The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis

Journal of Pediatric Urology (2010) 6, 212e231

FETAL UROLOGY

The Society for Fetal Urology consensus statement on the evaluation and management of antenatal hydronephrosis Hiep T. Nguyen a,*, C.D. Anthony Herndon b, Christopher Cooper c, John Gatti d, Andrew Kirsch e, Paul Kokorowski a, Richard Lee a, Marcos Perez-Brayfield f, Peter Metcalfe g, Elizabeth Yerkes h, Marc Cendron a, Jeffrey B. Campbell i a

Department of Urology, Children’s Hospital, Boston, MA, USA Division of Urology, Children’s Hospital of Alabama, Birmingham, AL, USA c Department of Urology, University of Iowa Medical Center, Iowa City, IA, USA d Department of Urology, Children’s Mercy Hospital, Kansas City, KA, USA e Department of Urology, Children’s Healthcare of Atlanta, Atlanta, GA, USA f Division of Urology, HIMA-San Pablo, University of Puerto Rico, San Juan PR, Puerto Rico g Department of Urology, Stollery Children’s Hospital, Edmonton, Alberta, Canada h Department of Urology, Children’s Memorial Hospital, Chicago, IL, USA i Department of Pediatric Urology, The Children’s Hospital, Aurora, CO, USA b

Received 26 January 2010; accepted 13 February 2010 Available online 15 April 2010

KEYWORDS Hydronephrosis; Radiological imaging; Children; Prenatal diagnosis

Abstract The evaluation and management of fetuses/children with antenatal hydronephrosis (ANH) poses a significant dilemma for the practitioner. Which patients require evaluation, intervention or observation? Though the literature is quite extensive, it is plagued with bias and conflicting data, creating much confusion as to the optimal care of patients with ANH. In this article, we summarized the literature and proposed recommendations for the evaluation and management of ANH. ª 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Urology, Children’s Hospital Boston, 300 Longwood Avenue, Hunnewell-353, Boston, MA 02115, USA. Tel.: þ1 617 355 6842; fax: þ1 617 730 0474. E-mail address: [email protected] (H.T. Nguyen). 1477-5131/$36 ª 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2010.02.205

Consensus statement for prenatal hydronephrosis

Introduction Dilation of the fetal renal collecting system, antenatal hydronephrosis (ANH), is one of the most common abnormalities detected on prenatal ultrasonography (US), reported in approximately 1e5% of all pregnancies. ANH represents a wide spectrum of urological conditions, ranging from transient dilation of the collecting system to clinically significant urinary tract obstruction or vesicoureteric reflux (VUR). With the advent of routine prenatal US, children with urinary tract obstruction or reflux are being detected prior to the development of complications such as urinary tract infection (UTI), kidney stones and renal dysfunction or failure. These complications might be averted by early diagnosis. Consequently, the goals in evaluating children with ANH are to prevent these potential complications and to preserve renal function. However, not all findings on prenatal US represent pathology; many are transient and have no clinical significance. The dilemma therefore is to distinguish children who require follow up and intervention from those who do not. While the use of prenatal US as a screening tool for identifying urological anomalies has not been shown to improve postnatal outcomes, more patients are undergoing prenatal counseling for the discovery of ANH [1]. Currently, the definition of ANH is variable, and the clinical management of ANH has not been systematically defined. Consequently, the diagnosis of ANH may cause significant parental anxiety and physician uncertainty when it comes to pre- and postnatal management. In addition, because its evaluation can be quite extensive, the management of ANH has a significant cost impact on our current healthcare system. Concerns over litigation due to failure to diagnose an anomaly may also shape the postnatal evaluation. This consensus statement reviews the current literature on the diagnosis and management of ANH and proposes a unified approach to the care of the fetus/child with ANH.

213 The current literature was summarized and general recommendations were developed based upon current available clinical evidence. To date, there are no comprehensive prospective studies that correlate the risk of pathology with varying degrees of ANH or those aspects of ANH that predict postnatal diagnosis or kidney outcome. In addition, given the broad nature of this topic and lack of an adequate number of prospective studies, we were unable to perform any additional, detailed meta-analysis of the literature other than those already reported. Consequently, this consensus statement is limited by the generally retrospective nature of the data available. Recommendations proposed in this statement may change in the future depending on the results of prospective studies.

Fetal urinary tract: anatomy, physiology and US appearance Around the 5th week of gestation, the ureteric buds arise from the posterior aspect of the lower portion of the mesonephric ducts. They grow posteriorly into the sacral portion of the intermediate mesoderm, the metanephric blastema. The complex interaction between these two structures leads to renal development that continues throughout gestation and is completed just before the 36th week. The fetal kidneys have a lobulated external appearance and ascend from their pelvic position during the 6e9th week. They can be well visualized by US at the 12e13th week, with distinct renal architecture seen by the 20th week (Fig. 1). From the 12th week to the 40th week, the renal length increases from 1.0 to 2.7 cm, APD from 0.8 to 2.6 cm, and transverse diameter from 0.9 to 2.6 cm [2]. Urine formation is first seen at the 5e8th week; however, it is principally an unmodified plasma filtrate since tubular function starts around the 14th week. The urine output is

Methodology A literature search of PubMed, OVID, EMBASE and the Cochrane Library databases from 1993 to July 2009 was performed for articles reporting on children with prenatal hydronephrosis and who had postnatal evaluation. Ten terms for hydronephrosis were combined (hydronephrosis, pelviectasis, pelvocaliectasis, pyelectasis, hydroureteronephrosis, renal pelvic dilation (RPD), anteroposterior diameter (APD), oligohydramnios, calyceal dilation, and ureteral dilation) with six terms for prenatal (prenatal, newborn, antenatal, fetal, prenatal diagnosis and natural history). Reference lists of research articles, reviews, and texts were simultaneously searched to ensure that we acquired all of the relevant articles. We excluded articles that only contained non-human subjects, editorials, letters, and comments. We did include some case reports for rare entities and reviews/practice guidelines for references and assessment of current practice recommendations. We screened 3581 citations; 410 articles were reviewed in depth because they contained information pertinent to the topics discussed below.

Figure 1 Normal appearance of a fetal kidney (arrow). Note the presence of the renal pyramids (dark, less echogenic structures within the kidney), which can be mistaken for dilated calyces.

214 approximately 5 cc/h at the 20th week and increases to 50 cc/h by the 40th week [3]. At about the same time that the ureteric buds appear, the partitioning of the cloaca begins, forming the urogenital sinus anteriorly and the anal canal posteriorly. The upper part of the urogenital sinus between the allantois and the mesonephric ducts then differentiates to form the bladder. The fetal bladder can be visualized on US by the 10e14th week, and its emptying can be seen by the 15th week (Fig. 2). The bladder capacity is observed to range from 10 cc at the 30th week to 50 cc at term [3]. Early in gestation the amniotic fluid is principally a transudate of the amnion, while later it is composed of fetal urine and lung fluid. The amniotic volume becomes principally dependent on urine production around the 16th week, ranging from 380 cc at the 20th week to 800 cc at the 28e40th week [4]. A rough estimate of the amount of amniotic fluid can be determined by US, by measuring the amniotic fluid index (AFI). The AFI is the score obtained by adding centimeters of depth of four pockets of fluid. Polyhydramnios is defined as an amniotic volume greater than 1500 cc (AFI > 20e24). The etiology for polyhydramnios includes esophageal obstruction, multicystic kidney, mesoblastic nephroma, and some urinary obstructive processes. In contrast, oligohydramnios is defined as an amniotic volume less than 500 cc, as indicated by the absence of pockets of fluid greater than 2 cm on US or AFI < 5e6. The etiology for oligohydramnios includes amnion nodosum, amniotic fluid leak, urinary tract obstruction, and renal dysplasia. The consequences of having oligohydramnios include the development of pulmonary hypoplasia, Potter’s syndrome (flat nose, recessed chin, low-set ears, bowed legs, small chest, tales equinovares, and hypoplastic hands) and limb deformities.

H.T. Nguyen et al.

Defining ANH Currently, the measurement of the APD of the renal pelvis as visualized in the transverse plane is the most studied parameter for assessing ANH in utero [5e9]. APD is a surrogate measurement of potential disease, but cannot specifically identify pathology. A simple threshold APD value which separates normal from abnormal does not exist, as even severe cases of ANH have the potential to resolve without incident while mild degrees of ANH have the potential to progress [6]. Potential factors affecting APD include gestational age [10e12], hydration status of the mother [13,14], and the degree of bladder distention [15]. Since the dimensions of the renal pelvis may normally increase with gestational age, most investigators have adjusted threshold APD values for early and later gestational age. Varying the minimal APD threshold for normal can significantly alter the positive predictive value of APD as a measure of ANH and postnatal pathology (Table 1). To date there is no consensus on the optimal APD threshold for determining the need for postnatal follow up. Coplen et al. [16]. suggests that a cut-off of 15 mm is ideal for determining obstruction, yielding a sensitivity of 73% and specificity of 82%. Ismaili et al. [17]. noted that a late gestational age cut-off of 10 would detect only 23% of abnormal kidneys, whereas a cut-off of 7 mm detected 68%. One large meta-analysis estimated that only 11.9% of total pathology presented with late gestational age APD less than 9 mm, while 39% of total pathology was noted at APD levels less than 15 [18]. Other investigators have demonstrated similar results [19]. What appears certain is that lower cutoffs will be more sensitive in detecting postnatal pathology; however, the trade off is in higher false positive rates. It is also apparent that the likelihood of pathology increases with increasing APD. Large prospective studies to correlate the degree of ANH with risk of pathology are clearly needed to provide answers to these questions. The use of APD has certain disadvantages and limitations. APD is only one measurement of collecting system dilatation and may not accurately reflect the degree of hydronephrosis. There have been no formal studies to determine the inter- and intra-observer reproducibility of APD measurement. Additionally, APD does not consider calyceal dilation or parenchymal changes (such as increased echogenicity or parenchymal thinning) that may reflect more severe cases of obstruction.

Grading system

Figure 2 Normal appearance of a fetal bladder (B). It can be recognized as a cystic structure in between the umbilical arteries (as seen by Doppler).

A number of grading systems have been utilized, each with its own unique characteristics and limitations. Perhaps the most basic is the traditional grading system, in which the grade of hydronephrosis is characterized as mild, moderate, or severe. The utility of this system has been improved by the use of the terms pelviectasis (dilation of the renal pelvis), pelvicaliectasis (dilation of the renal pelvis and calyces), and caliectasis (dilation of the calyces) to describe the extent of the hydronephrosis. The highly subjective nature of this system inevitably results in poor inter-rater reliability. A more objective measure of the degree of hydronephrosis is

Consensus statement for prenatal hydronephrosis Table 1

215

True positive (TP) and positive predictive value (PPV) of urological pathology based upon APD.

