PAEDIATRIC UROLOGY - EAU GUIDELINES 2016 (2/4)

3.5.Hypospadias

3.5.1.Epidemiology, aetiology and pathophysiology

3.5.1.1.Risk factors

Risk factors associated with hypospadias are likely to be genetic, placental and/or environmental [178] (LE: 2b). Interactions between genetic and environmental factors may help explain non-replication in genetic studies of hypospadias. Single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases [179] (LE: 2b; GR: B).



  • An additional member with hypospadias is found in 7% of families [180].
  • Endocrine disorders can be detected in rare cases.
  • Babies of young or old mothers and babies with a low birth weight have a higher risk of hypospadias [180].
  • A significant increase in the incidence of hypospadias over the last 25 years suggests a role for environmental factors (hormonal disruptors and pesticides) [181-184]. Though this information has been questioned [185].
  • The use of oral contraceptives prior to pregnancy has not been associated with an increased risk of hypospadias in offspring [186] (LE: 2a; GR: B).
A Dutch case-control study confirmed that genetic predisposition possibly plays a role in anterior and middle hypospadias, in contrast, the posterior phenotype was more often associated with pregnancy-related factors, such as primiparity, preterm delivery, and being small for gestational age. Hormone-containing contraceptive use after conception increased the risk of middle and posterior hypospadias, while multiple pregnancies were associated with the posterior form in particular [187] (LE: 2a).

3.5.2.Classification systems

Hypospadias are usually classified based on the anatomical location of the proximally displaced urethral orifice:
  • Distal-anterior hypospadias (located on the glans or distal shaft of the penis and the most common type of hypospadias);
  • Intermediate-middle (penile);
  • Proximal-posterior (penoscrotal, scrotal, perineal).
The pathology may be much more severe after skin release.

3.5.3.Diagnostic evaluation

Most hypospadias patients are easily diagnosed at birth (except for the megameatus intact prepuce variant).
Diagnosis includes a description of the local findings:
  • Position, shape and width of the orifice;
  • Presence of atretic urethra and division of corpus spongiosum;
  • Appearance of the preputial hood and scrotum;
  • Size of the penis;
  • Curvature of the penis on erection.
The diagnostic evaluation also includes an assessment of associated anomalies, which are:
  • Cryptorchidism (in up to 10% of cases of hypospadias);
  • Open processus vaginalis or inguinal hernia (in 9-15%).
Severe hypospadias with unilaterally or bilaterally impalpable testis, or with ambiguous genitalia, requires a complete genetic and endocrine work-up immediately after birth to exclude DSD, especially congenital adrenal hyperplasia.
Urine trickling and ballooning of the urethra requires exclusion of meatal stenosis. The relationship between the severity of the hypospadias and the associated anomalies of the upper- or lower urinary tract were not confirmed in a systematic literature review [188] (LE: 3).

3.5.4.Management

Differentiation between functionally necessary and aesthetically feasible operative procedures is important for therapeutic decision-making.
The functional indications for surgery are:
  • Proximally located meatus;
  • Ventrally deflected or spraying urinary stream;
  • Meatal stenosis;
  • Curved penis.
The cosmetic indications, which are strongly linked to the psychology of the parent or future patient’s psychology, are:
  • Abnormally located meatus;
  • Cleft glans;
  • Rotated penis with abnormal cutaneous raphe;
  • Preputial hood;
  • Penoscrotal transposition;
  • Split scrotum.
As all surgical procedures carry the risk of complications, thorough pre-operative counselling of the parents is crucial.
The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate size, to bring the neomeatus to the tip of the glans, if possible, and to achieve an overall acceptable cosmetic appearance of the genitalia [181] (LE: 4; GR: C) (see Figure 3).
The use of magnifying spectacles and fine synthetic absorbable suture materials (6/0-7/0) is required. As in any penile surgery, exceptional prudence should be adopted with the use of cautery. Knowledge of a variety of surgical reconstructive techniques, wound care and post-operative treatment are essential for a satisfactory outcome. Pre-operative hormonal treatment with local or parenteral application of testosterone, dihydrotestosterone or beta-chorionic gonadotropin is usually limited to patients with proximal hypospadias, a small appearing penis, reduced glans circumference or reduced urethral plate [189]. The effect of pre-operative hormonal stimulation on operative outcomes after hypospadias repair remains unclear according to systematic review [190,191].

3.5.4.1.Age at surgery

The age at surgery for primary hypospadias repair is usually 6-18 (24) months [181] (LE: 4; GR: C). However, earlier repair between 4 and 6 months of age has been reported recently [192,193] (LE: 3; GR; B). Age at surgery is not a risk factor for urethroplasty complication in pre-pubertal tubularised incised plate urethroplasty (TIP) repair [192] (LE: 2b).

3.5.4.2.Penile curvature

If present, penile curvature is often released by degloving the penis (skin chordee) and by excision of the connective tissue of the genuine chordee on the ventral aspect of the penis in up to 70% [194]. The urethral plate has well vascularised connective tissue and does not cause curvature in most cases. The residual curvature is caused by corporeal disproportion and requires straightening of the penis, mostly using dorsal midline plication or orthoplasty or ventral corporotomies with or without grafting [195,196] (LE: 2b; GR: B). No systematic review or meta-analyses related to this subject is currently available.

3.5.4.3.Preservation of the well-vascularised urethral plate

The mainstay of hypospadias repair is preservation of the well-vascularised urethral plate and its use for urethral reconstruction has become standard practice in hypospadias repair [197]. Mobilisation of the corpus spongiosum/urethral plate and the bulbar urethra decreases the need for urethral plate transection [196] (LE: 2b; GR: B). Urethral plate elevation and urethral mobilisation with TIP resulted in focal devascularisation of the neourethra with symptomatic stricture development [198] (LE: 2b).
If the urethral plate is wide, it can be tubularised following the Thiersch-Duplay technique. If the plate is too narrow to be simply tubularised, it is recommended that a midline-relaxing incision of the plate, followed by reconstruction according to the Snodgrass-Orkiszewski technique, is performed in distal hypospadias, as well as in proximal hypospadias (though the complication rate is higher) [199-203].
The onlay technique is preferred in proximal hypospadias and if a plate is unhealthy or too narrow [194]. For distal forms of hypospadias, a range of other techniques are available (e.g. TIP, Mathieu, urethral advancement) [204] (LE: 2b; GR: B).
If the continuity of the urethral plate cannot be preserved, a modification of the tubularised flap, such as a tube-onlay, an inlay-onlay flap, or onlay flap on albuginea is used to prevent urethral stricture [205-207] (LE: 3 ). In this situation, as well as in severe scrotal or penoscrotal hypospadias, the Koyanagi technique or two-stage procedure may be preferable, reported complication rate is 61 and 68%, respectively [208,209] (LE: 3; GR: C). The use of dorsal inlay skin grafts may allow an increased number of single-stage repairs to be performed [210].

3.5.4.4.Re-do hypospadias repairs

For re-do hypospadias repairs, no definitive guidelines can be given. All the above-mentioned procedures are used in different ways and are often modified according to the individual needs of the patient.
Figure 3: Algorithm for the management of hypospadias

DSD=disorders of sex development; GAP=glans approximation procedure; TIP=tubularised incised plate urethroplasty; MAGPI=meatal advancement and glanuloplasty incorporated.

3.5.4.5.Urethral reconstruction

Following formation of the neo-urethra, the procedure is completed by glansplasty and by reconstruction of the penile skin. If there is a shortage of skin covering, the preputial double-face technique or placement of the suture line into the scrotum may be used. In countries where circumcision is not routinely performed, preputial reconstruction can be considered. However, in the TIP repair, the parents should be advised that use of a preputial dartos flap reduces the fistula rate [199,200] (LE: 2b; GR: B).

3.5.4.6.Urine drainage and wound dressing

Urine is drained with a transurethral dripping stent, or with a suprapubic tube. Some surgeons use no drainage after distal hypospadias repair. Circular dressing with slight compression, as well as prophylactic antibiotics during surgery, are established procedures [211] (LE: 4; GR: C). Post-operative prophylaxis after hypospadias repair is controversial [212,213] (LE: 2b). A large variety of duration of stenting and dressing is described. No recommendation can be given due to the low level of evidence.

3.5.4.7.Outcome

A literature review on distal TIP urethroplasty found significant clinical heterogeneity with some limitations to the comparability of the data; one should expect a predictable outcome with complication rates below 10% (fistula, meatal stenosis, dehiscence, recurrent ventral curvature, and haematoma) [214,215]. A systematic review of the Mathieu and TIP repairs of distal hypospadias found similar incidence of fistula (3.4-3.6%), and higher incidence of meatal stenosis in TIP (3.0% vs. 0.6% in Mathieu) after six to twelve months follow-up [216]. Another systematic review and meta-analysis found no difference in fistula, meatal stenosis or glans dehiscence, but better cosmesis in TIP repair [203,217].
The complication rate of TIP and onlay repairs of primary severe hypospadias is similar, 24% and 27%, respectively. It is higher in free graft and in preputial island tube urethroplasty [194]. Staged buccal mucosa graft requires a redo grafting in 13% of patients, after the second stage more than one third of patients have complications, mostly with some degree of graft fibrosis [218]. Low surgeon volume independently increases the risk of fistula, stricture or diverticulum repair [215] (LE: 3). Ventral corporeal grafting for severe penile curvature gives good long-term results and safety profiles for erectile function [219] (LE: 2b).

3.5.5.Follow-up

Long-term follow-up is necessary up to adolescence to detect urethral stricture, voiding dysfuntions and recurrent penile curvature. Up to half of complications requiring reoperation present after the first year post-operatively [220] (LE: 2b).
Overall, between 7% and 67% of patients operated on for hypospadias end up with an obstructive flow (24.6% in TIP). These children should be followed until adulthood to clarify the clinical significance. Spontaneous improvement has been described [221,222] (LE: 2a). Urine flow is significantly lower in patients after hypospadias surgery, especially in those who had corrected chordee, than in controls, but without significant association with lower urinary tract symptoms (LUTS) [223] (LE: 2a).
Objective scoring systems have been developed in order to evaluate the results of hypospadias surgery [224] (LE: 2b) and cosmetic appearance (HOPE) [225] (LE: 2a). The Pediatric Penile Perception Score is a reliable instrument to assess penile self-perception in children after hypospadias repair, and for appraisal of the surgical result by parents and uninvolved urologists [226] (LE: 2a).
Adolescents and adults, who have undergone hypospadias repair in childhood, have a slightly higher rate of dissatisfaction with penile size, especially proximal hypospadias patients, but their sexual behaviour is not different from that of control groups [227,228] (LE: 2a-b).
3.5.6.Summary of evidence and recommendations for the management of hypospadias
Summary of evidence
LE
The suggested age at surgery for primary hypospadias repair is 6-24 months.
4
The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate size, to bring the new meatus to the tip of the glans, if possible, and to achieve an overall acceptable cosmetic appearance.
4
Sexual functions are usually well preserved.
2b
Recommendations
GR
At birth, differentiate isolated hypospadias from disorders of sex development which are mostly associated with cryptorchidism or micropenis.
A
Differentiate between functionally necessary (functional indications) and aesthetically feasible operative procedures (psychological, cosmetic indications).
A
Ensure that parents receive thorough pre-operative counselling.
A
For distal hypospadias, use original and modified tubularised incised plate urethroplasty or Mathieu procedure. Use the onlay urethroplasty or two-stage procedures in more severe hypospadias. A treatment algorithm is presented (see Figure 3).
B
Ensure long-term follow-up, up to adolescence, to detect urethral stricture, voiding dysfunctions and recurrent penile curvature.
A
Use the new objective scoring systems to assist in evaluating the functional and cosmetic outcome.
A

3.6.Congenital penile curvature

3.6.1.Epidemiology, aetiology and pathophysiology

Penile curvature may be ventral, dorsal or lateral. Most ventral curvatures are associated with hypospadias due to chordee or ventral dysplasia of cavernous bodies [229]. Similarly, dorsal curvature is mostly associated with exstrophy/epispadias complex [230]. Isolated curvature is not frequent with an incidence of 0.6 % [231] (LE: 2) and is caused by asymmetry of the cavernous bodies [229,232]. Curvature > 30° is considered clinically significant; curvature > 60° may interfere with satisfactory sexual intercourse in adulthood [233] (LE: 4).

