Committee I

Committee IX

Pediatric Congenital Anomalies

Prof. Hesham A Badawy, MD, Professor of Urology, Kasr El-Ainy Medical School, Cairo University

Prof. Hany AR Morsi, MD,Professor of Urology, Kasr El-Ainy Medical School, Cairo University

Prof. Mohamad Yousef, MD Professor of Urology, Faculty of Medicine, Alexandria University

Ass. Prof. Ahmad A Elderwy, MD,Assistant Professor of Urology, Faculty of Medicine, Assiut University

Ass. Prof. Ahmed MN Sakr, MD, Assistant Professor of Urology, Faculty of Medicine, Zagazig University

Dr. Ahmad Abdelhalim, MD , Lecturer of Urology, Mansoura Urology and Nephrology Center, Mansoura University

Contents
IX.1 Abbreviations
  • AAP - American Academy of Pediatrics
  • AUA - American Urologic Association
  • ARM - Anorectal Malformation
  • BBD - Bladder and Bowel Dysfunction
  • BOO - Bladder Outlet Obstruction
  • CAIS - Complete Androgen Insensitivity Syndrome
  • CAH - Congenital Adrenal Hyperplasia
  • CAP - Continuous Antibiotic Prophylaxis
  • DO - Detrusor Overactivity
  • DMSA - Dimercaptosuccinic Acid
  • DSD - Disorders of Sex Development
  • EAU - European Association of Urology
  • ESPU - European Association of Pediatric Urology
  • 5Fr - Five French
  • GnRH - Gonadotrophin Releasing Hormone
  • hCG - Human Chorionic Gonadotrophin
  • IV - Intravenous
  • MACE - Malone Antegrade Continence Enema
  • MAGPI - Meatoplasty And Glans Plasty
  • MIP - Megameatus Intact Prepuce
  • MCUG - Micturating Cystourethrogram
  • MGD - Mixed Gonadal Dysgenesis
  • MRI - Magnetic resonance imaging
  • PAIS - Partial Androgen Insensitivity Syndrome
  • PUV - Posterior Urethral Valves
  • US - Ultrasound
  • UDT - Undescended Testis
  • UPJ - Ureteropelvic Junction
  • UVJ - Ureterovesical Junction
  • UTIs - Urinary Tract Infections
  • VUR - Vesicoureteral Reflux
  • VUDS - Videourodynamics
  • VCUG - Voiding Cystourethography
  • WBCs - White Blood Cells

IX.2 Introduction:

This guideline document is based mainly on the guidelines compiled by the European Association of Urology (EAU), The European Association of Pediatric Urology (ESPU) as well as the American Urological Association (AUA) guidelines. It is not intended to cover the entire field of pediatric urology but rather a number of common clinical pathologies in pediatric urological practice. It integrates some local experts’ opinions based on Egyptian healthcare practice and socioeconomic circumstances.

IX.3 SCROTAL:

IX.3.1 Cryptorchidism or Undescended testis:
A true undescended testis is on its normal path of descent but is halted on its way down to the scrotum. Depending on the location, the testes may be palpable or not, as in the case of testes arrested in the inguinal canal. Cryptorchidism or undescended testis (UDT) is one of the most common pediatric disorders identified at birth. The main reasons for treatment are increased risks of impairment of fertility potential and testicular malignancy. Successful scrotal relocation of the testis (orchiopexy), may reduce but does not totally prevent these potential long-term sequelae. The most useful classification of undescended testes is into palpable and non-palpable testes. Approximately 80% of all UDT are palpable. The current standard of therapy according to the European and North American guidelines is orchiopexy. Hormonal therapy which played an important role in the past, has very few advocates.(1)

IX.3.2 Diagnosis:
  1. History obtained from obstetric notes at time of delivery.
  2. Scrotal palpation of testes for quality (size and consistence) and position.
  3. Primary care providers (pediatrician, family physician) should refer infants with a history of cryptorchidism (detected at birth), who do not have spontaneous testicular descent by six months to an appropriate surgical specialist for timely evaluation.
  4. All phenotypic male newborns with bilateral, nonpalpable testes should be evaluated for possible DSD (disorder of sexual development), particularly those with severe types of hypospadias.
  5. Imaging studies cannot determine with certainty that a testis is present or not. Ultrasound (US) lacks the diagnostic sensitivity to detect the testis confidently or establish the absence of an intra-abdominal testis Consequently, the use of different imaging modalities, such as US or Magnetic resonance imaging (MRI), for undescended testes is limited and only recommended in specific and selected clinical scenarios (e.g. identification of Müllerian structures in cases with suspicion of DSDs).
  6. In boys with retractile testes, the position of the testes should be monitored annually to check for secondary reascent(1).
IX.3.1.2       Management:
• IX.3.1.2.1 Undescended Testes:

Timing of surgery: Because undescended testes rarely descend after the age of 6 months, treatment should be started at that age, and should be finished by twelve months, or eighteen months at the latest, to avoid progressive loss of germ cells and Leydig cells.

Hormonal treatment: most of the studies on hormonal treatment have been of poor quality, with heterogeneous and mixed patient populations, testis location, schedules and dosages of hormonal administration. Additionally, long-term data are almost completely lacking. Short-term side effects of hormonal treatment include increased scrotal erythema and pigmentation, the general consensus is that hormonal treatment is not recommended.(1)

Human chorionic gonadotropin Human chorionic gonadotropin stimulates endogenous testosterone production and is administered by intramuscular injecti Several dose and administration schedules are reported. There is no proven difference between 1.5 IU and weight-based doses up to 3.0 IU every other day for fourteen days. Similar response rates were achieved with 500 IU once weekly and 1.50 IU three times weekly. However, there is evidence that dosing frequency might affect testicular descent rates. Fewer lower dose injections per week for five weeks seem to be superior to one higher dose every seven to ten days for three weeks with regard to testicular descent.

Gonadotropin-releasing hormone Gonadotropin-releasing hormone analogues (e.g., buserelin and gonadorelin) are available as nasal sprays, thus avoiding painful intramuscular injections. A typical dosage regimen consists of 1.2 mg per day in three divided doses, for four weeks. Success rates are wide ranging, from 9 to 60%, due to multiple treatment strategies and heterogeneous patient populations

Medical therapy for fertility potential Hormonal treatment may improve fertility indices and therefore serve as an additional tool to orchidopexy. There is no difference in treatment with GnRH before (neo-adjuvant) or after (adjuvant) surgical orchidolysis and orchidopexy in terms of increasing fertility index, which may be a predictor for fertility later in life. It is still unknown whether this effect on testicular histology persists into adulthood but it has been shown that men who were treated in childhood with buserelin had better semen analyses compared with men who had childhood orchidopexy alone or placebo treatment.(1)

It is reported that hCG treatment may be harmful to future spermatogenesis through increased apoptosis of germ cells, including acute inflammatory changes in the testes and reduced testicular volume in adulthood.

Palpable undescended testes: Surgical management (orchidofunicolysis via inguinal or scrotal approach) is the mainstay of treatment.

Inguinal orchidopexy Inguinal orchidopexy is a widely-used technique with a high success rate of up to 92%. Important steps include mobilisation of the testis and spermatic cord to the level of the internal inguinal ring, with dissection and division of all cremasteric fibres, to prevent secondary retraction and detachment of the gubernaculum. The patent processus vaginalis needs to be ligated proximally at the level of the internal ring, because an unidentified or inadequately repaired patent processus vaginalis is an important factor leading to failure of orchidopexy]. Any additional pathology has to be taken care of, such as removal of an appendix testis (hydatid of Morgagni). At this moment, the size of the testis can be measured and the connection of the epididimis to the testis can be judged and described in the protocol. Some boys have a significant dissociation between testis and epididymis which is prognostically bad for fertility. Finally, the mobilised testicle needs to be placed in a sub-dartos pouch within the hemi-scrotum without any tension. In case the length achieved using the above-mentioned technique is still inadequate, the Prentiss manoeuvre, which consists of dividing the inferior epigastric vessels and transposing the spermatic cord medially, in order to provide a straight course to the scrotum, might be an option. With regard to fixation sutures, if required, they should be made between the tunica vaginalis and the dartos musculature.(2)

Scrotal orchidopexy Low-positioned, palpable undescended testis can be fixed through a scrotal incision including division of the gubernaculum, and the processus vaginalis needs to be probed to check for patency. Otherwise, fixation in the scrotum is carried out correspondingly to the inguinal approach. In up to 20% of cases, an inguinal incision will be compulsory to correct an associated inguinal hernia. Any testicular or epididymal appendages can be easily identified and removed. A systematic review shows that the overall success rates ranged from 88 to 100%, with rates of recurrence and post-operative testicular atrophy or hypotrophy < 1%.(3)

Non-palpable testes (20% of undescended testes, the aim is to determine whether a testis is present or not. If a testis is found, the decision has to be made to remove it or bring it down to the scrotum. It is essential to have a thorough re-examination under general anesthesia, since a previously non-palpable testis might be identifiable and subsequently change the surgical approach to standard inguinal orchidopexy. Otherwise, the easiest and most accurate way to locate an intra-abdominal testis is diagnostic laparoscopy. Subsequent removal or orchidolysis and orchidopexy can be carried out using laparoscopy and a scrotal incision. If an ipsilateral scrotal nubbin is suspected, and contralateral compensatory testicular hypertrophy is present, a scrotal incision with removal of the nubbin, thus confirming the vanishing testis, is an option avoiding the need for laparoscopy.(3-5)

Among the 20% of non-palpable testes, 50-60% are intra-abdominal, canalicular or peeping (right inside the internal inguinal ring). The remaining 20% are absent and 30% are atrophic or rudimentary. Orchidopexy of an intra-abdominal testis is a surgical challenge. Usually, testes lying > 2 cm above the internal inguinal ring may not reach the scrotum without division of the testicular vessels. Under such circumstances, a Fowler-Stephens orchidopexy may be an option. The key feature of the procedure is proximal transection of the testicular vessels, with conservation of the collateral arterial blood supply, via the deferential artery and cremasteric vessels. Transection of the testicular vessels puts the test is at risk of hypotrophy or atrophy if the collateral blood supply is insufficient. The testicular survival rate in the one-stage Fowler-Stephens technique varies between 50 and 60%, with success rates increasing up to 90% for the two-stage procedure. The advantages of two-stage orchidopexy, with the second part done usually six months after the first, are to allow for development of collateral blood supply and to create greater testicular mobility. In addition, preservation of the gubernaculum may also decrease the chance of testicular atrophy.(3-5)

IX.3.2 Ectopic Testes:
•If the position of a testis is outside its normal path of descent and outside the scrotum, the testis is considered to be ectopic. The most common aberrant position is in the superficial inguinal pouch. Sometimes an ectopic testis can be identified in a femoral, perineal, pubic, penile or even contralateral position. Usually, there is no possibility for an ectopic testis to descend spontaneously to the correct position; therefore, it requires surgical intervention. In addition, an ectopic testis might not be palpable due to its position.(3-5)

IX.3.3 Retractile Testes:
•Retractile testes are is one which have completed its descent into a proper scrotal position but can be found again in a suprascrotal position along the path of their normal descent. This is due to an overactive cremasteric reflex. Retractile testes can be easily manipulated down to the scrotum and remain there at least temporarily. There is no indication for orchidopexy in truly retractile testes. However, since one third can ascend (testicular reascent), they should be monitored carefully.(6)

IX.3.4 Undescended Testes after Puberty:
In a study on 51 men diagnosed with inguinal unilateral undescended testis and a normal contralateral one, with no previous therapy, significant germ cell activity at different maturation levels was found in nearly half of them. More importantly, the incidence of intratubular germ cell neoplasia was 2%. The Panel consensus of the ESPU recommends orchiectomy in post-pubertal boys with an undescended testis and a normal contralateral one in a scrotal position.(6)

IX.3.5 Undescended Testes and Malignancy:
•In a landmark Swedish study, with a cohort of almost 17,000 men treated surgically for undescended testes and followed long term, it was found that management of undescended testes before the onset of puberty decreased the risk of testicular cancer. The relative risk of testicular cancer was reduced from 5.4 to 2.2 compared to the Swedish general population among those who underwent orchidopexy before thirteen years of age and those treated after thirteen years of age. A systematic review and meta-analysis of the literature have also concluded that pre-pubertal orchidopexy may reduce the risk of testicular cancer and that early surgical intervention is indicated in boys with undescended testes.

IX.3.6 Complications of surgical Therapy:
•Surgical complications are usually uncommon, with testicular atrophy being the most serious. A systematic review revealed an overall atrophy rate for primary orchidopexy of 1.83%, 28.1% for one-stage Fowler-Stephens procedure, and 8.2% for the two-stage approach. Other rare complications comprise testicular ascent and vas deferens injury besides local wound infection, dehiscence, and hematoma.(5)



Table IX:1 Recommendations for management of undescended testis

Recommendation

strength rating
1. In boys with retractile testes, providers should assess the position of the testes at least annually to monitor for secondary ascent. Strong
2. Do not offer medical or surgical treatment for retractile testes until puberty. Strong
3. Perform surgical orchidolysis and orchidopexy before the age of twelve months, and by eighteen months at the latest. Strong
4. Evaluate male neonates with bilateral non-palpable testes for possible disorders of sex development. Strong
5. Providers should not perform ultrasound (US) or other imaging modalities in the evaluation of boys with cryptorchidism prior to referral, as these studies rarely assist in decision making. Strong
6. Perform a diagnostic laparoscopy to locate an intra-abdominal testicle. Strong
7. In prepubertal boys with nonpalpable testes, examination under anesthesia should be performed to reassess for palpability of testes. If nonpalpable, surgical or laparoscopic exploration and, if indicated, abdominal orchidopexy should be performed. Strong
8. In boys with a normal contralateral testis, surgical specialists may perform an orchiectomy (removal of the undescended testis) if a boy has a normal contralateral testis and either very short testicular vessels and vas deferens, dysmorphic or very hypoplastic testis, or postpubertal age Weak
9. Hormonal therapy in unilateral undescended testes is of no benefit for future paternity Weak
10. Offer endocrine treatment in case of bilateral undescended testes. Weak
11. Inform the patient/caregivers about the increased risk of a later malignancy and infertility with an undescended testis in post-pubertal boys or older. Weak

IX.3.7 References:

1. Penson D, Krishnaswami S, Jules A, McPheeters ML. Effectiveness of Hormonal and Surgical Therapies for Cryptorchidism: A Systematic Review. Pediatrics [Internet]. 2013 Jun 1;131(6):e1897–907. Available from: http://pediatrics.aappublications.org/cgi/doi/10.1542/peds.2013-0072

2. Koni A, Ozseker HS, Arpali E, Kilinc E, Dogan HS, Akyol A, et al. Histopathological Evaluation of Orchiectomy Specimens in 51 Late Postpubertal Men with Unilateral Cryptorchidism. J Urol [Internet]. 2014 Oct;192(4):1183–8. Available from: http://www.jurology.com/doi/10.1016/j.juro.2014.05.048

3. Patil KK, Green JSA, Duffy PG. Laparoscopy for impalpable testes. BJU Int [Internet]. 2005 Apr;95(5):704–8. Available from: http://doi.wiley.com/10.1111/j.1464-410X.2005.05434.x

4. PARSONS JK, FERRER F, DOCIMO SG. The Low Scrotal Approach to the Ectopic or Ascended Testicle: Prevalence of a Patent Processus Vaginalis. J Urol [Internet]. 2003 May;169(5):1832–3. Available from: http://www.jurology.com/doi/10.1097/01.ju.0000055606.02062.00

5. Hadziselimovic F, Herzog B. The importance of both an early orchidopexy and germ cell maturation for fertility. Lancet [Internet]. 2001 Oct;358(9288):1156–7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673601062742

6. Tasian GE, Hittelman AB, Kim GE, DiSandro MJ, Baskin LS. Age at Orchiopexy and Testis Palpability Predict Germ and Leydig Cell Loss: Clinical Predictors of Adverse Histological Features of Cryptorchidism. J Urol [Internet]. 2009 Aug;182(2):704–9. Available from: http://www.jurology.com/doi/10.1016/j.juro.2009.04.032

IX.4 Hydrocele:

Hydrocele is defined as a collection of fluid between the parietal and visceral layers of the tunica vaginalis. Primary hydrocele results from patency or incomplete obliteration of the processus vaginalis. This may result in the formation of various types of communicating hydrocele; a large open processus vaginalis allowing passage of abdominal viscera results in clinical hernia. If complete obliteration of the processus vaginalis occurs with patency of mid-portion, a hydrocele of the cord occurs. Scrotal hydroceles without associated patency of the processus vaginalis are also encountered in newborns. Non-communicating hydroceles, based on an imbalance between the secretion and re-absorption of this fluid, are found secondary to minor trauma, testicular torsion, epididymitis or varicocele operation (due to ligation of the lymphatics).
IX.4.1.1 Diagnosis:
Diagnosis is based on history taking and physical examination with transillumination. Hydroceles are not reducible but fluctuate in size and are not associated with symptoms. Ultrasound may be indicated if a hernia is suspected.
IX.4.2 Management:
Hydroceles have a great tendency to resolve spontaneously and the risk of testicular damage on follow-up and observation is minimal or non-existent. Accordingly, there is no indication for surgical intervention before 12 to 18 months.