Reference

No. of pts

APD (mm)

% ANH

% TP

% PPV

Economou (1994) [143] Persutte (1997) [144] Morin (1996) [145] Owen (1996) [146] Langer (1996) [147] Livera (1989) [148] Fasolato (1998) [149] Arger (1985) [8] Rosendahl (1990) [150] Johnson (1992) [151] Gunn (1988) [152]

6645 5529 5900 3804 2170 3521 1775 6279 4586 7502 3228

2e3 4 4 5 5 5 6 10 10 10 15

1.96 5.50 2.20 0.80 4.40 0.85 3.80 1.26 0.39 0.37 1.92

0.04 0.50 0.08 0.30 0.60 0.17 0.50 0.55 0.28 0.16 0.22

2.3 9.2 2.9 40 14 20 18 44 77 43 11

APD. There is near uniform agreement that an APD greater than 15 mm represents severe or significant hydronephrosis, and most would agree that a value of 4e5 mm is an appropriate threshold for considering the APD to be abnormal [16,18,20e25]. With this in mind, ANH can be classified in the 2nd and 3rd trimester using APD thresholds for which the best available evidence provides prognostic information (Table 2). An estimate of the distribution of severity of ANH is provided in Table 3. In 1993, the Society for Fetal Urology (SFU) proposed a 5point numerical grading system based on the postnatal appearance of the renal pelvis, calyces, and renal parenchyma (Fig. 3) [26]. This grading system is a spectrum, with grade 1 demonstrating normal parenchymal thickness and only renal pelvis splitting, and grade 4 revealing distention of the renal pelvis and calyces in addition to parenchymal thinning. This system has been shown to have good intrarater, but modest inter-rater, reliability [27]. One of the limitations of this system is the difficulty in classifying a kidney with segmental calyceal dilation or renal parenchymal thinning. It has been proposed that sub-classifying SFU grade 4 hydronephrosis into segmental (4A) and diffuse (4B) cortical thinning may improve inter-rater reliability and clinical correlation [27,28]. The Japanese Society of Pediatric Urology has also proposed a (minor) modification of the SFU grading system in an effort to improve inter-rater reliability [29]. As an alternative to the SFU grading system, Shapiro et al. [30] have proposed a hydronephrosis index (HI), a quantitative measure in which HI (percentage) Z 100  (renal area e renal pelvis/calyces)/(renal area). The HI appears to correlate well with SFU grades 3 and 4 hydronephrosis, and may be more sensitive at detecting a change in the degree of hydronephrosis [31].

Other sonographic parameters In addition to the degree of hydronephrosis, a number of other sonographic parameters have been utilized to predict

postnatal outcomes. Renal findings such as poor corticomedullary differentiation (lack of US visualization of the renal pyramids) [32], increased echogenicity [33], and the presence of renal cysts[34] have been associated with the loss of functional renal parenchyma. The presence of a perinephric urinoma can be seen in association with severe urinary obstruction [35]. ANH is more likely to be associated with postnatal pathology when it is associated with parenchymal thinning, calyceal dilatation, ureteral dilatation, chromosomal anomalies or multiple system malformations [28,36e38]. Maizels et al. have reported that patients with ANH (APD >4 mm) and abnormal additional features (enlarged renal length, caliectasis, progressive caliectasis, a duplex kidney, ureterectasis, and/or a dilated bladder) required extensive postnatal urologic care and were 12.9 times more likely to die than when additional features were normal [39]. Fetal bladder sagittal length has also been found to be predictive of postnatal renal function; Maizels et al. reported an increasing incidence of postnatal azotemia and surgical intervention in fetuses with progressive bladder and upper urinary tract dilation [40]. It is well recognized that the degree of hydronephrosis can vary with distension of the fetal bladder. In an effort to account for this variability, Leung et al. have proposed a different hydronephrosis index (HI), where HI Z APD/urinary bladder volume, and have established normative values from 20 to 38 weeks gestation [15]. Oligohydramnios appears to be one of the most important predictive factors for postnatal pathology. In patients with ANH (APD > 5 mm), multivariate analyses have identified oligohydramnios and megacystis to be predictive of urethral obstruction, and oligohydramnios to be predictive of chronic renal failure or death [42,43]. Similarly, in patients with posterior urethral valves (PUV), multivariate analysis has identified oligohydramnios to be predictive of chronic renal failure [44]. Zaccara et al. have also reported

Table 3 Table 2

Definition of ANH by APD.

Degree of ANH

Second trimester

Third trimester

Mild Moderate Severe

4 to <7 mm 7 to 10 mm >10 mm

7 to <9 mm 9 to 15 mm >15 mm

Estimated breakdown of ANH by severity.

Degree of ANH

% of ANH

Mild Moderate Severe

56.7e88 10.2e29.8 1.5e13.4

Adapted from Ahmad and Green (2005) [20].

216

H.T. Nguyen et al.

Figure 3 The Society for Fetal Urology Hydronephrosis Grading System (http://www.uab.edu/images/peduro/SFU/sfu_grading_ on_web/sfu_grading_on_web.htm).

oligohydramnios (AFI < 25th percentile) to be predictive of chronic renal failure or death in patients with PUV [41]. Oligohydramnios, dilated posterior urethra (keyhole sign), ANH, thick-walled bladder, and increased renal echogenicity are worrisome signs for severe bladder outlet obstruction that warrant counseling and possible fetal intervention such as early delivery or vesicoamniotic shunting [44e46].

Predictive value of APD-defined ANH for pathology Based on a large systematic review of the current literature, the risk of any postnatal pathology is 11.9% for mild, 45.1% for moderate, and 88.3% for severe ANH [18]. The most common postnatal pathologic findings and their relative frequencies are presented in Table 4.

Table 4

An association between increasing incidence of postnatal pathology and degree of hydronephrosis holds true for most diagnoses. Key exceptions to this trend include VUR and distal ureteral obstruction. The incidence of VUR between groups of children with mild, moderate, and severe ANH is not significantly different (P Z 0.10) [18]. Furthermore, the reported incidence of VUR in children with ANH may not be appreciably different from the general population [47]. This implies that the presence or severity of ANH may have no reflection upon the presence of VUR, and further belies the efficacy of renal US in screening for VUR. Distal ureteral obstruction becomes more likely as the ANH increases from mild to moderate; however, there is a slight decrease in likelihood in the severe category. This may reflect the preponderance of

Risk of specific postnatal pathologic conditions by the degree of ANH. % ANH [95% CI]

UPJ VUR PUV Ureteral obstruction Other

Mild

Moderate

Severe

4.9 4.4 0.2 1.2 1.2

17.0 14.0 0.9 9.8 3.4

54.3 8.5 5.3 5.3 14.9

[2.0e11.9] [1.5e12.1] [0.0e1.4] [0.2e8.0] [0.3e4.0]

[7.6e33.9] [7.1e25.9] [0.2e2.9] [6.3e14.9] [0.5e19.4]

Other Z prune belly syndrome, VATER syndrome, solitary kidney, renal mass, and unclassified. Adapted from Lee et al. (2006) [18].

[21.7e83.6] [4.7e15.0] [1.2e21.0] [1.4e18.2] [3.6e44.9]

Consensus statement for prenatal hydronephrosis

217

type I and II megaureters, which can have significant ureteral dilatation with fewer renal pelvic effects [48]. Rather than relying on a single antenatal study to determine postnatal pathology, additional examinations are often used to help identify fetuses at higher risk. Many investigators report the use of repeat examinations periodically during the antenatal period [18]. At least one retrospective investigation suggested that a second US later in the pregnancy that has stable or reduced moderate ANH (APD < 10) near uniformly predicts eventual resolution without surgical intervention [25]. Additional prospective investigations into the prognostic value of repeated prenatal measures of APD may prove useful in reducing the need for postnatal evaluation.

obstruction (Fig. 5) [38]. Its incidence in children with ANH varies greatly between studies from 5% to 64% of patients [49,51,52]. The variability corresponds to differences in the management of these children, from early surgery to close observation until renal function deterioration or progression of hydronephrosis occurs. Currently, the incidence of UPJ obstruction in children with ANH is approximately 10e 30%. Several retrospective studies reported a surgical intervention rate of 38e52% [53,54]. However, randomized trials suggested that only 19e25% of children with prenatally diagnosed UPJ obstruction require surgical intervention [55,56]. There exists an increased incidence of other urological abnormalities, such as VUR and multicystic dysplastic kidney (MCDK), with UPJ obstruction [57].

The etiology of ANH and the incidence of postnatal pathology

Vesicoureteric reflux

The etiology of ANH includes: transient dilation of the collecting system, upper/lower urinary tract obstructive uropathy, and non-obstructive processes such as VUR, megaureters, and prune belly syndrome (Table 5).

Transient hydronephrosis Most children with an antenatal history of renal pelvis and calyces dilation ultimately resolve their hydronephrosis. The etiology of this finding may be related to a narrowing of the ureteropelvic junction (UPJ) or natural kinks and folds that occur early in development that resolve as the patient matures. The differentiation of transient hydronephrosis versus clinically significant UPJ obstruction remains one of the most controversial challenges in modern pediatric urology. Nevertheless, the incidence of transient hydronephrosis ranges from 41 to 88%[1,36,49] (Fig. 4). Most children with a pelvic dilation less than 6 mm diagnosed during the 2nd trimester or less than 8 mm diagnosed during the 3rd trimester have transient hydronephrosis [1]. In contrast, the incidence of transient hydronephrosis is only 40% in children with an APD less than 10e12 mm detected during the 3rd trimester [36,50].

UPJ obstruction The finding of pelvicalyceal dilatation without ureteral dilatation, commonly unilateral, is highly suggestive of UPJ Table 5

The etiology of ANH.

Etiology

Incidence

Transient hydronephrosis UPJ obstruction VUR UVJ obstruction/megaureters Multicystic dysplastic kidney PUV/urethral atresia Ureterocele/ectopic ureter/duplex system Others: prune belly syndrome, cystic kidney disease, congenital ureteric strictures and megalourethra

41e88% 10e30% 10e20% 5e10% 4e6% 1e2% 5e7% Uncommon

The finding of a variable degree of hydronephrosis or hydroureteronephrosis may suggest the possibility of VUR (Fig. 6); however, no reliable findings definitively diagnose reflux on fetal US [58]. Numerous studies have demonstrated that VUR occurs in 10e20% of patients with ANH [59e61]. The incidence of reflux appears to increase with the degree of sonographic dilation postnatally; however, the degree of dilation does not correlate with the grade of VUR [59]. In addition, a normal postnatal US does not exclude reflux [61e63]. In one prospective study [64], 15% of children with mild prenatal hydronephrosis (>4 mm to <10 mm) had VUR and 43% of these children had a normal postnatal renal US.

Ureterovesical junction (UVJ) obstruction/ megaureters The combination of prenatal hydronephrosis and ureteral dilation and a normal bladder suggests a megaureter (Fig. 7). Megaureters can be refluxing, obstructed, non-refluxing/ non-obstructed, and refluxing/obstructed. Prenatal ultrasonography has lead to more frequent postnatal diagnosis of primary megaureters [65e67]. Few studies have focused on the prenatally detected megaureter, and none correlated prenatal findings with postnatal outcomes. In children with ANH, the incidence of primary megaureters is approximately 5e10%. The majority (up to 72%) will spontaneously resolve during postnatal follow up [68,69].

Multicystic dysplastic kidney The presence of multiple, non-communicating cysts of various sizes and no evidence of identifiable renal parenchyma is characteristic of an MCDK (Fig. 8). Most patients are identified prenatally after 16 weeks of gestation. In some patients, MCDK may be confused with UPJ obstruction. In children with ANH, the reported incidence of MCDK is approximately 4e6% [1,51,70]. A renal length of <62 mm as measured on the first postnatal US is associated with complete involution of MCDK after birth [71].

Posterior urethral valves/urethral atresia The identification of: 1) prenatal hydronephrosis (often bilateral); 2) dilated, thick-walled bladder that fails to

218

Figure 4

H.T. Nguyen et al.