3.6.2.Diagnostic evaluation

Diagnosis is made during hypospadias or epispadias repair using an artificial erection [234]. The isolated anomaly is usually not recognised until later in childhood because the appearance of the penis is normal. The curvature is only observed during erections.

3.6.3.Management

The treatment is surgical. An artificial erection is used to determine the degree of curvature and to check symmetry after the repair [234].
In hypospadias, chordee related to the tethering of the ventral skin and to the spongiosal pillars is first released. Only in a few cases, the penile curvature is caused by a short urethral plate, which should be cut. To repair the corporeal angulation in the isolated curvature, or curvature associated with hypospadias, different techniques of plication of corpora cavernosa (orthoplasty) are used [233].
In exstrophy/epispadias complex, a combination of complete release of the urethral body from the corpora and a different kind of corporoplasty with or without corporotomy is usually necessary to achieve a straight penis [235,236].
3.6.4.Summary of evidence and recommendations for the management of congenital penile curvature
Summary of evidence
LE
Congenital penile curvature > 30° is considered clinically significant; curvature > 60° may interfere with satisfactory sexual intercourse in adulthood.
4
Recommendations
LE
GR
Diagnose congenital penile curvature during hypospadias or epispadias repair using an artificial erection.
4
B
Perform surgery to treat congenital penile curvature.
4
B

3.7.Varicocele in children and adolescents

3.7.1.Epidemiology, aetiology and pathophysiology

Varicocele is defined as an abnormal dilatation of testicular veins in the pampiniformis plexus caused by venous reflux. It is unusual in boys under 10 years of age and becomes more frequent at the beginning of puberty. It is found in 14-20% of adolescents, with a similar incidence during adulthood. It appears mostly on the left side (78-93% of cases). Right-sided varicoceles are less common; they are usually noted only when bilateral varicoceles are present and seldom occur as an isolated finding [237-239].
Varicocele develops during accelerated body growth and increased blood flow to the testes, by a mechanism that is not clearly understood. Genetic factors may be present. An anatomic abnormality leading to impaired venous drainage is expressed by the considerable prevalence of the left side condition where the internal spermatic vein drains into the renal vein. Varicocele can induce apoptotic pathways because of heat stress, androgen deprivation and accumulation of toxic materials. Severe damage is found in 20% of adolescents affected, with abnormal findings in 46% of affected adolescents. Histological findings are similar in children or adolescents and in infertile men. In 70% of patients with grade II and III varicocele, left testicular volume loss was found.
Several authors reported on reversal of testicular growth after varicocelectomy in adolescents [240,241]. The average proportion of catch-up growth of 76.4% (range: 52.6-93.8%) has been found according to a recent meta-analysis [242] (LE: 2a). However, this may partly be attributable to testicular oedema associated with the division of lymphatic vessels [243] (LE: 2).
In about 20% of adolescents with varicocele, fertility problems will arise [244]. The adverse influence of varicocele increases with time. Improvement in sperm parameters has been demonstrated after adolescent varicocelectomy [245-247] [248] (LE: 1).

3.7.2.Classification systems

Varicocele is classified into 3 grades:
  • Grade I - Valsalva positive (palpable at Valsalva manoeuvre only);
  • Grade II - palpable (palpable without the Valsalva manoeuvre);
  • Grade III - visible (visible at distance) [249].

3.7.3.Diagnostic evaluation

Varicocele is mostly asymptomatic, rarely causing pain. It may be noticed by the patient or parents, or discovered by the paediatrician at a routine visit. The diagnosis depends upon the clinical finding of a collection of dilated and tortuous veins in the upright posture; the veins are more pronounced when the patient performs the Valsalva manoeuvre. The size of both testicles should be evaluated during palpation to detect a smaller testis.
Venous reflux into the plexus pampiniformis is diagnosed using Doppler US colour flow mapping in the supine and upright position [250]. Venous reflux detected on US only is classified as subclinical varicocele. To discriminate testicular hypoplasia, the testicular volume is measured by US examination or by orchidometer. In adolescents, a testis that is smaller by > 2 mL or 20% compared to the other testis is considered to be hypoplastic [251] (LE: 2).
Extension of Wilms tumour into the renal vein and inferior vena cava can cause a secondary varicocele. A renal US should be routinely added in pre-pubertal boys and in isolated right varicocele (LE: 4).
In order to assess testicular injury in adolescents with varicocele, supranormal FSH and LH responses to the luteinising hormone-releasing hormone (LHRH) stimulation test are considered reliable, because histopathological testicular changes have been found in these patients [246,252].

3.7.4.Management

There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later. Beneficial effect of pubertal screening and treatment for varicocele regarding chance of paternity has been questioned according to a corresponding questionnaire in adult patients [253] (LE: 4).
The recommended indication criteria for varicocelectomy in children and adolescents are [238]:
  • varicocele associated with a small testis;
  • additional testicular condition affecting fertility;
  • bilateral palpable varicocele;
  • pathological sperm quality (in older adolescents);
  • symptomatic varicocele [253].
Testicular (left + right) volume loss in comparison with normal testes is a promising indication criterion, once the normal values are available [254]. Repair of a large varicocele, causing physical or psychological discomfort, may also be considered. Other varicoceles should be followed-up until a reliable sperm analysis can be performed (LE: 4).
Surgical intervention is based on ligation or occlusion of the internal spermatic veins. Ligation is performed at different levels:
  • inguinal (or subinguinal) microsurgical ligation;
  • suprainguinal ligation, using open or laparoscopic techniques [255-258].
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 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 [255,257]. 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 [243,255,256,259] (LE: 2). The methods of choice are subinguinal or inguinal microsurgical (microscopic) repairs, or suprainguinal open or laparoscopic lymphatic-sparing repairs [255,257,260,261]. Intrascrotal application of isosulphan blue was recommended to visualise the lymphatic vessels [262,263]. In suprainguinal approach, an artery sparing varicocelectomy may not offer any advantage in regards to catch-up growth and is associated with a higher incidence of recurrent varicocele [264,265].
Angiographic occlusion of the internal spermatic veins also meets the requirements of lymphatic sparing repair. It is based on retrograde or antegrade sclerotisation of the internal spermatic veins [266,267]. However, although this method is less invasive and may not require general anaesthesia, it is associated with radiation burden, which is less controllable in the antegrade technique [238,266,267] (LE: 2).
3.7.5.Summary of evidence and recommendations for the management of varicocele
Summary of evidence
LE
Varicocele becomes more frequent at the beginning of puberty and is found in 14-20% of adolescents. Fertility problems are expected in up to 20% of adolescents with a varicocele.
Pubertal patients with a left grade II and III varicocele have the left testis smaller in up to 70%; in late adolescence the contralateral right testis also becomes smaller.
1b
After adolescent varicocelectomy, left testis catch-up growth and improvement in sperm parameters has been demonstrated.
1a
There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later.
1b
Division of testicular lymphatics leads to hydrocele in up to 40 % and to testicular hypertrophy.
1b
Recommendations
LE
GR
Examine varicocele in the standing position and classify into three grades.
4
A
Use scrotal US to detect venous reflux without Valsalva manoeuvre in the supine and upright position and to discriminate testicular hypoplasia.
In pre-pubertal boys and in isolated right varicocele perform standard renal US to exlude a retroperitoneal mass.
Perform surgery for:
varicocele associated with a small testis (size difference of > 2 mL or 20%);
additional testicular condition affecting fertility;
pathological sperm quality (in older adolescents);
bilateral palpable varicocele;
symptomatic varicocele.
2
B
Use some form of optical magnification (microscopic or laparoscopic magnification) for surgical ligation.
2
B
Use lymphatic-sparing varicocelectomy to prevent hydrocele formation and testicular hypertrophy.
2
A
US=ultrasound.

3.8.Urinary tract infections in children

3.8.1.Epidemiology, aetiology and pathophysiology

Urinary tract infections (UTIs) represent the most common bacterial infection in children [268-270]. In neonates, the symptoms differ in many aspects from those in infants and children. 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 [271-274].
The incidence varies depending on age and sex. One meta-analysis showed in the first three months of life UTIs were present in 7.5% of girls, 2.4% (CI: 1.4-3.5) of circumcised boys, and 20.1% (CI: 16.8-23.4) of uncircumcised boys, who presented with fever [272]. In the first year of life, UTIs are more common in boys (3.7%) than girls (2%). Later, the incidence of UTIs changes to ~3% in pre-pubertal girls and 1% in pre-pubertal boys [272-275].
E. coli is found in ~75% of UTIs and is more frequent in community-acquired than nosocomial. In the latter, Klebsiella pneumoniae, Enterobacter spp., Enterococcus spp., Pseudomonas spp. and Candida spp. are more frequent than in community-acquired UTIs. Neonatal UTI is frequently complicated by bacteraemia. In a retrospective study, 12.4% of blood cultures from neonates admitted for UTI were positive for bacteraemia [276], however, it is less frequent in community-acquired than in nosocomial UTI [276,277].

3.8.2.Classification systems

There are five widely used classification systems according to the site, episode, severity, symptoms and complicating factors. For acute treatment, site and severity are most important.

3.8.2.1.Classification according to site

Lower urinary tract (cystitis) is an inflammatory condition of the urinary bladder mucosa with general signs and symptoms including infection, dysuria, frequency, urgency, malodorous urine, enuresis, haematuria, and suprapubic pain.
Upper urinary tract (pyelonephritis) is a diffuse pyogenic infection of the renal pelvis and parenchyma. The onset of pyelonephritis is generally abrupt. Clinical signs and symptoms include fever (> 38°C), chills, costovertebral angle or flank pain, and tenderness. Older children may report cystitis symptoms along with fever/flank pain. Infants and children may have non-specific signs such as poor appetite, failure to thrive, lethargy, irritability, vomiting or diarrhoea.

