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REVIEW

Lower urinary tract function in childhood; normaldevelopment and common functional disturbances

T. Neve us1

and U. Sille n2

1 Department of Womens and Childrens Health, Uppsala University, Uppsala, Sweden2 Paediatric Urology Unit, Queen Silvias Childrens Hospital, Goteborg, Sweden

Received 22 November 2011,revision requested 2 April 2012,revision received 28 May 2012,accepted 10 September 2012Correspondence: T. Neve us, MD,PhD, Department of Womensand Childrens Health, UppsalaUniversity Childrens Hospital,Uppsala University, 751 85 Upp-sala, Sweden.E-mail: [email protected]

AbstractThis review aims to provide researchers and clinicians involved with theadult lower urinary tract with background knowledge regarding the earlydevelopment of bladder function and its most common disturbances in

childhood. Bladder development begins in weeks 4 6 and the detrusormuscle is formed during weeks 9 12 of gestation. Higher CNS centres areinvolved in micturition at birth, and the infant usually wakes up, at leastbriey, to void. Voiding during the rst years of life is often incomplete,owing to detrusor-sphincter dyscoordination, but this disappears whenbladder control is attained. Approximately 5 10% of 7-year-old childrensuffer from daytime incontinence and/or nocturnal enuresis, and a few percent of them will not outgrow it. Daytime incontinence in childhood isusually attributable to detrusor overactivity, although it is unclear to whatextent it is the detrusor or the micturition reex per se that is overactive.Enuresis nocturnal incontinence is caused by either nocturnal polyuria

and/or nocturnal detrusor overactivity, in both cases combined with higharousal thresholds. Bladder problems in childhood constitute a risk factorfor the development or persistence of bladder problems in adulthood.Keywords children, enuresis, foetal development, incontinence, infants,lower urinary tract, urodynamics.

This review is a brief overview of the normal evolu-tion of lower urinary tract (LUT) function from foetallife until the age when bladder control is attained.The most common disturbances of this function, thatis, urge incontinence and nocturnal enuresis, are alsodescribed. The pathogenic mechanisms behind theseconditions are discussed but space does not permit usto go into the clinical management here. Neither willwe be able to provide information regarding otherimportant types of LUT dysfunction such as dysfunc-tional voiding, neurogenic bladder or malformations.

Throughout this document, we will use globallyaccepted paediatric LUT terminology as described bythe International Childrens Continence Society (ICCS;Neveus et al. 2006).

Foetal development of the LUT and function

The bladder begins to develop early, in gestationalweeks 4 6, from the urogenital sinus, which, in turn,is formed through demarcation from the cloaca. Theureter and the vesicoureteral junction are formedfrom the ureteric bud, an outgrowth on the Wolfanduct. The ureteric bud also elongates and grows intothe metanephros the kidney-forming mesenchyme and makes contact with the nephrons. An abnor-mally high position of the ureteric bud on theWolfan duct is thought to be responsible forprimary vesico-ureteric reux (VUR), with a lateral-ized ureteral insertion in the bladder. This displace-ment of the ureteric bud can also cause renal

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dysplasia, which is often seen together with VUR(Murer et al. 2007).

In studies of the human foetus, scattered muscle cellsare seen in the bladder as early as the 9th week of gesta-tion, in the 12th week the three-layered wall structure isevident and the bladder wall thickness then increases in

a linear fashion throughout foetal life (Koerner et al.2006). The external sphincter appears rst as a horse-shoe-shaped structure around the urethra (Ludwikow-ski et al. 2001). Development of a circular muscularstructure at the bladder neck has also been noted. Thislatter structure has been shown to be hypertrophic inthe male foetus towards the end of gestation, whichmay be one of the explanations for the difference inbladder function variables between male and femaleneonates (Oswald et al. 2006).

Regarding development of LUT function during foe-tal life, changes in the intrinsic properties of thesmooth muscle and peripheral neurotransmission haveto be considered. In animal studies, it has been shownthat compliance in the bladder wall is poor duringearly gestation when urine production starts, butincreases during the second half of foetal life, anevolution partly due to a gradual switch from collagenIII to I (Sze ll et al. 2003, Oswald et al. 2006).Increased tone as well as increased spontaneous activ-ity in the detrusor has also been documented as thefoetus evolves. This activity is not nerve mediated andmay be necessary to promote voiding when the neuro-nal control is incomplete and storage capacity minimal(Ekman et al. 2009). The human bladder has some

reservoir capacity at 16 weeks of gestation. A decreasein spontaneous detrusor activity and tone, concomi-tant with increased activity in the bladder outlet, bothcontribute to an enhanced storage function as the foe-tus matures (Sze ll et al. 2003).

