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Urologic Problems of the Neonate: An Update
Clin Perinatol 34 (2007) 667–679
Urologic Problems of the Neonate: An Update Hrair-George O. Mesrobian, MD, MSc Department of Urology, Division of Pediatric Urology, Medical College of Wisconsin, Children’s Hospital of Wisconsin, 9000 W. Wisconsin Avenue, Children’s Hospital Office Building, Suite 606, Milwaukee, WI 53226, USA
During the last 2 decades of the twentieth century, maternal sonography became integrated into routine prenatal care. As a result, numerous anomalies are now detected in the fetus. This practice has had a profound influence on the presentation and natural history of urologic problems in the neonate. Genitourinary anomalies are the most common organ system anomaly detected by the routine use of maternal sonography. In an attempt to reflect the clinical scenario, this article is divided into two main parts. The first part addresses the clinical questions raised by prenatally detected anomalies, abdominal masses, urosepsis, urinary retention, scrotal masses, and abnormal external genitalia. The second part is a discussion of specific anomalies with respect to evaluation and management, including controversies, and optimum timing for referral to a tertiary care center. The selected anomalies include renal anomalies, tumors, the exstrophy complex, urogenital anomalies, ambiguous genitalia, posterior urethral valves, scrotal anomalies, spina bifida, and common urologic syndromes such as the triad syndrome. Our knowledge regarding the pathophysiology and therefore treatment of these conditions is constantly expanding and changing. This article represents an updated version of the article originally published in the August 2004 issue of Pediatric Clinics. Space constraints do not allow this article to be comprehensive and the reader is referred to urologic texts for additional information.
A version of this article entitled ‘‘Urologic problems of the neonate’’ by Hrair-George O. Mesrobian, MD, Anthony H. Balcom, MD, and Charles T. Durkee, MD appeared in Pediatric Clinics: Common Issues and Concerns in the Newborn Nursery, Part II (Volume 51, Issue 4, August 2004). E-mail address: [email protected] 0095-5108/07/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2007.09.004 perinatology.theclinics.com
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Clinical presentation of urologic problems in the neonate Prenatally detected urologic anomalies Hydronephrosis is the most common urologic anomaly detected in the fetus. It can be unilateral or bilateral, with or without oligohydramnios. The kidneys, bladder, and amniotic fluid are normally visualized by ultrasound as early as 12 weeks, using either a transabdominal or an endovaginal technique [1]. As pregnancy progresses, the appearance of the kidneys becomes better defined. The bladder can be observed to fill and empty and volumes can be derived. Normally, the fetal renal pelvis is not observed by ultrasound. It is generally accepted that an anteroposterior measurement of greater than 5 mm at 20 weeks’ gestation and 8 mm at 33 weeks’ gestation may be associated with the need of neonatal intervention [2]. Oligohydramnios may be associated with renal dysplasia or urinary tract obstruction such as posterior urethral valves, and constitutes one of the clearest indications for referral to a tertiary care center. Despite the technical accuracy of modern sonographic equipment, the diagnosis of a specific disease presenting with prenatal hydronephrosis is not firmly established until following birth. In the neonate, the work-up consists of a repeat renal ultrasound followed by a voiding cystourethrogram. The latter will detect anomalies that may be causing the hydronephrosis (for example an ectopic ureterocoele) or that may be associated with the hydronephrosis, such as vesicoureteral reflux. The sensitivity and specificity of ultrasound in diagnosing other urologic anomalies is low. For example, persistent nonvisualization of the bladder is highly suggestive of a bladder or cloacal exstrophy; however, in one series, only in 3 out of 25 was this diagnosis made prospectively [3]. The differential diagnosis includes more life-threatening conditions such as gastroschisis, if a deficiency of the ventral abdominal wall is identified. Prompt referral to a tertiary center is desirable. Urosepsis and urinary retention In general, the probability that a febrile infant might have a urinary tract infection (UTI) is 5% [4]. In newborns and up to 8 weeks of age, this probability may be much higher [5]. Although febrile UTIs are commonly considered to be more prevalent in females, the risk appears to be greatest for the uncircumcised male. Thus, the possibility of a UTI being present in a febrile newborn or infant should be high on the list in the differential diagnosis and should guide the subsequent work-up. The definitive diagnostic test is a positive urine culture obtained through suprapubic aspiration or urethral catheterization. A false-positive culture obtained via a bag specimen may lead to inappropriate treatment and misdiagnosis. The urinalysis, which is immediately available, is suggestive but not diagnostic. This is so because although the leukocyte esterase test has high sensitivity, it lacks in specificity; conversely, the nitrite test behaves in the opposite direction
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[4]. When combined with microscopic findings, the sensitivity approaches 100% when all three are positive, and the specificity is 100% when all three are negative. When a UTI has been diagnosed, treatment with broad-spectrum intravenous antibiotics is paramount. Once a clinical response has been documented, evaluation with a voiding cystourethrogram and ultrasound study of the kidneys are indicated. The incidence of structural urinary tract anomaliesdvesicoureteral reflux, posterior urethral valves, ureteral ectopia or ureterocoeles, ureteropelvic junction (UPJ) disease and other less common anomaliesdat this young age is 30% to 50% [4]. Recently, Edmondson et al have reported on the value of positional instillation cystography (PIC) which can detect occult reflux in 82% of children with febrile urinary tract infections. A muti-institutional prospective randomized trial is under way to further determine the clinical significance of PIC positive reflux [24]. A substantial number of these will require surgical treatment; therefore, the ultrasound study should be obtained as soon as the diagnosis of UTI is made. If the initial ultrasound study reveals normal kidneys, the voiding cystourethrogram can be delayed until the newborn has been deemed to respond clinically to antibiotics. Rarely is percutaneous drainage of an obstructed and infected renal moiety indicated in addition to antibiotics. Urinary retention in the newborn is alarming. Most are expected to void within the first 8 hours of life, although voiding can normally occur for the first time at the 24th hour! It is important to emphasize that a normal void or even a normal stream does not rule out the presence of significant lower urinary tract obstruction. The muscular bladder may initially compensate by expressing urine with a normal stream in the face of significant urethral obstruction. The presence of a suprapubic mass on palpation in a boy, for example, is very suspicious of posterior urethral valves. Other causes for urinary retention include ectopic ureterocoeles (especially in girls), spina bifida, pelvic teratoma, and urogenital sinus anomalies. The latter is usually associated with hydrocolpos or metrocolpos, or both. The work-up should always begin with an abdominal ultrasound study following catheter drainage of the bladder. Anomalies of external genitalia, including acute scrotal conditions Acute scrotal masses and anomalies of the external genitalia are a cause for alarm in the newborn period, and must be handled with great sensitivity toward the family. Whereas hypospadias occurs in 1 out of 250 live male births, associated findings such as bilateral undescended gonads must raise a red flag and intersex suspected [6]. The presence of ambiguous genitalia is a medical emergency requiring a precise diagnosis. In general, one should assess whether one or two gonads are descended or even palpated. Their presence rules out female pseudohermaphrotism because ovaries do not descend. Examination of the phallus for size and configuration is essential. The