3.8.2.2.Classification according to episode

The first UTI may be a sign of anatomical anomalies that may predispose to complications of UTI and potential renal damage [278]. Anatomical evaluation is recommended (see below). Recurrent infection can be divided into unresolved and persistent infection.
In unresolved infection, initial therapy is inadequate for elimination of bacterial growth in the urinary tract (inadequate therapy, inadequate antimicrobial urinary concentration [poor renal concentration/gastrointestinal malabsorption], and infection involving multiple organisms with differing antimicrobial susceptibilities).
Persistent infection is caused by re-emergence of bacteria from a site within the urinary tract coming from a nidus for persistent infection that cannot be eradicated (e.g. infected stones, non-functioning or poorly functioning kidneys/renal segments, ureteral stumps after nephrectomy, necrotic papillae in papillary necrosis, urachal cyst, urethral diverticulum, periurethral gland, vesicointestinal, rectourethral or vesicovaginal fistulas). The same pathogen is identified in recurrent infections, but episodes of sterile urine may occur during and shortly following antimicrobial treatment.
In re-infection, each episode can be caused by a variety of new infecting organisms, in contrast to bacterial persistence in which the same infecting organism is always isolated. However, the most common general pathogenic species is E. coli, which occurs in many different serotypes. Therefore, recurrent E. coli UTI does not equate to infection with the same organism.

3.8.2.3.Classification according to severity

In simple UTI, children may have only mild pyrexia; are able to take fluids and oral medication; are only slightly or not dehydrated; and have a good expected level of compliance. When a low level of compliance is expected, such children should be managed as those with severe UTI. In severe UTI, infection is related to the presence of fever of > 39°C, the feeling of being ill, persistent vomiting, and moderate or severe dehydration.

3.8.2.4.Classification according to symptoms

Asymptomatic bacteriuria indicates attenuation of uropathogenic bacteria by the host, or colonisation of the bladder by non-virulent bacteria that are incapable of activating a symptomatic response (no leukocyturia, no symptoms). Asymptomatic UTI includes leukocyturia but no other symptoms.
A symptomatic UTI, includes irritative voiding symptoms, suprapubic pain (cystitis), fever and malaise (pyelonephritis). Cystitis may represent early recognition of an infection destined to become pyelonephritis, or bacterial growth controlled by a balance of virulence and host response.

3.8.2.5.Classification according to complicating factors

In uncomplicated UTI, infection occurs in a patient with a morphologically and functionally normal upper and lower urinary tract, normal renal function and competent immune system. This category includes mostly isolated or recurrent bacterial cystitis and is usually associated with a narrow spectrum of infecting pathogens that are easily eradicated by a short course of oral antimicrobial agents. Patients can be managed on an outpatient basis, with an emphasis on documenting resolution of their bacteriuria, followed by elective evaluation for potential anatomical or functional abnormalities of the urinary tract [279].
All neonates, most patients with clinical evidence of pyelonephritis, and all children with known mechanical or functional obstructions of the urinary tract, are considered to have complicated UTI. Mechanical obstruction is commonly due to the presence of posterior urethral valves, strictures or stones, independent of their location. Functional obstruction often results from LUT dysfunction (LUTD) of either neurogenic or non-neurogenic origin and dilating vesicoureteral reflux (VUR). Patients with complicated UTI require hospitalisation and parenteral antibiotics. Prompt anatomical evaluation of the urinary tract is critical to exclude the presence of significant abnormalities [280]. If mechanical or functional abnormalities are present, adequate drainage of the infected urinary tract is necessary.

3.8.3.Diagnostic evaluation

3.8.3.1.Medical history

Medical history includes the question of a primary (first) or secondary (recurring) infection; possible malformations of the urinary tract (e.g. pre- or postnatal US screening); prior operation; family history; and whether there is constipation or presence of LUTS.

3.8.3.2.Clinical signs and symptoms

Neonates with pyelonephritis or urosepsis can present with non-specific symptoms (failure to thrive, jaundice, hyperexcitability and without fever). UTI is the cause of fever in 4.1-7.5% of children who present to a paediatric clinic [281-283]. Septic shock is unusual, even with very high fever. Signs of a UTI may be vague and unspecific in small children, but later on, when they are > two years old, frequent voiding, dysuria and suprapubic, abdominal or lumbar pain can be detected.

3.8.3.3.Physical examination

Physical examination includes a general examination of the throat, lymph nodes, abdomen (constipation, palpable and painful kidney, or palpable bladder), flank, the back (stigmata of spina bifida or sacral agenesis), genitalia (phimosis, labial adhesion, vulvitis, epididymo-orchitis), and temperature.

3.8.3.4.Urine sampling, analysis and culture

Urine sampling has to be performed before any antimicrobial agent is administered. The technique for obtaining urine for urinalysis as well as culture affects the rate of contamination, which influences interpretation of the results. Especially in early infancy it can be challenging and depends on the mode of urine sampling [284].
3.8.3.4.1.Urine sampling
Urine must be collected under defined conditions and investigated as soon as possible to confirm or exclude UTI, especially in children with fever. In neonates, infants and non-toilet-trained children, there are four main methods with varying contamination rates and invasiveness to obtain urine:
(1) Plastic bag attached to the cleaned genitalia: This technique is most often used in daily practice. It is helpful when the culture results are negative. Also, if the dipstick is negative for both leukocyte esterase and nitrite, or microscopic analysis is negative for both pyuria and bacteriuria, UTI can be excluded without the need for confirmatory culture [285]. However, if the genitalia are not cleaned and culture is delayed, a high incidence of false-positive results (85-99%) can be found [286,287].
(2) Clean-catch urine collection: The infant is placed in the lap of a parent or member of the nursing staff, who holds a sterile foil bowl underneath the infant’s genitalia. The infant is offered oral fluids and urine collection is awaited [288]. This is time consuming and requires proper instruction of the parents. There seems to be a good correlation between the results of urine culture obtained by this method and suprapubic aspiration (SPA), with a false-positive rate of 5% and false-negative rate of 12% [288,289]; however the contamination rate is higher compared to SPA [290].
(3) Bladder catheterisation: In female infants and also in neonates, this technique may be an alternative to SPA, however with a higher contamination rate [291]. In a prospective study using bladder catheterisation in febrile children aged < 36 months, contamination was defined by multiple pathogens, non-pathogens, or colony counts < 10,000 cfu/mL. True UTI was found in 10% of children and 14% of the cultures were contaminated. Univariate analysis of potential predictors identified age < six months, difficult catheterisation, and uncircumcised boys. In children < six months and uncircumcised boys a new, sterile catheter with each repeated attempt at catheterisation may lead to less contamination [292] otherwise SPA should be the method of choice.
(4) Suprapubic bladder aspiration: This is the most sensitive method to obtain an uncontaminated urine sample in this age group [292-294]. Using US to assess bladder filling, simplifies SPA and improves the diagnostic yield of obtaining a urine specimen from 60% to 97% [293,294]. Complications are rare and have been reported in only 0.22% of cases, ranging from transient haematuria to bowel perforation [295]. However, bladder puncture causes more pain than catheterisation in infants < 2 months old [296].
In older, toilet-trained, children who can void on command, after carefully retracting the foreskin and cleaning the glans penis in boys and spreading the labia and cleaning the periurethral area in girls, the use of clean catch, especially midstream urine, could be an acceptable technique for obtaining urine. After cleaning the urethral meatus and perineum with gauze and liquid soap twice, the risk of contamination was reduced from 23.9% (41/171) to 7.8% (14/171) in a randomised trial [297].
If the clinical situation necessitates, and for differential diagnosis of sepsis, it is most appropriate to obtain an adequate urine sample by catheterisation or SPA [289]. In infants, a bag can only be used if the dipstick is negative, otherwise the urine should be obtained through catheterisation or SPA. This is also recommended in children, who are severely ill and a UTI needs to be excluded or confirmed. Blood sampling is dependent on the clinical situation.
3.8.3.4.2.Urinalysis
There are three methods that are commonly used for urinalysis:
(1) Dipsticks: These are appealing because they provide rapid results, do not require microscopy, and are ready to use. Leukocyte esterase (as a surrogate marker for pyuria) and nitrite (which is converted from dietary nitrates by most Gram-negative enteric bacteria in the urine) are the most frequent markers, and are usually combined in a dipstick test. The conversion of dietary nitrates to nitrites by bacteria takes approximately 4 h in the bladder [289,298]. However, nitrite is not a very sensitive marker for infants, who empty their bladder frequently, and not all urinary pathogens reduce nitrate to nitrite. The test is helpful when the result is positive, because it is highly specific (i.e. there are few false-positive results) [289,299].
Table 1: Sensitivity and specificity of component of urinalysis, alone and in combination[289]*
Test
Sensitivity (Range), %
Specificity (Range), %
Leukocyte esterase test
83 (67-94)
78 (64-92)
Nitrite test
53 (15-82)
98 (90-100)
Leukocyte esterase or nitrite test positive
93 (90-100)
72 (58-91)
Microscopy, white blood cells
73 (32-100)
81 (45-98)
Microscopy, bacteria
81 (16-99)
83 (11-100)
Leucocyte esterase test, nitrite test or microscopy positive
99.8 (99-100)
70 (60-92)
*Reproduced with permission from Pediatrics 2011 Sep;128(3):595-610, Copyright© 2011 by the AAP [289].
(2) Microscopy: This is the standard method of assessing pyuria after centrifugation of the urine with a threshold of 5 white blood cells (WBCs) per high-power field (25 WBC/μL) [295]. In uncentrifuged urine, > 10 WBC/μL has been demonstrated to be sensitive for UTI [300] and this could perform well in clinical situations [301]. However, this is rarely done in an outpatient setting.
(3) Flow imaging analysis technology: This is being used increasingly to classify particles in uncentrifuged urine specimens [302]. The numbers of WBCs, squamous epithelial cells and red cells correlate well with those found by manual methods [289].
3.8.3.4.3.Urine culture
After negative results for dipstick, microscopic or automated urinalysis, urine culture is generally not necessary, especially if there is an alternative source of fever. If the dipstick result is positive, confirmation by urine culture is strongly recommended.
It is unclear what represents a significant UTI. In severe UTI, > 105 cfu/mL can be expected. However, the count can vary and be related to the method of specimen collection, diuresis, and time and temperature of storage until cultivation occurs [274]. The classical definition of > 105 cfu/mL of voided urine is still used to define a significant UTI [303,304]. The American Academy of Pediatric Guidelines on Urinary Tract Infection suggest that the diagnosis should be on the basis of the presence of both pyuria and at least 105 cfu/mL. However, some studies have shown that, in voided specimens, < 104 organisms may indicate a significant UTI [305,306]. If urine is obtained by catheterisation, 103 - 105cfu/mL is considered to be positive, and any counts obtained after SPA should be considered as significant. Mixed cultures are indicative of contamination.
Table 2: Criteria for UTI in children (adapted from the EAU Guidelines on Urological Infections [307])
Urine specimen from suprapubic bladder puncture
Urine specimen from bladder catheterisation
Urine specimen from midstream void
Any number of cfu/mL (at least 10 identical colonies)
> 103 - 105 cfu/mL
> 104 cfu/mL with symptoms
> 105 cfu/mL without symptoms
Pyuria without bacteriuria (sterile pyuria) may be due to incomplete antibiotic treatment, urolithiasis, or foreign bodies in the urinary tract, and infections caused by Mycobacterium tuberculosis or Chlamydia trachomatis.