It has also been shown in animal studies that theneonatal detrusor has an increased or different reactiv-ity to stimuli. Stimulation with a cholinergic agonistleads to multi-phasic contraction in the neonatal blad-der and uni-phasic contractions in the adult. Thisresemblance between the neonatal pattern and detrusoroveractivity made the authors speculate about delayedmaturation as an explanation for the latter condition(Ekman et al. 2009).

Bladder function in neonates and infants

Most studies of the normal infant bladder rely on the4-h voiding observation, which is non-invasive andgives information regarding storage and emptyingcapacity (Holmdahl et al. 1996), but a limited numberof cystometric studies have also been performed.

Less than 10% of healthy neonates and infants havecystometrically detectable detrusor overactivity, a

nding that contradicts the above suggestion of detru-sor overactivity as an immaturity phenomenon (Yeunget al. 1995, Jansson et al. 2005). On the other hand,an increased reactivity of the detrusor muscle duringthe rst months of life has been detected whencomparing cystometric versus free voiding studies;

catheter-based investigations can induce voiding con-tractions at much lower bladder volumes (Fig. 1;Bachelard et al. 1999). This nding might be a paral-lel to the increased spontaneous activity seen in thefoetal and neonatal detrusor in experimental animals,as discussed above. The phenomenon probably alsoexplains the lower voided volumes seen in cystometricinvestigations in the neonatal period and during therst couple of months as compared with the volumesobserved in free voiding studies (Fig. 2; Sillen 2004).After infancy, the picture is reversed: the children voidsmaller volumes than their cystometric bladdercapacity (Sille n 2004). This latter relation betweencatheter-based and free voiding volumes remains duringchildhood and is probably explained by voluntary post-ponement of voiding in catheter-based investigations.

In both cystometric and free voiding studies, detru-sor-sphincter dyscoordination has been shown to be anormal part of the voiding pattern in neonates andinfants. In free voiding studies, it is recognized asinterrupted voiding dened as two voidings within5 10 min, with the lowest residual after the secondvoiding. This is clearly an immaturity phenomenon as itis seen in 60% of premature infants but then decreasesand disappears when voluntary bladder control is

achieved (Jansson et al. 2000). In cystometric investiga-tions, dyscoordination at voiding has been found in anumber of investigations of neonates and infants as anintermittent increase in sphincter electromyography(EMG) during the voiding contraction and a concomi-tant uctuation in voiding pressure and the urinarystream (Fig. 1; Jansson et al. 2005, Olsen et al. 2010).An interrupted ow pattern was also observed in younginfant boys, in studies where urinary ow was recordedwith an ultrasound probe (Olsen et al. 2010). It isunknown whether this physiological dyscoordination isonly an expression of immature nervous control or if the increased excitability of the detrusor, discussedabove, is also responsible. Support for the latter theory,however, is provided by the fact that infants withknown overactivity during lling, such as boys withposterior urethral valves, are especially prone to inter-rupted voiding (Holmdahl et al. 1998).

Neonates and infants do not empty their bladdercompletely every time they void, but usually at leastonce per four hours there is no residual urine (Holm-dahl et al. 1996). The dyscoordination at voidingabove discussed is probably responsible for the incom-plete emptying, which is in accord with the fact that

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emptying becomes complete when bladder control is

achieved, that is, when coordination becomes normal(Jansson et al. 2000).Sexual differences in neonatal and infantile bladder

function have been observed, mainly regarding voidingpressure that is higher in male infants (median120 cm H 2 O; Fig. 1; Jansson et al. 2000, 2005). Theexplanation for this is probably the dyscoordinationthat effectively closes the outow during detrusor con-traction. The high pressure levels, however, are onlygenerated when bladder capacity is low. Therefore,the increased reactivity of the detrusor musclediscussed above might inuence the generation of highpressure by inducing contractions at low bladder vol-ume. But this does not in itself explain the differencebetween the sexes, as dyscoordination and increasedexcitability have also been found in female neonates.The most obvious difference is the longer urethra inmales, which is probably responsible for increasedoutow resistance. The more pronounced bladderneck muscles in the male foetus at the end of gesta-tion, mentioned above, might have the same effect(Oswald et al. 2006).