The operation consists of ligation of the patent processus vaginalis via inguinal incision and the distal stump is left open, whereas in hydrocele of the cord the cystic mass is excised or unroofed.

The scrotal approach (Lord or Jaboulay technique) is used in the treatment of a secondary non-communicating hydrocele.

Table IX:2 Recommendations for Hydrocele management

Recommendation

strength rating
1. In the majority of infants, observe hydrocele for twelve months prior to considering surgical treatment. Strong
2. Perform early surgery if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology. Strong
3. Perform a scrotal ultrasound in case of doubt about the character of an intrascrotal mass. Strong

IX.4.3 References:

1. Stylianos S, Jacir NN, Harris BH. Incarceration of inguinal hernia in infants prior to elective repair.J Pediatr Surg [Internet]. 1993 Apr;28(4):582–3. Available from: https://linkinghub.elsevier.com/retrieve/pii/0022346893906658

2. Oh JH, Chung HS, Yu HS, Kang TW, Kwon D, Kim S-O. Hydrocelectomy via scrotal incision is a valuable alternative to the traditional inguinal approach for hydrocele treatment in boys. Investig Clin Urol [Internet]. 2018;59(6):416. Available from: https://icurology.org/DOIx.php?id=10.4111/icu.2018.59.6.416

3. Alp BF, Irkilata HC, Kibar Y, Zorba U, Sancaktutar AA, Kaya E, et al. Comparison of the inguinal and scrotal approaches for the treatment of communicating hydrocele in children. Kaohsiung J Med Sci [Internet]. 2014 Apr;30(4):200–5. Available from: http://doi.wiley.com/10.1016/j.kjms.2013.11.006

IX.5 Acute Scrotum:

Causes of acute scrotal pain:
  1. Ischemia:
    • Torsion of the testis (synonymous with torsion of the spermatic cord); Intravaginal; extravaginal (prenatal or neonatal)
    • Appendicular torsion, testis or epididymis
    • Testicular infarction due to compressive hydrocele or hernia
    • Testicular infarction due to other vascular insult (cord injury, thrombosis)
  2. Trauma:
    • Testicular rupture
    • Intratesticular hematoma, testicular contusion Hematocele
  3. Infectious conditions:
    • Acute epididymistis
    • Acute epididymoorchitiss
    • Acute orchitis
    • Abscess (intratesticulr, intravaginal, scrotal skin, cutaneous cysts)
    • Gangrenous infections (Fournier’s gangrene)
  4. Inflammatory conditions:
    • Henoch-Schonlein purpur (HSP) vasculitis of scrotal wall.
    • Fat necrosis, scrotal wall
  5. Henria:
    • Incarcerated, strangulated inguinal hernia, with or without associated testicular ischemia
  6. Acute or chronic events:
    • Spermatocele, rupture or hemorrhage
    • Hydrocele, rupture, hemaorrhage or infection
    • Testicular tumor with rupture, hemorrhage, infarction or infection

IX.5.1 Diagnosis

It is of paramount importance to distinguish patients with torsion of the testis from those with epididymitis or torsion of the appendix testis to avoid testicular loss, which can occur in a few hours. Typically, patients with torsion of the testis or appendix testis, present with excruciating pain and vomiting. The duration of symptoms is relatively shorter in testicular torsion and torsion of the appendix testes, compared to epididymitis. Early on, the location of the pain can help in differentiation. In testicular torsion, the pain is localized to the testis, and to the upper pole of the testis in appendicular torsion, whereas it is localized to the epididymis in epdidymitis/epididymo-orchitis A horizontal position of the testis (involved and contralateral testis) is more frequent in testicular torsion than in epididymitis. Elevation of the scrotum may reduce pain in epididymitis, but not in testicular torsion. Fever occurs more often in epididymitis. A normal urinalysis does not exclude epididymitis, similarly, an abnormal urinalysis does not exclude testicular torsion. When history and physical examination are still not conclusive, doppler US is useful to evaluate acute scrotum, with 63.6 -100% sensitivity and 97-100% specificity, a positive predictive value of 100% and negative predictive value of 97.5%. Doppler US may reduce the number of scrotal exploration but it may also show a misleading arterial flow in the early phases of torsion and in partial or intermittent torsion. Of key importance, persistent arterial flow does not exclude testicular torsion. So, at the end, in case of doubt it is always better to explore than to lose a testis.

IX.5.2 Management:

IX.5.2.1 Testicular torsion:
Manual detorsion is done by outward rotation of the testis unless the pain increases or if there is evident resistance. If successful, there is immediate relief of pain and normal examination. This is followed by immediate bilateral orchiopexy. Torsion of the appendix testis can be managed non-operatively using anti-inflammatory analgesics, particularly in those presenting late. It is re-emphasized that surgical exploration is strongly recommended in case of doubt, to avoid testicular loss.
IX.5.3 Epididymitis
In pre-pubertal boys, apart from an underlying pathology in 25%, in the majority, the etiology is unclear, with a negative urine culture. Nevertheless, antibiotic treatment is often started. Epididymitis is usually self-limiting and with supportive care (minimal physical activity and analgesics), it heals without any sequelae. Rarely, bacterial epididymitis can be complicated by abscess and surgical exploration is required. Table IX:3 Recommendations for management of acute scrotum

Recommendation

strength rating
1. Testicular torsion is a pediatric urological emergency and requires immediate treatment Strong
2. In neonates with testicular torsion perform orchidopexy of the contralateral testicle. In prenatal torsion; the timing of surgery is usually dictated by clinical findings. Weak
3. Base the clinical decision on physical examination. The use of Doppler ultrasound to evaluate acute scrotum is useful, but this should not delay the intervention. Strong
4. Manage torsion of the appendix testis conservatively. Perform surgical exploration in equivocal cases and in patients with persistent pain Strong
5. Perform urgent surgical exploration in all cases of testicular torsion within 24 hours of symptom onset. Strong

IX.5.4 References

1. Cavusoglu YH, Karaman A, Karaman I, Erdogan D, Aslan MK, Varlikli O, et al. Acute scrotum - - etiology and management. Indian J Pediatr [Internet]. 2005 Mar;72(3):201–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15812112

2. Mäkelä E, Lahdes-Vasama T, Rajakorpi H, Wikström S. A 19-Year Review of Paediatric Patients with Acute Scrotum. Scand J Surg [Internet]. 2007 Mar 22;96(1):62–6. Available from: http://journals.sagepub.com/doi/10.1177/145749690709600112
3. H. M, R. P, C. K, I. G. The incidence and investigation of acute scrotal problems in children. Pediatr Surg Int [Internet]. 2002 Jul 1;18(5–6):435–7. Available from: http://link.springer.com/10.1007/s00383-002-0806-3
4. Schalamon J, Ainoedhofer H, Schleef J, Singer G, Haxhija EQ, Höllwarth ME. Management of acute scrotum in children—the impact of Doppler ultrasound. J Pediatr Surg [Internet]. 2006 Aug;41(8):1377–80. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022346806003095

5. Murphy FL, Fletcher L, Pease P. Early scrotal exploration in all cases is the investigation and intervention of choice in the acute paediatric scrotum. Pediatr Surg Int [Internet]. 2006 May 7;22(5):413–6. Available from: http://link.springer.com/10.1007/s00383-006-1681-0

6. SOMEKH E, GORENSTEIN A, SEROUR F. Acute Epididymitis in Boys: Evidence of a PostInfectious Etiology. J Urol [Internet]. 2004 Jan;171(1):391–4. Available from: http://www.jurology.com/doi/10.1097/01.ju.0000102160.55494.1f

IX.6 Varicocele in children and adolescents:

Varicocele is unusual in boys under ten years of age and becomes more frequent at the beginning of puberty. It results from venous reflux, leading to an abnormal dilatation of testicular veins in the pampiniform plexus. It is reported in 14-20% of adolescents (similar to incidence during adulthood). It is left sided in 90% of cases. Right-sided varicoceles are rather uncommon and usually noted with bilateral varicoceles and seldom occur as an isolated finding. Doppler US in the supine and upright position can detect venous reflux and this is classified as subclinical varicocele.
IX.6.1 Diagnosis:
Varicocele is usually noticed by the patient or his parents or discovered by the pediatrician at a routine visit. It is mostly asymptomatic and rarely causes pain. Diagnosis must rely on dilated veins detected clinically in the upright position with an impulse on Valsalva manoeuvre and not on detection of reflux by Doppler ultrasound which is considered as subclinical varicocele
IX.6.1.1 Varicocele is classified into 3 grades:
  • Grade I - Valsalva positive (palpable at Valsalva only)
  • Grade II - palpable (palpable without Valsalva)
  • Grade III - visible (visible at distance).
Testicular size should be assessed by ultrasound or an orchidometer. A testis that is smaller by > 2 mL or 20% compared to the other testis is considered to be hypoplastic.

It is not ethical to ask for a semen analysis in such age group and the decision to interfere is based only on the presence of testicular hypoplasia at the time of diagnosis or on follow-up
IX.6.2 Management:
    The recommended indication criteria for varicocelectomy in children and adolescents are:
  • Varicocele associated with a small testis.
  • Additional testicular condition affecting fertility
  • Bilateral palpable varicocele.
  • Pathological sperm quality (in late adolescents only).
  • Symptomatic varicocele or a large varicocele, causing physical or psychological discomfort.
  • Surgical intervention consists of ligation of the internal spermatic veins.
  • Inguinal (or subinguinal) using optical magnification or microsurgical approach to avoid injury to the artery and lymphatics.
  • Supra-inguinal ligation where less veins are found, with less liability of hydrocele formation but higher incidence of recurrence. Injury of the testicular artery at that level does not have a deleterious effect on the testis or its catch up growth.
The advantage of the former is the lower invasiveness of the procedure, while the advantage of the latter is a considerably lower number of veins to be ligated and safety of the incidental division of the internal spermatic artery at the suprainguinal level.

For surgical ligation, some form of optical magnification (microscopic or laparoscopic) should be used because the internal spermatic artery is 0.5 mm in diameter at the level of the internal ring. The recurrence rate is usually < 10%.

Lymphatic-sparing varicocelectomy is preferred to prevent hydrocele formation and testicular hypertrophy development and to achieve a better testicular function according to the LHRH stimulation test. The methods of choice are subinguinal or inguinal microsurgical (microscopic) repairs, or suprainguinal open or laparoscopic lymphatic-sparing repairs.

• Microsurgical varicocele repair in adolescents with varicocele significantly increases paternity rates and decreases time to conception post-operatively. Patients with varicocele who underwent microsurgical varicocele repair had increased sperm parameters and 3.63 times greater odds of paternity than controls who did not undergo varicocele surgery




Table IX:4 Recommendations for varicole management

Recommendation

strength rating
1. Examine varicocele in the standing position and classify into three grades. Strong
2. Use scrotal ultrasound to detect venous reflux without Valsalva manoeuvre in the supine and upright position and to discriminate testicular hypoplasia. Strong
3. In all pre-pubertal boys with a varicocele and in all isolated right varicoceles perform standard renal ultrasound to exclude a retroperitoneal mass. Strong
4. Inform caregivers and patients and offer surgery for:
  • Varicocele associated with a persistent small testis (size difference of > 2 mL or 20%);
  • Varicocele associated with additional testicular condition affecting fertility (cryptorchidism, history of torsion, trauma);
  • Varicocele associated with pathological sperm quality (in older adolescents);
  • • Symptomatic varicocele.
Weak
5. Use some form of optical magnification (microscopic or laparoscopic magnification) for surgical ligation. Strong
6- Use lymphatic-sparing varicocelectomy to prevent hydrocele formation and testicular hypertrophy. Strong
In a meta-analysis of twelve RCTs conducted by the ESPU it was found that varicocele treatment improved testicular volume and increased total sperm concentration when compared with observation. Lymphatic sparing surgery significantly decreased hydrocele rates. However, the ultimate effects on fertility potential and paternity remain unknown.

The complications include hydrocele formation which is the commonest complication, as well as, recurrence of varicocele (10%)

IX.6.3 References:

1. Children and Adolescents: A Systematic Review and Meta-analysis from the European Association of Urology/European Society for Paediatric Urology Guidelines Panel. Eur Urol [Internet]. 2019 Mar;75(3):448–61. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0302283818307310

2. Çayan S, Şahin S, Akbay E. Paternity Rates and Time to Conception in Adolescents with Varicocele Undergoing Microsurgical Varicocele Repair vs Observation Only: A Single Institution Experience with 408 Patients. J Urol [Internet]. 2017 Jul;198(1):195–201. Available from: http://www.jurology.com/doi/10.1016/j.juro.2017.01.066

3. Locke JA, Noparast M, Afshar K. Treatment of varicocele in children and adolescents: A systematic review and meta-analysis of randomized controlled trials. J Pediatr Urol [Internet]. 2017 Oct;13(5):437–45. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1477513117302991

4. Fast AM, Deibert CM, Van Batavia JP, Nees SN, Glassberg KI. Adolescent varicocelectomy: does artery sparing influence recurrence rate and/or catch-up growth? Andrology [Internet]. 2014 Mar;2(2):159–64. Available from: http://doi.wiley.com/10.1111/j.2047- 2927.2013.00142.x



IX.7 PENILE

IX.7.1 Circumcision:
IX.7.1.1 Epidemiology
Approximately two-thirds of circumcisions are performed for religious reasons, primarily among Muslims and Jews (in whom circumcision is nearly universal). Approximately 57% of newborn males are circumcised before discharge from the hospital, with the remainder undergoing circumcision in other settings (office based or surgical) or remaining uncircumcised. In 2012, the American Academy of Pediatrics (AAP) released its most recent policy statement and technical report on circumcision. The statement endorses the health benefits of newborn male circumcision, including a reduction in the risk of urinary tract infections (UTIs) in the first year after birth, reduction in the heterosexual transmission of HIV and other STDs, and reduction in the risk of penile cancer

IX.7.1.2 Procedure, Postoperative Care, and Complications
Local anesthesia is administered as either a dorsal penile nerve block or a subcutaneous ring block with 1% plain lidocaine (other local anesthetics, such as bupivacaine, may also be used). Topical 4% lidocaine cream have also been used as analgesics during newborn circumcision. The most common contraindications to newborn circumcision are penile torsion, chordee, and penoscrotal webbing. Surgical circumcision is performed with general anesthesia, typically after 6 months of age. The inner and outer foreskin are marked circumferentially, and the skin is removed. Hemostasis is achieved with bipolar cautery, and the skin edges are approximated with fine absorbable sutures and/or surgical skin glue. It is common for the head of the penis to appear red and swollen for the first 1 to 2 weeks after circumcision. Fibrinous exudate and crusting on the glans are also common and are often mistaken for pus by parents.