3.8.3.5.Imaging

3.8.3.5.1.Ultrasound
Renal and bladder US within 24 hours is advised in infants with febrile UTI to exclude obstruction of the upper and lower urinary tract. Abnormal results are found in 15% of cases, and 1-2% have abnormalities that require prompt action (e.g. additional evaluation, referral, or surgery) [289]. In other studies, renal US revealed abnormalities in up to 37% of cases, whereas voiding cystourethrography (VCUG) showed VUR in 27% of cases [277]. Dilating VUR is missed by US in around one third of cases [308]. Post-void residual urine should be measured in toilet-trained children to exclude voiding abnormalities as a cause of UTI. Elevated post-void residual urine volume predictis recurrence of UTIs in toilet-trained children [309].
3.8.3.5.2.Radionuclide scanning
Changes in dimercaptosuccinic acid (DMSA) clearance during acute UTI indicate pyelonephritis or parenchymal damage, correlated well with the presence of dilating reflux and the risk of further pyelonephritis episodes, breakthrough infections [310] and future renal scarring. In the acute phase of a febrile UTI (up to four to six weeks), DMSA-scan can demonstrate pyelonephritis by perfusion defects. Renal scars can be detected after three to six months. [308,311]. These findings are different in neonates. After the first symptomatic, community-acquired UTI, the majority of renal units with VUR grade III or higher had normal early DMSA scanning [312]. See also Chapter 3.13 on VUR.
3.8.3.5.3.Voiding cystourethrography
The gold standard to exclude or confirm VUR is VCUG. Due to the risk of renal scarring, VCUG is recommended after the first episode of febrile UTI in boys and girls depending on sex, age and clinical presentation (see Figure 4 and Table 4) (see also Chapter 3.13). The timing of VCUG does not influence the presence or severity of VUR [313,314]. Performance of early VCUG in patients with proven sterile urine does not cause any significant morbidity [315]. Another option is doing DMSA first, followed by VCUG if there is renal cortical uptake deficiency after UTI (see Chapter 3.13).

3.8.3.6.Bladder and bowel dysfunction

Bladder and bowel dysfunction (BBD) are risk factors for which each child with UTI should be screened upon presentation. Normalisation of micturition disorders or bladder over-activity is important to lower the rate of UTI recurrence. If there are signs of BBD at infection-free intervals, further diagnosis and effective treatment are strongly recommended [316-319]. Treatment of constipation leads to a decrease in UTI recurrence [320-322]. Therefore, exclusion of BBD is strongly recommended in any child with febrile and/or recurrent UTI, and it should be treated if there is evidence of BBD.

3.8.4.Management

3.8.4.1.Administration route

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; and complicated pyelonephritis (e.g. urinary obstruction). As a result of the increased incidence of urosepsis and severe pyelonephritis in newborns and infants aged < 2 months, parenteral antibiotic therapy is recommended. Electrolyte disorders with life-threatening hyponatraemia and hyperkalaemia based on pseudo-hypoaldosteronism can occur in these cases [323,324].
Parental combination treatment with ampicillin and an aminoglycoside (e.g. tobramycin or gentamicin) or respectively a third-generation cephalosporin achieves excellent therapeutic results (high efficacy of aminoglycosides, respectively cephalosporins against common uropathogens;enterococcus gap is closed with ampicillin). Compared to the division in two doses, a daily single dose of aminoglycosides is safe and effective [280,325,326].
The choice of agent is also based on local antimicrobial sensitivity patterns, and should later be adjusted according to sensitivity testing of the isolated uropathogen [289]. Especially in infancy, not all available antibiotics are approved by the national health authorities. In uncomplicated nephritis, both oral and parenteral treatment can be considered, because both are equally effective in children without urinary tract abnormalities. Some studies have demonstrated that once daily parenteral administration of gentamicin or ceftriaxone in a day treatment centre is safe, effective and cost-effective in children with UTI [325,327,328].

3.8.4.2.Duration of therapy

Prompt adequate treatment of UTI can prevent the spread of infection and renal scarring. Outcomes of short courses (one to three days) are inferior to those of seven to fourteen-day courses [289]. In newborns and young infants with a febrile UTI, up to 20% may have a positive blood culture [276,280]. In late infancy, there are no differences between strategies regarding the incidence of parenchymal scars, as diagnosed with DMSA scan [329]. Some recent studies using exclusively oral therapy with a third-generation cephalosporin (e.g. cefixime or ceftibuten) have demonstrated that this is equivalent to the usual two to four days intravenous therapy followed by oral treatment [326,330-332]. Similar data have been shown for amoxicillin-clavulanate [333], however, these antibiotics are associated with increasing rates of resistance. If ambulatory therapy is chosen, adequate surveillance, medical supervision and, if necessary, adjustment of therapy must be guaranteed. In the initial phase of therapy, a close ambulant contact to the family is advised [334].
In complicated UTI, uropathogens other than E. coli, such as Proteus mirabilis, Klebsiella spp., Pseudomonas aeruginosa, enterococci and staphylococci, are more often the causative pathogens [280]. Parenteral treatment with broad-spectrum antibiotics is preferred. A temporary urinary diversion (suprapubiccystostomy or percutaneous nephrostomy) might be required in case of failure of conservative treatment in obstructive uropathy. Acute focal bacterial nephritis (lobar nephronia) is a localised bacterial infection of the kidney that presents as an inflammatory mass without abscess formation. This may represent a relatively early stage of renal abscess. For the majority of children, the pathogenesis is related to ascending infection due to pre-existing uropathy, especially vesicorenal reflux or urinary obstruction (megaureter). Prolonged intravenous antibiotic treatment is sufficient in most cases [335], and intravenous and oral therapy tailored to the pathogen identified in culture is recommended [336].
Figure 4: Algorithm for disease management of first febrile UTI

BBD=Bladder Bowel Dysfunction; DMSA=technetium99-labelled dimercaptosuccinic acid; MRI=magnetic resonance imaging; UTI=urinary tract infection; VCUG=voiding cystourethrography; VUR=vesicoureteral reflux.

3.8.4.3.Antimicrobial agents

There is a great difference in the prevalence of antibiotic resistance of uropathogenic E. coli in different countries, with an alarmingly high resistance in Iran and Vietnam [337]. There are upcoming reports of UTIs caused by extended spectrum ß-lactamase-producing enterobacteriaceae (ESBL) in children. In one study from Turkey, 49% of the children < 1 year of age and 38% of those > 1 year of age had ESBL-producing bacteria that were resistant to trimethoprim/sulfamethoxazole in 83%, to nitrofurantoin in 18%, to quinolones in 47%, and to aminoglycosides in 40% [338]. Fortunately, the outcome appears to be the same as for children with non-ESBL-producing bacteria, despite the fact that initial intravenous empirical antibiotic therapy was inappropriate in one study [339].
Table 3: Frequently used antibacterial substances for the therapy of urinary tract infections in infants and children*
Chemotherapeutics
Daily dosage
Application
Comments
Parenteral cephalosporins
Group 3a, e.g. cefotaxime
Group 3b, e.g. ceftazidime
Ceftriaxone
100-200 mg/kg
(Adolesc.: 3-6 g)
100-150 mg/kg
(Adolesc.: 2-6 g)
75 mg/kg
i.v. in 2-3 D
i.v. in 2-3 D
i.v. in 1 D
Oral cephalosporins
Group 3, e.g. ceftibuten
Group 3, e.g. cefixime
Group 2, e.g. cefpodoxime proxetil
Group 2, e.g. cefuroximaxetil
Group 1, e.g. cefaclor
9 mg/kg
(Adolesc.: 0.4 g)
8-12 mg/kg
(Adolesc.: 0.4 g)
8-10 mg/kg
(Adolesc.: 0.4 g)
20-30 mg/kg
(Adolesc.: 0.5-1 g)
50 -100 mg/kg
(Adolesc.: 1.5-4 g)
p.o. in 1-2 D
p.o. in 1-2 D
p.o. in 1-2 D
p.o. in 2 D
p.o. in 3 D
p.o. in 2-3 D
Trimethoprim or
Trimethoprim/sulfamethoxazole
5-6 mg/kg
5-6 mg/kg (TMP-Anteil)
(Adolesc.: 320 mg)
p.o. in 2 D
p.o. in 2 D
Ampicillin
Amoxicillin
Amoxicillin/clavulanic acid (parenteral)
Amoxicillin/clavulanic acid (oral)
Piperacillin
100-200 mg/kg
(Adolesc.: 3-6 g)
50-100 mg/kg
(Adolesc.: 1.5-6 g)
60-100 mg/kg
(Adolesc.: 3.6-6.6 g)
45-60 mg/kg
(Amoxicillinfraction) (Adolesc.: 1500 + 375 mg)
300 mg/kg
i.v. in 3 D
i.v. in 3-4 D
p.o. in 2-3 D1
p.o. in 2-3 D
i.v. in 3 D
i.v. in 3 D
p.o. in 3 D
p.o.in 3 D
i.v. in 3-4 D
Ampicillin and Amoxicillin are not eligible for calculated therapy
Tobramycin
Gentamicin
5 mg/kg (Adolesc.: 3-5 mg/kg, max.0.4 g)
5 mg/kg (Adolesc.: 3-5 mg/kg, max. 0.4g)
i.v. in 1 D
i.v. in 1 D
Drug monitoring
Ciprofloxacin
Children and adolesc. (1-17 years of age): 20-30 mg/kg (max. D: 400 mg) (parenterally)
Children and adolesc. (1-17 years of age): 20-40 mg/kg (max. D 750 mg) (orally)
i.v. in 3 D
p.o. in 2 D
Approved in most European countries as second- or third line medication for complicated UTIs, “reserve-antibiotic”!
Nitrofurantoin
3-5 mg
p.o. in 2 D
Contraindicated in the case of renal insufficiency
* Reproduced with permission from the International Consultation on Urological Diseases (ICUD), International Consultation on Urogenital Infections, 2009. Copyright © by the European Association of Urology [340].
Dosage for adolescents in paracentesis, if differing. 1 Infants 2 D, children 1-12 ys. 3 D.
Table 4: Recommendations for calculated antibacterial therapy of pyelonephritis dependent on age and severity of the infection*
Diagnosis
Proposal
Application
Duration of therapy
LE
Pyelonephritis during the first 0-6 months of life
Ceftazidime +
Ampicillin1 or
Aminoglycoside +
Ampicillin1
3-7 days parenterally, for at least 2 days after defervescence, then oral therapy2
In newborns: parenteral therapy for 7-14 days, then oral therapy2
10 (-14) days
Newborns 14-21 days
4
Uncomplicated pyelonephritis after 6 months of age
Cephalosporin group 32
Orally (initially parenterally, if necessary)
(7-)10 days
1
Complicated pyelonephritis/urosepsis (all ages)
Ceftazidime +
Ampicillin1 or
Aminoglycoside +
Ampicillin1
7 days parenterally, then oral therapy2
10-14 days
4
* Reproduced with permission from the International Consultation on Urological Diseases (ICUD), International Consultation on Urogenital Infections, 2009. Copyright © by the European Association of Urology [340].
1 after receipt of microbiological findings (pathogen, resistance) adaptation of therapy.
2 i.v.: e.g. cefotaxime; orally: e.g. cefpodoxime proxetil, ceftibuten, cefixime.
Table 5: Frequently used antibacterial agents used for the treatment of cystitis and cystourethritis
(Dosages for children up to 12 years of age)*
Chemotherapeutics
Daily dosage
Application
Oral cephalosporins
Group 1, e.g. cefaclor
50 (-100) mg/kgbw
p.o. in 2-3 D
Group 1, e.g. cefalexin
50 mg/kgbw
p.o. in 3-4 D
Group 2, e.g. cefuroximaxetil
20-30 mg/kgbw
p.o. in 2 D
Group 2, e.g. cefpodoxime proxetil
8-10 mg/kgbw
p.o. in 2 D
Group 3, e.g. ceftibuten
9 mg/kgbw
p.o. in 1 D
Trimethoprim
5-6 mg/kgbw
p.o. in 2 D
Trimethoprim/sulfamethoxazole
5-6 mg/kgbw (TMP-fraction)
p.o. in 3 D
Amoxicillin/clavulanic acid
37.5-75 mg/kgbw (Amoxicillin-fraction)
p.o. in 3 D
Nitrofurantoin
3-5 mg/kgbw
p.o. in 2 D
* Reproduced with permission from the International Consultation on Urological Diseases (ICUD), International Consultation on Urogenital Infections, 2009. Copyright© by the European Association of Urology [340].