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average phallic size in the term male infant is 3.5 cm measured from the symphysis pubis to the stretched glans. In addition, the diameter of the term male penis is 1 to 1.5 cm. A phallic length of less than 2 cm at any gestational age should raise concern [7]. The presence or absence of a uterus can be assessed by pelvic sonography. Laboratory evaluation includes determination of chromosomal sex and biochemical findings. The urogenital sinus is evaluated by retrograde injection of contrast defining the confluence of the vagina and urethra. In the newborn period, the presence of an acute scrotal condition may be subtle and may consist initially of scrotal redness and a mass. The nature of the mass (cystic or solid) can be determined by transillumination. A hydrocoele readily transilluminates, whereas extravaginal torsion of the spermatic cord does not. The differential diagnosis in the latter situation includes an incarcerated hernia, a scrotal hematoma, or a testicular tumor. An incarcerated hernia warrants prompt surgical correction, not only to preserve bowel integrity but also to avoid ipsilateral spermatic cord compression and testicular ischemia. Unlike the treatment of testicular torsion in adolescents, salvage of a neonatal torsed testis remains an exceedingly rare occurrence [8] (Fig. 1). Most pediatric urologists will recommend exploration and contralateral testicular fixation if the baby is stable and the risks of anesthesia are not increased by comorbidities. Otherwise, the contralateral fixation is postponed until the neonate’s overall condition has improved. Occasionally the diagnosis cannot be established, and exploration may become mandatory, so as not to overlook other conditions, such as an incarcerated inguinal hernia. Neonatal testicular tumors are rare. The most recent report from the Prepubertal Testicular Tumor registry describes gonadal stromal tumors as the most common, followed by yolk sac tumors and mature teratoma [9]. Orchiectomy can be curative in the latter situation.
Fig. 1. Extravaginal torsion of testis with necrosis at exploration in newborn. Black arrow points to the twisted spermatic cord.
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Urologic anomalies in the neonate Renal anomalies and tumors Unilateral or bilateral ureteropelvic junction disease, renal duplication anomalies with hydronephrosis of one of the moieties (usually the upper pole), and multicystic kidney disease are the most common anomalies. Occasionally, a multicystic kidney on one side may be associated with UPJ disease on the opposite side, with the combination leading to varying degrees of renal failure (Fig. 2A, B). The neonate may be asymptomatic when the anomaly is detected during the course of maternal sonography or less commonly nowadays, presenting with an abdominal mass or urosepsis. The impact of prenatal sonography on the postnatal management of renal anomalies has been variably documented [10]. In general, unilateral disease with a normal contralateral kidney rarely constitutes an emergency. An exception might be the newborn in whom a hydronephrotic upper pole moiety is associated with a large unilateral ectopic ureterocoele obstructing the bladder outlet. Although the initial postnatal ultrasound study can visualize the ureterocoele in the bladder as a large filling defect, a voiding cystourethrogram confirms the diagnosis and associated findings such as vesicoureteral reflux and bladder outlet obstruction. It is desirable to start prophylactic antibiotics until definitive surgical treatment. Less common but life-threatening renal anomalies include infantile polycystic kidney disease and solid tumors. The former is associated with a poor prognosis. An emergent nephrectomy may be required because of respiratory embarrassment induced by the sheer size of these kidneys. The most common renal tumor in the newborn is the mesoblastic nephroma, which is unilateral and is cured with a nephrectomy. The differential diagnosis, however, should include a neuroblastoma
Fig. 2. (A) Multicystic kidney removed because of hypertension. (B) Burnt-out solitary kidney secondary to ureteropelvic junction obstruction (thin white arrow) removed at time of kidney transplantation. Thick arrow points to remaining sliver of parenchyma on top of a distended and tense hydronephrotic renal pelvis.
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arising in the retroperitoneum and engulfing the kidney, and less commonly a teratoma. Finally, no discussion of renal anomalies in the newborn is complete without mentioning nephrolithiasis. With the improved care and outcome of premature neonates, diuretic use has led to a 2.5% to 11% incidence of renal calcifications, depending on the weight of the baby [11]. Nephrolithiasis is induced by the high doses of diuretics (especially furosemide) required to treat bronchopulmonary dysplasia, the prolonged half-life of furosemide in premature infants, and secondary hyperparathyroidism. Urinary calcium excretions as high as 30 mg/kg/day have been recorded (normal is ! 1.24) [12]. Fortunately, these calculi rarely cause symptoms or obstructive hydronephrosis. Treatment is medical and nonoperative, and consists of administration of chlorothiazide. Bladder and cloacal exstrophy The exstrophic complex of anomalies ranges from epispadias to cloacal exstrophy. The most common anomaly consists of classic bladder exstrophy (Fig. 3), in which the bladder is situated on the anterior abdominal wall, with partial midline separation of the symphysis pubis. In boys, the penis is short, stubby, and curves toward the abdominal wall. The urethra consists of a plate, the perineum is displaced anteriorly, and the umbilicus is absent. In girls, the vagina can be identified underneath the urethral plate inferiorly and the clitoris is bifid [13]. The kidneys are normal and, remarkably, there are very few associated anomalies. The diagnosis is rarely made prenatally and most parents are ill prepared to understand the implications of exstrophy. They should be reassured regarding their baby’s sexual identity and that the anomaly is treatable with surgery. At birth, the exstrophic bladder is protected by an inert barrier and kept moist by directed humidified air. As
Fig. 3. Classic exstrophy of the bladder in boy. Arrow points to epispadiac penis with absence of urethra and dorsal penile curvature. Both testes were descended and the kidneys normal by ultrasound.