It has traditionally been assumed that micturition inthe neonate occurs as a purely spinal reex, without

involvement of the pontine micturition centre and the

frontal cortex. This assumption has now been chal-lenged. One reason to believe that higher CNS centresare involved is the fact that most term neonates andinfants wake up, or at least show signs of arousal,before voiding (Yeung et al. 1995, Jansson et al.2005). This awakening and arousal mechanism onlyfunctions in a minority preterm children, on the otherhand (Sille n et al. 2000). This difference indicates thatthe CNS connections involved in the voiding reex aresufciently mature in full-term neonates to inuencecentres of importance for arousal, when activated by afull bladder. Furthermore, neither preterm nor full-term infants void at constant bladder volumes (Sille n2004), an observation that also supports the conceptof the voiding reex as associated with the brain asearly as in the neonatal period.

Summary of immature bladder function characteris-tics

(1) Free voiding studies.(a) Interrupted voiding.(b) Incomplete emptying.(c) Voiding once or twice every 2 h.(d) The child wakes up or shows signs of arousal

at voiding.

Premature voiding Voiding(BC 15 mL)

Bachelard et al, 1999

Figure 1 Urodynamic study in 1 monthold boy showing premature voiding con-traction and voiding at low bladder vol-ume. Note dyscoordination at voidingwith increased EMG signal.

Fullterminfants

0

20

40

60

80

100

120

140

4 2 0 2 4 6

Age (months)

B l a d d e r c a p a c i

t y ( m L )

Prematureinfants

Cystometric

Free voiding

Expected

Figure 2 Cystometric and free voidingbladder capacity in premature (19) andfull-term (12) infants. Formula for esti-mation of expected bladder capacityaccording to International ChildrensContinence Society standarisation (1).


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(2) Cystometry.(a) Increased excitability of detrusor with voiding

contraction at low volume.(b) Overactive contractions rarely seen (10%).(c) Cystometric capacity lower as compared with

free voiding.

(d) Dyscoordination at voiding.(e) High voiding pressure in males.

Normal development in childhood

Both maturation of the CNS and adequate social cir-cumstances are necessary for the development of vol-untary bladder control. Potty training can be verybenecial, provided it is kind and not forceful. Ideally,it should be initiated when the child starts to be inter-ested in what is happening. The childs interest usuallystarts at about 18 months of age, when he or shereports I have voided. The next step is when thechild recognizes I am starting to void, followed bythe ability to postpone voiding for a few moments. Atthis stage, the child is able to reach the toilet in timefor voiding. Before reaching complete continence, thechild must be able to start voiding at any bladder vol-ume and also to interrupt voiding voluntary. Beingsocially continent means that the child takes care of the whole voiding situation from start to nish, a skillthat is usually achieved at 5 6 years of age (Janssonet al. 2005).

As mentioned above, the immature detrusor-sphinc-ter dyscoordination disappears at the age when blad-

der control is achieved. Furthermore, bladder capacityhas been found to increase stepwise during toilettraining, a fact that is probably attributable to theability to hold urine voluntarily. The voidingfrequency is decreased from approximately once perhour in the neonatal period to 7 8 times per day inthe toddler.

It should be noted that it is possible to make thechild dry much earlier if he or she is regularly put onthe potty by a parent who has learned to recognizethe childs signs of imminent voiding. The degree of maturation for such training to be possible is presentalready in the rst year of life. This type of trainingwas used in Western countries before the era of super-absorbable diapers and is still practiced in countrieswith other traditions and nancial standards. Suchearly training has been shown to improve the childsability to empty the bladder completely and shouldprobably be encouraged in children with recurrenturinary tract infections (Duong et al. 2010).

Summary of bladder function at toilet-training age(1) Free voiding studies.

(a) Emptying complete.(b) Voiding 7 8 times a day.

(c) Stepwise increase in voided volumes.(d) The child takes an interest in his/her own toi-

leting.(2) Cystometry.

(a) Cystometric capacity higher than voided vol-umes.

(b) Urethral sphincter relaxed during voiding.(c) Voiding detrusor pressure decreased to adultlevels.