3.8.4.4.Chemoprophylaxis

Long-term antibacterial prophylaxis should be considered in cases of high susceptibility to UTI and risk of acquired renal damage. Some recently published prospective, randomised studies do not support the efficacy of antibacterial prophylaxis [341-344]. The Australian PRIVENT study demonstrated risk reduction using trimethoprim-sulfamethoxazole in children from birth to 18 years of age who had at least one symptomatic UTI (19% of the placebo group and 13% of the antibiotic group) [330] (see also Chapter 3.13 on Vesico-ureteral reflux).
Table 6: Drugs for antibacterial prophylaxis*
Substance
Prophylactic dosage
(mg/kg bw/d)
Limitations in neonates and infants
Trimethoprim**
1
Until six weeks of age
Trimethoprim
Sulfamethoxazole
1-2
10-15
Not recommended under two months of age
Nitrofurantoin**
1
Until three months of age
Cefaclor
10
No age limitations
Cefixim
2
Preterms and newborns
Ceftibuten
2
***
Cefuroximaxetil
5
***
* Reproduced with permission from the International Consultation on Urological Diseases (ICUD), International Consultation on Urogenital Infections, 2009. Copyright © by the European Association of Urology [340].
** Substances of first choice are nitrofurantoin and trimethoprim. In exceptional cases, oral cephalosporin can be used.
*** In Germany, ceftibuten is not approved for infants < 3 months old.

3.8.4.5.Monitoring of UTI

With successful treatment, urine usually becomes sterile after 24 hours, and leukocyturia normally disappears within three to four days. Normalisation of body temperature can be expected within 24-48 hours after the start of therapy in 90% of cases. In patients with prolonged fever and failing recovery, treatment-resistant uropathogens or the presence of congenital uropathy or acute urinary obstruction should be considered. Immediate US examination is recommended in these cases.
Procalcitonin (among other laboratory inflammatory parameters such as C-reactive protein and leukocyte count) can be used as reliable serum marker for early prediction of renal parenchymal inflammation with first febrile UTI [345]. In patients with febrile UTI, serum electrolytes and blood cell counts should be obtained.
3.8.5.Summary of evidence and recommendations for the management of UTI in children
Summary of evidence
LE
Urinary tract infection represents the most common bacterial infection in children < 2 years of age. The incidence varies depending on age and sex.
1b
Classifications are made according to the site, episode, severity, symptoms and complicating factors. For acute treatment, site and severity are most important.
2b
The number of colony forming units (cfu) in the urine culture can vary and is related to the method of specimen collection, diuresis, and time and temperature of storage until cultivation occurs.
2b
The classical definition of > 105 cfu/mL of voided urine is still used to define a significant UTI.
3
Changes in DMSA clearance during acute UTI indicate pyelonephritis or parenchymal damage. If it is positive, reflux may be present.
2a
Recommendations
LE
GR
Take a medical history, assess clinical signs and symptoms and perform a physical examination to diagnose children suspected of harbouring a UTI.
3
A
Exclude bladder- and bowel dysfunction in any child with febrile and/or recurrent UTI.
3
A
Do not delay diagnosis and treatment of bladder-bowel-dysfunction.
2a
A
Collect an uncontaminated urine sample in an infant through suprapubic bladder aspiration.
Bladder catheterisation is an alternative (traumatic especially in boys).
2a
B
Do not use plastic bags to 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.
2a
B
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 WBCs, squamous epithelial cells and red cells correlate well with manual methods.
2a
B
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.
2a
B
Treat UTIs with four to seven day courses of oral or parenteral therapy.
Do not use of short courses (1-3 days) since outcomes are inferior.
1b
B
Offer long-term antibacterial prophylaxis in case of high susceptibility to UTI and risk of acquired renal damage and LUTS.
1b
B
Treat complicated UTI, with broad-spectrum antibiotics (parenteral).
1b
B
In infants with febrile UTI, use renal and bladder ultrasound to exclude obstruction of the upper and lower urinary tract.
3
B
In all infants, exclude VUR after the first episode of febrile UTI, using VCUG or a DMSA-scan first (in case of a positive DMSA-scan, follow-up with VCUG).
2a
B
In boys > 1 year of age, exclude VUR after the second febrile UTI.
DMSA=dimercaptasuccinic acid; LUTS=lower urinary tract symptoms; UTI=urinary tract infections;
VCUG=voiding cystourethography; VUR=vesicoureteral reflux; WBC=white blood cell.

3.9.Day-time lower urinary tract conditions

3.9.1.Epidemiology, aetiology and pathophysiology

Day-time LUT conditions are conditions that present with LUTS, including urgency, urge incontinence, weak stream, hesitancy, frequency and UTIs without overt uropathy or neuropathy. Following the newest terminology document by the International Children’s Continence Society (ICCS), ‘day-time lower urinary tract (LUT) conditions’ is the new term used to group together functional incontinence problems in children [346]. After any possible underlying uropathy or neuropathy has been excluded, a problem of incontinence in children is grouped into the category of ‘day-time LUT conditions’. Night-time wetting is known as ‘enuresis’.
Due to the relationship between the bladder and bowel, concomitant bladder and bowel disturbances have been labelled as bladder bowel dysfunction (BBD). The use of the terms dysfunctional elimination syndrome (DES) or voiding dysfunction are discouraged. BBD is an umbrella term that can be subcategorised into LUT dysfunction and bowel dysfunction.
Although exact data are unavailable, it is clear that the incidence of day-time LUT conditions is increasing. Awareness and better access to specialised health care can be one of the reasons for this observation. Reported prevalence ranges widely from 2% to 20% [347-351]. This wide variation might reflect the variation in definitions used. In recent studies, bowel dysfunction is observed in > 50 % of children suffering LUT dysfunction [352,353].

3.9.2.Classification systems

Various functional disorders of the detrusor-sphincter complex may occur during the sophisticated early development of normal mechanisms of micturition control. LUT conditions are therefore thought to be the expression of incomplete or delayed maturation of the bladder sphincter complex. Normal day-time control of bladder function matures between two and three years of age, while night-time control is normally achieved between three and seven years of age [347]. There are two main groups of LUTD, namely, filling-phase dysfunctions and voiding-phase dysfunctions. As compared to the general population, in children LUT conditions present with higher prevalence of comorbidities such as Attention Deficit and Hyperactivity Disorder (ADHD) [354,355].

3.9.2.1.Filling-phase dysfunctions

In filling-phase dysfunctions, the detrusor can be overactive, as in overactive bladder (OAB), or underactive, as in underactive bladder (UAB). Some children habitually postpone micturition leading to voiding postponement.

3.9.2.2.Voiding-phase (emptying) dysfunctions

In voiding-phase (emptying) dysfunctions, sphincter and pelvic floor interference during detrusor contraction is the main dysfunction. The general term for this condition is dysfunctional voiding. Different degrees of dysfunction are described, depending on the strength of interference with the sphincter and pelvic floor. Weak interference results in staccato voiding, while stronger interference results in interrupted voiding and straining, due to an inability to relax during voiding.

3.9.3.Diagnostic evaluation

A non-invasive screening, consisting of history-taking, clinical examination, uroflow, US and voiding diary, is essential to reach a diagnosis [355]. In the paediatric age group, where the history is taken from both the parents and child together, a structured approach is recommended using a questionnaire. Many signs and symptoms related to voiding and wetting will be unknown to the parents and should be specifically requested, using the questionnaire as a checklist. A voiding diary is mandatory to determine the child’s voiding frequency and voided volumes as well as the child’s drinking habits. History-taking should also include assessment of bowel function. Some dysfunctional voiding scores have recently been developed and validated [356,357]. For evaluation of bowel function in children, the Bristol Stool Scale is an easy-to-use tool [358,359].
Upon clinical examination, genital inspection and observation of the lumbosacral spine and the lower extremities are necessary to exclude obvious uropathy and neuropathy. Uroflow with post-void residual evaluates the emptying ability, while an upper urinary tract US screens for secondary anatomical changes. A voiding diary provides information about storage function and incontinence frequency, while a pad test can help to quantify the urine loss.
In the case of resistance to initial treatment, or in the case of former failed treatment, re-evaluation is warranted and further video-urodynamic (VUD) studies may be considered. Sometimes, there are minor, underlying, urological or neurological problems, which can only be suspected using VUD. In these cases, structured psychological interviews to assess social stress should be added [360] (LE: 1b; GR: A).
In the case of anatomical problems, such as posterior urethral valve problems, syringocoeles, congenital obstructive posterior urethral membrane (COPUM) or Moormann’s ring, it may be necessary to perform further cystoscopy with treatment. If neuropathic disease is suspected, MRI of the lumbosacral spine and medulla can help to exclude tethered cord, lipoma or other rare conditions.