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soon as feasible, the baby is transported to a tertiary care center for immediate surgical closure. Early closure within the first 72 hours of life is advocated. Long-term outcome of exstrophy closure is quite good, with preservation of renal and sexual function, achievement of normal appearing abdominal wall and genitalia, and urinary continence rates approaching 80% [14]. Cloacal exstrophy presents more challenges to the patient and the surgical team. This anomaly is a form of ventral abdominal wall defect consisting of an omphalocoele on top of a vesicointestinal plate inferiorly. The intestinal plate divides the bladder into two halves and contains the opening of the terminal ileum and the hindgut. In the male, the corpora are widely separated and the penis is diminutive. Associated anomalies are common and involve the gastrointestinal, vertebral, skeletal, and urinary systems. A multidisciplinary approach in a tertiary care center offers the best opportunity for a successful outcome. Posterior urethral valves The most common form of posterior urethral valves (or membrane) occurs just distal to the prostate, in the membranous portion of the male urethra. Because of early onset during development, valves can cause severe bilateral hydronephrosis and oligohydramnios. On the other hand, the variability in the degree of obstruction and in the response of the bladder is such that renal architecture and function may be preserved. Therefore, the spectrum of presentation in the newborn may range from renal failure, pulmonary hypoplasia, and abdominal ascites to normal voiding, with the diagnosis established only by virtue of prenatally detected hydronephrosis [15]. Consequently, when suspected, referral to a tertiary care center is essential. A few fetuses will be candidates for prenatal intervention, with the placement of a vesicoamniotic shunt [16] requiring postnatal removal and definitive surgical treatment. The diagnosis is suggested by sonography with hydronephrosis and distention and thickening of the bladder wall. The voiding cystourethrogram establishes the diagnosis with the typical appearance of the posterior urethra (Fig. 4). Placement of a simple 5 or 8 French feeding tube in the bladder while awaiting definitive treatment can be life-saving. The prune belly or triad syndrome enters in the differential diagnosis of posterior urethral valves, both prenatally and during imaging. Both conditions can be associated with hydronephrosis, a dilated posterior urethra, and oligohydramnios. The triad syndrome consists of absence of abdominal wall musculature, cryptorchidism, and hydronephrosis. The incidence is approximately 1 in 50,000 live births and it occurs almost exclusively in males. As with posterior urethral valves, the degree of renal failure at presentation can vary. In-utero intervention via placement of vesicoamniotic shunt has been advocated when oligohydramnios is documented (Fig. 5). Postnatal management is individualized. Many newborns require CIC (intermittent
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Fig. 4. Voiding cystourethrogram in newborn boy who has posterior urethral valves. White arrow points to valves with proximal dilation and elongation of the posterior urethra. Thick black arrow points to bladder with hypertrophy of its neck. Grade V vesicoureteral reflux is seen in one of the ureters (thin black arrow).
catheterization) or creation of a vesicostomy for the treatment of urinary retention. Subsequent surgical treatment may include a bilateral orchidopexy, ureteral tapering and reimplantation, and in some cases, an abdominoplasty later on in life. Fertility has been difficult to achieve, although in-vitro techniques have resulted in successes.
Fig. 5. Typical appearance of the belly in the Triad syndrome. Note the vesicoamniotic shunt that was placed in utero for oligohydramnios and the bilateral undescended testicles.
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Spina bifida The introduction of folic acid in the diet of pregnant mothers and to a variable extent, elective termination of pregnancy when the anomaly is detected prenatally, have resulted in a reduction in the incidence of newborns with spina bifida over the last 2 decades [17]. Nevertheless, spina bifida continues to occur and presents multiple challenges best addressed by a multidisciplinary team of neonatologists, neurosurgeons, orthopedic specialists, and urologists. The long-term urologic goals are prevention of upper tract deterioration and urinary tract infections, and promotion of urinary continence. In the newborn period and after the spinal defect has been surgically closed, treatment is expectant. Occasionally urinary retention occurs; it is treated best with intermittent catheterization and is usually transient [18]. Hydronephrosis with or without reflux is present in up to 20% of patients at birth. In addition to careful monitoring, prophylactic antibiotics may be indicated to prevent pyelonephritis and its consequences. Urodynamic studies to evaluate the exact nature of bladder dysfunction are undertaken during the first 3 months of life. Depending on the findings, prophylactic CIC may be indicated [18] in some cases, although most newborns are successfully managed with careful imaging and instituting CIC at the first sign of hydronephrosis [19]. Most recently, successful in-utero closure of the spinal defect has been achieved at an average median age of 24 weeks’ gestation [20]. The anticipated benefits of improved lower extremity and bladder function and subsequent quality of life have to await long-term follow-up. Urogenital sinus anomalies and imperforate anus Newborns presenting with a single perineal opening may have a urogenital sinus anomaly or a persistent cloaca (Fig. 6). The anus in the latter situation is imperforate. In the newborn period, the urologic management is focused on adequate drainage of the bladder. Frequently, CIC can fulfill this objective; however, creation of a vesicostomy may be required in many patients because of mechanical difficulty with CIC. Careful imaging of the upper urinary tracts is mandatory to screen for associated anomalies such as renal agenesis, fusion anomalies, and hydronephrosis. Associated anomalies such as hemivertebrae or sacral agenesis may be present. Definitive surgical reconstruction is undertaken at or around 1 year of age. Newborns with imperforate anus have a high incidence of associated urologic anomalies, especially in the male with a high lesion [21]. Early screening with upper and lower tract imaging can result in their recognition and potentially prevent serious morbidity. Associated urinary tract anomalies include vesicoureteral reflux, unilateral renal agenesis, fusion anomalies, and hydronephrosis. Spinal cord anomalies, when present, can lead to neurogenic bladder dysfunction. Treatment of the associated anomalies is disease specific.
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Fig. 6. Urogenital sinus anomaly. Arrow points to single opening of vagina and urethra. The confluence of the two was proximal to the outlet.
Genital anomalies Hypospadias is the most common genital anomaly in boys. It does not require any treatment in the newborn period. Circumcision should be avoided, because the presence of the foreskin is a necessary ingredient in the completion of a successful repair later on in infancy. One should be aware of the megameatus intact-prepuce variant of hypospadias, which may not be discovered until a circumcision is initiated or completed. In this variant, the ventral prepuce is intact. When discovered following a dorsal slit at the time of the circumcision, it is advised to abort the procedure, apply Vaseline gauze on the incision, and refer the patient to a pediatric urologist. Associated anomalies include chordee (ventral curvature of the penile shaft), penoscrotal inversion, bifid scrotum, and cryptorchidism. Hypospadias is repaired in infancy and may require more than one stage. Other urethral anomalies in the newborn include urethral duplication, megalourethra, and urethral diverticulum. The latter may cause lower urinary tract obstruction secondary to an obstructing valvelike projection of the anterior lip of the diverticulum into the urethra [22]. In fact, the condition is sometimes referred to as anterior urethral valves. Although the prepuce is not an anomaly, contraindications to circumcision in the newborn are worthwhile mentioning. These include the presence of hypospadias, chordee without hypospadias, concealed penis or penile engulfment (Fig. 7), and penoscrotal webbing or scrotal transposition. Pematurity with a small penis and a known bleeding diathesis are additional contraindications. Conversely, 50% of patients who have a bleeding diathesis come to the clinician’s attention for the first time with postcircumcision bleeding. Thus, any significant bleeding following a circumcision requires a full hematologic evaluation. Finally, circumcisions are best deferred in the presence of other associated conditions requiring surgical treatment.