Common functional disturbances:epidemiology and comorbidity

It is obvious that the complex maturation processdescribed above does not always go smoothly. Chil-dren become socially continent at different ages, andin some cases, bladder control is not achieved or isachieved only temporarily. The most common LUTdisturbances by far are nocturnal enuresis anddaytime incontinence owing to detrusor overactivity.

According to the ICCS standardization document,the word enuresis , synonymous with nocturnal incon-tinence, is used to denote the involuntary leakage of urine during sleep in discrete portions (as opposed tocontinuous dribbling) in a child aged 5 years or more.If the enuretic child also exhibits daytime LUTsymptoms such as urgency, frequency or daytimeincontinence, the enuresis is subspecied as non-monosymptomatic enuresis. The term diurnal enure-sis should be avoided, instead speaking of daytimeincontinence . Urge incontinence simply means daytime

incontinence in a child who also experiences urgency(Neveus et al. 2006).

The prevalence of enuresis and daytime inconti-nence across the paediatric age span is illustrated inTable 1 (Hellstro m et al. 1990, Hirasing et al. 1997,Bakker et al. 2002, So derstro m et al. 2004). As canbe noted, these are very common conditions and theymay persist for many years or even into adulthood. Ithas also been shown that for the enuretic child whowets his or her bed every night, the chance of sponta-neous resolution before adulthood is signicantlylower than for children with more sporadic enuresis(Yeung et al. 2006). Enuresis is more common among

Table 1 Prevalence of daytime incontinence and enuresis indifferent ages

5 years 7 years 10 yearsTeenage Adults

Daytimeincontinence (%)

10 15 5 10 3 8 2 5 1 3

Nocturnalenuresis (%)

10 15 5 10 3 7 1 4 0.5 2




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boys than girls, while for daytime incontinence the sit-uation is the reverse (Hellstro m et al. 1990, Bakkeret al. 2002).

There is a considerable epidemiologic overlapbetween daytime incontinence and nocturnal enuresis(Hellstro m et al. 1990, Bakker et al. 2002), reecting

their overlapping pathogenetic mechanisms. It shouldalso be mentioned that constipation, with or withoutfaecal incontinence, is often part of the picture,especially in children with daytime incontinence(So derstro m et al. 2004). These children are also athigher than normal risk at developing urinary tractinfections (Loening-Baucke 1997).

Daytime incontinence

The typical child with daytime incontinence is a girl(although boys are certainly no rarities) who alsoexperiences some degree of urgency symptoms. Shemay have to run to the toilet very often or has made ahabit of postponing micturition as long as possibleusing various holding manoeuvres such as standingon tiptoe or squatting with her heel pressed againstthe perineum. Urinary tract infections are quitecommon in these children, as is constipation (Loening-Baucke 1997). Only very little research has been car-ried out on the inheritability of the condition, butrecent work suggests that it does indeed often run infamilies (von Gontard et al. 2011).

It may be safely assumed that the most commonmechanism underlying paediatric daytime incontinence

is detrusor overactivity (Cisternino & Passerini-Glazel1995). These children do not suffer from stress incon-tinence. But what underlies the detrusor overactivity ismuch more difcult to determine. Far too much spec-ulation regarding pathogenesis has relied on researchcarried out in adults.

Detrusor overactivity during bladder lling isbelieved to be the central cause of urge incontinence.Studies in adults, however, indicate that involuntarydetrusor contractions are often preceded by involun-tary sphincter relaxation more or less as in the nor-mal micturition indicating that in these cases it isthe micturition reex per se, not the detrusor contrac-tion, that is pathologically easy to elicit (Artibani1997, McLennan et al. 2001). The explanation for theincreased detrusor and/or sphincter excitability is notknown. As it is seen in a relatively large number of young children and as increased excitability is seen inthe neonatal detrusor, a delayed maturation can beput forward as a possibility. Connections betweendetrusor overactivity and delayed maturation are alsosupported by the involvement of afferent unmyeli-nated C-bres in detrusor overactivity (Yokoyamaet al. 2004), bres which are involved in foetal and

neonatal micturition but not in the mature reex.A positive bladder cooling reex in up to 50% of these children points in the same pathogenetic direc-tion (Gladh et al. 2004), as this reex has been shownto be positive in healthy infants, but after 2 4 yearsof age is considered to be a sign of spinal damage.