3.9.4.Management

Treatment of LUTD consists of LUT rehabilitation, mostly referred to as urotherapy, meaning non-surgical, non-pharmacological, treatment of LUT function. It is a very broad therapy field, incorporating many treatments used by urotherapists and other healthcare professionals [361]. In case of comorbidity due to bowel problems it is advised to treat the bowel first, since bowel problems may sustain any bladder problems [358]. Urotherapy can be divided into standard therapy and specific interventions. It is strongly advised not to use terms such as “standard therapy” or “maintenance therapy” without defining the design of these treatments.

3.9.4.1.Standard therapy

In case of combined bladder- and bowel dysfunction it is advised to treat the bowel dysfunction first [353] as LUTS may disappear after successful management of bowel dysfunction. Standard urotherapy is defined as non-surgical, non-pharmacological, treatment for LUTD. It can include the following components:
  • Information and demystification, which includes explanation about normal LUT function and how a particular child deviates from normal function.
  • Instruction about what to do about the problem, i.e. regular voiding habits, sound voiding posture, avoiding holding manoeuvres, etc.
  • Lifestyle advice, regarding fluid intake, prevention of constipation, etc.
  • Registration of symptoms and voiding habits using bladder diaries or frequency-volume charts.
  • Support and encouragement via regular follow-up by the caregiver.
A success rate of 80% has been described for urotherapy programmes, independent of the components of the programme. However, the evidence level is low as most studies of urotherapy programmes are retrospective and non-controlled. A recently published multicentre controlled trial of cognitive treatment, placebo, oxybutynin, bladder and pelvic floor training did not report better results with oxybutynin and pelvic floor training compared to standard therapy [360] (LE: 1b; GR: A).

3.9.4.2.Specific interventions

As well as urotherapy, there are some specific interventions, including physiotherapy (e.g. pelvic floor exercises), biofeedback, alarm therapy and neurostimulation. Although good results with these treatment modalities have been reported, the level of evidence remains low, since only a few RCTs were published [320,361-366]. Two RCTs on underactive bladder without neurophatic disease have recently been published. Transcutaneous interferential electrical stimulation and animated biofeedback with pelvic floor exercise have been shown to be effective [367,368]. In some cases, pharmacotherapy may be added. Antispasmodics and anticholinergics have been shown to be effective, though the level of evidence level was low. Some studies on orthosypathicomimetics have been published with a low level of evidence [369].
A few RCTs have been published, one on tolterodine showed safety but not efficacy [370], while another on propiverine showed both safety and efficacy [371] (LE: 1). The difference in results is probably due to study design. Despite the low level of evidence for the use of anticholinergics and antimuscarinics, their use is recommended (GR: B) because of the large number of studies reporting a positive effect on OAB symptoms. Although α-blocking agents are used occasionally, an RCT showed no benefit [372]. Botulinum toxin injection seems promising, but can only be used off-label [373]. Other new treatment modalities such as sacral nerve stimulation are described in case series only and there is no evidence for their usefulness. These new treatment modalities can only be recommended for standard therapy resistant cases [374]. A recent standardisation document of ICCS on treatment of day-time incontinence gives an excellent overview of treatment modalities [354].
3.9.5.Summary of evidence and recommendations for the management of day-time lower urinary tract conditions
Summary of evidence
LE
The term; ‘Bladder bowel dysfunction’ is to be used rather than ‘dysfunctional elimination syndrome and voiding dysfunction’.
4
Day-time LUTS has a high prevalence (2% to 20%).
2
Recommendations
LE
GR
Use a stepwise approach, starting with the least invasive treatment in managing day-time LUTD in children.
4
B
Initially offer urotherapy involving: non-invasive training and re-education, and non-invasive neurostimulation.
2
B
If present, treat BBD bowel dysfunction first, before treating the LUT condition.
2
B
Use pharmacotherapy (mainly antispasmodics and anticholinergics) as second-line therapy.
1
C
Re-evaluate in case of therapy resistance; this may consist of videourodynamics and MRI of lumbosacral spine, guiding to off-label treatment (e.g. some of the non-licensed drugs in children, botulinum toxin injection and sacral nerve stimulation). Such treatment should only be offered in highly experienced centres.
3
C
BBD=Bladder Bowel Dysfunction; LUT=lower urinary tract; LUTD=lower urinary tract dysfunction;
MRI=magnetic resonance imaging.

3.10.Monosymptomatic enuresis

3.10.1.Epidemiology, aetiology and pathophysiology

Enuresis is synonymous to intermittent nocturnal incontinence. It is a frequent symptom in children. With a prevalence of 5-10% at seven years of age, it is one of the most prevalent conditions in childhood. With a spontaneous yearly resolution rate of 15%, it is considered relatively benign [375,376]. Nocturnal enuresis is considered primary when a child has not yet had a prolonged period of being dry. The term “secondary nocturnal enuresis” is used when a child or adult begins wetting again after having stayed dry.
However, seven out of 100 children wetting the bed at age seven will take this condition into adulthood. As it is a stressful condition, which puts a high psychological burden on children resulting in low self-esteem, treatment is advised from the age of six to seven years onwards. Treatment is unnecessary in younger children in whom spontaneous cure is likely. The child’s mental status, family expectations, social issues and cultural background need to be considered before treatment can be started.
Genetically, enuresis is a complex and heterogeneous disorder. Loci have been described on chromosomes 12, 13 and 22 [377].
Three factors play an important pathophysiological role:
  • high night-time urine output;
  • night-time low bladder capacity or increased detrusor activity;
  • arousal disorder.
Due to an imbalance between night-time urine output and night-time bladder capacity, the bladder can become easily full at night and the child will either wake up to empty the bladder or will void during sleep if there is a lack of arousal from sleep [375-377]. Recently, attention has been given to the chronobiology of micturition in which the existence of a circadian clock in kidney, brain and bladder [378] (LE: 1; GR: A).

3.10.2.Classification systems

Enuresis is the condition describing the symptom of incontinence during night. Any wetting during sleep above the age of five years is enuresis. However, most importantly, there is a single symptom only. Children with other LUTS and enuresis are said to have non-monosymptomatic enuresis [375]. Thorough history-taking, excluding any other day-time symptoms, is mandatory before diagnosing monosymptomatic enuresis. Any associated urinary tract symptoms make the condition a ‘day-time LUT condition’ [377].
The condition is described as ‘primary’ when the symptom has always existed and the patient has not been dry for a period longer than six months. The condition is described as ‘secondary’, when there has been a symptom-free interval of six months.

3.10.3.Diagnostic evaluation

The diagnosis is obtained by history-taking. In a patient with monosymptomatic enuresis, no further investigations are needed. A voiding diary, which records day-time bladder function and night-time urine output, will help to guide the treatment. An estimate of night-time urine production can be obtained by weighing diapers (nappies) in the morning and adding the volume of the morning void. Measuring the day-time bladder capacity gives an estimate of bladder capacity compared to normal values for age [379].
Ultrasound of the urinary tract is not recommended but, when available, it can be used to exclude underlying pathology. In most children, bedwetting is a familial problem, with most affected children found to have a history of bedwetting within the family. A urinary dipstick may help differentiate between true enuresis resulting from polyuria due to diabetes insipidus.

3.10.4.Management

Before using alarm treatment or medication, simple therapeutic interventions should be considered.

3.10.4.1.Supportive treatment measures

Explaining the condition to the child and the parents helps to demystify the problem. Eating and drinking habits should be reviewed, stressing normal fluid intake during the day and reducing fluid intake in the hours before sleep. Keeping a chart depicting wet and dry nights has been shown to be successful.
Counselling, provision of information, positive reinforcement, and increasing (and supporting) motivation of the child should be introduced first. A recent Cochrane review shows that simple behavioural interventions can be effective. However, other proven therapies like enuresis alarm and tricyclic antidepressants are more effective [380] (LE:1a; GR: A).

3.10.4.2.Alarm treatment

Alarm treatment is the best form for arousal disorder (LE: 1; GR: A). Initial success rates of 80% are realistic, with low relapse rates, especially when night-time diuresis is not too high and bladder capacity is not too low [381].

3.10.4.3.Medication

In the case of high night-time diuresis, success rates of 70% can be obtained with desmopressin (DDAVP), either as tablets (200-400 μg), or as sublingual DDAVP oral lyophilisate (120-240 μg). A nasal spray is no longer recommended due to the increased risk of overdose [382,383] (LE: 1; GR: A). Relapse rates are high after DDAVP discontinuation [379] however recently, structured withdrawal has shown lower relapse rates [384] (LE: 1; GR: A).
In the case of small bladder capacity, treatment with antispasmodics or anticholinergics is possible [379]. However, when these medications are necessary, the condition is no longer considered to be monosymptomatic. Imipramine, which has been popular for treatment of the enuresis, achieves only a moderate response rate of 50% and has a high relapse rate. Furthermore, cardiotoxicity and death from overdose are described, its use should therefore be discouraged as the first-line therapy [385] (LE: 1; GR: C).
Figure 5 presents stepwise assessement and management options for nocturnal enuresis.
Figure 5: Assessment and management of nocturnal enuresis

Ab=antibody; Ach=acetylcholine.
3.10.5.Summary of evidence and recommendations for the management of monosymptomatic enuresis
Summary of evidence
LE
Chronobiology of micturition in which the existence of a circadian clock has been proven in kidney, brain and bladder and disturbances in this chronobiology play a major role in the pathophysiology of enuresis.
1
Recommendations
LE
GR
Do not treat children < 5 years of age in whom spontaneous cure is likely.
2
A
Use voiding diaries or questionnaires to exclude day-time symptoms.
2
A
Perform a urine test to exclude the presence of infection or potential causes such as diabetes insipidus.
2
B
Offer supportive measures in conjunction with other treatment modalities, of which pharmacological and alarm treatment are the two most important. When used alone they have limited success.
1
A
Offer alarm treatment for arousal disorder with low relapse rates. There may be family compliance problems.
1
A
Offer desmopressin for the treatment of night-time diuresis. The response rate is high around 70%; relapse rates are high.
1
A
Ensure structured withdrawal of desmopressin to improve relapse rates.
1
A
Ensure that the parents should be well informed about the problem. The advantages and disadvantages of each of the two treatment modalities should be explained.The choice of the treatment modality can be made during parental counselling.
4
B