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The testes originate in the retroperitoneum just lateral to the mesonephros. Subsequently, during gestation they descend to the level of the internal ring, where they reside until shortly before birth. Their final descent into the scrotum is completed shortly before or following birth. Given this long and tortuous route, it is amazing that so many complete the journey! Cryptorchidism or testicular maldescent is the most common of all anomalies in boys. Its incidence ranges from 33% in prematurity to 3% in full-term boys. It is essential to carefully document the presence or absence of a testis in the newborn period. It is also desirable to palpate the scrotum for the presence of appendages or what might represent an atrophic testicle secondary to prenatal torsion of the spermatic cord. In this situation, the contralateral descended testis may exhibit compensatory hypertrophy (length exceeding 2 cm). The combination of compensatory hypertrophy on the descended side and an empty scrotum on the undescended side is associated with prenatal torsion, the so-called ‘‘vanishing testis syndrome’’ [23]. The latter situation requires elective exploration to confirm the diagnosis and contralateral testicular fixation early on of the descended testis, which is now a solitary organ. The distinction is useful because exploration for an undescended testis is normally performed later on in infancy, before the first birthday. The main indications for orchidopexy are to preserve the fertility potential and, by placing the gonad in an accessible location, to facilitate the detection of a tumor should one develop later on in adult life. It is not known yet if early orchidopexy prior or at 1 year of age results in prevention of testis tumors in adulthood. Female genital anomalies in the newborn are rare. When labial adhesions are present, concern is occasionally raised regarding potential associated anomalies, such as intersex conditions or a urogenital sinus anomaly. Urologic consultation may be required to better delineate the anatomy. Occasionally,
Fig. 7. Example of a contraindication toneonatal circumcision: a concealed penis. Definitive surgical treatment is undertaken in infancy.
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examination under anesthesia following lysis of the labial adhesions and cystoscopy might be indicated. Imperforate hymen may rarely be associated with a suprapubic mass from accumulated vaginal secretions. The diagnosis is established following an ultrasound and an elective hymenectomy is undertaken. Finally, a red and swollen scrotum is always cause for concern. The differential diagnosis includes torsion of the spermatic cord, a hernia, or a hydrocoele. The latter may cause bluish discoloration of the overlying scrotal skin. Most noncommunicating hydrocoeles regress in time. A rapid increase or decrease in the size of the hydrocoele usually indicates the presence of a patent processus vaginalis and requires early exploration and repair. References [1] Seeds JW. Borderline genitourinary tract anomalies. Semin Ultrasound CT MR 1998;19(4): 347–54. [2] Tam JC, Hodson EM, Choong KKL, et al. Postnatal diagnosis and outcome of urinary tract abnormalities detected by antenatal ultrasound. Med J Aust 1994;160:633–7. [3] Gearhart JP, Ben Chaim J, Jeffs RD, et al. Criteria for the prenatal diagnosis of classic bladder exstrophy. Obstet Gynecol 1995;85(6):961–4. [4] American Academy of Pediatrics Committee on Quality Improvement and Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999; 103:843–52. [5] Lin DS, Huang SH, Lin CC, et al. Urinary tract infection in febrile infants younger than eight weeks of age. Pediatrics 2000;105(2):e20. [6] Rajfer J, Walsh PC. The incidence of intersexuality in patients with hypospadias and cryptorchidism. J Urol 1976;116:769–70. [7] Donahoe PK, Powell DM, Lee MM. Clinical management of intersex abnormalities. Curr Probl Surg 1991;28:513–79. [8] Stone KT, Kass EJ, Caciarlli AA, et al. Management of suspected antenatal torsion: what is the best strategy? J Urol 1995;153:782–4. [9] Kay R. Prepubertal testicular tumor registry. J Urol 1993;140:1109–12. [10] Van Savage JG, Mesrobian H-GJ. The impact of prenatal sonography on the morbidity and outcome of patients with renal duplication anomalies. J Urol 1995;153:768–70. [11] Gilanz V, Fernal W, Reid BS, et al. Nephrolithiasis in premature infants. Radiology 1985; 154(1):107–10. [12] Noe NH, Bryant JF, Roy S III, et al. Urolithiasis in preterm neonates associated with furosemide therapy. J Urol 1984;132:93–4. [13] Mesrobian H-GJ. Exstrophy of the bladder. In: King L, editor. Urologic surgery in neonates and young infants. Philadelphia: W.B. Saunders and Company; 1988. p. 265–90. [14] Grady RW, Mitchell ME. Exstrophy and epispadias anomalies in adult and pediatric urology, vol. 3. 4th edition. Lippincott Williams & Wilkins; 2002;49B:e2269. [15] Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 week gestation: incidence and outcome. Am J Obstet Gynecol 1995;172: 479–86. [16] Freedman AL, Johnson MP, Smith CA, et al. Long term outcome in children after antenatal intervention for obstructive uropathies. Lancet 1999;354:374–7. [17] Stevenson RE. Decline in prevalence of neural tube defects in a high risk region of the United States. Pediatrics 2000;106(4):677–83.
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[18] Bauer SB, Hallet M, Khoshbin S, et al. The predictive value of urodynamic evaluation in the newborn with myelodysplasia. JAMA 1984;152:650–2. [19] Klose AG, Sacket CK, Mesrobian H-G. Management of children with myelodysplasia: urologic alternatives. J Urol 1990;144:1446–9. [20] Koh CJ, Defilippo RE, Borer JG, et al. Lower urinary tract function after fetal closure of myelomeningocele. J Urol 2003;169(4):106. [21] Shaul DB, Harrison EA. Classification of anorectal malformation: initial approach, diagnostic test, and colostomy. Semin Pediatr Surg 1997;6:187–95. [22] Mesrobian H-G. Pediatric urethral diverticulum. In: Graham SD, editor. Glenn’s urologic surgery. 5th edition. Philadelphia, New York: Lippincott-Raven; 1998. p. 795–7. [23] Mesrobian H-G, Chassaignac JM, Laud PW. The presence or absence of an impalpable testis can be predicted from clinical observations alone. BJU Int 2002;90:97–9. [24] Edmondson JD, Maizels M, Alpert SA, et al. Multi-institutional experience with PIC cystography-Incidence of occult vesicoureteral reflux in children with febrile urinary tract infections. Urology 2006;67(3):608–11.