Transient hydronephrosis in the right kidney as seen on the prenatal US that resolved completely by the first postnatal US.

empty; 3) dilated posterior urethra; and 4) decreased amniotic fluid suggests the presence of lower urinary tract obstruction (LUTO) (Fig. 9). Unlike the unilateral upper tract dilation found commonly on prenatal ultrasonography, LUTO carries a worse prognosis with increase mortality and morbidity due to pulmonary hypoplasia and renal damage [72]. The incidence of LUTO ranges from 1 in 2000e25,000 live births [73e75]. In general, the sensitivity in accurately diagnosing LUTO ranges from 21% to 100%, with an average of approximately 50% [75e78]. LUTO diagnosed during the 1st and 2nd trimester is equally likely from PUV or varying degrees of urethral atresia [79]. However, the earlier the prenatal diagnosis of LUTO is made the more likely it is to be associated with urethral atresia [76,80,81].

Ureterocele/ectopic ureter/duplex system The finding of upper pole hydroureteronephrosis with a thin-walled cystic structure in the base of the bladder is

suggestive of the diagnosis of a ureterocele (Fig. 10), while the same finding without an associated intravesical cystic structure is suggestive of an ectopic ureter. These two etiologies of ANH are commonly associated with a duplex system. Ureterocele, ectopic ureters and duplex systems are often readily identified on prenatal ultrasonography, with an incidence of 5e7% [1,51,70]. Although the pathology is easily suspected prenatally, postnatal work up, including a voiding cystourethrogram (VCUG) and possible renal scan, is required to clearly define the anatomy and to guide further management. Interestingly, prenatal identification does not appear to improve the rate of renal salvage in patients with duplication anomalies [82]. Other more infrequent conditions presenting with prenatal hydronephrosis include prune belly syndrome, cystic kidney disease, congenital ureteric strictures, and megalourethra. Unlike the other causes of ANH, these are uncommon.

The natural history of ANH

Figure 5 The appearance of a UPJ obstruction on the prenatal US. Note the dilated renal pelvis and calyces without an associated dilated ureter.

The current literature is replete with retrospective reviews of children with a history of ANH focusing primarily on specific outcome diagnoses. These generally apply a wide range of inclusion criteria or definitions of hydronephrosis and limited correlation of pre- and postnatal degree of hydronephrosis. However, there are a limited number of prospective studies[21,83e85] and meta-analyses[18,86] that allow some conclusions regarding the natural history of ANH. With regard to variation during pregnancy, it appears that resolution of hydronephrosis during the prenatal period carries little likelihood of any clinically significant postnatal sequelae. The vast majority of the cases of hydronephrosis diagnosed during the second trimester have been noted to resolve during follow-up imaging in the third trimester. Additionally, with rare exceptions, hydronephrosis that resolved or improved from the second to third trimester has not been associated with clinically significant postnatal pathology. In contrast, cases in which the hydronephrosis was stable/persistent or worsened during pregnancy have been much more variable. There is

Consensus statement for prenatal hydronephrosis

219

Figure 6 The appearance of VUR on the prenatal US. Note the change in the degree of hydronephrosis (arrows) during scanning (S Z spine).

some correlation with the more severe grades of hydronephrosis and subsequent postnatal abnormalities requiring surgical intervention, but those with and without pathology in this group are fairly evenly split. The timing of diagnosis may have useful prognostic value. Those diagnosed in the first trimester with hydronephrosis are more likely to have a poor outcome. However, most studies related to early diagnosis are focused, retrospective reviews that work backwards from a grim outcome and lack any perspective of the incidence or scope of earliest diagnosis. In comparison, those diagnosed during the second trimester have an overall favorable prognosis. The hydronephrosis tends to resolve or improve in the majority (approximately 80%), and few ultimately will require surgical intervention (<5%) [24,49]. The favorable prognosis is better supported for those with milder hydronephrosis and represents the majority of cases in large, screened populations [25]. In contrast, those diagnosed in the 3rd trimester appear to have higher rates of postnatally confirmed pathology that may require operative intervention [19]. Given the variable timing of antenatal US, this may represent the same patient population found to have persistent or worsening hydronephrosis and significant pathology in the 2nd trimester. The postnatal evaluation of ANH is widely variable due to the diversity in the definitions of hydronephrosis and

Figure 7 The appearance of a UVJ obstruction on the prenatal US. Note the kidney is minimally dilated (thick arrow) while there is significant dilation of the ureter (thin arrow).

specific inclusion criteria used in the studies reported in the literature. It appears that about 30e40% of ANH persists postnatally, and of that roughly the same percentage will resolve spontaneously (Table 6). The timing of resolution is quite variable, occurring during the first few years of life. This variability may be due to the limited follow up in most studies. Despite the variability in underlying diagnoses, the trend is for earlier resolution with milder grades of hydronephrosis, with the majority of SFU grade 1e2 hydronephrosis resolving by 18 months of age [1]. If increasing hydronephrosis occurs, it generally does so early in life, often during the first year. Finally, operative repair (primarily for UPJ obstruction) has been required in approximately 25% of cases, with a range from 5% to 50% depending on the study [7,50,87]. The actual likelihood of surgery is perhaps the least valuable parameter, given the variable criteria used for selection and the differing considerations for surgical intervention. Severe pathology and surgical intervention are much more common with

Figure 8 The appearance of an MCDK on the prenatal US. Note the multiple, non-communicating cysts of various sizes.

220

H.T. Nguyen et al.

Figure 9 The appearance of PUV on the prenatal US. Note the dilated ureter and renal pelvis (first panel) accompanied by a dilated bladder with a dilated posterior urethra (arrow).

higher degrees of hydronephrosis (SFU grade 3e4) [56]; however, multiple studies have also shown the need for surgical intervention in a small percentage of those with mild degrees of hydronephrosis [88].

Antenatal radiological evaluation for ANH In the United States, most prenatal US scans are performed in the mid-second trimester. It is generally recommended that the prenatal identification of hydronephrosis (APD > 4 mm in the 2nd or > 7 mm in the 3rd trimester) warrants further follow up in the prenatal period. Depending on the gender, gestational age, presence of ureteral dilation, presence of bilaterality, amniotic fluid volume status and APD of the renal pelvis, some patients should be regularly imaged throughout pregnancy, while others may have a repeat US deferred until late in the 3rd trimester. When the diagnosis is uncertain, magnetic resonance imaging (MRI) may be helpful in providing additional anatomical information. The presence of mild hydronephrosis will be the most common classification of renal dilation identified. A repeat US is recommended, and the timing of this study is left to the discretion of the obstetrician. Most of these cases will have at least one repeat US performed in the 3rd trimester to gauge progression or resolution. A significant number of these cases will resolve completely and may not need further follow up [24]. The supportive data for this recommendation are anecdotal but it appears to be reasonable. In situations in which mild hydronephrosis is diagnosed or persists during the 3rd trimester, postnatal imaging is warranted. In comparison, the risk of postnatal urinary tract anomalies is much greater in patients in whom an increase in the degree of hydronephrosis between the 2nd and 3rd trimester is detected or is moderate/severe, i.e. >10 mm in the 3rd trimester [89]. Consequently, further postnatal evaluation in these patients is highly recommended. The presence of findings suspicious for PUV (oligohydramnios, dilated bladder, bilateral hydroureteronephrosis, male gender) warrants monitoring throughout pregnancy. A level 3 US should be performed to exclude other organ system abnormalities. Depending on the severity of oligohydramnios, fetal imaging every 4 weeks may be needed.

However, in the presence of increasing oligohydramnios, fetal intervention such as vesicoamniotic shunting may be offered. The ideal time period to offer prenatal intervention for suspected bladder outlet obstruction appears to be the mid-second trimester. This will allow for the return of amniotic fluid, in an effort to promote fetal lung development. A gross predictor of renal function may be obtained by performing a fetal bladder tap and analysis of fetal urine biochemistries and electrolytes (reviewed by Clark et al., 2003) [90]. Due to the first pass of urine into the bladder, it is recommended to make all decisions based on a repeat fetal bladder tap within 48 h of the initial bladder decompression. If favorable urine electrolytes are obtained (Table 7), fetal intervention may be offered as an option. In terms of renal salvage, to date no randomized trial with data exists (reviewed by Morris and Kilby, 2009) [91]. Currently, the PLUTO trial is underway in order to clarify the utility of fetal bladder diversion or vesicoamniotic shunting for fetal survival, fetal lung development and renal salvage. Several centers in the US have specialized in prenatal intervention.

Figure 10 The appearance of a ureterocele (U) on the prenatal US (B Z bladder).

Consensus statement for prenatal hydronephrosis Table 6

221

Incidence of ANH resolution during the 3rd trimester and after birth.

Reference

APD (mm) (gestational age at diagnosis)

Livera (1989) [148] Corteville (1991) [153] Mandell (1991) [154] Adra (1995) [155] Podevin (1996) [156] Morin (1996) [145] Stocks (1996) [157] Persutte (1997) [144] Dudley (1997) [158] Jawson (1999) [84] Chudleigh (2001) [159] Sairam (2001) [49] Feldman et al. (2001) [24] Signorelli et al. (2005) [25]

>10 (at 28 wks) >4 (<33 wks) >7 (>33 wks) >5 (<20 wks) >8 (>20 wks) >4 (<33 wks) >7 (>33 wks) >4 (<24 wks) >8 (>32 wks) >4 (<20 wks) >10 (>24 wks) >4 (<33 wks) >7 (>33 wks) 4e10 (>28 wks) >5 (14e18 wks) > 5 (16e26 wks) > 5 (16e26 wks) >4 (<23 wks) >10 (>28 wks) >4 (<20 wks) >7 (>30 wks) 4e10 (>28 wks)

Most recently, the Philadelphia group presented their longterm data for a select group of patients, which included only patients with favorable urine electrolytes and 2nd trimester intervention [92]. Although this paper suffered from selection bias, it appears that patients with bladder outlet obstruction benefited from targeted prenatal intervention. For further discussions on management and controversies in fetal intervention, refer to recent reviews by Wu and Johnson [93], Thomas [94], Morris and Kilby [95], and Yiee and Wilcox [96].

Imaging modalities used in the evaluation of ANH Renal/bladder ultrasound US is the most common imaging modality utilized to monitor the urinary tract in the pediatric population. Its ease of use and absence of radiation make it an excellent instrument to follow renal dilation that is identified both

Table 7

Resolution 3rd trimester

After birth

29%

54% 31%

21%

55%

31%

36%

56%

43%

45%

27% 30%

6%

34% 36% 55% 56% 64%

67% 47% 18%

56%

prenatally and postnatally. However, hydration status, bladder filling and operator skill have been shown to influence the predictive value of this imaging modality [97]. Infants are relatively dehydrated at birth, which impacts the recommended timing of the initial renal/bladder US. In the absence of LUTO, the initial scan should be performed no sooner than the second day of life. Factors such as renal length, AP renal pelvis diameter), presence of renal cyst, renal parenchymal thickness and ureteral dilatation should be measured. It is important to image the urinary bladder as well as upper urinary system during the assessment. For example, a ureterocele resulting in hydronephrosis may be identified in the bladder. When comparing serial US scans, the degree of hydration and status of bladder filling should be taken into account. While US imaging provides adequate anatomic detail in the absence of radiation exposure, it is a relatively poor independent predictor of those patients that will need surgical intervention [98]. In order to standardize evaluations, it is recommended that all postnatal images be interpreted with the SFU classification system. It should be

Favorable urinary electrolytes and their predictive values for the absence of renal dysplasia.