Electrocautery should never be used during circumcision except if bipolar is used Complications of circumcision include postoperative bleeding and/or hematoma, meatal stenosis, and removal of too much or too little foreskin, as well as rare but clinically significant complications, such as urethral injury or glans amputation. Complication rates were higher when the circumcision was performed by a nonmedical provider and for children aged 12 months to 12 years. Monopolar diathermy should be avoided in all cases

IX.7.2 References:

1. Oster J. Further fate of the foreskin. Incidence of preputial adhesions, phimosis, and smegma among Danish schoolboys. Arch Dis Child [Internet]. 1968 Apr 1;43(228):200–3. Available from: https://adc.bmj.com/lookup/doi/10.1136/adc.43.228.200

2. Wiswell TE. The Prepuce, Urinary Tract Infections, and the Consequences. Pediatrics [Internet]. 2000 Apr 1;105(4):860–2. Available from:http://pediatrics.aappublications.org/lookup/doi/10.1542/peds.105.4.860

3. Miernik A, Hager S, Frankenschmidt A. Complete Removal of the Foreskin – Why? Urol Int [Internet]. 2011;86(4):383–7. Available from: https://www.karger.com/Article/FullText/324835

4. To T, Agha M, Dick PT, Feldman W. Cohort study on circumcision of newborn boys and subsequent risk of urinary-tract infection. Lancet [Internet]. 1998 Dec;352(9143):1813–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0140673698023927

5. Ladenhauf HN, Ardelean MA, Schimke C, Yankovic F, Schimpl G. Reduced bacterial colonisation of the glans penis after male circumcision in children – A prospective study. J Pediatr Urol [Internet]. 2013 Dec;9(6):1137–44. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1477513113001046

6. Larke NL, Thomas SL, dos Santos Silva I, Weiss HA. Male circumcision and penile cancer: a systematic review and meta-analysis. Cancer Causes Control [Internet]. 2011 Aug 22;22(8):1097– 110. Available from: http://link.springer.com/10.1007/s10552-011-9785-9

IX.8 Hypospadias:

Hypospadias is the second most common birth defect in males, potentially affecting both urinary and sexual function of the penis. New understanding of the anatomy of hypospadias during the last 20 years has led to changes in both means for straightening associated ventral curvature and performing urethroplasty, while also improving cosmetic outcomes
IX.8.1 Anatomy:
Hypospadias represents arrested penile development. Consequently, the urethral opening can occur from the perineum, where fusion of urethral folds begins, to the proximal glans near the point this fusion normally is completed. The epithelial strip extending from the meatus to the tip of the glans is referred to as the urethral plate, representing tissues that should have completed urethral tubularization. The glans does not fuse ventrally under the meatus, resulting in two “wings” to either side of the urethral plate. Along the shaft, the corpus spongiosum diverges along the lateral margins of the urethral plate to join ipsilateral glans wings.

Typically, there is no frenulum, and ventral preputial development is incomplete whereas the dorsal aspect is formed, creating a dorsal hood. A variant of distal hypospadias termed the megameatus intact prepuce (MIP) presents with a normal foreskin, and so may not be detected until circumcision is performed or the skin becomes retractable (2). Ventral curvature of the penis may be noted, especially with more proximal hypospadias. Ventral curvature is found in approximately 15% of boys with distal forms of hypospadias, and in over 50% of those with the meatus on the proximal penile shaft or in the scrotum or perineum. Bending in distal cases most often is less than 30 degrees and will not prevent intercourse, whereas curvature greater than 30 degrees more often found in proximal cases may preclude penetration. Proximal cases additionally may have deep midline clefts in the scrotum and/or transposition of the scrotum higher than usual alongside the penile shaft. Defects in the hormonal processes of masculinization have long been implicated in hypospadias.

IX.8.2 Preoperative hormone stimulation:
No study confirms benefits of preoperative androgen therapy before hypospadias repair. Use has been advocated for the small appearing penis and/or glans, to potentially reduce ventral curvature, and to improve vascularity to skin before reoperations. Both topical and parenteral testosterone therapy have been used, with no apparent advantage to either route of administration. Parenteral regimens utilize testosterone enanthate 2 mg/kg given IM 5 and 2 weeks preoperatively, or every 3–4 weeks for three injections. Testosterone enanthate 2 mg/kg/wk can be administered topically twice daily for 3 weeks

IX.8.2.1 Timing of surgery: . (3)
A report from the American Academy of Pediatrics in 1996 suggested the optimal time for elective male genital surgery is between 6 and 12 months
IX.8.3 Surgical repair:
IX.8.3.1 Distal Hypospadias:
A recent survey of pediatric urologists indicated the most commonly used technique for distal repairs is TIP. This procedure involves tubularization of the urethral plate facilitated by midline incision to achieve a satisfactory neourethra caliber without skin flaps. meatoplasty and glans plasty (MAGPI) or flip-flap are less widely used nowadays.

IX.8.3.2 Proximal Hypospadias:
TIP can also be used to correct midshaft hypospadias and many cases with more proximal defects. The main contraindication is ventral curvature resulting in urethral plate transection to facilitate straightening. The main alternative to TIP when the urethral plate is maintained is only flap, but if the plate is transected either a 1-stage tubularized prepucial flap (Duckett) or 2-stage graft urethroplasty is required.

IX.8.3.3 Correcting Penile Curvature:
When the penis develops with curvature, all tissues on the ventral aspect may be relatively shortened, including shaft skin, dartos, corpus spongiosum, urethral plate, and corpus cavernosa. Most apparent curvature resolves when the shaft skin is released during degloving, sometimes facilitated by excision of dartos. While excision of the corpus spongiosum and urethral plate may also lessen curvature, in most cases some extent of curvature persists due to corpora cavernosa disproportion. Bending less than 30 degrees can be readily straightened by midline dorsal plication popularized by Baskin. Typically, curvature greater than 30 degrees after degloving and excision of dartos has led to transection of the urethral plate with subsequent ventral corporal grafting or using just 3 transverse incisions in the ventral tunica from 3 to 9 area without grafting.

Table IX:5 Recommendations for Hypospadias management

Recommendation

strength rating
1. At birth, differentiate isolated hypospadias from disorders of sex development which are mostly associated with cryptorchidism or micropenis. Strong
2. Counsel caregivers on functional indications for surgery, aesthetically feasible operative procedures (psychological, cosmetic indications) and possible complications. Strong
3. In children diagnosed with proximal hypospadias and a small appearing penis, reduced glans circumference or reduced urethral plate, pre-operative hormonal androgen stimulation treatment is an option but the body of evidence to accentuate its harms and benefits is inadequate. Weak
4. For distal hypospadias, offer Duplay-Thiersch urethroplasty, original and modified tubularised incised plate urethroplasty; use the onlay urethroplasty or two-stage procedures in more severe hypospadias. Correct significant (> 30 degrees) curvature of the penis. Weak
5. Ensure long-term follow-up to detect urethral stricture, voiding dysfunctions and recurrent penile curvature, ejaculation disorder, and to evaluate patient ́s satisfaction. Strong
6. Use validated objective scoring systems to assist in evaluating the functional and cosmetic outcome. Strong

IX.8.4 References:

1. Springer A, van den Heijkant M, Baumann S. Worldwide prevalence of hypospadias. J Pediatr Urol [Internet]. 2016 Jun;12(3):152.e1-152.e7. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1477513115004544

2. van Rooij IALM, van der Zanden LFM, Brouwers MM, Knoers NVAM, Feitz WFJ, Roeleveld N. Risk factors for different phenotypes of hypospadias: results from a Dutch case-control study. BJU Int [Internet]. 2013 Jul;112(1):121–8. Available from: http://doi.wiley.com/10.1111/j.1464- 410X.2012.11745.x

3. Rynja SP, de Jong TPVM, Bosch JLHR, de Kort LMO. Testosterone prior to hypospadias repair: Postoperative complication rates and long-term cosmetic results, penile length and body height. J Pediatr Urol [Internet]. 2018 Feb;14(1):31.e1-31.e8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S147751311730431X

4. Perlmutter AE, Morabito R, Tarry WF. Impact of patient age on distal hypospadias repair: A surgical perspective. Urology [Internet]. 2006 Sep;68(3):648–51. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0090429506007448

5. Castagnetti M, El-Ghoneimi A. Surgical Management of Primary Severe Hypospadias in Children: Systematic 20-Year Review. J Urol [Internet]. 2010 Oct;184(4):1469–75. Available from: http://www.jurology.com/doi/10.1016/j.juro.2010.06.044

6. Baskin LS, Duckett JW, Ueoka K, Seibold J, Snyder HM. Changing Concepts of Hypospadias Curvature Lead to More Onlay Island Flap Procedures. J Urol [Internet]. 1994 Jan;151(1):191–6. Available from: http://www.jurology.com/doi/10.1016/S0022-5347%2817%2934915-7

7. El-Kassaby A-W, Al-Kandari AM, Elzayat T, Shokeir AA. Modified Tubularized Incised Plate Urethroplasty for Hypospadias Repair: A Long-Term Results of 764 Patients. Urology [Internet]. 2008 Apr; 71(4):611–5. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0090429507025125

8. Snodgrass W, Yucel S. Tubularized Incised Plate for Mid Shaft and Proximal Hypospadias Repair. J Urol [Internet]. 2007 Feb; 177(2):698–702. Available from: http://www.jurology.com/doi/10.1016/j.juro.2006.09.104

9. Schwentner C, Gozzi C, Lunacek A, Rehder P, Bartsch G, Oswald J, et al. Interim Outcome of the Single Stage Dorsal Inlay Skin Graft for Complex Hypospadias Reoperations. J Urol [Internet]. 2006 May; 175(5):1872–7. Available from: http://www.jurology.com/doi/10.1016/S0022-5347%2805%2901016-5

10. Koyanagi T, Nonomura K, Yamashita T, Kanagawa K, Kakizaki H. One-Stage Repair of Hypospadias: Is There No Simple Method Universally Applicable to All Types of Hypospadias? J Urol [Internet]. 1994 Oct; 152(4):1232–7. Available from: http://www.jurology.com/doi/10.1016/S0022-5347%2817%2932556-9

11. Spinoit A-F, Poelaert F, Groen L-A, Van Laecke E, Hoebeke P. Hypospadias Repair at a Tertiary Care Center: Long-Term Followup is Mandatory to Determine the Real Complication Rate. J Urol [Internet]. 2013 Jun;189(6):2276–81. Available from: http://www.jurology.com/doi/10.1016/j.juro.2012.12.100

12. Wang F, Xu Y, Zhong H. Systematic review and meta-analysis of studies comparing the perimeatal-based flap and tubularized incised-plate techniques for primary hypospadias repair. Pediatr Surg Int [Internet]. 2013 Aug 21;29(8):811–21. Available from: http://link.springer.com/10.1007/s00383-013-3335-3

IX.9 Neurogenic Bladder Dysfunction/ Spinal Dysraphism:

IX.9.1 General principles:
o Patients with spinal dysraphism should be managed with a multidisciplinary approach and offered lifelong follow-up.

o A child born with spinal dysraphism should be offered urologic care once the diagnosis is established. Without appropriate urologic management, 60-80% may develop urological problems within the first few years of life and less than 5% become continent.

o There are two prevalent general philosophies for the urologic management of children born with spina bifida: a proactive and an expectant approach. A proactive approach is recommended. Every bladder should be considered as a potentially hostile highpressure bladder. Therefore, the bladder should be drained with an indwelling catheter until the spinal defect is closed. Clean intermittent catheterization (CIC) practice and training should be initiated shortly after spinal closure and patient stabilization (1-3) . CIC is better tolerated by patients and accepted by their families if started early in life. More importantly, early proactive management was shown to decrease the risk of renal damage and UTI, improve continence and reduce the need for later bladder augmentation (2, 4, 5) . CIC can be later discontinued in patients with underactive sphincter and those with low postvoid residual (PVR) and no signs of bladder outlet obstruction (detrusor-sphincter dyssynergia) on urodynamics (UDS), but a very close follow-up is still warranted as the bladder dynamics may change overtime (1) .

o Closure of the spinal defect should be performed as early as possible. Prompt postnatal closure is essential to prevent infection and protect the exposed neural tissues from additional trauma. Prompt repair of open spina bifida is associated with decreased risk of neurogenic bladder, neurodevelopmental delay and ventriculoperitoneal shunt infection (6-9) .

o Treatment is tailored according to the pattern of lower urinary dysfunction determined by urodynamic studies. The type, level and severity of neurological lesion have poor correlation with the pattern of lower urinary tract dysfunction. Figure 1 provides summary for the scheme of management of neurogenic bladder according to the pattern of detrusor and sphincter dysfunction (10)

IX.9.2 Baseline evaluation:
(Open/Closed Spina Bifida, Anorectal Malformation (ARM), Spinal cord injuries, others):

IX.9.2.1 Open Spina Bifida:
Basic evaluation of a child born with spinal dysraphism should include renal bladder ultrasound at birth, renal function testing after the first week of life, voiding cystourethrogram (VCUG) after closure of the spinal defect and urodynamic testing or preferably videourodynamics (VUDS) between 2-3 months of birth

o Urodynamic reporting should include information on the bladder capacity, maximal detrusor pressure, the presence of detrusor overactivity (DO) and detrusor leak point pressure (10,12)

o Interpretation of UDS in the newborn period may be difficult and reference ranges do not exist (1)

.
IX.9.2.2 Closed Spinal Dysraphism:
o Patients with suspicion of closed spinal dysraphism should be investigated with spinal ultrasound and MRI in children < 3 months and MRI in older children (11,13). If Spinal ultrasound is a good screening test in infants < 3 months. If spinal ultrasound is abnormal, equivocal or limited, in infants < 3months, a spinal MRI should be ordered (14, 15).

o In patients with closed spinal dysraphism, baseline UDS should be performed before spinal cord untethering surgery. Any change of baseline urodynamic information is considered a sign of cord tethering and warrant neurosurgical intervention

o UDS should also be performed if there is a strong suspicion of neurogenic bladder in older children (voiding pattern, incontinence, upper or lower urinary tract changes)

IX.9.2.3 Anorectal Malformation and Cloacal Anomalies (ARM):
o Patients with anorectal malformation should be investigated in the neonatal period with renal and spinal ultrasound due to the likelihood of associated renal and intraspinal abnormality (17,18) Baseline UDS should be obtained in the first few months of life after initial colostomy or definitive pull-through is performed. Repeat UDS is required if the patient suffers persistent or worsening urinary and/or fecal incontinence, upper tract damage or UTI on subsequent follow-up. A change of baseline UDS warrants spinal MRI and possibly spinal cord-untethering.

IX.9.3 Medical treatment:
IX.9.3.1 Anticholinergic medications:
o Patients with detrusor overactivity and/or elevated detrusor pressure on urodynamic studies should be started on anticholinergic medications, even within the first months of life (1, 3, 11,19). Oxybutynin is the only well-investigated anticholinergic drug in children and has been safely used in this age group (dosage 0.1 – 0.2 mg/kg body weight/8 hours). The use of oral anticholinergics is associated with dose-dependent adverse effects, more commonly: dry mouth, facial flushing and constipation (20,21) . Anticholinergics are known to treat detrusor overactivity, lower the bladder storage pressure, decrease upper tract damage and the need for bladder augmentation. Other anticholinergic medications (e.g. tolterodine, solifenacin, trospium chloride and propiverine) have been safely used off-label in children

IX.9.3.2 ẞ3 agonists (e.g. mirabegron):
o Could be used as an alternative to or in combination with anticholinergics in patients with detrusor overactivity, but there are limited reports on their use in children

IX.9.3.3 α-Adrenergic antagonists:
o Can theoretically decrease bladder outlet resistance, facilitate bladder emptying and lower the bladder pressure. In reality, α-adrenergic antagonists are ineffective in children with neurogenic bladder. In a randomized, double-blind, placebo-controlled trial, different dosage regimens of tamsulosin did not result in a significant reduction of the detrusor leak point pressure, compared to placebo

IX.9.3.4 Continuous Antibiotic Prophylaxis:
o There is no strong evidence to support the routine use of continuous antibiotic prophylaxis (CAP) in patients maintained on CIC. The use of CAP is associated with increased bacterial resistance without decreasing the risk of UTIs and new renal scarring . However, it may be prudent to consider antibiotic prophylaxis for patients with high-grade VUR, recurrent UTIs or unfavorable bladder dynamics

IX.9.3.5 Bowel Management:
o Bowel management is an integral part of the care of a child with neurogenic bladder. Regular bowel emptying should be ensured in children with neurogenic bladder. Bowel management improves fecal continence, social integration and the patient’s quality of life, and could potentially reduce the risk of UTIs. A graduated approach for bowel management is recommended. Bowel management should start with laxatives, rectal suppositories, retrograde enemas. digital evacuation, transanal irrigation systems or Malone antegrade continence enema stoma should be considered

IX.9.3.6 Follow-up:
o Children with neurogenic bladder should be offered lifelong multidisciplinary followup. The frequency of urological follow-up, however, varies. Close follow-up is recommended during infancy and in adolescence. Children are at a higher risk of developing spinal cord tethering during these periods of rapid growth (42,43). The rapid growth rate is reduced once they become toddlers. Toddlers and adults born with spina bifida can be followed on annual or biannual bases (44) . Basic evaluation during followup should include: history, physical examination and renal-bladder ultrasound. Further testing with VCUG, UDS or DMSA is considered if there is a change in the severity of hydronephrosis or bladder wall thickening, change of continence or recurrent UTIs.

o During follow-up, history should focus on voiding or CIC frequency, urine leakage, symptoms suggestive of UTI, medication compliance, bowel habits and any changes of the neurological status.

o In patients with deterioration of the upper and/or lower urinary tract function, neurological evaluation including a total spine MRI, is warranted to exclude secondary tethered cord or worsening of hydrocephalus

IX.9.4 Urinary tract infection:
o The diagnosis of urinary tract infection in patients on CIC is problematic. There are no universally accepted criteria to define UTI in patients maintained on CIC. The diagnosis of UTI should be based on a positive urine analysis and a positive urine culture of properly collected urine specimen in a symptomatic patient . Only patients with symptomatic UTI should receive antibiotic treatment. Asymptomatic bacteriuria in patients maintained on CIC requires no treatment.