3.11.Management of neurogenic bladder

3.11.1.Epidemiology, aetiology and pathophysiology

Neurogenic detrusor-sphincter dysfunction (NDSD) can develop as a result of a lesion at any level in the nervous system. This condition contributes to various forms of LUTD, which may lead to incontinence, UTIs, VUR, and renal scarring. Surgery may be required to establish adequate bladder storage and drainage. If not managed properly, NDSD can potentially cause renal failure, requiring dialysis or transplantation. The main goals of treatment are prevention of urinary tract deterioration and achievement of continence at an appropriate age.
The management of neurogenic bladder sphincter dysfunction in children has undergone major changes over the years. Although nappies (diapers), permanent catheters, external appliances, Crede’s manoeuvre and various forms of urinary diversion have been acceptable treatment methods, these are now reserved for only a small number of resistant patients. The introduction of clean intermittent catheterisation (IC) has revolutionised the management of children with neurogenic bladder. Not only has it made conservative management a very successful treatment option, but it has also made surgical creation of continent reservoirs a very effective treatment alternative, with a good outcome for quality of life and kidney protection [386-388].
Neurogenic bladder in children with myelodysplasia presents with various patterns of DSD within a wide range of severity. About 15% of neonates with myelodysplasia have no signs of neuro-urological dysfunction at birth. However, there is a high chance of progressive changes in the dynamics of neurological lesions with time. Even babies with normal neuro-urological function at birth have a one in three risk of developing either detrusor sphincter dyssynergia or denervation by the time they reach puberty. At birth, the majority of patients have normal upper urinary tracts, but nearly 60% of them develop upper tract deterioration due to infections, bladder changes and reflux [389-392].
The most common presentation at birth is myelodysplasia. The term myelodysplasia includes a group of developmental anomalies that result from defects in neural tube closure. Lesions may include spina bifida occulta, meningocele, lipomyelomeningocele, or myelomeningocele. Myelomeningocele is by far the most common defect seen and the most detrimental. Traumatic and neoplastic spinal lesions of the cord are less frequent in children. Additionally, different growth rates between the vertebral bodies and the elongating spinal cord can introduce a dynamic factor to the lesion. Scar tissue surrounding the cord at the site of meningocele closure can tether the cord during growth.
In occult myelodysplasia, the lesions are not overt and often occur with no obvious signs of neurological lesion. In nearly 90% of patients, however, a cutaneous abnormality overlies the lower spine, and this condition can easily be detected by simple inspection of the lower back [393].
Total or partial sacral agenesis is a rare congenital anomaly that involves absence of part or all of one or more sacral vertebrae. This anomaly can be part of the caudal regression syndrome, and must be considered in any child presenting with anorectal malformation (ARM). Patients with cerebral palsy may also present with varying degrees of voiding dysfunction, usually in the form of uninhibited bladder contractions (often due to spasticity of the pelvic floor and sphincter complex) and wetting.
Bladder sphincter dysfunction is poorly correlated with the type and spinal level of the neurological lesion.

3.11.2.Classification systems

The purpose of any classification system is to facilitate the understanding and management of the underlying pathology. There are various systems of classification of neurogenic bladder.
Most systems of classification were formulated primarily to describe those types of dysfunction secondary to neurological disease or injury. Such systems are based on the localisation of the neurological lesion and the findings of the neuro-urological examination. These classifications have been of more value in adults, in whom neurogenic lesions are usually due to trauma and are more readily identifiable.
In children, the spinal level and extent of congenital lesion are poorly correlated with the clinical outcome. Urodynamic and functional classifications have therefore been more practical for defining the extent of the pathology and planning treatment in children.
The bladder and sphincter are two units working in harmony to make a single functional unit. The initial approach should be to evaluate the state of each unit and define the pattern of bladder dysfunction. According to the nature of the neurological deficit, the bladder and sphincter may be in either an overactive or inactive state:
  • the bladder may be overactive with increased contractions, and low capacity and compliance, or inactive with no effective contractions;
  • the outlet (urethra and sphincter) may be independently overactive causing functional obstruction, or paralysed with no resistance to urinary flow;
  • these conditions may present in different combinations.
This is mainly a classification based on urodynamic findings. The understanding of the pathophysiology of disorders is essential to plan a rational treatment plan for each individual patient. In meningomyelocele, most patients will present with hyper-reflexive detrusor and dyssynergic sphincter, which is a dangerous combination as pressure is built up and the upper tract is threatened.

3.11.3.Diagnostic evaluation

3.11.3.1.Urodynamic studies

Since the treatment plan mainly depends upon a good understanding of the underlying problem in the LUT, a well-performed urodynamic study is mandatory in the evaluation of each child with neurogenic bladder.
As the bony level often does not correspond with the neurological defect present, and as the effect of the lesion on bladder function cannot be entirely determined by radiographic studies or physical examination, the information gained from a urodynamic study is crucial. A urodynamic study also provides the clinician with information about the response of the vesicourethral unit to therapy, as demonstrated by improvement or deterioration in follow-up.
It is important to determine several urodynamic parameters, including:
  • the bladder capacity;
  • the intravesical filling pressure;
  • the intravesical pressure at the moment of urethral leakage;
  • the presence or absence of reflex detrusor activity;
  • the competence of the internal and external sphincteric mechanisms;
  • the degree of coordination of the detrusor and sphincteric mechanisms;
  • the voiding pattern;
  • the post-voiding residual urine volume.
3.11.3.1.1.Method of urodynamic study
There is very little comparative data evaluating the complexity and invasiveness of urodynamic testing for neurogenic bladders in children.
3.11.3.1.2.Uroflowmetry
As uroflowmetry is the least invasive of all urodynamic tests, it can be used as an initial screening tool. It provides an objective way of assessing the efficiency of voiding, and, together with an ultrasonographic examination, the residual urine volume can also be determined. Unlike in children with non-neurogenic voiding dysfunction, uroflowmetry will rarely be used as a single investigational tool in children with neurogenic bladders, as it does not provide information on bladder storage, yet it may be very practical to monitor emptying in the follow-up. The main limitation of a urodynamic study is the need for the child to be old enough to follow instructions and void on request.
Recording of pelvic floor or abdominal skeletal muscle activity by electromyography (EMG) during uroflowmetry can be used to evaluate coordination between detrusor and the sphincter. As it is a non-invasive test, combined uroflowmetry and EMG may be very useful in evaluating sphincter activity during voiding [394-397] (LE: 3; GR: C).

3.11.3.2.Cystometry

Although moderately invasive and dependent on a cooperative child, cystometry in children provides valuable information regarding detrusor contractility and compliance. The amount of information obtained from each study is related to the degree of interest and care given to the test.
It is important to be aware of the alterations in filling and emptying detrusor pressures as the infusion rates change during cystometry. Slow fill cystometry (filling rate < 10 mL/min) is recommended by the ICCS for use in children [398]. However, it has been suggested that the infusion rate should be set according to the child’s predicted capacity, based on age and divided by 10 or 20 [376].
Several clinical studies using conventional artificial fill cystometry to evaluate neurogenic bladder in children have reported that conventional cystometry provides useful information for diagnosis and follow-up of children with neurogenic bladder [399-404]. All of the studies were retrospective clinical series and lacked comparison with natural fill cystometry, so that the grade of recommendation for an artificial cystometry in children with neurogenic bladder is not high (LE: 4). Additionally, there is evidence suggesting that natural bladder behaviour is altered during regular artificial filling cystometry [405-408].
Conventional cystometry in infants is useful for predicting future deterioration. Urodynamic parameters, such as low capacity, compliance and high leak-point pressures, are poor prognostic factors for future deterioration. Resolution of reflux is less likely to happen in such bladders [399,403,405] (LE: 4). Although there are only a few studies on natural fill cystometry in children with neurogenic bladder, the results suggest that natural fill cystometry detects new findings compared with diagnoses delivered by conventional cystometry [406] (LE: 3). However, the comparison between natural- and artificial fill cystometry has not been performed against a gold standard, making it difficult to conclude which study is a true reflection of natural bladder behaviour. Findings in the non-neurogenic adult population have questioned the reliability of natural fill cystometry, as it has shown a high incidence of bladder over-activity in totally normal asymptomatic volunteers [409]. The main disadvantage of natural fill cystometry is that it is labour-intensive and time-consuming. Moreover, because of the transurethral catheter used during this study, false-positive findings caused by the catheter are possible. Especially in children, the recording of events is difficult and there is an increased risk of artefacts, which makes interpretation of the huge amount of data even more difficult. Natural fill cystometry remains a new technique in the paediatric population. More data need to be gathered in a standard way before it can be widely accepted [397].
The timing of the first urodynamic study is not clear. However, repeat studies should be done in a child with neurogenic bladder who are not responsive to the initial treatment or in whom a change in treatment or an intervention is planned.

3.11.4.Management

The medical care of children with myelodysplasia with a neurogenic bladder requires constant observation and adaptation to new problems. In the first years of life, the kidneys are highly susceptible to back-pressure and infection. During this period, the emphasis is on documenting the pattern of NDSD, and assessing the potential for functional obstruction and VUR. The early study and treatment of patients is essential for decreasing renal impairment, reducing the need for surgery and improving the continence options [410].
A simple algorithm can be used for management of these patients (Figure 6).
Figure 6: Algorithm for the management of children with myelodysplasia with a neurogenic bladder

CAP=continuous anitbiotic prophylaxis; CIC=clean intermittent catheterisation; US=ultrasound; VCUG=voiding cystourethrography; VUD=videourodynamic; VUR=vesicoureteric reflux.

3.11.4.1.Investigations

An abdominal US obtained as soon as possible after birth will detect hydronephrosis or other upper genitourinary tract pathology. Following US, a VCUG, preferably a VUD study should be obtained to evaluate the LUT. Measurement of residual urine during both US and cystography should also be done. These studies provide a baseline for the appearance of the upper and lower urinary tracts, can facilitate the diagnosis of hydronephrosis or VUR, and can help identify children at risk for upper genitourinary tract deterioration and impairment of renal function.
A urodynamic evaluation can be done after some weeks, and needs to be repeated at regular intervals, in combination with evaluation of the upper tract [411-413] (LE: 3; GR: B).

3.11.4.2.Early management with intermittent catheterisation

Overwhelming experience gained over the years with early management of neurogenic bladder in infants has led to a consensus that children do not have upper tract deterioration when managed early with IC and anticholinergic medication. IC should be started soon after birth in all babies, especially in those with signs of possible outlet obstruction [319,411,414-421] (LE: 2; GR: B). Babies without any clear sign of outlet obstruction IC may be delayed but these babies should be monitored for UTIs and upper tract changes.
The early initiation of IC in the newborn period makes it easier for parents to master the procedure and for children to accept it, as they grow older [422,423].
Early management results in fewer upper tract changes, but also better bladder protection and lower incontinence rates. It has been suggested that increased bladder pressures due to detrusor sphincter dyssynergia causes secondary changes of the bladder wall. These fibroproliferative changes in the bladder wall may cause further loss of elasticity and compliance, resulting in a small non-compliant bladder with progressively elevated pressures.
Early institution of IC and anticholinergic drugs may prevent this in some patients [388,421,424] (LE: 3). The retrospective evaluation of patients has also shown that significantly fewer augmentations were required in patients with an early start of IC [415,420] (LE: 4).