Urologic Problems of the Neonate: An Update Hrair-George O. Mesrobian, MD, MSc Department of Urology, Division of Pediatric Urology, Medical College of Wisconsin, Children’s Hospital of Wisconsin, 9000 W. Wisconsin Avenue, Children’s Hospital Office Building, Suite 606, Milwaukee, WI 53226, USA
During the last 2 decades of the twentieth century, maternal sonography became integrated into routine prenatal care. As a result, numerous anomalies are now detected in the fetus. This practice has had a profound influence on the presentation and natural history of urologic problems in the neonate. Genitourinary anomalies are the most common organ system anomaly detected by the routine use of maternal sonography. In an attempt to reflect the clinical scenario, this article is divided into two main parts. The first part addresses the clinical questions raised by prenatally detected anomalies, abdominal masses, urosepsis, urinary retention, scrotal masses, and abnormal external genitalia. The second part is a discussion of specific anomalies with respect to evaluation and management, including controversies, and optimum timing for referral to a tertiary care center. The selected anomalies include renal anomalies, tumors, the exstrophy complex, urogenital anomalies, ambiguous genitalia, posterior urethral valves, scrotal anomalies, spina bifida, and common urologic syndromes such as the triad syndrome. Our knowledge regarding the pathophysiology and therefore treatment of these conditions is constantly expanding and changing. This article represents an updated version of the article originally published in the August 2004 issue of Pediatric Clinics. Space constraints do not allow this article to be comprehensive and the reader is referred to urologic texts for additional information.
A version of this article entitled ‘‘Urologic problems of the neonate’’ by Hrair-George O. Mesrobian, MD, Anthony H. Balcom, MD, and Charles T. Durkee, MD appeared in Pediatric Clinics: Common Issues and Concerns in the Newborn Nursery, Part II (Volume 51, Issue 4, August 2004). E-mail address: [email protected] 0095-5108/07/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.clp.2007.09.004 perinatology.theclinics.com
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Clinical presentation of urologic problems in the neonate Prenatally detected urologic anomalies Hydronephrosis is the most common urologic anomaly detected in the fetus. It can be unilateral or bilateral, with or without oligohydramnios. The kidneys, bladder, and amniotic fluid are normally visualized by ultrasound as early as 12 weeks, using either a transabdominal or an endovaginal technique [1]. As pregnancy progresses, the appearance of the kidneys becomes better defined. The bladder can be observed to fill and empty and volumes can be derived. Normally, the fetal renal pelvis is not observed by ultrasound. It is generally accepted that an anteroposterior measurement of greater than 5 mm at 20 weeks’ gestation and 8 mm at 33 weeks’ gestation may be associated with the need of neonatal intervention [2]. Oligohydramnios may be associated with renal dysplasia or urinary tract obstruction such as posterior urethral valves, and constitutes one of the clearest indications for referral to a tertiary care center. Despite the technical accuracy of modern sonographic equipment, the diagnosis of a specific disease presenting with prenatal hydronephrosis is not firmly established until following birth. In the neonate, the work-up consists of a repeat renal ultrasound followed by a voiding cystourethrogram. The latter will detect anomalies that may be causing the hydronephrosis (for example an ectopic ureterocoele) or that may be associated with the hydronephrosis, such as vesicoureteral reflux. The sensitivity and specificity of ultrasound in diagnosing other urologic anomalies is low. For example, persistent nonvisualization of the bladder is highly suggestive of a bladder or cloacal exstrophy; however, in one series, only in 3 out of 25 was this diagnosis made prospectively [3]. The differential diagnosis includes more life-threatening conditions such as gastroschisis, if a deficiency of the ventral abdominal wall is identified. Prompt referral to a tertiary center is desirable. Urosepsis and urinary retention In general, the probability that a febrile infant might have a urinary tract infection (UTI) is 5% [4]. In newborns and up to 8 weeks of age, this probability may be much higher [5]. Although febrile UTIs are commonly considered to be more prevalent in females, the risk appears to be greatest for the uncircumcised male. Thus, the possibility of a UTI being present in a febrile newborn or infant should be high on the list in the differential diagnosis and should guide the subsequent work-up. The definitive diagnostic test is a positive urine culture obtained through suprapubic aspiration or urethral catheterization. A false-positive culture obtained via a bag specimen may lead to inappropriate treatment and misdiagnosis. The urinalysis, which is immediately available, is suggestive but not diagnostic. This is so because although the leukocyte esterase test has high sensitivity, it lacks in specificity; conversely, the nitrite test behaves in the opposite direction
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[4]. When combined with microscopic findings, the sensitivity approaches 100% when all three are positive, and the specificity is 100% when all three are negative. When a UTI has been diagnosed, treatment with broad-spectrum intravenous antibiotics is paramount. Once a clinical response has been documented, evaluation with a voiding cystourethrogram and ultrasound study of the kidneys are indicated. The incidence of structural urinary tract anomaliesdvesicoureteral reflux, posterior urethral valves, ureteral ectopia or ureterocoeles, ureteropelvic junction (UPJ) disease and other less common anomaliesdat this young age is 30% to 50% [4]. Recently, Edmondson et al have reported on the value of positional instillation cystography (PIC) which can detect occult reflux in 82% of children with febrile urinary tract infections. A muti-institutional prospective randomized trial is under way to further determine the clinical significance of PIC positive reflux [24]. A substantial number of these will require surgical treatment; therefore, the ultrasound study should be obtained as soon as the diagnosis of UTI is made. If the initial ultrasound study reveals normal kidneys, the voiding cystourethrogram can be delayed until the newborn has been deemed to respond clinically to antibiotics. Rarely is percutaneous drainage of an obstructed and infected renal moiety indicated in addition to antibiotics. Urinary retention in the newborn is alarming. Most are expected to void within the first 8 hours of life, although voiding can normally occur for the first time at the 24th hour! It is important to emphasize that a normal void or even a normal stream does not rule out the presence of significant lower urinary tract obstruction. The muscular bladder may initially compensate by expressing urine with a normal stream in the face of significant urethral obstruction. The presence of a suprapubic mass on palpation in a boy, for example, is very suspicious of posterior urethral valves. Other causes for urinary retention include ectopic ureterocoeles (especially in girls), spina bifida, pelvic teratoma, and urogenital sinus anomalies. The latter is usually associated with hydrocolpos or metrocolpos, or both. The work-up should always begin with an abdominal ultrasound study following catheter drainage of the bladder. Anomalies of external genitalia, including acute scrotal conditions Acute scrotal masses and anomalies of the external genitalia are a cause for alarm in the newborn period, and must be handled with great sensitivity toward the family. Whereas hypospadias occurs in 1 out of 250 live male births, associated findings such as bilateral undescended gonads must raise a red flag and intersex suspected [6]. The presence of ambiguous genitalia is a medical emergency requiring a precise diagnosis. In general, one should assess whether one or two gonads are descended or even palpated. Their presence rules out female pseudohermaphrotism because ovaries do not descend. Examination of the phallus for size and configuration is essential. The