IX.9.5 Principles of Surgical Management of Neurogenic Voiding Dysfunction:
IX.9.5.1 Indications for surgery:
o Treatment of neurogenic bladder in children and adolescents is primarily conservative. Surgery should be considered only if there is upper tract damage, recurrent symptomatic UTIs or failure to achieve urinary continence despite maximal conservative management.

o Preserving the upper urinary tract should always be the primary goal of treatment of neurogenic bladder. Upper tract safety should not be compromised to achieve urinary continence.

    Surgery for neurogenic bladder in children mainly aims at:
  • Improving the bladder storage characteristics (intra-detrusor botulinum toxin injection, bladder augmentation, continent or incontinent urinary diversion)
  • Increasing the bladder outlet resistance in patients with bladder outlet insufficiency pursuing continence.
  • Facilitation of intermittent catheterization (creation of continent catheterizable channels) in patients with difficult transurethral CIC.
Surgical intervention, except for incontinent diversion, does not eliminate the need for CIC. Conversely, CIC becomes even more crucial after bladder augmentation or procedures to increase bladder outlet resistance. Major bladder or bladder outlet reconstruction should only be performed in centers with enough expertise in these complex reconstructive procedures with a well-structured follow-up plan.

IX.9.6 Botulinum toxin A injection:
Botulinum toxin A (Botox A) injection into the detrusor muscle can be used in patients with low capacity,

Overactive or poorly compliant bladders refractory to anti-muscarinic treatment. Botulinum toxin A injection is more effective in patients with detrusor overactivity (DO), relative to those with poor compliance and no DO.

There is weak evidence to support botulinum toxin A injection into the urethral sphincter to decrease urethral resistance as a temporary solution in patients with high bladder pressure who are not capable of or do not wish to perform CIC.

IX.9.7 Bladder Augmentation:
A variable proportion (12-38%) of neurogenic bladder patients may require bladder augmentation. Bladder augmentation should be only considered if medical treatment or intra-detrusor botox injection fails to achieve favorable bladder storage characteristics.

The long-term risk of surgical and metabolic complications of bladder augmentation should be carefully weighed against its benefits

A continent catheterizable channel can be offered at the time of bladder augmentation for patients who are not able to perform transurethral CIC, due to anatomic problem, social circumstance or sensate urethras.

Patients who receive bladder augmentation should commit to lifelong follow-up owing to the wellknown surgical and metabolic consequences including acid-base and electrolyte disturbance, vitamin B12 deficiency, loss of bone mineral density and affection of linear growth, change of bowel habits, increased risk of urinary stones and UTIs, renal deterioration and increased risk of malignancy.

Ureterocystoplasty can avoid the complications of enterocystoplasty in properly selected patients. Nevertheless, reaugmentation may be required in up to 73% of patients. Autoaugmentation, with detrusor-myotomy or partial detrusorectomy, generally has a low success rate

IX.9.8 Incontinent Cutaneous Urinary Diversion:
Incontinent urinary diversion (cutaneous vesicostomy, ileal or colonic conduits, ileovesicostomy) is an option in patients with high pressure bladders who are unable or unwilling to perform CIC, due to anatomic problems or social circumstances.

Refluxing uretero-cutaneoustomy can also be considered as a temporizing measure in patients with high-grade VUR and recurrent febrile UTIs

Neurostimulation/neuromodulation and somatic-to-autonomic nerve anastomosis are still experimental in children with neurogenic bladder

IX.9.8.1 Procedures to Increase Bladder Outlet Resistance:
Weak or insufficient bladder outlet resistance is a safe situation for upper tract safety. No pharmacotherapy has proved efficient to increase bladder outlet resistance. Surgical procedures for bladder outlet insufficiency produce fixed resistance at the level of bladder outlet and may adversely change bladder dynamics, even in patients with Low bladder compliance has been reported in approximately one third and upper tract changes in about 50% of patients following procedures to increase bladder outlet resistance. These risks should be carefully discussed when counseling patients and families before bladder outlet surgery. Additionally, close and lifelong follow-up is mandatory following these procedures. Simultaneous bladder augmentation should be considered in patients with poor preoperative bladder dynamics.

It is preferable to combine procedures to increase bladder outlet resistance with creation of continent catheterizable channel; since catheterization through a reconstructed a bladder neck or a urethra compressed by a sling is not sometimes easy.

Autologous or synthetic slings: provide a continence rate of 40-100% and are more successful in females. Sling procedures are usually combined with bladder augmentation or other bladder outlet procedures.

Bladder neck injection with a bulking agent generally has a low success rate (10-40%) and the results are not durable.

Bladder Neck Closure with a Continent Catheterizable Channel is usually kept as the last resort to achieve urinary continence after all other measures fail. Bladder neck closure has a high success rate, but patients should be warned against the risk of bladder stones, bladder perforation and upper tract deterioration if not compliant to CIC and regular bladder irrigations.

Surgical Treatment of Vesicoureteral Reflux: treatment of VUR in neurogenic bladder patients should primarily focus on improving bladder dynamics and lowering the risk of UTIs. Surgery for VUR isreserved for patients with recurrent symptomatic UTIs after bladder dynamics have been optimized. Endoscopic treatment of VUR has a high failure rate in patients with neurogenic bladder. Simultaneous ureteral reimplantation should be discussed in patients with high-grade symptomatic VUR undergoing bladder or bladder outlet reconstruction (46, 47).

Surgical Options for Bowel Management including Malone Antegrade Continence Enema (MACE), cecostomy buttons and diverting stomas should be discussed with a bowel specialist after failure of other measures to achieve fecal continence.

IX.9.9 References:
1. Stein R, Bogaert G, Dogan HS, Hoen L, Kocvara R, Nijman RJM, et al. EAU/ESPU guidelines on the management of neurogenic bladder in children and adolescent part I diagnostics and conservative treatment. Neurourology and urodynamics. 2019 Nov 13. PubMed PMID: 31724222.
2. Edelstein RA, Bauer SB, Kelly MD, Darbey MM, Peters CA, Atala A, et al. The long-term urological response of neonates with myelodysplasia treated proactively with intermittent catheterization and anticholinergic therapy. The Journal of urology. 1995 Oct;154(4):1500-4. PubMed PMID: 7658577.
3. Routh JC, Cheng EY, Austin JC, Baum MA, Gargollo PC, Grady RW, et al. Design and Methodological Considerations of the Centers for Disease Control and Prevention Urologic and Renal Protocol for the Newborn and Young Child with Spina Bifida. The Journal of urology. 2016 Dec;196(6):1728-34. PubMed PMID: 27475969. Pubmed Central PMCID: 5201100.
4. Kaefer M, Pabby A, Kelly M, Darbey M, Bauer SB. Improved bladder function after prophylactic treatment of the high risk neurogenic bladder in newborns with myelomentingocele. The Journal of urology. 1999 Sep;162(3 Pt 2):1068-71. PubMed PMID: 10458433.
5. Dik P, Klijn AJ, van Gool JD, de Jong-de Vos van Steenwijk CC, de Jong TP. Early start to therapy preserves kidney function in spina bifida patients. European urology. 2006 May;49(5):908-13. PubMed PMID: 16458416.
6. Gaskill SJ. Primary closure of open myelomeningocele. Neurosurgical focus. 2004 Feb 15;16(2):E3. PubMed PMID: 15209486.
7. Gamache FW, Jr. Treatment of hydrocephalus in patients with meningomyelocele or encephalocele: a recent series. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 1995 Aug;11(8):487-8. PubMed PMID: 7585688.
8. Pinto FC, Matushita H, Furlan AL, Alho EJ, Goldenberg DC, Bunduki V, et al. Surgical treatment of myelomeningocele carried out at 'time zero' immediately after birth. Pediatric neurosurgery. 2009; 45(2):114-8. PubMed PMID: 19307745.
9. Tarcan T, Onol FF, Ilker Y, Alpay H, Simsek F, Ozek M. The timing of primary neurosurgical repair significantly affects neurogenic bladder prognosis in children with myelomeningocele. The Journal of urology. 2006 Sep; 176(3):1161-5. PubMed PMID: 16890717.
10. de Jong TP, Klijn AJ. Urodynamic studies in pediatric urology. Nature reviews Urology. 2009 Nov; 6(11):585-94. PubMed PMID: 19890338.
11. Bauer SB, Austin PF, Rawashdeh YF, de Jong TP, Franco I, Siggard C, et al. International Children's Continence Society's recommendations for initial diagnostic evaluation and follow-up in congenital neuropathic bladder and bowel dysfunction in children. Neurourology and urodynamics. 2012 Jun; 31(5):610-4. PubMed PMID: 22532312.
12. Bauer SB, Nijman RJ, Drzewiecki BA, Sillen U, Hoebeke P, International Children's Continence Society Standardization S. International Children's Continence Society standardization report on urodynamic studies of the lower urinary tract in children. Neurourology and urodynamics. 2015 Sep; 34(7):640-7. PubMed PMID: 25998310.
13. Raghavendra BN, Epstein FJ, Pinto RS, Subramanyam BR, Greenberg J, Mitnick JS. The tethered spinal cord: diagnosis by high-resolution real-time ultrasound. Radiology. 1983 Oct;149(1):123-8. PubMed PMID: 6611916.
14. Hughes JA, De Bruyn R, Patel K, Thompson D. Evaluation of spinal ultrasound in spinal dysraphism. Clinical radiology. 2003 Mar;58(3):227-33. PubMed PMID: 12639529.
15. Jehangir S, Adams S, Ong T, Wu C, Goetti R, Fowler A, et al. Spinal cord anomalies in children with anorectal malformations: Ultrasound is a good screening test. Journal of pediatric surgery. 2019 Oct 24. PubMed PMID: 31708202.
16. Meyrat BJ, Tercier S, Lutz N, Rilliet B, Forcada-Guex M, Vernet O. Introduction of a urodynamic score to detect pre- and postoperative neurological deficits in children with a primary tethered cord. Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery. 2003 Nov;19(10-11):716-21. PubMed PMID: 14557893.
17. Maerzheuser S, Jenetzky E, Zwink N, Reutter H, Bartels E, Grasshoff-Derr S, et al. German network for congenital uro-rectal malformations: first evaluation and interpretation of postoperative urological complications in anorectal malformations. Pediatric surgery international. 2011 Oct;27(10):1085-9. PubMed PMID: 21792651.
18. Shaul DB, Harrison EA. Classification of anorectal malformations--initial approach, diagnostic tests, and colostomy. Seminars in pediatric surgery. 1997 Nov;6(4):187-95. PubMed PMID: 9368270.
19. Lee JH, Kim KR, Lee YS, Han SW, Kim KS, Song SH, et al. Efficacy, tolerability, and safety of oxybutynin chloride in pediatric neurogenic bladder with spinal dysraphism: a retrospective, multicenter, observational study. Korean journal of urology. 2014 Dec;55(12):828-33. PubMed PMID: 25512818. Pubmed Central PMCID: 4265718.
20. Giramonti KM, Kogan BA, Halpern LF. The effects of anticholinergic drugs on attention span and short-term memory skills in children. Neurourology and urodynamics. 2008;27(4):315-8. PubMed PMID: 17828786.
21. Veenboer PW, Huisman J, Chrzan RJ, Kuijper CF, Dik P, de Kort LM, et al. Behavioral effects of long-term antimuscarinic use in patients with spinal dysraphism: a case control study. The Journalof urology. 2013 Dec;190(6):2228-32. PubMed PMID: 23792150.
22. Guerra LA, Moher D, Sampson M, Barrowman N, Pike J, Leonard M. Intravesical oxybutynin for children with poorly compliant neurogenic bladder: a systematic review. The Journal of urology. 2008 Sep;180(3):1091-7. PubMed PMID: 18639290.
23. Humblet M, Verpoorten C, Christiaens MH, Hirche H, Jansen K, Buyse G, et al. Long-term outcome of intravesical oxybutynin in children with detrusor-sphincter dyssynergia: with special reference to age-dependent parameters. Neurourology and urodynamics. 2015 Apr;34(4):336-42. PubMed PMID: 24436114.
24. Bolduc S, Moore K, Lebel S, Lamontagne P, Hamel M. Double anticholinergic therapy for refractory overactive bladder. The Journal of urology. 2009 Oct;182(4 Suppl):2033-8. PubMed PMID: 19695628.
25. Bolduc S, Moore K, Nadeau G, Lebel S, Lamontagne P, Hamel M. Prospective open label study of solifenacin for overactive bladder in children. The Journal of urology. 2010 Oct;184(4 Suppl):1668-73. PubMed PMID: 20728124.
26. Ellsworth PI, Borgstein NG, Nijman RJ, Reddy PP. Use of tolterodine in children with neurogenic detrusor overactivity: relationship between dose and urodynamic response. The Journal of urology. 2005 Oct;174(4 Pt 2):1647-51; discussion 51. PubMed PMID: 16148673.
27. Reddy PP, Borgstein NG, Nijman RJ, Ellsworth PI. Long-term efficacy and safety of tolterodine in children with neurogenic detrusor overactivity. Journal of pediatric urology. 2008 Dec;4(6):428- 33. PubMed PMID: 19013412.
28. Schulte-Baukloh H, Murtz G, Heine G, Austin P, Miller K, Michael T, et al. Urodynamic effects of propiverine in children and adolescents with neurogenic bladder: results of a prospective longterm study. Journal of pediatric urology. 2012 Aug;8(4):386-92. PubMed PMID: 21907623.
29. El Helou E, Labaki C, Chebel R, El Helou J, Abi Tayeh G, Jalkh G, et al. The use of mirabegron in neurogenic bladder: a systematic review. World journal of urology. 2019 Dec 5. PubMed PMID: 31802206.
30. Krhut J, Borovicka V, Bilkova K, Sykora R, Mika D, Mokris J, et al. Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity-Prospective, randomized, doubleblind, placebo-controlled study. Neurourology and urodynamics. 2018 Sep;37(7):2226-33. PubMed PMID: 29603781.
31. Park JS, Lee YS, Lee CN, Kim SH, Kim SW, Han SW. Efficacy and safety of mirabegron, a beta3- adrenoceptor agonist, for treating neurogenic bladder in pediatric patients with spina bifida: a retrospective pilot study. World journal of urology. 2019 Aug;37(8):1665-70. PubMed PMID: 30511212.
32. Wollner J, Pannek J. Initial experience with the treatment of neurogenic detrusor overactivity with a new beta-3 agonist (mirabegron) in patients with spinal cord injury. Spinal cord. 2016 Jan;54(1):78-82. PubMed PMID: 26503222.
33. Homsy Y, Arnold P, Zhang W. Phase IIb/III dose ranging study of tamsulosin as treatment for children with neuropathic bladder. The Journal of urology. 2011 Nov;186(5):2033-9. PubMed PMID: 21944133.
34. Clarke SA, Samuel M, Boddy SA. Are prophylactic antibiotics necessary with clean intermittent catheterization? A randomized controlled trial. Journal of pediatric surgery. 2005 Mar;40(3):568- 71. PubMed PMID: 15793737.
35. Zegers SH, Dieleman J, van der Bruggen T, Kimpen J, de Jong-de Vos van Steenwijk C. The influence of antibiotic prophylaxis on bacterial resistance in urinary tract infections in children with spina bifida. BMC infectious diseases. 2017 Jan 12;17(1):63. PubMed PMID: 28081719. Pubmed Central PMCID: 5228098.
36. Akil I, Ozen C, Cengiz B. Do patients with neurogenic bladder treated with clean intermittentcatheterization need antibacterial prophylaxis? Turkish journal of medical sciences. 2016 Jun 23;46(4):1151-4. PubMed PMID: 27513418.
37. Burgers RE, Mugie SM, Chase J, Cooper CS, von Gontard A, Rittig CS, et al. Management of functional constipation in children with lower urinary tract symptoms: report from the Standardization Committee of the International Children's Continence Society. The Journal of urology. 2013 Jul;190(1):29-36. PubMed PMID: 23313210.
38. Vande Velde S, Van Biervliet S, Van Renterghem K, Van Laecke E, Hoebeke P, Van Winckel M. Achieving fecal continence in patients with spina bifida: a descriptive cohort study. The Journal of urology. 2007 Dec;178(6):2640-4; discussion 4. PubMed PMID: 17945290.
39. Alhazmi H, Trbay M, Alqarni N, Alyami F, Khatab A, Almannie R, et al. Long-term results using a transanal irrigation system (Peristeen((R))) for treatment of stool incontinence in children with myelomeningocele. Journal of pediatric urology. 2019 Feb;15(1):34 e1- e5. PubMed PMID: 30245057.
40. Ausili E, Focarelli B, Tabacco F, Murolo D, Sigismondi M, Gasbarrini A, et al. Transanal irrigation in myelomeningocele children: an alternative, safe and valid approach for neurogenic constipation. Spinal cord. 2010 Jul;48(7):560-5. PubMed PMID: 20084075.
41. Malone PS, Ransley PG, Kiely EM. Preliminary report: the antegrade continence enema. Lancet. 1990 Nov 17;336(8725):1217-8. PubMed PMID: 1978072.
42. Lais A, Kasabian NG, Dyro FM, Scott RM, Kelly MD, Bauer SB. The neurosurgical implications of continuous neurourological surveillance of children with myelodysplasia. The Journal of urology. 1993 Dec;150(6):1879-83. PubMed PMID: 8230524.
43. Phuong LK, Schoeberl KA, Raffel C. Natural history of tethered cord in patients with meningomyelocele. Neurosurgery. 2002 May;50(5):989-93; discussion 93-5. PubMed PMID: 11950401.
44. Duplisea JJ, Romao RL, MacLellan DL, Cox AR, Anderson PA. Urological Follow-up in Adult Spina Bifida Patients: Is There an Ideal Interval? Urology. 2016 Nov;97:269-72. PubMed PMID: 27364867.
45. Madden-Fuentes RJ, McNamara ER, Lloyd JC, Wiener JS, Routh JC, Seed PC, et al. Variation in definitions of urinary tract infections in spina bifida patients: a systematic review. Pediatrics. 2013 Jul;132(1):132-9. PubMed PMID: 23796735.
46. Wang JB, Liu CS, Tsai SL, Wei CF, Chin TW. Augmentation cystoplasty and simultaneous ureteral reimplantation reduce high-grade vesicoureteral reflux in children with neurogenic bladder. Journal of the Chinese Medical Association: JCMA. 2011 Jul;74(7):294-7. PubMed PMID: 21783093.
47. Helmy TE, Hafez AT. Vesicouretral reflux with neuropathic bladder: studying the resolution rate after ileocystoplasty. Urology. 2013 Aug;82(2):425-8. PubMed PMID: 23639239.