3.11.4.3.Medical therapy

At present, oxybutynin, tolterodine, trospium and propiverine are the most frequently used drugs, with oxybutynin being the most studied. The dosage for oxybutynin is 0.1-0.3 mg/kg given three times daily. In case of side effects intravesical administration may be considered.
Two different forms of tolterodine have been investigated in children with neurogenic bladder. The extended release formulation of tolterodine has been found to be as efficient as the instant release form, with the advantages of being single dose and less expensive. Although the clinical outcome is encouraging, the level of evidence is low for anticholinergic medication because there are no controlled studies [424-431] (LE: 3; GR: B). The use of medication to facilitate emptying in children with neurogenic bladder has not been well studied in the literature. A few studies investigating the use of α-adrenergic blockade in children with neurogenic bladder have reported a good response rate, but the studies lacked controls, and long-term follow-up is warranted [432] (LE: 4; GR: C).
Botulinum toxin injections: In neurogenic bladders that are refractory to anticholinergics, injection of botulinum toxin into the detrusor muscle is a novel treatment alternative. Initial promising results in adults has resulted in its use in children. It has been shown that this treatment has beneficial effects on clinical and urodynamic variables. Complete continence was achieved in 65-87% of patients; in most studies mean maximum detrusor pressure was reduced to at least 40 cmH2O and bladder compliance was increased to at least 20 cmH2O/mL. However, findings are limited by the lack of controlled trials and studies involving small patient numbers [373,433-437]. Botulinum toxin seems to be more effective in bladders with obvious detrusor muscle over-activity, whereas non-compliant bladders without obvious contractions are unlikely to respond [438-443].
The most commonly used dose of botulinum toxin is 10 U/kg with a maximum dose of 200 U. No dose study has been performed in children and there is no evidence regarding the optimal dose. Currently, it is unclear how many times this treatment can be repeated, although repetitive treatment has been found to be safe in adults [373,444-446].
Injection of botulinum toxin in therapy-resistant bladders appears to be an effective and safe treatment alternative (LE: 3; GR: C). Urethral sphincter botulinum-A toxin injection has been shown to be effective in decreasing urethral resistance and improve voiding. The evidence is still too low to recommend its routine use in decreasing outlet resistance, but it could be considered as an alternative in refractory cases [447,448].

3.11.4.4.Management of bowel incontinence

Children with neurogenic bladder have disturbances of bowel function as well as urinary function. Bowel incontinence in these children is frequently unpredictable. It is related to the turnover rate of faecal material in the anal area after evacuation, the degree of intactness of sacral cord sensation and motor function, and reflex reactivity of the external anal sphincter [449].
Bowel incontinence is managed most commonly with mild laxatives, such as mineral oil, combined with enemas to facilitate removal of bowel contents. A regular and efficient bowel emptying regimen is often necessary to maintain faecal continence, and may have to be started at a very young age. With antegrade or retrograde enemas, most children will have decreased constipation problems and may attain some degree of faecal continence [450-454] (LE: 3).
Biofeedback training programmes to strengthen the external anal sphincter have not been shown to be more effective than a conventional bowel management programme in achieving faecal continence [455]. Electrostimulation of the bowel may also offer a variable improvement in some patients [456] (LE: 3; GR: C).

3.11.4.5.Urinary tract infection

Urinary tract infections are common in children with neurogenic bladders. In the absence of reflux, UTIs should be treated symptomatically. Although bacteriuria is seen in more than half of children on clean IC, patients who are asymptomatic do not need treatment [457-459] (LE: 3). Patients with VUR should usually be placed on prophylactic antibiotics to reduce the incidence of pyelonephritis, which can potentially lead to renal damage [460,461].

3.11.4.6.Sexuality

Sexuality, while not an issue in childhood, becomes progressively more important as the patient gets older. This issue has historically been overlooked in individuals with myelodysplasia. However, patients with myelodysplasia do have sexual encounters. Studies indicate that at least 15-20% of males are capable of fathering children and 70% of females can conceive and carry a pregnancy to term. It is therefore important to counsel patients about sexual development in early adolescence.

3.11.4.7.Bladder augmentation

Children with a good response to anticholinergic treatment and an overactive sphincter may be continent between catheterisations. Bladder pressure and development of the upper urinary tract will determine whether additional treatment is necessary or not. Therapy-resistant overactivity of the detrusor, or small capacity and poor compliance, will usually need to be treated by bladder augmentation. A simple bladder augmentation using intestine may be carried out if there is any bladder tissue, a competent sphincter and/or bladder neck, and a urethra that can be catheterised.
Stomach is rarely used as an augmenting patch because of the associated complications [462]. Ileal or colonic patches are frequently used for augmenting the bladder, with either equally useful. Despite some advantages (e.g. avoiding mucus, decreased malignancy rate and fewer complications), alternative urothelium preserving techniques, such as autoaugmentation and seromuscular cystoplasty, have not proven to be as successful as standard augmentation with intestine [463,464].

3.11.4.8.Bladder outlet procedures

Children with detrusor overactivity and underactive sphincters will have better protection of their upper tracts, although they will be severely incontinent. Initial treatment is IC (as it might reduce the degree of incontinence and offers much better control over UTIs) with anticholinergic drugs. At a later age, the outlet resistance will be increased in order to render them continent. No available medical treatment has been validated to increase bladder outlet resistance. Alpha-adrenergic receptor stimulation of the bladder neck has not been very effective [465-470].
When conservative measures fail, surgical procedures need to be considered for maintaining continence. Although a simple augmentation is sufficient for most low-capacity, high-pressure bladders, augmentation with additional bladder outlet procedures is required when both the bladder and outlet are deficient. Bladder outlet procedures include bladder neck reconstruction or other forms of urethral reconstruction.
Various procedures can be used on the bladder neck to increase resistance, but all of them may complicate transurethral catheterisation. Augmentation with surgical closure of the bladder neck may be required primarily, or as a secondary procedure in certain rare clinical situations. In this situation, a continent stoma will be required. However, most surgeons prefer to leave the bladder neck and urethra patent as a safety precaution. Application of artificial urinary sphincters (AUS) in children is another option, which gives the patient the opportunity to void spontaneously. The largest paediatric series in the literature reports a continence rate over 85% [471]. However, the decision to implant an AUS in a child raises the issue of mechanical failure (> 30%), revision of the functioning sphincter (> 15%) and surgical complication (15%). Although, advancement of newer devices decreased these numbers [471].

3.11.4.9.Continent stoma

Augmentation with an additional continent stoma is utilised primarily after failure of previous bladder outlet surgery. It is also advisable when an inability to catheterise transurethrally is likely. An abdominal wall continent stoma may be particularly beneficial to wheelchair-bound spina bifida patients, who often have difficulty with urethral catheterisation or are dependent on others to catheterise the bladder. For continence with augmentation and an abdominal wall stoma, an adequate bladder outlet mechanism is essential.

3.11.4.10.Total bladder replacement

Total bladder replacement in anticipation of normal voiding in children is very rare, as there are infrequent indications for a total cystectomy, with preservation of the bladder outlet and a competent urethral sphincter. This type of bladder replacement is much more common in adult urological reconstruction. Any type of major bladder and bladder outlet construction should be performed in centres with sufficient experience in the surgical technique, and with experienced healthcare personnel to carry out post-operative follow-up [472-474].

3.11.5.Follow-up

Neurogenic bladder patients require lifelong supervision, and the monitoring of renal and bladder function is extremely important. Periodic investigation of upper tract changes, renal function and bladder status is mandatory. Repeat urodynamic tests are therefore needed more frequently (every year) in younger children and less frequently in older children. From the urological viewpoint, a repeat urodynamic study is warranted when the patient has a change in symptoms or undergoes any neurosurgical procedure. In the case of any apparent changes in the upper urinary tract and LUT, or changes in neurological symptoms, a more detailed examination including urodynamics and spinal MRI is indicated.
Renal failure can progress slowly or occur with startling speed in these children. Patients who have undergone reconstructive procedures using intestine should be regularly followed up for complications such as infection, stone formation, reservoir rupture, metabolic changes, and malignancy [472].
The risk of malignancy in enteric augmentations has been reported to be higher than expected, and the risk increases with length of follow-up. Malignancy occurs in 0.6-2.8% of patients during median follow-up of 13-21 years [475-480]. In a study including 153 patients with a median follow-up time of 28 years [477], malignancy was found in 4.5%. The malignancy seemed to be associated with coexisting carcinogenic stimuli or with the inherent risk present with bladder exstrophy. Although there is poor data on follow-up schemes; after a reasonable follow-up time (e.g. 10 years), an annual diagnostic work-up including cystoscopy should be considered.
3.11.6.Summary of evidence and recommendations for the management of neurogenic bladder
Summary of evidence
LE
Neurogenic detrusor-sphincter dysfunction may result in different forms of LUTD and ultimately result in incontinence, UTIs, VUR, and renal scarring.
2a
In children, the most common cause of NDSD is myelodysplasia (a group of developmental anomalies that result from defects in neural tube closure).
2
Bladder sphincter dysfunction correlates poorly with the type and level of the spinal cord lesion. Therefore, urodynamic and functional classifications are more practical in defining the extent of the pathology and in guiding treatment planning.
2a
Children with neurogenic bladder can have disturbances of bowel function as well as urinary function which require monitoring and, if needed, management.
2a
The main goals of treatment are prevention of urinary tract deterioration and achievement of continence at an appropriate age.
2a
Injection of botulinum toxin into the detrusor muscle in children who are refractory to anticholinergics, has been shown to have beneficial effects on clinical and urodynamic variables.
2a
Recommendations
LE
GR
In all babies, start intermittent catheterisation soon after birth, except for babies without any clear sign of outlet obstruction. If intermittent catheterisation is delayed, closely monitor babies for urinary tract infections and upper tract changes.
2
B
Use anticholinergic drugs as initial treatment in children with overactive bladders. Clinical improvement is common but usually insufficient.
2
B
Use injection of botulinum toxin into the detrusor muscle as an alternative in children who are refractory to anticholinergics.
2
B
Use a bladder augmentation procedure, using a segment of intestine, in case of therapy-resistant overactivity of the detrusor, or small capacity and poor compliance causing upper tract damage and incontinence.
2
B
Use augmentation with additional bladder outlet procedures when both the bladder and outlet are deficient. Simple augmentation will suffice in most low-capacity, high-pressure bladders.
3
B
Augment with an additional continent stoma after bladder outlet surgery and in patients with urethral catheterisation limitations.
3
B
Follow-up of neurogenic bladder patients will be life-long.
Follow-up includes monitoring of renal and bladder function as well as ensuring that sexuality and fertility issues receive particular care as the child gets older and moves into adulthood.
3
B
LUTD=lower urinary tract dysfunction; NDSD=neurogenic detrusor-sphincter dysfunction; UTI=urinary tract infection; VUR=vesicoureteral reflux.
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