If the micturition reex as such is not disturbed butdetrusor contractions appear without warning, oneexplanation could be that the excitation contractioncoupling to the detrusor is disturbed. Animal researchand research in adults have implicated a large numberof neurotransmitters and other factors as causative.The purinergic contribution to detrusor (over-)activitydeserves special mention here, as the pattern of ATP-specic receptors in the detrusor of adults with urgeincontinence both differ from that of controls and hassimilarities with that of small children (Moore et al.2001). These results again suggest that detrusor over-activity has similarities with early developmentalphases of bladder function.

Urge incontinence in childhood can also be second-ary to other problems. There is a well-documentedassociation between constipation and incontinence(Loening-Baucke 1997). The theory behind thisconnection is that the distended bowel compressingthe bladder may lead to an interruption of the normalperipheral inhibition of micturition provided by thesphincter and pelvic oor.

In conclusion, detrusor overactivity in childhoodcan be assumed to be pathogenetically multifactorial.The disturbance may be centrally or peripherally med-

iated, owing to motor or sensory disturbance, of amyogenic or perhaps a psychogenic nature. Mecha-nisms active at an earlier developmental phase of bladder function may be of aetiological importance.

Enuresis

The typical enuretic child is otherwise healthy and ismore often a boy than a girl. There may be concomi-tant daytime symptoms such as urgency or inconti-nence. Psychiatric symptoms are contrary to earlierbeliefs usually not present, but many enuretic chil-dren have low self-esteem because of their condition(Ha gglo f et al. 1997), and there is an overrepresenta-tion of children with hyperactivity and/or attentiondifculties in the bedwetting group (Duel et al. 2003).

Enuresis often runs in the family (Devlin 1991).This observation is, however, of little clinical use, as ithas been found that no predictions regarding progno-sis or therapeutic outcome can be extracted from fam-ily history.

The main pathogenic mechanism is the inability towake up in response to activation of the micturitionreex. As most neonates already have the ability to




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wake up at voiding (Yeung et al. 1995), the disturbancecan be suggested to be an early developmental errorrather than immaturity. Beside this evident cause,research in recent decades has established two patho-genic mechanisms as crucial to nocturnal enuresis: noc-turnal polyuria and nocturnal detrusor overactivity.

Many bedwetting children produce disproportion-ately large amounts of urine at night, and this noctur-nal polyuria may often, but not always, be explainedby a lack of the normal nocturnal peak in the releaseof vasopressin from the pituitary (Rittig et al. 1989).These children wet their beds because their urine pro-duction is greater than what can safely be stored intheir bladders. More support for the polyuria hypothe-sis is derived from the observation that bedwettingcan be provoked in some non-enuretic children just byhaving them drink lots of water before bedtime (Ras-mussen et al. 1996) and the fact that the vasopressinanalogue desmopressin makes many bedwetters dry

especially ones with polyuria (Hunsballe et al. 1995).There are, however, some modications to the

hypothesis. First, not all bedwetting children havepolyuria at night (Hunsballe et al. 1995). Second,some dry children are polyuric (and have nocturia;Mattsson & Lindstro m 1994). Third, the polyuriadoes not explain why the child does not wake up.Fourth, it is conceivable that in some cases the poly-uria may be the effect rather than the cause of theenuresis as lack of bladder distension, or sleepdisturbance per se, may increase urine production(Mahler et al. 2012).

Soon after the polyuria explanation was launchedand corroborated, other researchers discovered thatsome enuretic children wet their beds not because theirbladders are full but because they contract too easily.Ambulatory cystometric examinations of children withtherapy-resistant enuresis conrmed that nocturnaldetrusor overactivity is indeed common in this group(Yeung et al. 1999). Further albeit indirect evidence isthe epidemiological overlap between nocturnal enuresisand urge incontinence, the fact that enuretic children especially the non-polyuric ones void with smallervolumes than dry children (Neve us et al. 2001) and theexperience that anticholinergics may help.

Yet still, not all bedwetting children have detrusoroveractivity, many non-bedwetters have symptoms of detrusor overactivity i.e. urgency and we still needto explain why the children do not wake up.

It is often stated that the nocturnal bladder volume isreduced in enuretic children. This statement is in a waytrue but also quite misleading. The bladder is not ana-tomically small, but it tends to contract before it is full.