IX.10 Urinary Tract Infections

IX.10.1 Introduction:
Urinary tract infections (UTIs) are the most common bacterial infection in children (1-3). The incidence varies depending on age and sex. The prevalence is higher; there is a male predominance; infections not caused by Escherichia coli are more frequent; and there is a higher risk of urosepsis (4, 5).

Although urinary tract infection affects at least 3.6% of boys and 11% of girls, establishing the diagnosis is difficult in early childhood owing to the lack of specific urinary symptoms, difficulty in urine collection, and contamination of samples. Most children have a single episode and recover promptly (6).

IX.10.2 Diagnosis:
IX.10.2.1 Risk factors for urinary tract infection in children:
  • o Poor urine flow, dysfunctional voiding and/or constipation
  • o Previous urinary tract infection
  • o Recurrent fever of uncertain origin
  • o Antenatally diagnosed renal abnormality or evidence of spinal lesion
  • o Family history of vesicoureteric reflux or renal disease
  • o Enlarged bladder and/or abdominal mass
  • o Poor growth
  • o High blood pressure
IX.10.2.2 Clinical symptoms and signs:
Urinary tract infection is considered in all infants and children with:
(a) Unexplained fever of 38°C or higher after 24 hours at the latest.
(b) Symptoms and signs suggestive of urinary tract infection, including (6):
– Fever
– Non-specific symptoms, such as lethargy, irritability, malaise, failure to thrive, vomiting, poor feeding, abdominal pain, jaundice (in infants)
– Specific symptoms, such as frequency, dysuria, loin tenderness, dysfunctional voiding, changes to continence, haematuria, and offensive or cloudy urine.
- Septic shock is unusual, even with very high fever.
Localization of site of urinary tract infection:
o Child with bacteriuria and fever of 38°C or higher is considered to have acute pyelonephritis or upper urinary tract infection.
o Child with fever lower than 38°C, loin pain or tenderness, and bacteriuria is considered to have acute pyelonephritis or upper urinary tract infection.
o All other children with bacteriuria but no systemic symptoms or signs are considered to have cystitis or lower urinary tract infection.
IX.10.2.3 Physical examination:
• Non-specific: Throat, lymph node, temperature
• Specific:
- Abdomen and flank (constipation, palpable and painful kidney, or palpable bladder).
- Back (stigmata of spina bifida or sacral agenesis),
- Genitalia (phimosis, labial adhesion, vulvitis, epididymo-orchitis).

IX.10.2.4 Urine sampling, analysis and culture:
IX.10.2.4.1 Urine sampling:
(a) Clean catch urine collection, but if this is not possible, use Plastic bag attached to the cleaned genitalia but not cotton wool balls, gauze, or sanitary towels.
(b) If non-invasive techniques are not possible, use a catheter sample or suprapubic aspirate with ultrasound guidance.
If urine is to be cultured but cannot be cultured within 4 hours of collection, the sample should be refrigerated or preserved with boric acid immediately.

IX.10.2.4.2 Urinalysis:
a) Dipsticks:
          o Rapid, do not require microscopy, and are ready to use.
          o The test is helpful when the result is positive, because it is highly specific.
b) Microscopy: ≥ 5 WBC/μL in centrifuged urine or > 10 WBC/μL in uncentrifuged urine have been demonstrated to be sensitive for UTI (7).
c) Flow imaging analysis technology: to classify particles in uncentrifuged urine

IX.10.2.4.3 Urine culture:
          o Definition of UTI in children depends on method of urine sampling:
• Urine specimen from suprapubic bladder puncture → Any number of cfu/mL (at least 10 identical colonies)
• Urine specimen from bladder catheterization→ > 10³ - 105 cfu/mL
• Urine specimen from midstream void →
                   > 104 cfu/mL with symptoms
                   > 105 cfu/mL without symptoms
         o Indications for sending urine samples for culture:
• Upper urinary tract infection.
• Recurrent urinary tract infection.
• Under three years of age.
• No response to treatment within 48 hours.
• High to intermediate risk of serious illness.
• Positive result for leukocyte esterase or nitrite.
• Clinical symptoms and dipstick tests do not correlate.

IX.10.2.5 Imaging strategies:
1. Ultrasound:
                   o An ultrasound scan is required on diagnosis for all atypical infections.
                   o In infants with febrile UTI: urinary tract ultrasound is advised within 24 hours to exclude
                       obstruction.
                   o In toilet-trained children: Post-void residual (PVR) urine should be measured to exclude
                       dysfunctional voiding as a cause of UTI as elevated PVR volume predicts recurrence of UTIs in
                       toilet-trained children (8).
2. Radionuclide scanning:
Children younger than 3 years with atypical and/or recurrent urinary tract infection: do a DMSA (dimercaptosuccinic acid) scan 4-6 months after the acute infection to detect renal parenchymal defects (renal scars) while in the acute phase of a febrile UTI (up to 4-6 weeks), DMSA-scan can demonstrate pyelonephritis by perfusion defects.
3. Micturating cystourethrography (MCUG):
A micturating cystourethrogram (MCUG) is recommended after the first episode of febrile UTI in boys and girls depending on sex, age and clinical presentation also in atypical and recurrent infections in children below six months and in older children if there is poor urine flow, urinary tract dilatation on ultrasound, non-Escherichia coli infection or a family history of VUR. The timing of VCUG does not influence the presence or severity of VUR (9, 10). Prophylactic antibiotics should be given orally for three days, with MCUG taking place on the second day. Another option is doing DMSA first, followed by VCUG if there is renal cortical uptake deficiency after UTI.

IX.10.3 Acute Management:

o Infants and children with a high risk of serious illness should be referred urgently to the care of a pediatric specialist.
o Infants younger than 3 months with a possible UTI should be treated with parenteral antibiotics.
o Infants and children 3 months or older with acute pyelonephritis/upper urinary tract infection:
o Oral antibiotics with low resistance patterns are recommended for 7–10 days, for example cephalosporin or amoxycillin/clavulonic acid.
o If oral antibiotics cannot be used, Cephalosporins intravenous (IV) for 2–4 days followed by oral antibiotics for a total duration of 10 days.
o Infants and children 3 months or older with cystitis/lower urinary tract infection should be treated with oral antibiotics for 3 days. Trimethoprim, nitrofurantoin, cephalosporin or amoxicillin may be suitable.
o The parents or care givers should be advised to bring the infant or child for reassessment if the infant or child is still unwell after 24–48 hours. If an alternative diagnosis is not made, a urine sample should be sent for culture to identify the presence of bacteria and determine antibiotic sensitivity if urine culture has not already been carried out.
o Infants and children who receive aminoglycosides (gentamicin or amikacin), once daily dosing is recommended.
o Intramuscular treatment should be considered, if parenteral treatment is required and IV treatment is not possible.
o Infant or child who is on chemoprophylaxis and developed an infection, treatment should be with a different antibiotic, not a higher dose of the same antibiotic.
o Asymptomatic bacteriuria in infants and children should not be treated with antibiotics.

IX.10.4 Long - term Management:
a) Prevention of recurrence:
o Children who have had a UTI should be encouraged to drink an adequate amount.
o Children who have had a UTI should have ready access to clean toilets when required and should not be expected to delay voiding.
o Dysfunctional elimination syndromes and constipation should be addressed in infants and children who have had a UTI.
b) Antibiotic Prophylaxis:
o Antibiotic prophylaxis should not be routinely recommended in infants and childrenfollowing first-time UTI.
o Antibiotic prophylaxis may be considered in infants and children with recurrent UTI.
o Asymptomatic bacteriuria in infants and children should not be treated with
o Prophylactic antibiotics.

IX.10.5 Follow-up:

o When results are normal, a follow-up outpatient appointment is not routinely required.
o Infants and children who have recurrent UTI or abnormal imaging results should be assessed by a pediatric urologists and nephrologists.
o Assessment of infants and children with renal parenchymal defects should include height, weight, blood pressure and routine testing for proteinuria.
o Infants and children with a minor, unilateral renal parenchymal defect do not need longterm follow-up unless they have recurrent UTI or family history or lifestyle risk factors for hypertension.
o Infants and children who have bilateral renal abnormalities, impaired kidney function, raised blood pressure and/or proteinuria should receive monitoring and appropriate management by a pediatric nephrologist to slow the progression of chronic kidney disease.

Table IX:6 Oral antibiotics used in Pediatric UTI

Oral Antibiotics

Dosing

Notes
Amoxicillin and clavulanic acid 20–40 mg/kg divided q8h
Sulfamethoxazole andtrimethoprim (SMZTMP) 30–60 mg/kg SMZ, 6–12 mg/kg TMP divided q12
Cephalexin 50–100 mg/kg/day divided q6h
Cefixime 8 mg/kg/day
Cefpodoxime 10 mg/kg/day divided q12h Use in mixed aerobic-anaerobic UTIs
Ciprofloxacin Not recommended as a first choice in paediatrics, Can be used to treat MDR infections when there is no other safe and effective alternative. Limit to treat UTIs caused by Pseudomonas aeruginosa or other MDR gram-negative bacteria.
MDR= multidrug resistant

Table IX:7 Parentral Antibiotics used in pediatric UTI

Parentral Antibiotics

Dosing

Notes

Ceftriaxone

50–75 mg/kg/day IV/IM single dose or divided q12h

Contra-indicated in < 6 weeks of age; bilirubin may be displaced from albumin
Ampicillin 100 mg/kg/day IV/IM divided q8h << 2 weeks of age used in combo with gentamicin. Used in paediatrics allergic to cephalosporins. Initial therapy where either grampositive cocci or no organism is found in urinary sediment/h7>
Cefotaxime 150 mg/kg/day IV/IM divided q6-8h Safe in < 6 weeks of age Aged 2–8 weeks: Used in combo with ampicillin. Use in neonates and jaundiced paediatrics
Gentamicin < 7 days: 3.5–5 mg/kg/dose IV q24h < 5 years: 2.5 mg/kg/dose IV q8h or single daily dosing with normal renal function of 5–7.5 mg/kg/dose IV q24h ≥ 5 y: 2–2.5 mg/kg/dose IV q8h or single daily dosing with normal renal function; 5–7.5 mg/kg/dose IV q24h Monitor blood levels and kidney function if therapy extends > 48 hours; Empirical therapy should not be used for > 3 days. If empirical therapy is still required, consider changing to ceftriaxone


Table IX:8 Recommendations for urinary tract infections in pediatric patients

Recommendation

Strength rating

1. Take a medical history, assess clinical signs and symptoms and perform a physical examination to diagnose children suspected of having a urinary tract infection (UTI).

Strong

2. Exclude bladder and bowel dysfunction in any child with febrile and/or recurrent UTI and do not delay diagnosis and treatment of bladder-boweldysfunction.

Strong

3. The most effective way to collect an uncontaminated urine sample in an infant is through suprapubic bladder aspiration; bladder catheterisation is an alternative with a higher contamination rate.

Strong

4. Do not use plastic bags for urine sampling in non-toilet-trained children since it has a high risk of false-positive results. Clean catch urine is an acceptable technique for toilet-trained children.

Strong

5. Urinalysis by dipstick yields rapid results, but it should be used with caution. Microscopic investigation is the standard method of assessing pyuria after centrifugation. Using flow imaging analysis, the numbers of white blood cells (WBCs), squamous epithelial cells and red cells correlate well with manual methods.

Weak

6. Local antimicrobial susceptibility patterns should be used when deciding on empiric treatment and should cover the most common uropathogens (Escherichia coli, Enterococcus, Proteus, and Klebsiellaspecies).

Strong

7. The choice between oral and parenteral therapy should be based on patient age; clinical suspicion of urosepsis; illness severity; refusal of fluids, food and/or oral medication; vomiting; diarrhoea; non-compliance; complicated pyelonephritis.

Strong

8. Complicated or uncomplicated UTIs should be treated for 7–10 days. However, short-courses of therapy may be used in adolescent girls with non-toxic UTIs

Strong

9. Offer long-term antibacterial prophylaxis in case of high susceptibility to UTI and risk of acquired renal damage and lower urinary tract symptoms.

Weak

10. If during the use of prophylactic medication, a paediatric develops an infection: do not increase dose of current antibiotic, switch to a different agent.

Strong

11. Treat complicated UTI with broad-spectrum antibiotics (parenteral).

Weak

12. In infants with febrile UTI use renal and bladder ultrasound to exclude obstruction of the upper and lower urinary tract

Strong

13. In all infants, exclude vesicoureteral reflux (VUR) after the first episode of febrile UTI, using voiding cystourethography (VCUG) or a dimercaptosuccinic acid (DMSA) scan first (in case of a positive DMSA-scan, follow-up with VCUG). In boys more than one year of age, exclude VUR after the second febrile UTI.

Strong

14. Antibiotic treatment in the case of asymptomatic bacteriuria is not recommended

Strong


IX.10.6 References:
1. Hoberman, A., et al. Prevalence of urinary tract infection in febrile infants. J Pediatr, 1993. 123: 17.
2. Marild, S., et al. Incidence rate of first-time symptomatic urinary tract infection in children under 6 years of age. Acta Pediatr, 1998. 87: 549.
3. O’Brien, K., et al. Prevalence of urinary tract infection (UTI) in sequential acutely unwell children presenting in primary care: exploratory study. Scand J Prim Health Care, 2011. 29: 19.
4. Shaikh, N., et al. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J, 2008. 27: 302.
5. Zorc, J.J., et al. Clinical and demographic factors associated with urinary tract infection in young febrile infants. Pediatrics, 2005. 116: 644
6. National Institute for Health and Clinical Excellence. Urinary tract infection in children: diagnosis, treatment and long-term management. Clinical guideline 54. London: NICE, August 2007.
7. Hoberman, A., et al. Is urine culture necessary to rule out urinary tract infection in young febrile children? Pediatr Infect Dis J, 1996. 15: 304.
8. Chang, S.J., et al. Elevated postvoid residual urine volume predicting recurrence of urinary tract infections in toilet-trained children. Pediatr Nephrol, 2015. 30: 1131.
9. Doganis, D., et al. Timing of voiding cystourethrography in infants with first time urinary infection. Pediatr Nephrol, 2009. 24: 319.
10. Sathapornwajana, P., et al. Timing of voiding cystourethrogram after urinary tract infection. Arch Dis Child, 2008. 93: 229.
11. EAU Guidelines on Pediatric Urology, 2020. 3.8.5, page 39

IX.11 Congenital Upper Urinary Tract Obstruction (UPJ and UVJ obstruction):

IX.11.1 Antenatal Hydronephrosis (ANH)
Congenital urinary tract obstruction is distinct from obstruction in the mature kidney. Obstruction in the developing kidney induces various degrees of renal dysplasia and hypoplasia. With increasing usage of ultrasound (US) screening during pregnancy, most congenital obstructive uropathies are diagnosed prenatally and a rising number of patients are referred to the pediatric urologist for prenatal counseling. The vast majority of prenatally detected uropathies, however, does not require fetal interventions because of acceptable postnatal renal function and unacceptable high fetal morbidity and mortality secondary to the procedure. Consequently, prenatal counseling focuses on parental education and reassurance as well as on outlining a postnatal plan of management. Most cases of urinary tract obstruction that are discovered before birth will not produce clinical manifestations. Symptoms vary depending on age. The availability of only two treatment options for urinary tract obstruction, observation or surgery, has created a great deal of controversy when to intervene.

