (four male, one female) the presence or absence of fever was not documented. Table 1 illustrates the association with gender, the degree of hydronephrosis in follow up, and 5
ACCEPTED MANUSCRIPT the presence of VUR in patients who developed a UTI. Ten of the 15 males who developed a UTI were uncircumcised; boys who were uncircumcised were at a 7.8 fold increased risk of developing a UTI (P < 0.001).
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Of the 23 patients who developed a UTI, 12 had a negative initial screening VCUG. A subsequent VCUG/RNC was performed in 18 of 23 patients (78.3%) who had a UTI; only two (8.7%) had VUR, of which both were of high grade. In the five patients who were not
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evaluated with a subsequent VCUG/RNC, four (17.4%) had developed a UTI after undergoing screening VCUG and were not on ABP; the remaining patient had a non-febrile
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UTI. It was determined by their primary pediatric urologist that further evaluation for VUR was not clinically indicated. Of the 23 patients, the median age at which the UTI developed was three months (mean = 7.4, range = 1 month to 4 years). Two (8.7%) of the 23 patients developed a UTI while on ABP. One of these two patients had a UPJ obstruction and
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subsequently underwent pyeloplasty for progressive hydronephrosis and prolonged T ½. The other had an ectopic ureter with a high-grade refluxing lower pole system and underwent a
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common sheath ureteral reimplantation for a breakthrough UTI while on ABP.
Resolution of hydronephrosis and need for surgical intervention
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In the 760 patients, mild hydronephrosis was documented on the first postnatal US in 985 renal units. During follow up, complete resolution (no hydronephrosis) was observed in 663 renal units (67.30%), improved (defined as only pelviectasis, SFU Grade 2 now down to Grade 1) in 131 (13.3%), worsened (SFU Grade 3 or more) in 32 (3.3%) and unchanged (remained SFU Grades 1 or 2) in 158 (16.0%). The median time to resolution was approximately 24 months. It should be noted that US was performed every six months to yearly at the discretion of the treating urologist. Consequently, the median time to resolution
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ACCEPTED MANUSCRIPT observed in this study may be somewhat arbitrary. However, it does provide a rough estimate to help with parental counseling.
Thirteen of 760 (1.7%) underwent surgical intervention. Four of the 13 patients with VUR
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underwent antireflux surgery for persistent (> three years) high-grade reflux or for breakthrough UTIs. Both patients with PUV underwent endoscopic valve ablation. Six patients underwent pyeloplasty for progressive hydronephrosis with t ½ > 30 minutes on
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MAG-3 imaging. One patient underwent ureteral tapering and reimplant for an obstructed
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megaureter.
Discussion
In this population of children with mild antenatal and persistent postnatal hydronephrosis, VUR was identified in only 1.7% of the 63% who underwent a VCUG. This suggests that
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VUR is uncommon in children with mild ANH and that screening VCUG can be avoided in the majority of cases. Although commonly performed, VCUG is an invasive imaging modality that exposes infants to ionizing radiation, risk of UTI and is a stressful procedure for
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both the patient and the parents [10].
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Several studies have suggested that VCUG screening is necessary in children with mild ANH. Similar incidences of VUR (ranging from 12–25%) among different grades of ANH have been previously reported in the literature, suggesting the importance of investigation of this pathology even in mild cases [7,11]. Tibbails et al. found that 25% of newborns with normal postnatal US had VUR Grade 3 or higher. This warranted the recommendation for VCUG evaluation in all newborns with ANH, even those in which the hydronephrosis resolved in utero [12]. In contrast, other studies suggested that VCUG is not mandatory in children with
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ACCEPTED MANUSCRIPT ANH of Grade 2 or less [1,13,14,15]. Ismaili et al. observed in their cohort of 264 infants with mild ANH and a normal postnatal US, that 6.7% had VUR. However, the complication rate associated with performing the VCUG was 3.4% [10].
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In the present study, VUR was only identified in 1.7% of the children with mild ANH and mild hydronephrosis on the first postnatal US. In addition, four of the 23 children with mild ANH and a UTI developed the UTI after having a VCUG. Consequently, the authors’ propose
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that routine performance of VCUG for mild AHN is not necessary, but it should be performed for patients who have febrile or recurrent UTI during follow up. This recommendation would
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avoid unnecessary radiation exposure, discomfort and risk of UTI in children with mild ANH.
Moreover, it was observed that UTI occurred in 3.4% of children with mild ANH. Of the 37% who did not undergo a screening VCUG initially, only two (0.07%) patients presented with a
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subsequent UTI and were found to have VUR. Uncircumcised boys with mild ANH were at higher risk of developing a UTI compared to their circumcised counterparts. Twenty-two percent of the children who had a UTI (0.8% of those who underwent VCUG evaluation)
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developed it after undergoing routine VCUG. In a prior study, the incidence of UTI was reported to be 10% in children with mild ANH, 20% in those with moderate, and 40% in
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those with severe ANH [16]. In the present study, a low incidence of UTI in the mild group was similarly observed. This difference emphasizes that isolated mild AHN should be considered as a distinct entity from severe HN and HN associated with other renal abnormalities. Based on these findings and other prior studies [17,18], long-term ABP for children with mild ANH is not warranted.