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average phallic size in the term male infant is 3.5 cm measured from the symphysis pubis to the stretched glans. In addition, the diameter of the term male penis is 1 to 1.5 cm. A phallic length of less than 2 cm at any gestational age should raise concern [7]. The presence or absence of a uterus can be assessed by pelvic sonography. Laboratory evaluation includes determination of chromosomal sex and biochemical findings. The urogenital sinus is evaluated by retrograde injection of contrast defining the confluence of the vagina and urethra. In the newborn period, the presence of an acute scrotal condition may be subtle and may consist initially of scrotal redness and a mass. The nature of the mass (cystic or solid) can be determined by transillumination. A hydrocoele readily transilluminates, whereas extravaginal torsion of the spermatic cord does not. The differential diagnosis in the latter situation includes an incarcerated hernia, a scrotal hematoma, or a testicular tumor. An incarcerated hernia warrants prompt surgical correction, not only to preserve bowel integrity but also to avoid ipsilateral spermatic cord compression and testicular ischemia. Unlike the treatment of testicular torsion in adolescents, salvage of a neonatal torsed testis remains an exceedingly rare occurrence [8] (Fig. 1). Most pediatric urologists will recommend exploration and contralateral testicular fixation if the baby is stable and the risks of anesthesia are not increased by comorbidities. Otherwise, the contralateral fixation is postponed until the neonate’s overall condition has improved. Occasionally the diagnosis cannot be established, and exploration may become mandatory, so as not to overlook other conditions, such as an incarcerated inguinal hernia. Neonatal testicular tumors are rare. The most recent report from the Prepubertal Testicular Tumor registry describes gonadal stromal tumors as the most common, followed by yolk sac tumors and mature teratoma [9]. Orchiectomy can be curative in the latter situation.
Fig. 1. Extravaginal torsion of testis with necrosis at exploration in newborn. Black arrow points to the twisted spermatic cord.
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Urologic anomalies in the neonate Renal anomalies and tumors Unilateral or bilateral ureteropelvic junction disease, renal duplication anomalies with hydronephrosis of one of the moieties (usually the upper pole), and multicystic kidney disease are the most common anomalies. Occasionally, a multicystic kidney on one side may be associated with UPJ disease on the opposite side, with the combination leading to varying degrees of renal failure (Fig. 2A, B). The neonate may be asymptomatic when the anomaly is detected during the course of maternal sonography or less commonly nowadays, presenting with an abdominal mass or urosepsis. The impact of prenatal sonography on the postnatal management of renal anomalies has been variably documented [10]. In general, unilateral disease with a normal contralateral kidney rarely constitutes an emergency. An exception might be the newborn in whom a hydronephrotic upper pole moiety is associated with a large unilateral ectopic ureterocoele obstructing the bladder outlet. Although the initial postnatal ultrasound study can visualize the ureterocoele in the bladder as a large filling defect, a voiding cystourethrogram confirms the diagnosis and associated findings such as vesicoureteral reflux and bladder outlet obstruction. It is desirable to start prophylactic antibiotics until definitive surgical treatment. Less common but life-threatening renal anomalies include infantile polycystic kidney disease and solid tumors. The former is associated with a poor prognosis. An emergent nephrectomy may be required because of respiratory embarrassment induced by the sheer size of these kidneys. The most common renal tumor in the newborn is the mesoblastic nephroma, which is unilateral and is cured with a nephrectomy. The differential diagnosis, however, should include a neuroblastoma
Fig. 2. (A) Multicystic kidney removed because of hypertension. (B) Burnt-out solitary kidney secondary to ureteropelvic junction obstruction (thin white arrow) removed at time of kidney transplantation. Thick arrow points to remaining sliver of parenchyma on top of a distended and tense hydronephrotic renal pelvis.
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arising in the retroperitoneum and engulfing the kidney, and less commonly a teratoma. Finally, no discussion of renal anomalies in the newborn is complete without mentioning nephrolithiasis. With the improved care and outcome of premature neonates, diuretic use has led to a 2.5% to 11% incidence of renal calcifications, depending on the weight of the baby [11]. Nephrolithiasis is induced by the high doses of diuretics (especially furosemide) required to treat bronchopulmonary dysplasia, the prolonged half-life of furosemide in premature infants, and secondary hyperparathyroidism. Urinary calcium excretions as high as 30 mg/kg/day have been recorded (normal is ! 1.24) [12]. Fortunately, these calculi rarely cause symptoms or obstructive hydronephrosis. Treatment is medical and nonoperative, and consists of administration of chlorothiazide. Bladder and cloacal exstrophy The exstrophic complex of anomalies ranges from epispadias to cloacal exstrophy. The most common anomaly consists of classic bladder exstrophy (Fig. 3), in which the bladder is situated on the anterior abdominal wall, with partial midline separation of the symphysis pubis. In boys, the penis is short, stubby, and curves toward the abdominal wall. The urethra consists of a plate, the perineum is displaced anteriorly, and the umbilicus is absent. In girls, the vagina can be identified underneath the urethral plate inferiorly and the clitoris is bifid [13]. The kidneys are normal and, remarkably, there are very few associated anomalies. The diagnosis is rarely made prenatally and most parents are ill prepared to understand the implications of exstrophy. They should be reassured regarding their baby’s sexual identity and that the anomaly is treatable with surgery. At birth, the exstrophic bladder is protected by an inert barrier and kept moist by directed humidified air. As
Fig. 3. Classic exstrophy of the bladder in boy. Arrow points to epispadiac penis with absence of urethra and dorsal penile curvature. Both testes were descended and the kidneys normal by ultrasound.