Urinary compound

Sensitivity

Specificity

Positive predictive value

Negative predictive value

Sodium < 100 mg/dl Calcium < 8 mg/dl Osmolality < 200 mOsm/L Beta-2 Microglobulin < 4 mg/L Total protein < 20 mg/dL

0.56 1.00 0.83 0.17 0.67

0.64 0.27 0.82 0.36 0.91

0.56 0.43 0.71 1.00 0.80

0.88 1.00 0.90 0.44 0.83

Adapted from Johnson et al. (1994) [160].

222 noted that renal US protocols vary widely amongst different centers, which may impact grading and the requirement for additional imaging. For example, at some institutions, the radiologists require the patient to be nil per os for 4 h prior to the image. In contrast, aggressive hydration and preimaging Lasix are given at other institutions. This dichotomy without question will impact significantly not only the grading of the hydronephrosis but in some cases the indication for surgical intervention. Doppler US, as an adjunct to US, contributes additional information based on the fact that obstruction causes an increase in intrarenal arterial resistance resulting in a relative reduction in diastolic flow compared to systolic flow. Numerous studies have been performed evaluating the role of duplex Doppler for the diagnosis of renal obstruction with mixed results [99,100]. The use of duplex Doppler for the evaluation of renal obstructive disorders is currently controversial and, as a result, not widely utilized.

Voiding cystourethrogram/radionuclide cystogram It is generally recommended that a VCUG be performed when the anatomy of the lower urinary tract needs to be visualized (e.g. diagnosis of PUV, bladder diverticulum, ureteroceles). In contrast, a radionuclide cystogram is recommended for surveillance of VUR or diagnosis of VUR in siblings due to the lower degree of radiation exposure [101]. A lack of agreement exists concerning the need for a postnatal VCUG in the presence of antenatal hydronephrosis. This issue is further discussed below, in the postnatal radiological evaluation of ANH.

Renal scintigraphy Once hydronephrosis is detected by other imaging methods, usually US, dynamic renal scintigraphy (DRS) is considered to be an adjunct test that serves to estimate differential renal function and characterize the severity of obstruction. In general, DRS should be performed after 6 weeks to allow for renal maturation. In the United States, a single US finding of grade IV hydronephrosis usually prompts a followup DRS. The European Society for Pediatric Radiology recommends two renal US scans over at least 3 months prior to obtaining a DRS [102]. Differential renal function < 40% with impaired drainage (as indicated by T½ > 20 min), or worsening renal function by DRS is often the impetus for pyeloplasty in patients being observed with UPJ obstruction. In addition, DRS is a useful method for serial follow up and postoperative assessment of patients with UPJ obstruction and megaureter. Radiopharmaceuticals used for DRS are Tc-MAG3 and TcDTPA (see Table 8). Tc-MAG3 is 90% bound to plasma proteins and is principally cleared by tubular secretion. In addition to demonstrating parenchymal and collecting system definition, it also provides excellent functional quantification. These qualities and the fact that it requires lower radiation doses than other radiopharmaceuticals, make it the current agent of choice for evaluating renal function and drainage. In contrast, Tc-DTPA has little plasma protein binding and is cleared almost exclusively by glomerular filtration. It is rapidly filtered into the urine and therefore provides excellent visualization of the

H.T. Nguyen et al. pelvicalyceal system, ureter and bladder, but may not be retained in the renal parenchyma long enough for good visualization of parenchymal abnormalities. Also, since TcDTPA relies principally on glomerular filtration, results are often suboptimal in infants with immature kidneys and a low glomerular filtration rate (GFR) or in patients with compromised renal function. In these scenarios Tc-MAG3 is the preferred agent. Tc-DMSA is unique among the other commonly used radiopharmaceuticals in that it tightly binds to the renal tubular cells and only a small amount is excreted into the urine. Therefore, it allows excellent visualization of the renal parenchyma and is primarily used for evaluating cortical lesions such as scars that occur as a result of pyelonephritis or for the evaluation of renal dysplasia. However, due to the long biological half time, a higher overall radiation dose is delivered to the patient from the study. In an attempt to promote standardization of the technique, the SFU and the Pediatric Nuclear Medicine Council of the Society for Nuclear Medicine published guidelines for the ‘Well-tempered Diuresis Renogram’ in 1992 [103]. Its purpose was to allow easy comparison between studies and institutions. The guidelines standardize many of the facets of the study, including intravenous hydration, bladder catheter placement, patient position, data acquisition and analysis, timing of diuretic administration, and regions of interest for which to monitor the diuretic effect. However, in practice, local protocols are still frequently used which makes comparing results from different centers problematic. The classic recommendation for surgical intervention is an obstructive wash-out curve in which the T½ exceeds 20 min and a significant discrepancy in split renal function (<40%) is detected. One caveat to split renal function is the patient with severe bilateral hydronephrosis or obstruction. In this setting, split renal function is not an accurate indicator of overall renal function because of the absence of a normal contralateral kidney with which to compare the hydronephrotic kidney. In this scenario, the renal unit that demonstrates the least function should undergo repair. Although the indications for surgical intervention may appear straightforward, the drainage curve alone may be significantly altered if the child is dehydrated or furosemide is given too early in the massively hydronephrotic kidney. In addition, the actual renal function may be significantly over-represented in the large hydronephrotic kidney. Based on these inherent weaknesses of the study, the authors use the renal scan to document baseline renal function and as a complement to the renal US more than an independent predictor of obstruction.

Magnetic resonance urography As an imaging modality, MRU offers the advantages of providing a functional assessment and superior imaging detail without neonatal radiation exposure. MRU is still in its infancy in terms of development and application for prenatal hydronephrosis. A majority of the data for this modality come from the Emory group. MRU provides excellent anatomic imaging as well as functional determination in the classification of obstructed systems [104e 107]. In 2006, Kirsch et al. presented data that demonstrated an improvement in renal transit time as well as the

Consensus statement for prenatal hydronephrosis Table 8

223

Common radiopharmaceuticals used in renal scintigraphy.

Radiopharmaceutical

Renal handling

Application

99m

Principally cleared by tubular secretion Localizes and binds to the proximal convoluted tubules Glomerular filtration dependent for clearance

Renography Renal parenchymal imaging

99m

99m

Tc-Mercaptoacetyltriglycine (Tc-MAG3) Tc-Dimercaptosuccinic acid (Tc-DMSA)

Tc-Diethylenetriamine pentaacetic acid (Tc-DTPA)

Patlak score, which is a determinant of single kidney GFR [108]. As a determinant of predicting the need for pyeloplasty, Kaneyama et al. looked at the level of ureteral insertion into the renal pelvis. This group found that a ratio of greater than 0.3 for distance of ureteral insertion to the length of the calyx was predictive of the need for surgical intervention in UPJ obstruction [109]. Unfortunately, the level of scientific evidence in favor of the use of MRU for the evaluation of prenatal hydronephrosis is fairly poor. Few studies available for evaluation are controlled [110]. In addition, issues such as cost, availability of appropriate software and technology, and the need for sedation or anesthesia in most patients significantly limit the widespread application of this imaging modality.

Postnatal radiological evaluation of ANH The initial postnatal evaluation of fetal hydronephrosis depends in part on the degree of hydronephrosis seen during fetal evaluation. A recent retrospective study of nearly 8000 neonates showed that even in a low-risk population (fetal pelvic APD of 5 mm) the majority were found to have an increase in degree of hydronephrosis, while some had a non-progressing condition [111]. Currently, no distinguishing features exist that differentiate which of these children will develop progressive evidence of obstruction on subsequent postnatal follow up. One of the most important distinctions in the assessment of these children is determining which patients benefit from surgery. This distinction is important since unnecessary intervention exposes patients needlessly to the morbidity of surgery, while inappropriate observation places patients at risk of infection and renal parenchymal loss. Regardless, except in the most severe cases, most urologists will initially follow hydronephrotic kidneys with serial radiological exams and use decreasing differential renal function or worsening hydronephrosis as an indicator that surgery or advanced imaging may be required. The initial postnatal evaluation includes US, DRS and, more recently at some centers, MRI for the evaluation of hydronephrosis. Each of these diagnostic modalities has relative advantages and disadvantages (Table 9). Currently, no study is considered a gold standard for the evaluation of renal obstructive disorders and complete assessment typically involves a series of studies including US and DRS. In general, these studies provide either good anatomical or good functional information whereas none of these studies, save MRI, provide both. Some tests are more invasive than others, which also influences test selection. Consequently, a thoughtful

Renography

diagnostic strategy is necessary to proceed with appropriate management at minimal cost and morbidity to the patient.

Which neonates require postnatal evaluation? The degree of hydronephrosis is used to assist in decision making with regard to diagnostic imaging and treatment, and additionally provides some prognostic information. For example, SFU grades I and II hydronephrosis tend to resolve with time and usually only require US surveillance. It has been suggested that in cases of complete resolution of hydronephrosis, a repeat sonogram should be performed after 3 weeks when neonatal oliguria is no longer a confounding variable. In one study [25], 18% of cases of fetal hydronephrosis normalized and only one case required surgery (ureteral reimplantation) at follow up. An additional study documented two cases of complete hydronephrosis resolution where pyeloplasty was ultimately required [112]. In most studies that follow patients with mild pelviectasis (RPD < 10 mm), no significant uropathy is detected. However, close clinical follow up may be needed to monitor for UTI and progression of mild hydronephrosis during infancy [21]. One recent study showed a 12-fold increase in risk of pyelonephritis during infancy when hydronephrosis was detected in the first year of life [113]. These risk factors need to be discussed with the family. Because there are inaccuracies in the interpretation of hydronephrosis, the less severe cases (SFU grades IIIII) present a more controversial diagnostic dilemma. In many cases of moderate hydronephrosis (SFU grade III), DRS may be helpful in determining the timing and role of further studies. For example, a normal DRS would be followed by US, while an indeterminate DRS may require additional DRS or MRU. Erickson et al. reported that no cases of SFU III hydronephrosis have required surgery [114]. In contrast, Chertin et al. have shown that 50% of children followed conservatively went on to surgery [53]. However, one must recognize that the criteria for surgical intervention are variable and may be further confounded by the surgeon’s and parents’ wishes. For severe hydronephrosis (SFU IV), a functional evaluation is recommended since these patients are more likely to have significant urologic pathology and require surgical intervention. SFU IV hydronephrosis should prompt either DRS or MRU. For solitary kidneys or bilateral renal involvement, MRU may be superior as individual kidney function (GFR) may be assessed. However, cost, expertise, and availability limit the use of MRU currently. Likewise, DRS and MRU may not be available universally, and in such cases intravenous urogram may be the only test used.

224 Table 9

H.T. Nguyen et al. The advantages and disadvantages of various diagnostic modalities for the assessment of ANH.

Imaging study

Advantages

Disadvantages

Intravenous urogram

Good anatomy if function is good

Whitaker test

Only study that measures directly the pressure in the renal pelvis/bladder Inexpensive, portable, no contrast or radiation exposure Good functional and drainage information

Inaccurate if poor function, nephrotoxic contrast, radiation exposure Invasive, not reproducible, no functional information, radiation exposure No functional information, limited anatomy

US DRS

Gadolinium-enhanced MRU

Superior anatomical and functional information even if poor function or bilateral disease, no radiation, contrast non-nephrotoxic

Many protocols call for a VCUG to rule out VUR, especially in cases where the degree of hydronephrosis is moderate to severe. However, the likelihood of VUR, as opposed to obstructive conditions, decreases as the degree of hydronephrosis worsens [18]. Nonetheless, the presence or absence of VUR may affect surgical approach and need for antibiotic prophylaxis.