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ACCEPTED MANUSCRIPT Furthermore, in the present study’s population of children with mild antenatal and persistent postnatal hydronephrosis, 79.9% had improvement or resolution of their hydronephrosis, and only 3.3% were worse. Approximately 2% of the children with mild ANH eventually required surgical intervention (e.g. ureteral reimplants, ablation of PUVs and pyeloplasty). This study’s
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findings indicate that mild ANH is likely to resolve in the majority of the cases; however, in a small number of patients, it may represent a sign of an underlying, significant urological problem (i.e. those that required surgical intervention). Children with any degree of ANH are
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at greater risk of having urological pathology, compared to the normal population. The grade of hydronephrosis is correlated with the increased risk of urologic pathologies and could be
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used for making decision about further diagnostic imaging and treatment [19, 20].
In a recent meta-analysis, Lee et al. demonstrated that the risk of any urological pathology correlated with the degree of ANH, being 11.9% in the mild group, 45.1% in the moderate
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group, and 88.3% in the severe group [7]. Moderate and severe cases seem to be more often associated with obstructive pathologies such as UPJ obstruction and PUV, while mild ANH is often transient, with spontaneous prenatal or postnatal resolution in the majority of cases
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[1,21,22]. However, there is much debate as to whether urological pathologies such as VUR and UPJ obstruction that resolve without any sequelae (e.g. UTI) should be considered
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clinically significant. In a study of 213 infants with mild to moderate ANH, Sidhu et al. observed that significant uropathies were seen in 39% of the infants, although intervention was not required in most patients [18]. Consequently, it may be of greater clinical utility to determine the incidence of children with mild ANH who required medical/surgical intervention. In the present study’s patients, 2% of children with mild ANH required surgical intervention. It can be suggested that this lower rate would be of more relevance when counseling patients/families. However, follow up with US and clinical evaluation is
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ACCEPTED MANUSCRIPT mandatory in order to identify those rare patients with significant uropathies such as PUV despite having mild ANH.
The postnatal evaluation of mild isolated ANH is currently controversial, with some
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practitioners recommending full postnatal radiological evaluation while others do not [17]. Postnatal evaluation is needed to identify the underlying pathology, but it is not without associated disadvantages: time, expense, discomfort and radiation exposure from radiologic
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evaluation, the unintended consequences of false positives and the stress on the family. For children with mild or SFU Grade 1-2 hydronephrosis on the one-month US examination,
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some practitioners suggest discharging them from further surveillance with the recommendation that the child be seen again for UTI or pain [23,24], while others recommend serial USG examinations and UTI surveillance every six or twelve months [25] or in two to three years [26]. Based on the low incidence of observed pathologies, it can be proposed that
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they be followed with US yearly or every two years, until they are mature enough to verbalize signs of flank pain or dysuria to identify the few patients who may have clinically significant
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urological pathologies.
There are several limitations to the present study. First, this is a retrospective study. Not all
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patients underwent the same postnatal evaluation, and there was a potential for a UTI being missed during follow up. Second, while the median follow-up time was 23 months, longer follow-up time may provide more comprehensive information on the resolution, surgery and the incidence of UTI. Third, at the institution, the pediatric radiologists use a descriptive grading system in delineating the severity of the hydronephrosis. While, it is a more subjective system compared to the SFU grading system, it has good reliability when used to compare serial US. Finally, only patients who were referred to a tertiary care institution were
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ACCEPTED MANUSCRIPT evaluated and this would not account for those managed by their primary care physicians or at other referral institutions. There could be an inherent bias based on which patients were referred for specialized urology consultation and care. Despite these limitations, the authors’ believe that the findings provide further insights in the natural history of children with mild
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antenatal hydronephrosis.
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Conclusion
Given the low incidence of VUR in children with asymptomatic mild antenatal and postnatal
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hydronephrosis, screening VCUG is not routinely required. In addition, long-term ABP is similarly not required in this patient population due to the low rate of UTI. VCUG and longterm ABP should be reserved for those who present with recurrent UTIs. In the vast majority of cases, the mild hydronephrosis resolves or improves with time and less than 2% of children
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with mild ANH require surgical intervention. Together, these findings suggest that mild ANH
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is a relatively benign finding requiring specific but limited postnatal evaluation and follow up.
Source of funding: None declared
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Conflicts of interest: None declared The Ethics Committee of this Institution has approved the study.
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ACCEPTED MANUSCRIPT References [1] Malik M, Watson AR. Antenatally detected urinary tract abnormalities: more detection but less action. Pediatr Nephrol 2008; 23(6):897-904. [2] Cohen HL, Cooper J, Eisenberg P, Mandel FS, Gross BR, Goldman MA, et al.
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Normal length of fetal kidneys: sonographic study in 397 obstetric patients. Am J Roentgenol 1991; 157(3):545-8.
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The predictive value of the first postnatal ultrasound in children with antenatal
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[4] Pates JA, Dashe JS. Prenatal diagnosis and management of hydronephrosis. Early
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[6] Nguyen HT, Herndon CD, Campbell JB et al. The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis. J Pediatr
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Urol 2010; 6:212-31.