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soon as feasible, the baby is transported to a tertiary care center for immediate surgical closure. Early closure within the first 72 hours of life is advocated. Long-term outcome of exstrophy closure is quite good, with preservation of renal and sexual function, achievement of normal appearing abdominal wall and genitalia, and urinary continence rates approaching 80% [14]. Cloacal exstrophy presents more challenges to the patient and the surgical team. This anomaly is a form of ventral abdominal wall defect consisting of an omphalocoele on top of a vesicointestinal plate inferiorly. The intestinal plate divides the bladder into two halves and contains the opening of the terminal ileum and the hindgut. In the male, the corpora are widely separated and the penis is diminutive. Associated anomalies are common and involve the gastrointestinal, vertebral, skeletal, and urinary systems. A multidisciplinary approach in a tertiary care center offers the best opportunity for a successful outcome. Posterior urethral valves The most common form of posterior urethral valves (or membrane) occurs just distal to the prostate, in the membranous portion of the male urethra. Because of early onset during development, valves can cause severe bilateral hydronephrosis and oligohydramnios. On the other hand, the variability in the degree of obstruction and in the response of the bladder is such that renal architecture and function may be preserved. Therefore, the spectrum of presentation in the newborn may range from renal failure, pulmonary hypoplasia, and abdominal ascites to normal voiding, with the diagnosis established only by virtue of prenatally detected hydronephrosis [15]. Consequently, when suspected, referral to a tertiary care center is essential. A few fetuses will be candidates for prenatal intervention, with the placement of a vesicoamniotic shunt [16] requiring postnatal removal and definitive surgical treatment. The diagnosis is suggested by sonography with hydronephrosis and distention and thickening of the bladder wall. The voiding cystourethrogram establishes the diagnosis with the typical appearance of the posterior urethra (Fig. 4). Placement of a simple 5 or 8 French feeding tube in the bladder while awaiting definitive treatment can be life-saving. The prune belly or triad syndrome enters in the differential diagnosis of posterior urethral valves, both prenatally and during imaging. Both conditions can be associated with hydronephrosis, a dilated posterior urethra, and oligohydramnios. The triad syndrome consists of absence of abdominal wall musculature, cryptorchidism, and hydronephrosis. The incidence is approximately 1 in 50,000 live births and it occurs almost exclusively in males. As with posterior urethral valves, the degree of renal failure at presentation can vary. In-utero intervention via placement of vesicoamniotic shunt has been advocated when oligohydramnios is documented (Fig. 5). Postnatal management is individualized. Many newborns require CIC (intermittent
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Fig. 4. Voiding cystourethrogram in newborn boy who has posterior urethral valves. White arrow points to valves with proximal dilation and elongation of the posterior urethra. Thick black arrow points to bladder with hypertrophy of its neck. Grade V vesicoureteral reflux is seen in one of the ureters (thin black arrow).
catheterization) or creation of a vesicostomy for the treatment of urinary retention. Subsequent surgical treatment may include a bilateral orchidopexy, ureteral tapering and reimplantation, and in some cases, an abdominoplasty later on in life. Fertility has been difficult to achieve, although in-vitro techniques have resulted in successes.
Fig. 5. Typical appearance of the belly in the Triad syndrome. Note the vesicoamniotic shunt that was placed in utero for oligohydramnios and the bilateral undescended testicles.
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Spina bifida The introduction of folic acid in the diet of pregnant mothers and to a variable extent, elective termination of pregnancy when the anomaly is detected prenatally, have resulted in a reduction in the incidence of newborns with spina bifida over the last 2 decades [17]. Nevertheless, spina bifida continues to occur and presents multiple challenges best addressed by a multidisciplinary team of neonatologists, neurosurgeons, orthopedic specialists, and urologists. The long-term urologic goals are prevention of upper tract deterioration and urinary tract infections, and promotion of urinary continence. In the newborn period and after the spinal defect has been surgically closed, treatment is expectant. Occasionally urinary retention occurs; it is treated best with intermittent catheterization and is usually transient [18]. Hydronephrosis with or without reflux is present in up to 20% of patients at birth. In addition to careful monitoring, prophylactic antibiotics may be indicated to prevent pyelonephritis and its consequences. Urodynamic studies to evaluate the exact nature of bladder dysfunction are undertaken during the first 3 months of life. Depending on the findings, prophylactic CIC may be indicated [18] in some cases, although most newborns are successfully managed with careful imaging and instituting CIC at the first sign of hydronephrosis [19]. Most recently, successful in-utero closure of the spinal defect has been achieved at an average median age of 24 weeks’ gestation [20]. The anticipated benefits of improved lower extremity and bladder function and subsequent quality of life have to await long-term follow-up. Urogenital sinus anomalies and imperforate anus Newborns presenting with a single perineal opening may have a urogenital sinus anomaly or a persistent cloaca (Fig. 6). The anus in the latter situation is imperforate. In the newborn period, the urologic management is focused on adequate drainage of the bladder. Frequently, CIC can fulfill this objective; however, creation of a vesicostomy may be required in many patients because of mechanical difficulty with CIC. Careful imaging of the upper urinary tracts is mandatory to screen for associated anomalies such as renal agenesis, fusion anomalies, and hydronephrosis. Associated anomalies such as hemivertebrae or sacral agenesis may be present. Definitive surgical reconstruction is undertaken at or around 1 year of age. Newborns with imperforate anus have a high incidence of associated urologic anomalies, especially in the male with a high lesion [21]. Early screening with upper and lower tract imaging can result in their recognition and potentially prevent serious morbidity. Associated urinary tract anomalies include vesicoureteral reflux, unilateral renal agenesis, fusion anomalies, and hydronephrosis. Spinal cord anomalies, when present, can lead to neurogenic bladder dysfunction. Treatment of the associated anomalies is disease specific.
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Fig. 6. Urogenital sinus anomaly. Arrow points to single opening of vagina and urethra. The confluence of the two was proximal to the outlet.
Genital anomalies Hypospadias is the most common genital anomaly in boys. It does not require any treatment in the newborn period. Circumcision should be avoided, because the presence of the foreskin is a necessary ingredient in the completion of a successful repair later on in infancy. One should be aware of the megameatus intact-prepuce variant of hypospadias, which may not be discovered until a circumcision is initiated or completed. In this variant, the ventral prepuce is intact. When discovered following a dorsal slit at the time of the circumcision, it is advised to abort the procedure, apply Vaseline gauze on the incision, and refer the patient to a pediatric urologist. Associated anomalies include chordee (ventral curvature of the penile shaft), penoscrotal inversion, bifid scrotum, and cryptorchidism. Hypospadias is repaired in infancy and may require more than one stage. Other urethral anomalies in the newborn include urethral duplication, megalourethra, and urethral diverticulum. The latter may cause lower urinary tract obstruction secondary to an obstructing valvelike projection of the anterior lip of the diverticulum into the urethra [22]. In fact, the condition is sometimes referred to as anterior urethral valves. Although the prepuce is not an anomaly, contraindications to circumcision in the newborn are worthwhile mentioning. These include the presence of hypospadias, chordee without hypospadias, concealed penis or penile engulfment (Fig. 7), and penoscrotal webbing or scrotal transposition. Pematurity with a small penis and a known bleeding diathesis are additional contraindications. Conversely, 50% of patients who have a bleeding diathesis come to the clinician’s attention for the first time with postcircumcision bleeding. Thus, any significant bleeding following a circumcision requires a full hematologic evaluation. Finally, circumcisions are best deferred in the presence of other associated conditions requiring surgical treatment.