IX.11.2 Epidemiology:
Dilation of the UUT is a significant clinical challenge in deciding which patient will benefit from surgery. Ureteropelvic junction (UPJ) obstruction is defined as impairment of urine flow from the pelvis into the proximal ureter with subsequent dilation of the collecting system and the potential to damage nephrons if left untreated. It is the most common pathological cause of neonatal hydronephrosis (1). It has an overall incidence of 1:1,500 and a ratio of males to females of 2:1 in newborns. Ureterovesical junction (UVJ) obstruction is an obstructive condition of the distal ureter as it enters the bladder, commonly called a primary obstructive megaureter. Megaureters are the second most likely cause of neonatal hydronephrosis. They occur more often in males and are more likely to occur on the left side (2,3).

IX.11.3 Diagnostic Evaluation:
The widespread use of antenatal ultrasound during pregnancy has resulted in a higher detection rate (4). The challenge in the management of dilated UUT is to decide which child should be observed, which should be managed medically, and which requires surgical intervention.
                   o Antenatal ultrasound:
Usually performed between the 16th and 18th weeks of pregnancy, the kidneys are visualized routinely, when almost all amniotic fluid consists of urine. The most sensitive time for fetal urinary tract evaluation is the 28th week. If dilatation is detected, US should focus on:
              o Laterality, severity of dilatation, and echogenicity of the kidneys.
              o Hydronephrosis or hydro-ureteronephrosis.
              o Bladder volume and bladder emptying.
              o Sex of the child.
              o Amniotic fluid volume (5).
              o Postnatal ultrasound:
Since transitory neonatal dehydration lasts about 48 hours after birth, imaging should be performed following this period of postnatal oliguria. However, in severe cases (bilateral dilatation, solitary kidney, oligohydramnios), immediate postnatal sonography is recommended (6). Ultrasound should assess the anteroposterior diameter of the renal pelvis, calyceal dilatation, kidney size, thickness of the parenchyma, cortical echogenicity, ureters, bladder wall and residual urine.
             o Voiding cystourethrogram:
Conventional VCUG is the method of choice for primary diagnostic procedures. In newborns with identified UUT dilatation, it should exclude:
             o Vesicoureteral reflux (found in up to 25% of affected children) (7).
             o Urethral valves.
             o Ureteroceles.
             o Diverticula.
             o Neurogenic bladder.
             o Diuretic renography:
Diuretic renography is the most used diagnostic tool to detect the severity and functional significance of problems with urine transport. Technetium-99m (99mTc) mercaptoacetyltriglycine (MAG3) is the radionuclide of choice yet due to its non-availability in Egypt, DTPA is used. It is important to perform the study under standardized circumstances (hydration, transurethral catheter) after the fourth and sixth weeks of life (8). Oral fluid intake is encouraged prior to the examination. At fifteen minutes before the injection of the radionuclide, it is mandatory to administer normal saline intravenous infusion at a rate of 15 mL/kg over 30 minutes, and furosemide is 1 mg/kg for infants during the first year of life (9).

IX.11.4 Management:
• Antibiotic prophylaxis for antenatal hydronephrosis:
The benefits and harms of continuous antibiotic prophylaxis (CAP) vs. observation in patients with antenatal hydronephrosis are controversial. (10) Based on the currently available evidence, the benefits and harms of CAP in children with antenatal hydronephrosis remain unproven. Uncircumcised infants and infants with hydroureteronephrosis and high-grade hydronephrosis are more likely to develop a UTI. Continuous antibiotic prophylaxis should be reserved for this sub-group of children who are proven to be at high risk. (11)
              o UPJ obstruction:
It is crucial that management decisions are made based on serial investigations that have used the same technique and have been under standardized circumstances. Indications for surgical intervention comprise impaired split renal function (< 40%), a decrease of split renal function of > 10% in subsequent studies, poor drainage function after the administration of furosemide, increased anteroposterior diameter on US, and grade III and IV dilatation as defined by the Society for Fetal Urology (12).
             o Megaureter:
Non-operative management is the mainstay of treatment, provided adequate ureteral drainage is confirmed by a functional study such as a diuretic DTPA renal scan. Generally, low-dose prophylactic antibiotics within the first year of life are recommended for the prevention of UTIs (13). Spontaneous remission rates of up to 85% are reported in primary megaureter cases. Surgical management is reserved for megaureters with recurrent UTIs, deterioration of split renal function (20% difference or drop in function of 10% during follow up) and progressive obstruction. Data suggest that children with a ureteric diameter of > 10-15 mm are more likely to require intervention. Ureteral tailoring is usually required with ureteral diameter of more than 10 mm (14).

IX.11.5 Conclusion:
The use of routine perinatal sonography has resulted in increased detection of hydronephrosis caused by UPJ or UVJ obstruction. Meticulous and repeat postnatal evaluation is mandatory to try to identify obstructive cases at risk of renal deterioration and requiring surgical reconstruction. Surgical methods are quite standardized and have a good clinical outcome.

Table IX:9 Recommendations for Management of ANH

Recommendation

Strength rating

1. We recommend that ANH be diagnosed and its severity graded based on anteroposterior diameter (APD) of the fetal renal pelvis.

Strong

2. ANH is present if the APD is ≥4 mm in second trimester and ≥7 mm in the third trimester

Weak

3. all newborns with history of ANH should have postnatal ultrasound examination within the first week of life

Strong

4. In neonates with suspected posterior urethral valves, oligohydramnios or severe bilateral hydronephrosis, ultrasonography should be performed within 24-48 h of birth

Strong

5. voiding cystourethrography in postnatal investigations is indicated in:
• Patients with unilateral or bilateral hydronephrosis with renal pelvic APD > 10 mm, society of fetal urology (SFU) grade 3-4 or ureteric dilatation.
• Infants with antenatally detected hydronephrosis who develop a urinary tract infection.

Weak

6. Infants with moderate to severe unilateral or bilateral hydronephrosis (APD >10 mm) who do not show VUR should undergo diuretic renography

Strong

7. Offer continuous antibiotic prophylaxis to the subgroup of children with antenatal hydronephrosis who are at high risk of developing urinary tract infection like uncircumcised infants, children diagnosed with hydroureteronephrosis and high-grade hydronephrosis, respectively.

Weak

8. Decide on surgical intervention based on the time course of the hydronephrosis and the impairment of renal function.

Weak

9. Offer surgical intervention in case of an impaired split renal function due to obstruction less than 35% or a decrease of split renal function in subsequent studies by 5-10%, or increased anteroposterior diameter on serial US examinations, and grade IV dilatation as defined by the Society for Fetal Urology.

Weak

10. Offer pyeloplasty when ureteropelvic junction obstruction has been confirmed clinically or with serial imaging studies proving a substantially impaired or decrease in function.

Weak

11. Do not offer surgery as a standard for primary megaureters since the spontaneous remission rates are as high as 85%.

Strong


IX.11.6 References:

1. Lebowitz, R.L., et al. Neonatal hydronephrosis: 146 cases. Radiol Clin North Am, 1977. 15: 49.
2. Brown, T., et al. Neonatal hydronephrosis in the era of sonography. AJR Am J Roentgenol, 1987. 148: 959.
3. Koff, S.A. Problematic ureteropelvic junction obstruction. J Urol, 1987. 138: 390.
4. Gunn, T.R., et al. Antenatal diagnosis of urinary tract abnormalities by ultrasonography after 28 weeks’ gestation: incidence and outcome. Am J Obstet Gynecol, 1995. 172: 479.
5. Grignon, A., et al. Ureteropelvic junction stenosis: antenatal ultrasonographic diagnosis, postnatal investigation, and follow-up. Radiology, 1986. 160: 649.
6. Flashner, S.C., et al., Ureteropelvic junction, in Clinical Pediatric Urology. 1976, WB Saunders: Philadelphia.
7. Ebel, K.D. Uroradiology in the fetus and newborn: diagnosis and follow-up of congenital obstruction of the urinary tract. Pediatr Radiol, 1998. 28: 630.
8. O’Reilly, P., et al. Consensus on diuresis renography for investigating the dilated upper urinary tract. Radionuclides in Nephrourology Group. Consensus Committee on Diuresis Renography. J Nucl Med, 1996. 37: 1872.
9. Choong, K.K., et al. Volume expanded diuretic renography in the postnatal assessment of suspected ureteropelvic junction obstruction. J Nucl Med, 1992. 33: 2094.
10. Braga, L.H., et al. Pilot randomized, placebo controlled trial to investigate the effect of antibiotic prophylaxis on the rate of urinary tract infection in infants with prenatal hydronephrosis. J Urol, 2014. 191: 1501.
11. Silay, M.S., et al. The role of antibiotic prophylaxis in antenatal hydronephrosis: A systematic review. J Ped Urol, 2017. prior to print
12. Fernbach, S.K., et al. Ultrasound grading of hydronephrosis: introduction to the system used by the Society for Fetal Urology. Pediatr Radiol, 1993. 23: 478.
13. Sripathi, V., et al. Primary obstructive megaureter. J Pediatr Surg, 1991. 26: 826.
14. Peters, C.A., et al. Congenital obstructed megaureters in early infancy: diagnosis and treatment. J Urol, 1989. 142: 641.

IX.12 Congenital Lower Urinary Tract Obstruction:

The term congenital lower urinary tract obstruction (CLUTO) is used for a foetus, which shows during intrauterine US screening a dilatation of the upper and lower urinary tract. At that time of life, the diagnosis is usually based only on US examinations. There is a broad spectrum of conditions, which could cause an intrauterine dilatation of the urinary tract. Postpartum diagnosis comprises PUV in 56- 63%, urethral atresia/ dysplasia in 9%, urethral stenosis in 3-7%, anterior urethral valve in less than 1%, a prune belly syndrome in up to 25% and a dilating reflux in up to 13%. Cloacal malformation can be found in 5-15%, ureterocele in 1-2%, a Megacystis-Microcolon-intestinal hypoperistalsis syndrome in 1-3% and also a Megacystis-Megaureter Syndrome in 1%

IX.12.1 Posterior Urethral valves:
IX.12.1.1 Epidemiology and Etiology:
The incidence of posterior urethral valves (PUV) is 1 in 5,000–8,000 live births, which accounts for approximately 10% of all prenatally detected cases of urinary tract obstruction. PUV are classified as type I and type III valves (Young classification); however, presentation, diagnosis, treatment, and prognosis are similar. Type I valves comprise 95% of all PUVs and are leaflets, which extend from the verumontanum distally across the entire anterior circumference of the urethra leaving only a small channel along the posterior wall. Type II valves are no longer regarded as valves. Type III valves are diaphragmatic membranes distal to the verumontanum with a small central opening. The sequelae of congenital PUV are seen at all levels proximal to the obstruction secondary to high voiding pressure. The prostatic urethra is dilated and the bladder neck is hypertrophied and rigid. Detrusor muscle hypertrophy leads to bladder wall thickening and deterioration of bladder compliance. All PUV patients demonstrate hydroureteronephrosis and 50% have VUR. Various degrees of renal dysplasia (irreversible) and uropathy (reversible) are found. (1)

IX.12.1.2 Presentation and Diagnosis:
Sixty percent of patients present with tubular damage, which manifests as failure to concentrate and to eliminate urinary acids. Tubular damage worsens with age and high urine volumes contribute to the deterioration of renal and bladder function. Elevated voiding pressures cause pop-off mechanisms such as VUR, bladder diverticula, urinary ascites, and a patent urachus. Unilateral VUR that is associated with renal dysplasia is termed VURD syndrome (Valve Unilateral Reflux Dysplasia); its protective effect on renal function is controversial. Clinical manifestations of PUVs depend on the age of presentation. The most significant clinical problem of the neonate is pulmonary hypoplasia secondary to oligohydramnios accounting for most of the neonatal mortality. Urinary sepsis, renal insufficiency, and ascites are other common symptoms in the newborn period. The majority of older boys present with UTIs and/or voiding dysfunction. Most of PUVs are diagnosed with prenatal US. Classic US findings include bilateral hydroureteronephrosis, distended bladder and dilated posterior urethra (“keyhole sign”), as well as a thickened bladder wall. VCUG confirms the diagnosis by demonstrating a trabeculated bladder, elevated bladder neck, and dilated posterior urethra.
Radionuclide renal scans can provide valuable information regarding differential renal function and renal drainage. (2,3)

IX.12.1.3 Management:
PUV management begins with immediate bladder drainage. Five French (5Fr) feeding tubes and not Foley catheters are to be used for drainage because the latter have a smaller functional lumen and can induce significant bladder spasms with consecutive functional UVJ obstruction. The feeding tube is left for 5 to 7 days to facilitate the introduction of the endoscope in the miniature neonatal urethra and to reach the nadir serum creatinine. Once the patient is stabilized, within these 5 to 7 days, endoscopic valve incision is performed with a Bugbee electrode, resectoscope, laser, or cold knife at the 4 o’clock, 8 o’clock, and sometimes 12 o’clock position. Continued catheter drainage for 24 h reduces the risk for hematuria but is not imperative. If valve ablation cannot be performed (neonate too small for instrumentation or lack of a trained pediatric urologist), a vesicostomy is indicated.

Upper urinary tract diversion (ureterostomy, pyelostomy) is strictly reserved for patients who fail to respond to bladder drainage and continue to experience urosepsis, elevated creatinine (>2 mg/dl after 10 days of bladder drainage), and worsening hydroureteronephrosis. Only upper tract drainage that allows bladder cycling is recommended.

After valve ablation, a residual degree of dilatation is present in a good percentage of PUV patients, and should not push to ureteral reimplantation since the incidence of true stenosis at the ureterovesical junction is almost nil. Up to 30% of VUR will resolve spontaneously once the obstruction is relieved. Antibiotic prophylaxis is indicated for all cases of reflux. Antireflux procedures are very rarely indicated in valve patients. They should never be attempted in patients with high pressure bladders. Early administration of oxybutynin may improve bladder function. High-grade reflux is associated with a poor functioning kidney and is considered a poor prognostic factor. However, early removal of the renal unit seems to be unnecessary, as long as it causes no problems. A “valve bladder” describes a chronic condition in patients after adequate valve ablation that will lead to deterioration of the upper urinary tracts and to urinary incontinence. Polyuria, particularly at night, is another factor contributing to persistent dilatation of the upper tract, nocturnal overdistention of the bladder and eventually bladder dysfunction. Nocturnal catheter is beneficial in such cases. Patients with PUV commonly present with prolonged daytime and nighttime incontinence up to 20 years of age. (1-5)

Table IX:10 Recommendations for PUVs managment

Recommendation

Strength rating

1. Diagnose posterior urethral valves (PUV) initially by ultrasound but a voiding cystourethrogram (VCUG) is required to confirm the diagnosis.

Strong

2. Assess split renal function by dimercaptosuccinic acid scan or mercaptoacetyltriglycine (MAG3) clearance. Use serum creatinine as a prognostic marker.

Strong

3. Vesico-amniotic shunt antenatally is not recommended to improve renal outcome.

Weak

4. Offer endoscopic valve ablation after bladder drainage and stabilization of the child.

Strong

5. If primary ablation cannot be done due to nonavailability of appropriate instruments or due to technical reasons, the next preferred procedure is vesicostomy particularly in preterm infants in whom visualization or ablation of the valve is not possible.

Strong

6. If child is unstable (urosepsis) and the upper tracts are dilated and tortuous with deranged renal parameters despite 1 week of catheterization, higher diversion in the form of ureterostomy is indicated.