[7] Lee RS, Cendron M, Kinnamon DD, Nguyen HT. Antenatal hydronephrosis as a
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predictor of postnatal outcome: a meta analysis. Pediatrics 2006; 118(2):586-93. [8] Zanetta VC, Rosman BM, Bromley B, Shipp TD, Chow JS, Campbell JB, et al.
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ACCEPTED MANUSCRIPT [10] Ismaili K, Avni FE, Hall M. Results of systematic voiding cystourethrography in infants with antenatally diagnosed renal pelvis dilation. J Pediatr 2002; 141(1):21-4. [11] Estrada CR, Peters CA, Retik AB, Nguyen HT. Vesicoureteral reflux and urinary tract
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infection in children with a history of prenatal hydronephrosis: should voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis? J Urol 2009; 181(2):801-6.
ultrasound? Arch Dis Child 1996; 75(5):444-7.
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[12] Tibballs JM, De Bruyn R. Primary vesicoureteric reflux: how useful is postnatal
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[13] Yerkes EB, Adams MC, Pope JC, Brock JW. Does every patient with prenatal hydronephrosis need voiding cystourethrography? J Urol 1999; 162(3 Pt 2):1218-20. [14] Tombesi MM, Alconcher LF. Short-term outcome of mild isolated antenatal
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hydronephrosis conservatively managed. J Pediatr Urol 2012; 8(2):129-33. [15] de Kort EHM, Bambang Oetomo S, Zegers SHJ. The long-term outcome of antenatal hydronephrosis up 15 millimeters justifies a noninvasive postnatal follow-up. Acta Paediatr
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2008; 97(6):708-13.
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[16] Coelho GM, Bouzada MC, Pereira AK, Figueiredo BF, Leite MR, Oliveira DS, Oliveira EA. Outcome of isolated antenatal hydronephrosis: a prospective cohort study. Pediatr Nephrol 2007; 22(10):1727-34. [17] Koff SA. Postnatal management of antenatal hydronephrosis using an observational approach. Urology 2000; 55(5):609-11. [18] Sidhu G, Beyene J, Rosenblum ND. Outcome of isolated antenatal hydronephrosis: a systematic review and meta-analysis. Pediatr Nephrol 2006; 21(2):218-24.
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ACCEPTED MANUSCRIPT [19] Valent-Moric B, Zigman T, Cuk M, Zaja-Franulovic O, Malenica. Postnatal evaluation and outcome of infants with antenatal hydronephrosis. M.Acta Clin Creat 2011; 50(4):451-5. [20] Gökaslan F, Yalçınkaya F, Fitöz S, Özçeker ZB. Evaluation and outcome of antenatal
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hydronephrosis: a prospective study. Ren Fail 2012; 34(6):718-21. [21] Koff SA. Postnatal management of antenatal hydronephrosis using anobservational approach. Urology 2000; 55(5):609-11.
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[22] Odibo AO, Raab E, Elovitz M, Merrill JD, Macones GA. Prenatal mild pyelectasis: evaluating the thresholds of renal pelvic diameter associated with normal postnatal renal
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function. J Ultrasound Med 2004; 23(4):513-7.
[23] Wollenberg A, Neuhaus TJ, Willi UV, Wisser J. Outcome of fetal renal pelvic dilatation diagnosed during the third trimester. Ultrasound Obstet Gynecol 2005; 25(5):483-8.
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[24] Riccabona M, Avni FE, Blickman JG, Dacher JN, Darge K, Lobo ML, et al. Imaging recommendations in paediatric uroradiology. Minutes of the ESPR uroradiology task force session on childhood obstructive uropathy, high-grade fetal hydronephrosis, childhood
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haematuria, and urolithiasis in childhood. Pediatr Radiol. 2009; 39(8):891-8.
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[25] Coelho GM, Bouzada MC, Lemos GS, Pereira AK, Lima BP, Oliveira EA. Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation. J Urol 2008; 179 (1):284-9.
[26] van Eerde AM, Meutgeert MH, de Jong TP, Giltay JC. Vesico-ureteral reflux in children with prenatally detected hydronephrosis: a systematic review. Ultrasound Obstet Gynecol 2007; 29(4):463-9.
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Figure Legend
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Figure 1: Clinical outcomes of the 760 children with mild antenatal hydronephrosis.
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VCUG performed
2/1
Female=2 Male =4
1/1 3/1
2 2
Female=1
1/0
2 resolved 2 resolved 1 unchanged 1 progressed (pyeloplasty) 1 progressed (pyeloplasty)
2
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5
Male =3
4 resolved 1 unchanged 3 resolved
1
VUR 1 (Grade 3-4) underwent reimplant 0
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4/1
6
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Unspecified UTI
Female= 5
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Non-febrile UTI
Male=8
Hydronephrosis during follow-up 7 resolved 1 unchanged
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Febrile UTI
Unilateral/ Bilateral 4/4
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Gender
0 0 1 (Grade 5) underwent reimplant 0