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The testes originate in the retroperitoneum just lateral to the mesonephros. Subsequently, during gestation they descend to the level of the internal ring, where they reside until shortly before birth. Their final descent into the scrotum is completed shortly before or following birth. Given this long and tortuous route, it is amazing that so many complete the journey! Cryptorchidism or testicular maldescent is the most common of all anomalies in boys. Its incidence ranges from 33% in prematurity to 3% in full-term boys. It is essential to carefully document the presence or absence of a testis in the newborn period. It is also desirable to palpate the scrotum for the presence of appendages or what might represent an atrophic testicle secondary to prenatal torsion of the spermatic cord. In this situation, the contralateral descended testis may exhibit compensatory hypertrophy (length exceeding 2 cm). The combination of compensatory hypertrophy on the descended side and an empty scrotum on the undescended side is associated with prenatal torsion, the so-called ‘‘vanishing testis syndrome’’ [23]. The latter situation requires elective exploration to confirm the diagnosis and contralateral testicular fixation early on of the descended testis, which is now a solitary organ. The distinction is useful because exploration for an undescended testis is normally performed later on in infancy, before the first birthday. The main indications for orchidopexy are to preserve the fertility potential and, by placing the gonad in an accessible location, to facilitate the detection of a tumor should one develop later on in adult life. It is not known yet if early orchidopexy prior or at 1 year of age results in prevention of testis tumors in adulthood. Female genital anomalies in the newborn are rare. When labial adhesions are present, concern is occasionally raised regarding potential associated anomalies, such as intersex conditions or a urogenital sinus anomaly. Urologic consultation may be required to better delineate the anatomy. Occasionally,
Fig. 7. Example of a contraindication toneonatal circumcision: a concealed penis. Definitive surgical treatment is undertaken in infancy.
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examination under anesthesia following lysis of the labial adhesions and cystoscopy might be indicated. Imperforate hymen may rarely be associated with a suprapubic mass from accumulated vaginal secretions. The diagnosis is established following an ultrasound and an elective hymenectomy is undertaken. Finally, a red and swollen scrotum is always cause for concern. The differential diagnosis includes torsion of the spermatic cord, a hernia, or a hydrocoele. The latter may cause bluish discoloration of the overlying scrotal skin. Most noncommunicating hydrocoeles regress in time. A rapid increase or decrease in the size of the hydrocoele usually indicates the presence of a patent processus vaginalis and requires early exploration and repair. References [1] Seeds JW. Borderline genitourinary tract anomalies. Semin Ultrasound CT MR 1998;19(4): 347–54. [2] Tam JC, Hodson EM, Choong KKL, et al. Postnatal diagnosis and outcome of urinary tract abnormalities detected by antenatal ultrasound. Med J Aust 1994;160:633–7. [3] Gearhart JP, Ben Chaim J, Jeffs RD, et al. Criteria for the prenatal diagnosis of classic bladder exstrophy. Obstet Gynecol 1995;85(6):961–4. [4] American Academy of Pediatrics Committee on Quality Improvement and Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment and evaluation of the initial urinary tract infection in febrile infants and young children. Pediatrics 1999; 103:843–52. [5] Lin DS, Huang SH, Lin CC, et al. Urinary tract infection in febrile infants younger than eight weeks of age. Pediatrics 2000;105(2):e20. [6] Rajfer J, Walsh PC. The incidence of intersexuality in patients with hypospadias and cryptorchidism. J Urol 1976;116:769–70. [7] Donahoe PK, Powell DM, Lee MM. Clinical management of intersex abnormalities. Curr Probl Surg 1991;28:513–79. [8] Stone KT, Kass EJ, Caciarlli AA, et al. Management of suspected antenatal torsion: what is the best strategy? J Urol 1995;153:782–4. [9] Kay R. Prepubertal testicular tumor registry. J Urol 1993;140:1109–12. [10] Van Savage JG, Mesrobian H-GJ. The impact of prenatal sonography on the morbidity and outcome of patients with renal duplication anomalies. J Urol 1995;153:768–70. [11] Gilanz V, Fernal W, Reid BS, et al. Nephrolithiasis in premature infants. Radiology 1985; 154(1):107–10. [12] Noe NH, Bryant JF, Roy S III, et al. Urolithiasis in preterm neonates associated with furosemide therapy. J Urol 1984;132:93–4. [13] Mesrobian H-GJ. Exstrophy of the bladder. In: King L, editor. Urologic surgery in neonates and young infants. Philadelphia: W.B. Saunders and Company; 1988. p. 265–90. [14] Grady RW, Mitchell ME. Exstrophy and epispadias anomalies in adult and pediatric urology, vol. 3. 4th edition. Lippincott Williams & Wilkins; 2002;49B:e2269. [15] Gunn TR, Mora JD, Pease P. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 week gestation: incidence and outcome. Am J Obstet Gynecol 1995;172: 479–86. [16] Freedman AL, Johnson MP, Smith CA, et al. Long term outcome in children after antenatal intervention for obstructive uropathies. Lancet 1999;354:374–7. [17] Stevenson RE. Decline in prevalence of neural tube defects in a high risk region of the United States. Pediatrics 2000;106(4):677–83.
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[18] Bauer SB, Hallet M, Khoshbin S, et al. The predictive value of urodynamic evaluation in the newborn with myelodysplasia. JAMA 1984;152:650–2. [19] Klose AG, Sacket CK, Mesrobian H-G. Management of children with myelodysplasia: urologic alternatives. J Urol 1990;144:1446–9. [20] Koh CJ, Defilippo RE, Borer JG, et al. Lower urinary tract function after fetal closure of myelomeningocele. J Urol 2003;169(4):106. [21] Shaul DB, Harrison EA. Classification of anorectal malformation: initial approach, diagnostic test, and colostomy. Semin Pediatr Surg 1997;6:187–95. [22] Mesrobian H-G. Pediatric urethral diverticulum. In: Graham SD, editor. Glenn’s urologic surgery. 5th edition. Philadelphia, New York: Lippincott-Raven; 1998. p. 795–7. [23] Mesrobian H-G, Chassaignac JM, Laud PW. The presence or absence of an impalpable testis can be predicted from clinical observations alone. BJU Int 2002;90:97–9. [24] Edmondson JD, Maizels M, Alpert SA, et al. Multi-institutional experience with PIC cystography-Incidence of occult vesicoureteral reflux in children with febrile urinary tract infections. Urology 2006;67(3):608–11.