Both bladder distension and detrusor contractionsare strong arousal stimuli (Page & Valentino 1994).The bedwetting child can thus be regarded as a deep

sleeper almost by denition. This accords well withthe almost universal parental observation of enureticchildren being difcult to wake up at night and is alsosupported by studies on objective arousal thresholds(Wolsh et al. 1997). This does not, however, meanthat the sleep EEG of enuretic children is necessarily

different from that of dry children. Sleep stage distri-bution and other polysomnographical parameters donot consistently differ between enuretic and dry chil-dren (Bader et al. 2002), but they are more difcult toarouse from sleep at night.

The disorder of arousal in enuretic children mayhave underlying brainstem explanations, or it may,paradoxically, be caused by the arousal stimuli them-selves. If someone (or in this case the bladder) isalways knocking at the door, you end up ignoring itor even installing an extra lock. This mechanism mayexplain the observation that some enuretic childrenwith sleep apnoeas attributable to enlarged tonsils ornasal adenoids will become dry at night when theirupper airway obstruction is surgically removed(Weider et al. 1991).

In summary, the enuretic child wets his/her bedbecause either (i) bladder distention due to nocturnalpolyuria fails to wake him/her up or (ii) uninhibiteddetrusor contractions fail to wake him/her up, orboth. This is illustrated graphically in Figure 3.

There is now an increasing body of evidence indi-cating that all three pathogenetic disturbances may becaused by an underlying brainstem disturbance. Thelocus coeruleus (LC) in the upper pons is crucial for

arousal from sleep (Kayama & Koyama 1993) andoverlaps (functionally and anatomically) with the pon-tine micturition centre (Holstege et al. 1986). It is alsothe main nucleus of the central sympathetic nervoussystem and has direct and indirect axonal connectionswith the vasopressin-producing hypothalamic supraop-tic nucleus (Lightman et al. 1984).

Experiments measuring the startle blink reex(a test assessing brainstem contribution to alertness;

Nocturnal

polyuria

Detrusor

overactivity

High arousal thresholds

Day-timeincontinence

Urgency

Nocturia

Enuresis Enuresis

Enuresis

Sound,undisturbedsleep

Suspected major pathogenetic factors in nocturnal enuresis

Figure 3 Suspected major pathogenetic factors in nocturnalenuresis.




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Ornitz et al. 1999), overnight measurements of sym-pathetic and parasympathetic tone (using heart ratevariability analysis; Fujiwara et al. 2001) and theobservation that the antienuretic activity of imipra-mine is dependent on its main metabolite binding tothe LC (Danysz et al. 1985) all contribute to support-

ing the hypothesis that enuresis may be caused by adisturbance in this region.

Adulthood consequences of disturbances inchildhood

As mentioned above, not all incontinent or bedwettingchildren grow out of their condition. A schoolchildwith severe enuresis has a very real risk of continuingto wet the bed into adulthood if we are unable to curehim or her. The prevalence of enuresis in adulthood isapprox. 0.5% (Hirasing et al. 1997). It has also beenshown that micturition problems in childhood aresignicant risk factors for developing micturitionproblems in adulthood. More specically, adults withurge incontinence (as opposed to stress incontinence)have often suffered from enuresis or daytime inconti-nence as children (Kuh et al. 1999). This may reectan overexcitability of the detrusor or of the micturi-tion reex that does not disappear even when or if the child becomes dry.

Enuresis and/or daytime incontinence causes low self-esteem in the aficted children (or adults; Ha gglo f et al.1997). The psychosocial consequences of this areunknown, butprobably not trivial. Reports about enure-

sis being common among criminals, previously taken asevidence to the enuresis being caused by early trauma orpsychiatric regression (Stein & Susser 1965), probablyreect both the consequences of poor self-esteem and theoverrepresentation of children with neuropsychiatricdisorders such as attention decit hyperactivity disorder(ADHD) in the enuretic population.

Finally, the detrusor overactivity that underlies mostcases of daytime incontinence and many cases of enuresis is per se a risk factor for urinary tract infec-tions, VUR and kidney damage. There is thus everyreason for adult and paediatric urologists, nephrolo-gists and researchers to unite in their efforts to helpmake these children dry !

Conict of interest

The authors have no present or conceivable conictsof interest to report.

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