The timing of postnatal evaluation of hydronephrosis For unilateral fetal hydronephrosis with a normal contralateral kidney, postnatal evaluation should begin within the first week of life with a renal US [7,97]. Patients with an increased risk of UTI (e.g. girls, uncircumcised boys, moderate to severe antenatal hydronephrosis, familial VUR, etc.) should be placed on prophylactic antibiotics until the evaluation is performed and management discussed with the family [113]. For bilateral hydronephrosis and hydronephrosis in solitary kidneys or in patients with suspected bladder outlet obstruction, early postnatal imaging is suggested. Typically this occurs at the birthing hospital prior to newborn discharge from the hospital.

The role of VCUG in the evaluation of hydronephrosis VUR is considered to be a significant abnormality in some large neonatal series. However, it may not be considered as such in others. For example, if the fetal population consisted primarily of males with pyelectasis, then the diagnosis of high-grade VUR appears more prevalent [115]. In the United States and other countries where the practice of circumcision is common, it raises the question of the clinical relevance of making the diagnosis of VUR in a newborn boy at low risk of UTI throughout his lifetime. Most patients with VUR and low-grade hydronephrosis can be followed without surgical intervention [116]. High-grade VUR, however, may predict renal damage and may permit earlier diagnosis and need for long-term nephrologic care. In such cases, efforts should be directed at decreasing the risk of UTIs [61]. VCUG is frequently performed in conjunction with renal studies to rule out VUR as the cause of hydronephrosis. The

Limited information in bilateral disease, no anatomical information, interpretive error, 15% false negative/positives Expensive, not yet widely available due to the complexicity of the software protocol needed to process the MRI information, requires sedation and monitoring

presence of a dilated ureter lying posterior to the bladder helps distinguish megaureter from UPJ obstruction. When either diagnosis is a consideration, a VCUG to rule out VUR as the cause of dilatation should be performed. It should be kept in mind that VUR may coexist with UPJ obstruction in as many as 10% of children [117]. Currently, there is no clear evidence to support or to avoid postnatal imaging for VUR. Neither the grade of the hydronephrosis nor gender is a predictive factor for VUR in children with ANH. The overall incidence of VUR is up to 30% in children with ANH, including those with resolved hydronephrosis [7,18]. It remains unproven whether the identification and treatment of children with VUR confers any clinical benefit [118].

Follow-up evaluation for ANH Numerous studies have demonstrated that a single normal US within the first week of life is not adequate to verify absence of obstruction. A second US is recommended at 1 month of age as initial follow-up testing. The incidence of late worsening or recurrent hydronephrosis is approximately 1e5%, with this risk applying to all grades of initial hydronephrosis [112,119,120]. When there is late worsening or recurrence, the severity of hydronephrosis is quite significant, being of grade IIIIV, and the majority of the patients are likely to be symptomatic [119]. The timing of late worsening or recurrence has been observed to range from a few months to 5e6 years [112]. Consequently, longterm follow up is recommended, but the appropriate length of surveillance has yet to be determined. It also remains to be determined whether such follow up is warranted and cost-effective given the low incidence of late-occurring significant obstruction. Consequently, some practitioners have recommended discharging children with mild or grade III hydronephrosis on the 1-month US from further surveillance with the recommendation of seeing the child again for UTI or pain [19,102], while others have recommended serial US and UTI surveillance every 6 or 12 months[22] or in 2e3 years [121]. Future prospective studies will be needed to determine the most cost-effective and clinically appropriate follow-up protocol for children with ANH.

Consensus statement for prenatal hydronephrosis

225

Role of antibiotic prophylaxis in children with ANH The rationale for antibiotic prophylaxis in children with a history of ANH includes prevention of UTIs, as infants with hydronephrosis are at increased risk [113]. The risk of UTI increases with increasing grade of hydronephrosis [21,122]. Rates appear to be as high as 40% in children with SFU IV hydronephrosis [122], with another study estimating the cumulative incidence of UTI as 39%, 18% and 11% at 36 months of age for severe, moderate and mild RPD, respectively [21]. Several studies report a higher rate in girls compared to boys [21,113]. Children with hydronephrosis and obstructive drainage patterns on renal scan are at increased risk compared to those without obstructive patterns [122,123]. An increased risk is also associated with hydroureteronephrosis[124] even without reflux or without an obstructive pattern on renal scan [122]. These observations suggest that increased stasis and easier access to a urinary reservoir (such as in the case of hydroureter) increase the chance of developing a UTI. Of the studies reviewed, none were prospective randomized trials between antibiotics and no antibiotics in children with ANH. Therefore, the efficacy of antibiotic prophylaxis has not been proven. High rates of UTI have been noted despite prophylactic antibiotics in children with hydronephrosis [21]. Alconcher and Tombesi[125] similarly reported no statistical difference in the incidence of UTI in children with ANH on or off prophylactic antibiotics. In contrast, Estrada et al. [126]. observed that in children with a history of prenatal hydronephrosis with persistent grade II hydronephrosis secondary to VUR, the use of prophylactic antibiotics significantly reduced the risk of febrile UTIs. At present, unless part of a controlled trial, it seems prudent to consider use of a prophylactic antibiotic in an effort to prevent infant UTIs in high-risk populations, such as those with higher grades of hydronephrosis, hydroureteronephrosis, VUR, or obstructive drainage patterns.

Chromosomal evaluation for children with ANH ANH has been linked to a number of extra-genitourinary disorders, and its presence may be useful in their evaluation and diagnosis. A review published in 1998 revealed that Table 10

of 14 cases of rare chromosomal abnormalities, three had mild pyelectasis and a fourth was diagnosed with a horseshoe kidney. In a review of prenatal detection of trisomy 21, 9.1% had some degree of hydronephrosis [127], and it was found to be more common in fetuses with trisomy 21 compared to normal controls (17% vs 5%) [128]. Staebler et al. [129]. corroborated the increased incidence of serious abnormalities: significant chromosomal abnormalities were detected in 9% of fetuses with antenatal anomalies (including 3/22 of those with genito-urinary findings) and there was a 19% abnormality rate in fetuses with multiple anomalies (3/16 of these patients had a genitourinary abnormality). Another review found karyotype abnormalities in 0.125% of patients with an isolated genital finding on US (sexual ambiguity) and 0.027% with an isolated finding of hydronephrosis [129,130]. ANH, in isolation, had the lowest correlation with karyotype abnormalities of all organ systems examined [129]. Therefore, several authors do not believe that the risk of chromosome analysis (0.5e1% fetal loss) is justified for a low-risk diagnosis such as unilateral hydronephrosis or MCDK. However, Nicolaides et al. [131]. do advocate aggressive screening, as they detected chromosomal anomalies in 12% of their cases, and in 3% of isolated mild hydronephrosis. The vast majority of patients with ANH will be born without major anomalies, but prognostic information regarding future siblings may still be relevant. With respect to a UPJ obstruction, an entity named genuine hereditary hydronephrosis (GHH) has been shown to have an autosomal dominant inheritance and complete penetrance with linkage analysis locating the gene to chromosome 6 p [132,133]. Other families with multiple affected siblings have shown an autosomal dominant inheritance but with an incomplete penetrance pattern [134,135]. VUR has a well-documented familial inheritance pattern, with siblings of the index case reported to have a 5e50% risk of VUR [136e138]. Recent work demonstrated several loci potentially responsible for VUR, accounting for the significant variability seen clinically [139e141]. PUV have been reported to occur in families [142], but no genetic link has been identified and these cases account for only a small minority. While ANH is more common in fetuses with serious chromosomal anomalies, most sources do not recommend routine karyotyping for all cases of isolated hydronephrosis. However, this may be considered in the presence of

Recommendations for the prenatal evaluation of ANH.

Time of detection of ANH

Severity of ANH

APD (mm)

Recommendations

2nd Trimester

Mild Moderate Severe

<7 7e10 >10

Consider 3rd Trimester US 3rd Trimester US Repeat US in 3e4 weeks

3rd Trimester

Mild Moderate Severe

<9 9e15 >15

Postnatal evaluation Postnatal evaluation Repeat US in 2e3 weeks

Special considerations Unclear anatomy Oligohydramnios PUV suspected Increased renal echogenicity

Consider MRI Consider fetal urine sampling Consider fetal intervention, serial vesicocentesis, early delivery or termination based upon case-by-case analysis

226 Table 11

H.T. Nguyen et al. Recommendations for the postnatal evaluation of ANH.

Degree of unilateral ANH

Recommendation Results of postnatal US for prophylactic (at 2e4 weeks)a antibiotics (based on prenatal US)

Recommendation for VCUGb, d

Recommendation for follow-up US

Mild

Noc

1 year 1 year 3e6 months

Moderate

Yes

Severe

Yes

Special conditions

Recommendation for prophylactic antibiotics (based on prenatal US) Yes 1e3 days after birth

Noc No/Yesc Yes (2e4 weeks) (if þ VUR, Abx) Noc (stop Abx) Yes (2e4 weeks) (if þ VUR, Abx) (if e VUR, consider MAG3) Yes (2e4 weeks) (if þ VUR, Abx) (if e VUR, recommend MAG3) Recommendation for VCUGb

Bilateral moderate or severe ANH

Resolved (No hydro.) Mild (SFU IeII) Moderate/Severe (SFU IIIeIV) Resolved (No hydro.) Mild/Moderate/Severe (SFU IeIV) Resolved/Mild/ Moderate/Severe (SFU 0eIV) When to obtain postnatal US?

Bladder/urethral abnormalities: Diverticulum Bladder wall thickening Ureterocele Dilated posterior urethra Dilated ureter

Yes

1e3 days after birth

Yes

2e4 weeks

Decreased amniotic fluid

Yes

1e3 days after birth

Yes (1e7 days) (if þ VUR, Abx) (if e VUR, may need MAG3/DMSA) (if þ PUV, consider surgery) Yes (1e7 days) (if þ VUR, Abx) (if e VUR, may need MAG3/DMSA) (if þ PUV, consider surgery)

1 year 3e6 months

3e6 months

Recommendation for follow-up US

Depending on pathology

Depending on pathology

Yes (1e7 days) (if þ VUR, Depending on pathology Abx) (if e VUR, consider MAG3) Yes (1e7 days) Depending on pathology (if þ VUR, Abx) (if e VUR, consider MAG3/DMSA) (if þ PUV, consider surgery)

Abx Z antibiotics. a If compliance is a concern, US should be obtained within the first day of life. b If VCUG is recommended, prophylatic antibiotics should also be instituted. c Polling of the SFU membership indicated that when there is unilateral mild ANH that does not persist postnatally, only 25% would institute antibiotic prophylaxis and obtain a VCUG; when unilateral mild ANH does persist postnatally, 50% would do so. Consequently, the risk/benefits of antibiotics and VCUG should be discussed with the family to determine the appropriate choice for the individual patient. d Gender or race may influence the decision to obtain a postnatal VCUG.

multiple system anomalies. The presence of ANH in a patient likely increases the chances it will be seen in a sibling, but these rates have not yet been published.

ANH is unclear. We suggest an individualized approach, based on the general schedule given in Tables 10 and 11.