Strong

7. Monitor bladder and renal function life-long, in all patients.

Strong


IX.12.2 References:
1. Chua ME, Ming JM, Carter S, El Hout Y, Koyle MA, Noone D, et al. Impact of Adjuvant Urinary Diversion versus Valve Ablation Alone on Progression from Chronic to End Stage Renal Disease in Posterior Urethral Valves: A Single Institution 15-Year Time-to-Event Analysis. J Urol [Internet]. 2018 Mar;199(3):824–30. Available from: http://www.jurology.com/doi/10.1016/j.juro.2017.10.024
2. Shirazi M, Farsiani M, Natami M, Izadpanah K, Malekahmadi A, Khakbaz A. Which Patients Are at Higher Risk for Residual Valves After Posterior Urethral Valve Ablation? Korean J Urol [Internet]. 2014;55(1):64. Available from: https://icurology.org/DOIx.php?id=10.4111/kju.2014.55.1.64
3. Nawaz G, Hussain I, Muhammad S, Jamil MI, Rehman AU, Iqbal N, et al. Justification For ReLook Cystoscopy After Posterior Urethral Valve Fulguration. J Ayub Med Coll Abbottabad [Internet]. 29(1):30–2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28712168
4. Krahn CG, Johnson HW. Cutaneous vesicostomy in the young child: Indications and results. Urology [Internet]. 1993 Jun;41(6):558–63. Available from: https://linkinghub.elsevier.com/retrieve/pii/009042959390104I
5. Kim YH, Horowitz M, Combs A, Nitti VW, Libretti D, Glassberg KI. Comparative Urodynamic Findings After Primary Valve Ablation, Vesicostomy or Proximal Diversion. J Urol [Internet]. 1996 Aug;673–6. Available from: http://journals.lww.com/00005392-199608001-00028
IX.12.3 Duplex Systems and Ureterocele:
IX.12.3.1 Incidence and Embryology:
Duplication of the urinary tract has an incidence rate of 0.5% to 1.25% in postmortem series and is identified at prenatal US in 0.6% of pregnancies. Postnatal evaluation is only required if the duplex system is dilated or associated with a ureterocele. Duplex kidneys are seen approximately twice as frequently in female patients and are bilateral in one-fifth of cases. Duplex kidneys form because of premature branching, or duplication, of the ureteric bud before it interacts with the metanephros to form the kidney. The upper pole of the kidney ureter may insert ectopically into the prostatic urethra, ejaculatory duct, seminal vesicle, vas deferens, or epididymis in boys or the urethra or vagina in girls. In boys, all these structures lie above the external urethral sphincter; therefore, the ectopic insertion does not cause incontinence. This is not the case in girls, where an ectopic ureter might appear with persistent dribbling incontinence at presentation. Duplex systems may be associated with a cystic dilatation of the distal end of the upper moiety ureter as it inserts into the bladder, forming a cyst called a ureterocele. Prenatally diagnosed UTD in a duplex system may be caused by obstruction (of the upper moiety, usually by a ureterocele or an ectopic insertion, or of the lower moiety, usually due to UPJ obstruction) or VUR (more commonly into the lower moiety, it but could affect both moieties). (1,2)

IX.12.3.2 Diagnosis and Evaluation:
Postnatal renal tract US should be performed after 48 hours (if the UTD is unilateral) or more urgently if it is bilateral, as the ureterocele could cause bladder outlet obstruction (BOO), even if the baby appears to be voiding. Unilateral cases are subsequently investigated with VCUG to look for VUR and bladder emptying and with renography to assess the split function of the upper and lower moieties. Upper moieties associated with an obstructing ureterocele or an ectopic ureter are often dysplastic and poorly functioning. (3,4)

IX.12.3.3 Treatment Options and Outcomes:
All neonates with prenatal UTD in a duplex system should be started on prophylactic antibiotics. If there is suspicion for bladder outlet obstruction, the neonate requires catheterization and urgent evaluation with VCUG. Further management will depend on the presence of symptoms, such as febrile UTIs or voiding difficulty and the function of the affected moiety. VUR in completely duplicated systems may initially be treated conservatively with observation and antibiotic prophylaxis, although the resolution rate is less than that for VUR in simplex systems. (20% vs 50%, respectively, at 5-year follow-up). Surgical intervention depends on the underlying cause for the UTD. (3)

Ureterocele: Obstruction by a ureterocele may be initially treated endoscopically by puncturing the ureterocele, although this carries a risk of iatrogenic VUR. Failure of endoscopic management to relieve the obstruction may require a transurethral resection of the ureterocele. Alternatively, a more complex surgery may involve a heminephroureterectomy of the upper pole of the kidney, a ureteroureterostomy or excision of the ureterocele, and reimplantation. Small, asymptomatic, nonobstructive ureteroceles may not require any intervention. (1-9)

Ectopic Ureter: kidneys in girls with dribbling incontinence may be notoriously difficult to identify and are not always apparent at US. Magnetic resonance urography may be helpful to clarify the anatomy and diagnose the ectopic ureter. Ectopic ureters may be surgically managed with a ureteroureterostomy (the ectopic ureter is disconnected and anastomosed to the lower moiety ureter), heminephroureterectomy of the nonfunctioning (often small) upper moiety, or reimplantation of the ectopic ureter into the bladder. (5)

Table IX:11 Recommendationf of Diagnosis and Treatment Options for Ureterocele and Ectopic Ureter

Recommendation

Strength rating

Ureterocele

Diagnosis

Use ultrasound (US), radionuclide studies (mercaptoacetyltriglycine (MAG3)/dimercaptosuccinic acid (DMSA), voiding cystourethrography (VCUG), magnetic resonance urography, high-resolution magnetic resonance imaging (MRI), and cystoscopy to assess function, to detect reflux and rule out ipsilateral compression of the lower pole and urethral obstruction.

Weak

Treatment

Select treatment based on symptoms, function and reflux as well on surgical and parenteral choices: observation, endoscopic decompression, ureteral re-implantation, partial nephroureteretomy, complete primary reconstruction. Offer, early endoscopic decompression to patients with an obstructing ureterocele.

Weak

Ectopic ureter

Diagnosis

Use US, DMSA scan, VCUG or MRI for a definitive diagnosis.

Weak

Treatment

In non-functioning moieties with recurrent infections, heminephro-ureterectomy is a definitive solution. Ureteral reconstruction (ureteral re-implantation/ ureteroureterostomy/ureteropyelostomy and upper- pole ureterectomy) are other therapeutic option especially in cases in which the upper pole has function worth preserving.

Weak


IX.12.4 References:
1. Kwatra N, Shalaby-Rana E, Majd M. Scintigraphic features of duplex kidneys on DMSA renal cortical scans. Pediatr Radiol [Internet]. 2013 Sep 6;43(9):1204–12. Available from: http://link.springer.com/10.1007/s00247-013-2619-z
2. Meneghesso D, Castagnetti M, Della Vella M, Benetti E, Zucchetta P, Rigamonti W, et al. Clinicopathological correlation in duplex system ectopic ureters and ureteroceles: can preoperative workup predict renal histology? Pediatr Surg Int [Internet]. 2012 Mar 30;28(3):309–14. Available from: http://link.springer.com/10.1007/s00383-011-3032-z
3. Monfort G, Guys JM, Coquet M, Roth K, Louis C, Bocciardi A. Surgical management of duplex ureteroceles. J Pediatr Surg [Internet]. 1992 May;27(5):634–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/002234689290465J
4. Decter RM, Roth DR, Gonzales ET. Individualized Treatment of Ureteroceles. J Urol [Internet]. 1989 Aug;142(2 Part 2):535–7. Available from: http://www.jurology.com/doi/10.1016/S0022- 5347%2817%2938807-9
5. Roy Choudhury S, Chadha R, Bagga D, Puri A, Debnath PR. Spectrum of ectopic ureters in children. Pediatr Surg Int [Internet]. 2008 Jul 8;24(7):819–23. Available from: http://link.springer.com/10.1007/s00383-008-2172-2
6. Castagnetti M, El-Ghoneimi A. Management of duplex system ureteroceles in neonates and infants. Nat Rev Urol [Internet]. 2009 Jun;6(6):307–15. Available from: http://www.nature.com/articles/nrurol.2009.82
7. HAN MY, GIBBONS MD, BELMAN AB, POHL HG, MAJD M, RUSHTON HG. INDICATIONS FOR NONOPERATIVE MANAGEMENT OF URETEROCELES. J Urol [Internet]. 2005 Oct;174(4 Part 2):1652–6. Available from: http://www.jurology.com/doi/10.1097/01.ju.0000175943.95989.41
8. DeFOOR W, MINEVICH E, TACKETT L, YASAR U, WACKSMAN J, SHELDON C. Ectopic Ureterocele: Clinical Application of Classification Based on Renal Unit Jeopardy. J Urol [Internet]. 2003 Mar;169(3):1092–4. Available from: http://www.jurology.com/doi/10.1097/01.ju.0000049246.53911.04
9. Jesus LE, Farhat WA, Amarante ACM, Dini RB, Leslie B, Bägli DJ, et al. Clinical Evolution of Vesicoureteral Reflux Following Endoscopic Puncture in Children With Duplex System Ureteroceles. J Urol [Internet]. 2011 Oct;186(4):1455–9. Available from: http://www.jurology.com/doi/10.1016/j.juro.2011.05.057

IX.13 Vesicoureteric Reflux:

Vesicoureteric reflux (VUR) is a very common urological anomaly in children, with an incidence of nearly 1%. Controversy persists over the optimal management of VUR, particularly the choice of diagnostic procedures, treatment (medical, endoscopic, or surgical), and the timing of treatment. The choice of management depends on the presence of renal scars, clinical course, grade of reflux, ipsilateral renal function, bilaterality, bladder and bowel dysfunction (BBD), associated anomalies and the age of the patient (1,2).

IX.13.1 Initial Evaluation of the child with VUR:
IX.13.1.1 General evaluation
Standard: VUR and urinary tract infections may detrimentally affect the overall health and renal function in affected children. Therefore, on initial presentation the child with VUR should undergo a careful general medical evaluation including measurement of height, weight, blood pressure and serum creatinine if bilateral renal abnormalities are found. (3-5)

Recommendation: Urinalysis for proteinuria and bacteriuria is recommended. If the urinalysis indicates infection, a urine culture and sensitivity is recommended.

Option: A baseline serum creatinine may be obtained to establish an estimate of glomerular filtration rate (GFR) for future reference.

IX.13.1.2 Imaging Procedures
Recommendation: Because VUR and urinary tract infection may affect renal structure and function, performing renal ultrasound to assess the upper urinary tract is recommended.

The use of VCUG is recommended in patients with US findings of high-grade hydronephrosis, duplex kidneys with hydronephrosis, cortical abnormalities (as cortical thinning and irregularity, as well as increased echogenicity) ureterocele, ureteric dilatation, and abnormal bladders (as keyhole sign). (6-9)

Option: DMSA (technetium-99m-labeled dimercaptosuccinic acid) renal imaging can be obtained to assess the status of the kidneys for scarring and function.

The criterion standard in diagnosis of VUR is VCUG, especially at the initial work-up. This test provides precise anatomical detail and allows grading of VUR. Radionuclide studies for detection of reflux have lower radiation exposure than VCUG, but the anatomical details depicted are inferior. Recent studies on alternative imaging modalities for detection on VUR have yielded good results with voiding US and magnetic resonance VCUG.(10).


Grading system for VUR on VCUG, according to the International Reflux Study Committee (11):
Grade I: Reflux does not reach the renal pelvis; varying degrees of ureteral dilatation.
Grade II: Reflux reaches the renal pelvis; no dilatation of the collecting system; normal fornices.
Grade III: Mild or moderate dilatation of the ureter, with or without kinking; moderate dilatation of the collecting system; normal or minimally deformed fornices.
Grade IV: Moderate dilatation of the ureter with or without kinking; moderate dilatation of the collecting system; blunt fornices, but impressions of the papillae still visible
Grade V: Gross dilatation and kinking of the ureter, marked dilatation of the collecting system; papillary impressions no longer visible; intraparenchymal reflux.
              o Dimercaptosuccinic acid (DMSA) is the best nuclear agent for visualizing the cortical
             tissue and differential function between both kidneys. DMSA scans are therefore used
             to detect and monitor renal scarring. Patients with severe hydronephrosis and those
             whose hydronephrosis is sustained or progressive, need diuretic renogram to exclude
             obstruction.

IX.13.1.3 Optional investigations:
a) Video-urodynamic studies are only important in patients in whom secondary reflux is suspected, e.g. those with spina bifida or PUV.
b) In the case of LUTS, diagnosis and follow-up can be limited to non-invasive tests (e.g. voiding charts, US, or uroflowmetry).
c) Cystoscopy has a limited role in evaluating reflux, except for infravesical obstruction or ureteral anomalies e.g. ectopic ureter that might influence therapy.

IX.13.2 Initial Management of the Child with VUR

The goals of management of the child with VUR are to 1) prevent recurring febrile UTIs; 2) prevent renal injury; and 3) minimize the morbidity of treatment and follow-up.

IX.13.3 Children with Febrile Urinary Tract Infections

Offer immediate, parenteral antibiotic treatment for febrile breakthrough infections. A routine recommendation of VCUG at zero to two years of age after the first proven febrile UTI is the safest approach as the evidence for the criteria to selecting patients for reflux detection is weak. An alternative “top-down” approach is also an option; children with febrile infections and abnormal DMSA/renal US findings may have higher risk of developing renal scars and they should all be evaluated for reflux (12).

IX.13.4 The child with VUR less than one year of age

Recommendation: Continuous antibiotic prophylaxis is recommended for the child less than one year of age with VUR with a history of a febrile urinary tract infection. This approach is based on the greater morbidity from recurrent urinary tract infections found in this population.

Recommendation: In the absence of a history of febrile urinary tract infections, continuous antibiotic prophylaxis is recommended for the child less than one year of age with VUR grades III–V who is identified through screening.

Option: In the absence of a history of febrile urinary tract infections, the child less than one year of age with VUR grades I–II who is identified through screening may be offered continuous antibiotic prophylaxis.

IX.13.5 The child with UTI and VUR more than one year of age

Guidelines for management of VUR in the child more than one year of age are somewhat different from those for the child less than one year of age, reflecting several contributing elements that influence clinical outcomes. These include the greater likelihood of BBD, the lower probability of spontaneous resolution of VUR, lower risk of acute morbidity from febrile UTI and the greater ability of the child to verbally complain of symptoms to indicate acute infection. The management decision should be made with recognition of the clinical context, including the presence of BBD, patient age, VUR grade, the presence of scarring, and parental preferences. Given the individuality of each patient and their parental preferences, there can be no uniform guidelines of management.

Recommendation: If clinical evidence of bladder/bowl dysfunction is present (see "Initial evaluation of the child with VUR" above) treatment of bladder/bowel dysfunction is indicated, preferably before any surgical intervention for VUR is undertaken.

Recommendation: Continuous antibiotic prophylaxis is recommended for the child with bladder/bowel dysfunction and VUR due to the increased risk of urinary tract infection while bladder/bowel dysfunction is present and being treated.

Option: Continuous antibiotic prophylaxis may be considered for the child over one year of age with a history of urinary tract infections and VUR in the absence of bladder/bowel dysfunction.

Option: Observational management without continuous antibiotic prophylaxis, with prompt initiation of antibiotic therapy for urinary tract infections, may be considered for the child with VUR in the absence of bladder/bowel dysfunction, recurrent febrile urinary tract infections, or renal cortical abnormalities. While this approach is currently under investigation and therefore no firm recommendation can be made, preliminary data suggest that some groups of patients with VUR may do as well with this approach as with continuous antibiotic prophylaxis.

IX.13.6 Disease Management

There are two main treatment approaches: non-surgical and surgical. The traditional approach of initial medical treatment after diagnosis and shifting to interventional treatment in case of breakthrough infections and new scar formation needs to be challenged, because the treatment should be tailored to different risk groups.

IX.13.6.1 Non-surgical treatment:
It is based on the understanding that (13):
             o Vesicoureteric reflux resolves spontaneously, mostly in young patients with low-grade
               reflux. Resolution is nearly 80% in VUR grades I and II and 30-50% in VUR grades
               III-V within four to five years of follow-up. Spontaneous resolution is low for bilateral
               high-grade reflux.
             o Vesicoureteric reflux does not damage the kidney when patients are free of infection
               and have normal LUT function.
             o There is no evidence that correction of persistent low-grade reflux (grades I-III) without
               symptoms and normal kidneys offers a significant benefit.
             o There is no evidence that small scars can cause hypertension, renal insufficiency, or
               problems during pregnancy. Indeed, these are possible only in cases of severe bilateral
               renal damage.
             o The initial treatment for all VUR patients diagnosed within the first year of life as
               corrective surgical intervention is not advised.
             o It is strongly recommended to initially manage all VUR children presenting at age one
               to five years conservatively.

IX.13.6.1.1 The conservative approach:
1. Watchful waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in those with LUTD.
2. Circumcision during early infancy may be considered as part of the conservative approach because it is effective in reducing the risk of infection in normal children.
3. Regular follow-up with imaging studies (e.g. VCUG, nuclear cystography, or DMSA scan) to monitor spontaneous resolution and kidney status.
4. Should be dismissed in all cases of febrile breakthrough infections, despite prophylaxis, and intervention should be considered. (14)

IX.13.6.1.2 Continuous antibiotic prophylaxis (CAP)
CAP may not be needed in every reflux patient. Offer close surveillance without antibiotic prophylaxis to children presenting with lower grades of reflux and without symptoms. CAP is useful in patients with high-grade reflux in preventing recurrent infections by 50% but its use in preventing further renal scarring and its consequences (hypertension and renal failure) is not proven. Based on a risk classification system defines a high-risk group (uncircumcised males, infants / toilet-trained children, presence of BBD and high-grade reflux) who would benefit from an antibiotic prophylaxis significantly. It is recommended to use CAP until after children have been toilet-trained and ensuring that there is no LUTD. CAP has the cost of increased antimicrobial resistance (15).
Active surveillance of UTI is needed after CAP is discontinued. It is strongly advised that the advantages and disadvantages should be discussed in detail with the family.

IX.13.6.2 Surgical treatment:
Surgical treatment can be endoscopic injection of bulking agents or ureteral re-implantation. Surgical correction should be considered in symptomatic patients with persistent high-grade reflux (grades IV/V) especially if associated with abnormal renal parenchyma, or in patients presented after toilettraining. Offer surgical correction if parents prefer definitive therapy to conservative management. There is no consensus about the timing (usually after age of one year) and type of surgical correction. The outcome of open surgical correction is better than endoscopic correction for higher grades of reflux, whereas satisfactory results can be achieved by endoscopic injection for lower grades and those with LUTD. In high-risk patients who already have renal impairment, a more aggressive, multidisciplinary approach is needed.

IX.13.6.2.1 Subureteric Injection of Bulking Materials
Endoscopic subureteric injection of biodegradable bulking agents has become an alternative to longterm antibiotic prophylaxis and open surgical intervention in the treatment of VUR in children. Using cystoscopy, a bulking material is injected beneath the intramural part of the ureter in a submucosal location. The injected bulking agent elevates the ureteral orifice and the distal ureter, so that coaptation is increased. This results in narrowing of the lumen, which prevents reflux of urine into the ureter, while still allowing its antegrade flow.

Several bulking agents have been used over the past two decades. The most used agents nowadays are a solution of dextranomer/hyaluronic acid (Deflux™, Dexell®) and polyacrylatepolyalcohol copolymer hydrogel (Vantris®) (16).

In a meta-analysis of 5,527 patients and 8,101 renal units, the reflux resolution rate (by ureter) following one treatment for grades I and II reflux was 78.5%, 72% for grade III, 63% for grade IV, and 51% for grade V. If the first injection was unsuccessful, the second treatment had a success rate of 68% and the third treatment 34%. The aggregate success rate with one or more injections was 85%. The success rate was significantly lower for duplicated (50%) vs. single (73%) systems, and neuropathic (62%) vs. normal (74%) bladders. Studies with long-term follow-up have shown that there is a high recurrence rate (up to 20%) in two years (17).

Obstruction at UVJ may happen in the long-term follow-up after endoscopic correction of reflux. Patients with high-grade reflux and dilated ureters are at risk of late obstruction (18).

IX.13.6.2.2 Open Surgical Techniques
Various intra- and extravesical techniques have been described for the surgical correction of reflux. They all share the basic principle of lengthening the intramural part of the ureter by submucosal embedding of the ureter in a tunnel of 5:1 ratio to ureteral diameter. All techniques have been shown to be safe with a low rate of complications and excellent success rates (92-98%) (19).

The most popular and reliable open procedure is cross trigonal re-implantation described by Cohen (18). The main concern with this procedure is the difficulty of accessing the ureters endoscopically, if needed, when the child is older. Alternatives are suprahiatal re-implantation (Politano-Leadbetter technique) and extravesical procedure (Lich-Gregoir). In bilateral reflux, an intravesical anti-reflux procedure may be considered, because simultaneous bilateral extravesical reflux repair carries an increased risk of temporary post-operative urine retention (20). Vesicostomy / ureterostomy may be indicated as shunting maneuver till the definitive surgery is safely done.

IX.13.6.2.3 Laparoscopy and Robot-Assisted Techniques
Various anti-reflux surgeries have been performed with the robot and the extravesical approach is the most used. Operative times, costs and post-operative complications leading to secondary interventions are higher with laparoscopy, but post-operative pain and hospital stay is less compared to open surgery (21). Therefore, at present, a laparoscopic approach cannot be recommended as a routine procedure and should be limited to centers of excellence (22).

Table IX:12 Recommendations for VUR managment

Recommendation

Strength rating

1. Initially treat all patients diagnosed within the first year of life with continuous antibiotic prophylaxis, regardless of the grade of reflux or presence of renal scars.

Weak

2. Offer immediate, parenteral antibiotic treatment for febrile breakthrough infections

Strong

3. Offer definitive surgical or endoscopic correction to patients with frequent breakthrough infections.

Weak

4. Offer open surgical correction to patients with persistent high-grade reflux and endoscopic correction for lower grades of reflux.

Strong

5. Initially manage all children presenting at age one to five years conservatively.

Strong

6. Offer surgical repair to children above the age of one presenting with high-grade reflux and abnormal renal parenchyma.

Weak

7. Offer close surveillance without antibiotic prophylaxis to children presenting with lower grades of reflux and without symptoms.

Strong

8. Ensure that a detailed investigation for the presence of lower urinary tract dysfunction (LUTD) is done in all and especially in children after toilet-training. If LUTD is found, the initial treatment should always be for LUTD.

Strong

9. Offer surgical correction, if parents prefer definitive therapy to conservative management.

Strong

10. Select the most appropriate management option based on:
• The presence of renal scars;
• Clinical course;
• The grade of reflux;
• Ipsilateral renal function;
• Bilaterality;
• Bladder function;
• Associated anomalies of the urinary tract;
• Age and gender;
• Compliance;
• Parental preference.

Weak

11. In high-risk patients who already have renal impairment, a more aggressive, multidisciplinary approach is needed.

Strong


IX.13.7 References:

1. Lee, T., et al. Impact of Clinical Guidelines on Voiding Cystourethrogram Use and Vesicoureteral Reflux Incidence. J Urol, 2018. 199: 831.
2. Fanos, V., et al. Antibiotics or surgery for vesicoureteric reflux in children. Lancet, 2004. 364: 1720.
3. Skoog, S.J., et al. Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis. J Urol, 2010. 184: 1145.
4. Sillen, U., et al. The Swedish reflux trial in children: v. Bladder dysfunction. J Urol, 2010. 184: 298.
5. Sjostrom, S., et al. Spontaneous resolution of high grade infantile vesicoureteral reflux. J Urol, 2004. 172: 694.
6. Sjostrom, S., et al. Predictive factors for resolution of congenital high grade vesicoureteral reflux in infants: results of univariate and multivariate analyses. J Urol, 2010. 183: 1177.
7. Peters, C., et al. Vesicoureteral reflux associated renal damage: congenital reflux nephropathy and acquired renal scarring. J Urol, 2010. 184: 265.
8. Naseer, S.R., et al. New renal scars in children with urinary tract infections, vesicoureteral reflux and voiding dysfunction: a prospective evaluation. J Urol, 1997. 158: 566.
9. Blumenthal, I. Vesicoureteric reflux and urinary tract infection in children. Postgrad Med J, 2006. 82: 31.
10. Darge, K. Voiding urosonography with US contrast agents for the diagnosis of vesicoureteric reflux in children. II. Comparison with radiological examinations. Pediatr Radiol, 2008. 38: 54.
11. Medical versus surgical treatment of primary vesicoureteral reflux: report of the International Reflux Study Committee Pediatrics, 1981. 67: 392.
12. Preda, I., et al. Normal dimercaptosuccinic acid scintigraphy makes voiding cystourethrography unnecessary after urinary tract infection. J Pediatr, 2007. 151: 581.
13. Elder, J.S., et al. Pediatric Vesicoureteral Reflux Guidelines Panel summary report on the management of primary vesicoureteral reflux in children. J Urol, 1997. 157: 1846.
14. Preda, I., et al. Normal dimercaptosuccinic acid scintigraphy makes voiding cystourethrography unnecessary after urinary tract infection. J Pediatr, 2007. 151: 581.
15. Hoberman, A., et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med, 2014. 370: 2367.
16. Dogan, H.S., et al. Factors affecting the success of endoscopic treatment of vesicoureteral reflux and comparison of two dextranomer based bulking agents: does bulking substance matter? J Pediatr Urol, 2015. 11: 90.e1.
17. Lightner, D.J. Review of the available urethral bulking agents. Curr Opin Urol, 2002. 12: 333.
18. Okawada, M., et al. Incidence of ureterovesical obstruction and Cohen antireflux surgery after Deflux(R) treatment for vesicoureteric reflux. J Pediatr Surg, 2018. 53: 310.
19. Duckett, J.W., et al. Surgical results: International Reflux Study in Children--United States branch. J Urol, 1992. 148: 1674.
20. Lipski, B.A., et al. Voiding dysfunction after bilateral extravesical ureteral reimplantation. J Urol, 1998. 159: 1019.
21. Boysen, W.R., et al. Prospective multicenter study on robot-assisted laparoscopic extravesical ureteral reimplantation (RALUR-EV): Outcomes and complications. J Pediatr Urol, 2018. 14: 262.e1.
22. Austin, J.C., et al. Vesicoureteral reflux: who benefits from correction. Urol Clin North Am, 2010. 37: 243.

IX.14 Disorders of Sex Development (DSD):

The term ‘disorders of sex development (DSD) is proposed to indicate congenital conditions with atypical development of chromosomal, gonadal or anatomical sex. This term replaced the former terms: ‘intersex disorders’, ‘pseudohermaphroditism’ and ‘hermaphroditism’ (1). Overall, evidencebased literature on DSD is sparse. An exception is the risk of gonadal cancer, for which the level of evidence is higher (2).
DSD can present as prenatal diagnosis, neonatal diagnosis and late diagnosis. Prenatal diagnosis can be based on karyotype or US findings; neonatal diagnosis is based on genital ambiguity and late diagnosis is made on early or delayed puberty (3). Dealing with neonates with DSD requires a multidisciplinary approach, which should include specialized pediatric urologists, geneticists, neonatologists, endocrinologists, gynecologists, pediatric psychologists, ethicists, social workers and transition to adult care.

IX.14.1 Current classification of DSD conditions:

1- 46XX DSD group e.g. congenital adrenal hyperplasia (CAH) patients which represent approximately 80% of all DSD conditions. CAH are extremely important since they can be potentially life-threatening neonatal emergency because of salt loss phenomenon and immediate medical care is mandatory. (4)

2- 46XY DSD group e.g. the partial androgen insensitivity syndrome (PAIS) as well as the complete androgen insensitivity syndrome (CAIS).

3- Sex chromosome mosaicism DSD group (45X, 45X/46XY, 47XXY) e.g. the mixed gonadal dysgenesis (MGD). Many have normal male phenotype and others asymmetric genitalia with one side is more a labia majora with usually no palpable gonad (most likely to be a streak gonad).

4- Ovotesticular DSD group because of the presence of ovarian and testicular tissue in the same individual (one ovary and one testis or one or two ovotestes) meaning that both – female and male structures – live together. There is great variability in phenotype with uni- or bilateral undescended gonads.

5- Non-hormonal/non-chromosomal DSD group including newborns with cloacal Exstrophy, aphallia, and severe micropenis.

IX.14.2 Diagnostic evaluation:

IX.14.2.1 Findings suggesting the possibility of DSD are:
a) Apparent male: Severe hypospadias associated with bifid scrotum, undescended testis/testes with hypospadias and bilateral non-palpable testes in a full-term apparently male infant.
b) Apparent female: Clitoral hypertrophy of any degree, non-palpable gonads, vulva with single opening, indeterminate and ambiguous genitalia.

IX.14.2.2 Diagnostic work-up of neonates with DSD:
a) History (family, maternal, neonatal): parental consanguinity, previous DSD or genital anomalies, previous neonatal deaths, primary amenorrhea or infertility in other family members, maternal exposure to androgens and failure to thrive, vomiting, diarrhea of the neonate.

b) Physical examination: pigmentation of genital and areolar area, hypospadias or urogenital sinus, size of phallus, palpable and/or symmetrical gonads (mostly testis and virtually excludes 46XX DSD) and blood pressure. Medical photography can be useful but requires sensitivity and consent (5).

c) Investigations: serum 17-hydroxyprogesterone - serum electrolytes, LH, FSH, TST, cortisol and ACTH - adrenal steroids in urine – Karyotype – Ultrasound – Genitogram - hCG stimulation test to confirm presence of testicular tissue and androgen-binding studies.

d) Invasive diagnostics under general anesthesia: can be helpful in some cases.

i. Cystoscopy, to evaluate the urogenital sinus, the level of confluence, the vagina or utriculus, and the possible presence of a cervix at the top of the vagina.

ii. Laparoscopy allow a final diagnosis on the presence of impalpable gonads and on the presence of Müllerian structures. If indicated, a gonadal biopsy can be performed (6).

IX.14.3 Gender assignment:

Nowadays it is obvious and clear that open and complete communications with caregivers and eventually the affected person are mandatory. The lack of outcome data and different preferences make it extremely difficult to determine whether and when to pursue gonadal or genital surgery. Shared fully informed decision making is necessary, combining expert healthcare knowledge in a patient- and family-centered multidisciplinary setting. The goal of all involved should be to individualize and prioritize each patient. Surgical interventions in children with DSD only being applied in emergency conditions and it is better to delay unnecessary surgery to an age when the patient can give informed consent. Surgery that alters appearance is not urgent (7)

IX.14.4 Risk of tumor development:

Individuals with DSD have an increased risk of developing germ cell cancer in comparison with to the general population (8). The highest risk prevalence (30-50%) is seen in patients with 46XY gonadal dysgenesis and in some patients with 45X/46XY DSDs. Conversely, patients with testosterone biosynthesis disorders and androgen action disturbances show a much lower risk (1-15%) for carcinoma in situ (CIS) development during childhood and a limited tendency towards invasive progression of the lesions. Regarding clinical management a gonadal biopsy at the time of a possible orchidopexy, patients can be obtained for regular self-exams and annual ultrasound (2).

Table IX:13 Recommendations for DSD management

Recommendation

Strength rating

1. Newborns with DSD conditions warrant a multidisciplinary team approach.

Strong

2. Refer children to experienced centers where neonatology, pediatric endocrinology, pediatric urology, child psychology and transition to adult care are guaranteed.

Strong

3. Do not delay diagnosis and treatment of any neonate presenting with ambiguous genitalia since salt-loss in a 46XX CAH girl can be fatal.

Strong


IX.14.5 References:

1. Lee, P.A., et al. Consensus statement on management of intersex disorders. International Consensus Conference on Intersex. Pediatrics, 2006. 118 : e488.

2. Wolffenbuttel, K.P., et al. Gonadal dysgenesis in disorders of sex development: Diagnosis and surgical management. J Pediatr Urol, 2016. 12 : 411.

3. Maggi, M., et al. Standard operating procedures: pubertas tarda/delayed puberty--male. J Sex Med, 2013. 10: 285.

4. Lee, P.A., et al. Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care. Horm Res Paediatr, 2016. 85: 158.

5. Creighton, S., et al. Medical photography: ethics, consent and the intersex patient. BJU Int, 2002. 89: 67.

6. Chertin, B., et al. The use of laparoscopy in intersex patients. Pediatr Surg Int, 2006. 22: 405.

7. Mouriquand, P., et al. The ESPU/SPU standpoint on the surgical management of Disorders of Sex Development (DSD). J

8. Pediatr Urol, 2014. 10: 8.

9. Van der Zwan, Y.G., et al. Gonadal maldevelopment as risk factor for germ cell cancer: towards a clinical decision model. Eur Urol, 2015. 67: 692.