Research priorities

Recommendations As evidenced by the current literature, the optimal schedule for pre- and postnatal evaluation of children with

Collectively, the findings in this manuscript identify an obvious need for evidence-based conclusions on prenatal hydronephrosis. This consensus statement is sound but

Consensus statement for prenatal hydronephrosis a majority of its recommendations are not based on evidence that is level 1 or 2. Although there is a dire need for randomized studies, their development and subsequent implementation are extremely difficult to execute and will likely not occur for this diagnosis. One alternative to randomized clinical trials is a registry that serves as a data repository from which future hypotheses can be formulated and tested. The Prenatal Hydronephrosis Registry serves as such a repository that may serve to facilitate the development of future care pathways and clinical practice guidelines for the treatment of conditions that present with prenatal hydronephrosis.

Conflict of interest None of the authors have any financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work. None of the authors have any financial interest in the execution of the study or the publication of the paper.

Disclosures None.

References [1] Mallik M, Watson AR. Antenatally detected urinary tract abnormalities: more detection but less action. Pediatr Nephrol 2008;23:897. [2] Cohen HL, Cooper J, Eisenberg P, Mandel FS, Gross BR, Goldman MA, et al. Normal length of fetal kidneys: sonographic study in 397 obstetric patients. AJR Am J Roentgenol 1991;157:545. [3] van Otterlo LC, Wladimiroff JW, Wallenburg HC. Relationship between fetal urine production and amniotic fluid volume in normal pregnancy and pregnancy complicated by diabetes. Br J Obstet Gynaecol 1977;84:205. [4] Ross MG, Brace RA. National institute of child health and development conference summary: amniotic fluid biologye basic and clinical aspects. J Matern Fetal Med 2001;10:2. [5] Kitchens DM, Herndon CDA. Antenatal hydronephrosis. Curr Urol Rep 2009;10:126. [6] Pates JA, Dashe JS. Prenatal diagnosis and management of hydronephrosis. Early Hum Dev 2006;82:3. [7] Herndon CDA. Antenatal hydronephrosis: differential diagnosis, evaluation, and treatment options. ScientificWorldJournal 2006;1:50. [8] Arger PH, Coleman BG, Mintz MC, Snyder HP, Camardese T, Arenson RL, et al. Routine fetal genitourinary tract screening. Radiology 1985;156:485. [9] Grignon A, Filion R, Filiatrault D, Robitaille P, Homsy Y, Boutin H, et al. Urinary tract dilatation in utero: classification and clinical applications. Radiology 1986;160:645. [10] Anderson N, Clautice-Engle T, Allan R, Abbott G, Wells JE. Detection of obstructive uropathy in the fetus: predictive value of sonographic measurements of renal pelvic diameter at various gestational ages. AJR Am J Roentgenol 1995;164:719. [11] Bobrowski RA, Levin RB, Lauria MR, Treadwell MC, Gonik B, Bottoms SF. In utero progression of isolated renal pelvis dilation. Am J Perinatol 1997;14:423. [12] 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 function. J Ultrasound Med 2004;23:513.

227 [13] Babcook CJ, Silvera M, Drake C, Levine D. Effect of maternal hydration on mild fetal pyelectasis. J Ultrasound Med 1998; 17:539. [14] Robinson JN, Tice K, Kolm P, Abuhamad AZ. Effect of maternal hydration on fetal renal pyelectasis. Obstet Gynecol 1998;92:137. [15] Leung VY, Chu WC, Metreweli C. Hydronephrosis index: a better physiological reference in antenatal ultrasound for assessment of fetal hydronephrosis. J Pediatr 2009;154:116. [16] Coplen DE, Austin PF, Yan Y, Blanco VM, Dicke JM. The magnitude of fetal renal pelvic dilatation can identify obstructive postnatal hydronephrosis, and direct postnatal evaluation and management. J Urol 2006;176:724. [17] Ismaili K, Hall M, Donner C, Thomas D, Vermeylen D, Avni FE. Results of systematic screening for minor degrees of fetal renal pelvis dilatation in an unselected population. Am J Obstet Gynecol 2003;188:242. [18] Lee RS, Cendron M, Kinnamon DD, Nguyen HT. Antenatal hydronephrosis as a predictor of postnatal outcome: a metaanalysis. Pediatrics 2006;118:586. [19] Wollenberg A, Neuhaus TJ, Willi UV, Wisser J. Outcome of fetal renal pelvic dilatation diagnosed during the third trimester. Ultrasound Obstet Gynecol 2005;25:483. [20] Ahmad G, Green P. Outcome of fetal pyelectasis diagnosed antenatally. J Obstet Gynaecol 2005;25:119. [21] Coelho GM, Bouzada MC, Pereira AK, Figueiredo BF, Leite MR, Oliveira DS, et al. Outcome of isolated antenatal hydronephrosis: a prospective cohort study. Pediatr Nephrol 2007; 22:1727. [22] Coelho GM, Bouzada MCF, Lemos GS, Pereira AK, Lima BP, Oliveira EA. Risk factors for urinary tract infection in children with prenatal renal pelvic dilatation. J Urol 2008;179:284. [23] Estrada CR. Prenatal hydronephrosis: early evaluation. Curr Opin Urol 2008;18:401. [24] Feldman DM, DeCambre M, Kong E, Borgida A, Jamil M, McKenna P, et al. Evaluation and follow-up of fetal hydronephrosis. J Ultrasound Med 2001;20:1065. [25] Signorelli M, Cerri V, Taddei F, Groli C, Bianchi UA. Prenatal diagnosis and management of mild fetal pyelectasis: implications for neonatal outcome and follow-up. Eur J Obstet Gynecol Reprod Biol 2005;118:154. [26] Fernbach SK, Maizels M, Conway JJ. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol 1993;23:478. [27] Keays MA, Guerra LA, Mihill J, Raju G, Al-Asheeri N, Geier P, et al. Reliability assessment of Society for Fetal Urology ultrasound grading system for hydronephrosis. J Urol 2008; 180:1680. [28] Sibai H, Salle JL, Houle AM, Lambert R. Hydronephrosis with diffuse or segmental cortical thinning: impact on renal function. J Urol 2001;165:2293. [29] Shimada K, Kakizaki H, Kubota M, Taki M, Takeuchi H, Hiramatsu Y, et al. Standard method for diagnosing dilatation of the renal pelvis and ureter discovered in the fetus, neonate or infant. Int J Urol 2004;11:129. [30] Shapiro SR, Wahl EF, Silberstein MJ, Steinhardt G. Hydronephrosis index: a new method to track patients with hydronephrosis quantitatively. Urology 2008;72:536. [31] Venkatesan K, Green J, Shapiro SR, Steinhardt GF. Correlation of hydronephrosis index to society of fetal urology hydronephrosis scale. Adv Urol 2009;960490. [32] Chavhan G, Daneman A, Moineddin R, Lim R, Langlois V, Traubici J. Renal pyramid echogenicity in ureteropelvic junction obstruction: correlation between altered echogenicity and differential renal function. Pediatr Radiol 2008;38:1068. [33] Chi T, Feldstein VA, Nguyen HT. Increased echogenicity as a predictor of poor renal function in children with grade 3 to 4 hydronephrosis. J Urol 1898;175:2006.

228 [34] Daikha-Dahmane F, Dommergues M, Muller F, Narcy F, Lacoste M, Beziau A, et al. Development of human fetal kidney in obstructive uropathy: correlations with ultrasonography and urine biochemistry. Kidney Int 1997;52:21. [35] Miller M, Korzets Ze, Blumenfeld Y, Pomeranz M, Aviram R, Rathaus V, et al. Fetal urinoma as a sign of a dysplastic kidney. Pediatr Nephrol 2003;18:65. [36] Harding LJ, Malone PS, Wellesley DG. Antenatal minimal hydronephrosis: is its follow-up an unnecessary cause of concern? Prenat Diagn 1999;19:701. [37] Kent A, Cox D, Downey P, James SL. A study of mild fetal pyelectasia e outcome and proposed strategy of management. Prenat Diagn 2000;20:206. [38] Kleiner B, Callen PW, Filly RA. Sonographic analysis of the fetus with ureteropelvic junction obstruction. AJR Am J Roentgenol 1987;148:359. [39] Maizels M, Wang E, Sabbagha RE, Dinsmoor M, Seshadri R, Ginsberg N, et al. Late second trimester assessment of pyelectasis (SERP) to predict pediatric urological outcome is improved by checking additional features. J Matern Fetal Neonatal Med 2006;19:295. [40] Maizels M, Alpert SA, Houston JTB, Sabbagha RE, Parilla BV, MacGregor SN. Fetal bladder sagittal length: a simple monitor to assess normal and enlarged fetal bladder size, and forecast clinical outcome. J Urol 1995;172:2004. [41] Zaccara A, Giorlandino C, Mobili L, Brizzi C, Bilancioni E, Capolupo I, et al. Amniotic fluid index and fetal bladder outlet obstruction. Do we really need more? J Urol 2005;174: 1657. [42] Oliveira EA, Diniz JS, Cabral AC, Leite HV, Colosimo EA, Oliveira RB, et al. Prognostic factors in fetal hydronephrosis: a multivariate analysis. Pediatr Nephrol 1999;13:859. [43] Oliveira EA, Diniz JS, Cabral AC, Pereira AK, Leite HV, Colosimo EA, et al. Predictive factors of fetal urethral obstruction: a multivariate analysis. Fetal Diagn Ther 2000; 15:180. [44] Oliveira EA, Rabelo EAS, Pereira AK, Diniz JS, Cabral ACV, Leite HV, et al. Prognostic factors in prenatally-detected posterior urethral valves: a multivariate analysis. Pediatr Surg Int 2002;18:662. [45] Eckoldt F, Heling KS, Woderich R, Wolke S. Posterior urethral valves: prenatal diagnostic signs and outcome. Urol Int 2004; 73:296. [46] Kaefer M, Barnewolt C, Retik AB, Peters CA. The sonographic diagnosis of infravesical obstruction in children: evaluation of bladder wall thickness indexed to bladder filling. J Urol 1997;157:989. [47] Sargent MA. What is the normal prevalence of vesicoureteral reflux? Pediatr Radiol 2000;30:587. [48] Calisti A, Perrotta ML, Oriolo L, Ingianna D, Miele V. The risk of associated urological abnormalities in children with pre and postnatal occasional diagnosis of solitary, small or ectopic kidney: is a complete urological screening always necessary? World J Urol 2008. [49] Sairam S, Al-Habib A, Sasson S, Thilaganathan B. Natural history of fetal hydronephrosis diagnosed on mid-trimester ultrasound. Ultrasound Obstet Gynecol 2001;17:191. [50] Ransley PG, Dhillon HK, Gordon I, Duffy PG, Dillon MJ, Barratt TM. The postnatal management of hydronephrosis diagnosed by prenatal ultrasound. J Urol 1990;144:584. [51] Alladi A, Agarwala S, Gupta AK, Bal CS, Mitra DK, Bhatnagar V. Postnatal outcome and natural history of antenatally-detected hydronephrosis. Pediatr Surg Int 2000; 16:569. [52] Karnak I, Woo LL, Shah SN, Sirajuddin A, Ross JH. Results of a practical protocol for management of prenatally detected hydronephrosis due to ureteropelvic junction obstruction. Pediatr Surg Int 2009;25:61.

H.T. Nguyen et al. [53] Chertin B, Pollack A, Koulikov D, Rabinowitz R, Hain D, Hadas-Halpren I, et al. Conservative treatment of ureteropelvic junction obstruction in children with antenatal diagnosis of hydronephrosis: lessons learned after 16 years of follow-up. Eur Urol 2006;49:734. [54] Madden NP, Thomas DF, Gordon AC, Arthur RJ, Irving HC, Smith SE. Antenatally detected pelviureteric junction obstruction. Is non-operation safe? Br J Urol 1991;68:305. [55] Dhillon HK. Prenatally diagnosed hydronephrosis: the Great Ormond Street experience. Br J Urol 1998;81(Suppl. 2):39. [56] Palmer LS, Maizels M, Cartwright PC, Fernbach SK, Conway JJ. Surgery versus observation for managing obstructive grade 3 to 4 unilateral hydronephrosis: a report from the Society for Fetal Urology. J Urol 1998;159:222. _ Woo LL, Shah SN, Sirajuddin A, Kay R, Ross JH. [57] Karnak I, Prenatally detected ureteropelvic junction obstruction: clinical features and associated urologic abnormalities. Pediatr Surg Int 2008;24:395. [58] Zerin JM, Ritchey ML, Chang AC. Incidental vesicoureteral reflux in neonates with antenatally detected hydronephrosis and other renal abnormalities. Radiology 1993;187:157. [59] Brophy MM, Austin PF, Yan Y, Coplen DE. Vesicoureteral reflux and clinical outcomes in infants with prenatally detected hydronephrosis. J Urol 2002;168:1716. [60] Phan VR, Traubici J, Hershenfield B, Stephens D, Rosenblum ND, Geary DF. Vesicoureteral reflux in infants with isolated antenatal hydronephrosis. Pediatr Nephrol 2003;18:1224. [61] Herndon CD, McKenna PH, Kolon TF, Gonzales ET, Baker LA, Docimo SG. A multicenter outcomes analysis of patients with neonatal reflux presenting with prenatal hydronephrosis. J Urol 1999;162:1203. [62] Katzir Ze, Witzling M, Nikolov G, Gvirtz G, Arbel E, Kohelet D, et al. Neonates with extra-renal pelvis: the first 2 years. Pediatr Nephrol 2005;20:763. [63] Tibballs JM, De Bruyn R. Primary vesicoureteric refluxehow useful is postnatal ultrasound? Arch Dis Child 1996;75:444. [64] Gloor JM, Ramsey PS, Ogburn Jr PL, Danilenko-Dixon DR, DiMarco CS, Ramin KD. The association of isolated mild fetal hydronephrosis with postnatal vesicoureteral reflux. J Matern Fetal Neonatal Med 2002;12:196. [65] Baskin LS, Zderic SA, Snyder HM, Duckett JW. Primary dilated megaureter: long-term followup. J Urol 1994;152:618. [66] Liu HY, Dhillon HK, Yeung CK, Diamond DA, Duffy PG, Ransley PG. Clinical outcome and management of prenatally diagnosed primary megaureters. J Urol 1994;152:614. [67] Meyer JS, Lebowitz RL. Primary megaureter in infants and children: a review. Urol Radiol 1992;14:296. [68] McLellan DL, Retik AB, Bauer SB, Diamond DA, Atala A, Mandell J, et al. Rate and predictors of spontaneous resolution of prenatally diagnosed primary nonrefluxing megaureter. J Urol 2002;168:2177. [69] Shukla AR, Cooper J, Patel RP, Carr MC, Canning DA, Zderic SA, et al. Prenatally detected primary megaureter: a role for extended followup. J Urol 2005;173:1353. [70] Ahmadzadeh A, Tahmasebi M, Gharibvand MM. Causes and outcome of prenatally diagnosed hydronephrosis. Saudi J Kidney Dis Transpl 2009;1. [71] Rabelo EAS, Oliveira EA, Silva GS, Pezzuti IL, Tatsuo ES. Predictive factors of ultrasonographic involution of prenatally detected multicystic dysplastic kidney. BJU Int 2005;95: 868. [72] Peters CA, Reid LM, Docimo S, Luetic T, Carr M, Retik AB, et al. The role of the kidney in lung growth and maturation in the setting of obstructive uropathy and oligohydramnios. J Urol 1991;146:597. [73] Atwell JD. Posterior urethral valves in the British Isles: a multicenter B.A.P.S. review. J Pediatr Surg 1983;18:70.

Consensus statement for prenatal hydronephrosis [74] Dinneen MD, Duffy PG. Posterior urethral valves. Br J Urol 1996;78:275. [75] Anumba DO, Scott JE, Plant ND, Robson SC. Diagnosis and outcome of fetal lower urinary tract obstruction in the northern region of England. Prenat Diagn 2005;25:7. [76] Abbott JF, Levine D, Wapner R. Posterior urethral valves: inaccuracy of prenatal diagnosis. Fetal Diagn Ther 1998;13: 179. [77] Helin I, Persson PH. Prenatal diagnosis of urinary tract abnormalities by ultrasound. Pediatrics 1986;78:879. [78] Paduano L, Giglio L, Bembi B, Peratoner L, Benussi G. Clinical outcome of fetal uropathy. II. Sensitivity of echography for prenatal detection of obstructive pathology. J Urol 1991;146: 1097. [79] Robyr R, Benachi A, Daikha-Dahmane F, Martinovich J, Dumez Y, Ville Y. Correlation between ultrasound and anatomical findings in fetuses with lower urinary tract obstruction in the first half of pregnancy. Ultrasound Obstet Gynecol 2005;25:478. [80] Favre R, Kohler M, Gasser B, Muller F, Nisand I. Early fetal megacystis between 11 and 15 weeks of gestation. Ultrasound Obstet Gynecol 1999;14:402. [81] Jouannic JM, Hyett JA, Pandya PP, Gulbis B, Rodeck CH, Jauniaux E. Perinatal outcome in fetuses with megacystis in the first half of pregnancy. Prenat Diagn 2003;23:340. [82] Hulbert WC, Rabinowitz R. Prenatal diagnosis of duplex system hydronephrosis: effect on renal salvage. Urology 1998;51:23. [83] Bouzada MCF, Oliveira EA, Pereira AK, Leite HV, Rodrigues AM, Fagundes LA, et al. Diagnostic accuracy of fetal renal pelvis anteroposterior diameter as a predictor of uropathy: a prospective study. Ultrasound Obstet Gynecol 2004;24:745. [84] Jaswon MS, Dibble L, Puri S, Davis J, Young J, Dave R, et al. Prospective study of outcome in antenatally diagnosed renal pelvis dilatation. Arch Dis Child Fetal Neonatal Ed 1999;80: F135. [85] Upadhyay J, McLorie GA, Bolduc S, Ba ¨gli DJ, Khoury AE, Farhat W. Natural history of neonatal reflux associated with prenatal hydronephrosis: long-term results of a prospective study. J Urol 1837;169:2003. [86] Sidhu G, Beyene J, Rosenblum ND. Outcome of isolated antenatal hydronephrosis: a systematic review and metaanalysis. Pediatr Nephrol 2006;21:218. [87] Thornburg LL, Pressman EK, Chelamkuri S, Hulbert W, Rabinowitz R, Mevorach R. Third trimester ultrasound of fetal pyelectasis: predictor for postnatal surgery. J Pediatr Urol 2008;4:51. [88] Noe HN, Magill HL. Progression of mild ureteropelvic junction obstruction in infancy. Urology 1987;30:348. [89] Aviram R, Pomeranz A, Sharony R, Beyth Y, Rathaus V, Tepper R. The increase of renal pelvis dilatation in the fetus and its significance. Ultrasound Obstet Gynecol 2000;16:60. [90] Clark TJ, Martin WL, Divakaran TG, Whittle MJ, Kilby MD, Khan KS. Prenatal bladder drainage in the management of fetal lower urinary tract obstruction: a systematic review and meta-analysis. Obstet Gynecol 2003;102:367. [91] Morris RK, Kilby MD. An overview of the literature on congenital lower urinary tract obstruction and introduction to the PLUTO trial: percutaneous shunting in lower urinary tract obstruction. Aust N Z J Obstet Gynaecol 2009;49:6. [92] Biard JM, Johnson MP, Carr MC, Wilson RD, Hedrick HL, Pavlock C, et al. Long-term outcomes in children treated by prenatal vesicoamniotic shunting for lower urinary tract obstruction. Obstet Gynecol 2005;106:503. [93] Wu S, Johnson MP. Fetal lower urinary tract obstruction. Clin Perinatol 2009;36:377. [94] Thomas DF. Prenatally diagnosed urinary tract abnormalities: long-term outcome. Semin Fetal Neonatal Med 2008;13:189.

229 [95] Morris RK, Kilby MD. Congenital urinary tract obstruction. Best Pract Res Clin Obstet Gynaecol 2008;22:97. [96] Yiee J, Wilcox D. Management of fetal hydronephrosis. Pediatr Nephrol 2008;23:347. [97] Laing FC, Burke VD, Wing VW, Jeffrey Jr RB, Hashimoto B. Postpartum evaluation of fetal hydronephrosis: optimal timing for follow-up sonography. Radiology 1984;152:423. [98] Hafez AT, McLorie G, Bagli D, Khoury A. Analysis of trends on serial ultrasound for high grade neonatal hydronephrosis. J Urol 2002;168:1518. [99] Gill B, Bennett RT, Barnhard Y, Bar-Hava I, Girz B, Divon M. Can fetal renal artery Doppler studies predict postnatal renal function in morphologically abnormal kidneys? A preliminary report. J Urol 1996;156:190. [100] Kessler RM, Quevedo H, Lankau CA, Ramirez-Seijas F, Cepero-Akselrad A, Altman DH, et al. Obstructive vs nonobstructive dilatation of the renal collecting system in children: distinction with duplex sonography. AJR Am J Roentgenol 1993;160:353. [101] Ward VL, Strauss KJ, Barnewolt CE, Zurakowski D, Venkatakrishnan V, Fahey FH, et al. Pediatric radiation exposure and effective dose reduction during voiding cystourethrography. Radiology 2008;249:1002. [102] Riccabona M, Avni FE, Blickman JG, Dacher J-N, Darge K, Lobo ML, et al. Imaging recommendations in paediatric uroradiology: minutes of the ESPR workgroup session on urinary tract infection, fetal hydronephrosis, urinary tract ultrasonography and voiding cystourethrography, Barcelona, Spain, June 2007. Pediatr Radiol 2008;38(138). [103] Conway JJ, Maizels M. The ‘‘well tempered’’ diuretic renogram: a standard method to examine the asymptomatic neonate with hydronephrosis or hydroureteronephrosis. A report from combined meetings of The Society for Fetal Urology and members of The Pediatric Nuclear Medicine CouncileThe Society of Nuclear Medicine. J Nucl Med 1992;33:2047. [104] Jones RA, Perez-Brayfield MR, Kirsch AJ, Grattan-Smith JD. Renal transit time with MR urography in children. Radiology 2004;233:41. [105] Jones RA, Easley K, Little SB, Scherz H, Kirsch AJ, GrattanSmith JD. Dynamic contrast-enhanced MR urography in the evaluation of pediatric hydronephrosis: part 1, functional assessment. AJR Am J Roentgenol 2005;185:1598. [106] McDaniel BB, Jones RA, Scherz H, Kirsch AJ, Little SB, Grattan-Smith JD. Dynamic contrast-enhanced MR urography in the evaluation of pediatric hydronephrosis: part 2, anatomic and functional assessment of uteropelvic junction obstruction. AJR Am J Roentgenol 2005;185:1608. [107] McMann LP, Kirsch AJ, Scherz HC, Smith EA, Jones RA, Shehata BM, et al. Magnetic resonance urography in the evaluation of prenatally diagnosed hydronephrosis and renal dysgenesis. J Urol 2006;176:1786. [108] Kirsch AJ, McMann LP, Jones RA, Smith EA, Scherz HC, Grattan-Smith JD. Magnetic resonance urography for evaluating outcomes after pediatric pyeloplasty. J Urol 2006;176: 1755. [109] Kaneyama K, Yamataka A, Someya T, Itoh S, Lane GJ, Miyano T. Magnetic resonance urographic parameters for predicting the need for pyeloplasty in infants with prenatally diagnosed severe hydronephrosis. J Urol 2006;176:1781. [110] Perez-Brayfield MR, Kirsch AJ, Jones RA, Grattan-Smith JD. A prospective study comparing ultrasound, nuclear scintigraphy and dynamic contrast enhanced magnetic resonance imaging in the evaluation of hydronephrosis. J Urol 2003;170: 1330. [111] Ek S, Lidefeldt KJ, Varricio L. Fetal hydronephrosis; prevalence, natural history and postnatal consequences in an unselected population. Acta Obstet Gynecol Scand 2007;86: 1463.

230 [112] Gatti JM, Broecker BH, Scherz HC, Perez-Brayfield MR, Kirsch AJ. Antenatal hydronephrosis with postnatal resolution: how long are postnatal studies warranted? Urology 2001;57:1178. [113] Walsh TJ, Hsieh S, Grady R, Mueller BA. Antenatal hydronephrosis and the risk of pyelonephritis hospitalization during the first year of life. Urology 2007;69:970. [114] Erickson BA, Maizels M, Shore RM, Pazona JF, Hagerty JA, Yerkes EB, et al. Newborn society of fetal urology grade 3 hydronephrosis is equivalent to preserved percentage differential function. J Pediatr Urol 2007;3:382. [115] Yeung CK, Godley ML, Dhillon HK, Gordon I, Duffy PG, Ransley PG. The characteristics of primary vesico-ureteric reflux in male and female infants with pre-natal hydronephrosis. Br J Urol 1997;80:319. [116] Yerkes EB, Adams MC, Pope JC, Brock JW. Does every patient with prenatal hydronephrosis need voiding cystourethrography? J Urol 1999;162:1218. [117] Bomalaski MD, Hirschl RB, Bloom DA. Vesicoureteral reflux and ureteropelvic junction obstruction: association, treatment options and outcome. J Urol 1997;157:969. [118] Wheeler DM, Vimalachandra D, Hodson EM, Roy LP, Smith GH, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev 2004. CD00153. [119] Matsui F, Shimada K, Matsumoto F, Takano S. Late recurrence of symptomatic hydronephrosis in patients with prenatally detected hydronephrosis and spontaneous improvement. J Urol 2008;180:322. [120] Koff SA, Campbell K. Nonoperative management of unilateral neonatal hydronephrosis. J Urol 1992;148:525. [121] Van Eerde AM, Meutgeert MH, De Jong TPVM, Giltay JC. Vesico-ureteral reflux in children with prenatally detected hydronephrosis: a systematic review. Ultrasound Obstet Gynecol 2007;29:463. [122] Lee JH, Choi HS, Kim JK, Won H-S, Kim KS, Moon DH, et al. Nonrefluxing neonatal hydronephrosis and the risk of urinary tract infection. J Urol 2008;179:1524. [123] Yavascan O, Aksu N, Anil M, Kara OD, Aydin Y, Kangin M, et al. Postnatal assessment of growth, nutrition, and urinary tract infections of infants with antenatally detected hydronephrosis. Int Urol Nephrol 2009;1. [124] Song SH, Lee SB, Park YS, Kim KS. Is antibiotic prophylaxis necessary in infants with obstructive hydronephrosis? J Urol 2007;177:1098. [125] Alconcher L, Tombesi M. Mild antenatal hydronephrosis: management controversies. Pediatr Nephrol 2004;19:819. [126] Estrada CR, Peters CA, Retik AB, Nguyen HT. Vesicoureteral reflux and urinary tract infection in children with a history of prenatal hydronephrosisdshould voiding cystourethrography be performed in cases of postnatally persistent grade II hydronephrosis? J Urol 2008;181:801. [127] Yagel S, Anteby EY, Hochner-Celnikier D, Ariel I, Chaap T, Neriah ZB. The role of midtrimester targeted fetal organ screening combined with the "triple test" and maternal age in the diagnosis of trisomy 21: a retrospective study. Am J Obstet Gynecol 1998;178:40. [128] Dagklis T, Plasencia W, Maiz N, Duarte L, Nicolaides KH. Choroid plexus cyst, intracardiac echogenic focus, hyperechogenic bowel and hydronephrosis in screening for trisomy 21 at 11 þ 0 to 13 þ 6 weeks. Ultrasound Obstet Gynecol 2008;31:132. [129] Staebler M, Donner C, Van Regemorter N, Duprez L, De Maertelaer V, Devreker F, et al. Should determination of the karyotype be systematic for all malformations detected by obstetrical ultrasound? Prenat Diagn 2005;25:567. [130] Al-Kouatly HB, Chasen ST, Gilbert F, Ahner R, Alonso LM, Chervenak FA. Correlation between rare chromosomal abnormalities and prenatal ultrasound findings. Am J Med Genet 2002;107:197.

H.T. Nguyen et al. [131] Nicolaides KH, Cheng HH, Abbas A, Snijders RJ, Gosden C. Fetal renal defects: associated malformations and chromosomal defects. Fetal Diagn Ther 1992;7:1. [132] Izquierdo L, Porteous M, Paramo PG, Connor JM. Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction, with one locus assigned to chromosome 6p. Hum Genet 1992;89:557. [133] Paramo PG, Izquierdo L, Paramo Jr P, Llorente L, Diego A, Paez A, et al. Genuine hereditary hydronephrosis in a three-generation family. Clinicopathological and genetic implications with a review of the literature. Eur Urol 1991; 20:293. [134] Buscemi M, Shanske A, Mallet E, Ozoktay S, Hanna MK. Dominantly inherited ureteropelvic junction obstruction. Urology 1985;26:568. [135] Cohen B, Goldman SM, Kopilnick M, Khurana AV, Salik JO. Ureteropelvic junction obstruction: its occurrence in 3 members of a single family. J Urol 1978;120:361. [136] Ataei N, Madani A, Esfahani ST, Kejbafzadeh A, Ghaderi O, Jalili S, et al. Screening for vesicoureteral reflux and renal scars in siblings of children with known reflux. Pediatr Nephrol 2004;19:1127. [137] Bonnin F, Lottmann H, Sauty L, Garel C, Archambaud F, Baudouin V, et al. Scintigraphic screening for renal damage in siblings of children with symptomatic primary vesicoureteric reflux. BJU Int 2001;87:463. [138] Kenda RB, Fettich JJ. Vesicoureteric reflux and renal scars in asymptomatic siblings of children with reflux. Arch Dis Child 1992;67:506. [139] Briggs CE, Guo CY, Schoettler C, Rosoklija I, Silva A, Bauer SB, et al. A genome scan in affected sib-pairs with familial vesicoureteral reflux identifies a locus on chromosome 5. Eur J Hum Genet 2009. [140] Conte ML, Bertoli-Avella AM, de Graaf BM, Punzo F, Lama G, La Manna A, et al. A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity. Pediatr Nephrol 2008;23:587. [141] Kelly H, Molony CM, Darlow JM, Pirker ME, Yoneda A, Green AJ, et al. A genome-wide scan for genes involved in primary vesicoureteric reflux. J Med Genet 2007;44:710. [142] Schreuder MF, van der Horst HJ, Bokenkamp A, Beckers GM, van Wijk JA. Posterior urethral valves in three siblings: a case report and review of the literature. Birth Defects Res A Clin Mol Teratol 2008;82:232. [143] Economou G, Egginton JA, Brookfield DS. The importance of late pregnancy scans for renal tract abnormalities. Prenat Diagn 1994;14:177. [144] Persutte WH, Koyle M, Lenke RR, Klas J, Ryan C, Hobbins JC. Mild pyelectasis ascertained with prenatal ultrasonography is pediatrically significant. Ultrasound Obstet Gynecol 1997; 10:12. [145] Morin L, Cendron M, Crombleholme TM, Garmel SH, Klauber GT, D’Alton ME. Minimal hydronephrosis in the fetus: clinical significance and implications for management. J Urol 1996;155:2047. [146] Owen RJ, Lamont AC, Brookes J. Early management and postnatal investigation of prenatally diagnosed hydronephrosis. Clin Radiol 1996;51:173. [147] Langer B, Simeoni U, Montoya Y, Casanova R, Schlaeder G. Antenatal diagnosis of upper urinary tract dilation by ultrasonography. Fetal Diagn Ther 1996;11:191. [148] Livera LN, Brookfield DS, Egginton JA, Hawnaur JM. Antenatal ultrasonography to detect fetal renal abnormalities: a prospective screening programme. BMJ 1989;298:1421. [149] Fasolato V, Poloniato A, Bianchi C, Spagnolo D, Valsecchi L, Ferrari A, et al. Feto-neonatal ultrasonography to detect renal abnormalities: evaluation of 1-year screening program. Am J Perinatol 1998;15:161.

Consensus statement for prenatal hydronephrosis [150] Rosendahl H. Ultrasound screening for fetal urinary tract malformations: a prospective study in general population. Eur J Obstet Gynecol Reprod Biol 1990;36:27. [151] Johnson CE, Elder JS, Judge NE, Adeeb FN, Grisoni ER, Fattlar DC. The accuracy of antenatal ultrasonography in identifying renal abnormalities. Am J Dis Child 1992;146:1181. [152] Gunn TR, Mora JD, Pease P. Outcome after antenatal diagnosis of upper urinary tract dilatation by ultrasonography. Arch Dis Child 1988;63:1240. [153] Corteville JE, Gray DL, Crane JP. Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome. Am J Obstet Gynecol 1991;165:384. [154] Mandell J, Blyth BR, Peters CA, Retik AB, Estroff JA, Benacerraf BR. Structural genitourinary defects detected in utero. Radiology 1991;178:193. [155] Adra AM, Mejides AA, Dennaoui MS, Beydoun SN. Fetal pyelectasis: is it always ‘‘physiologic’’? Am J Obstet Gynecol 1995;173:1263.

231 [156] Podevin G, Mandelbrot L, Vuillard E, Oury JF, Aigrain Y. Outcome of urological abnormalities prenatally diagnosed by ultrasound. Fetal Diagn Ther 1996;11:181. [157] Stocks A, Richards D, Frentzen B, Richard G. Correlation of prenatal renal pelvic anteroposterior diameter with outcome in infancy. J Urol 1996;155:1050. [158] Dudley JA, Haworth JM, McGraw ME, Frank JD, Tizard EJ. Clinical relevance and implications of antenatal hydronephrosis. Arch Dis Child Fetal Neonatal Ed 1997;76:F31. [159] Chudleigh PM, Chitty LS, Pembrey M, Campbell S. The association of aneuploidy and mild fetal pyelectasis in an unselected population: the results of a multicenter study. Ultrasound Obstet Gynecol 2001;17:197. [160] Johnson MP, Bukowski TP, Reitleman C, Isada NB, Pryde PG, Evans MI. In utero surgical treatment of fetal obstructive uropathy: a new comprehensive approach to identify appropriate candidates for vesicoamniotic shunt therapy. Am J Obstet Gynecol 1994;170:1770.