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The efficacy of standard urotherapy in the treatment of nocturnal enuresis in children: A systematic review

Open AccessPublished:December 27, 2022DOI:https://doi.org/10.1016/j.jpurol.2022.12.011

      Summary

      Introduction

      Standard urotherapy in children with nocturnal enuresis (NE) is first-line treatment according to the current International Children's Continence Society (ICCS) guidelines. ICCS defines standard urotherapy as information and demystification, instruction in how to resolve lower urinary tract dysfunction, lifestyle advice, registration of symptoms and voiding habits, and support and encouragement. These interventions often are time consuming and some aspects of urotherapy, such as fluid restrictions, can be a frustrating process for a child, which emphasizes the importance of clarifying their relevance. The purpose of this review is to perform a systematic search in literature to evaluate the use of standard urotherapy in the treatment of children with primary NE (PNE).

      Study design

      A systematic literature search was conducted in MEDLINE, Embase, and CENTRAL based on the key concepts of standard urotherapy and NE. We identified 2,476 studies. After a systematic selection process using the Covidence tool, 39 studies were included. The quality of the studies was assessed by the QualSyst Checklist. Our protocol adheres to the PRISMA statement and was registered in PROSPERO database (CRD42020185611).

      Results

      Most of the 39 included studies scored low in quality. All studies combined several urotherapy interventions and studied different study populations. Twenty-two randomized controlled trials (RCTs) were included, which reported 0–92% of children being dry after urotherapy treatment. Three RCTs, all individualizing and optimizing drinking and voiding during the day and practicing optimal toilet posture, scored higher in quality based on the QualSyst score, and reported few children experiencing complete resolution of NE (5–33%). Eight studies compared the efficacy of urotherapy to a control group, however, conflicting results were found.

      Discussion

      This systematic review presents available literature in the field of standard urotherapy in the treatment of children with PNE. One possible explanation for low efficacy rates of urotherapy in NE is the large heterogeneity of the study populations and interventions. Additionally, the intervention period and the intensity of intervention can have an impact on the outcome.

      Conclusion

      The number of clinical studies on standard urotherapy in children with NE is limited and many of them are of poor quality. High quality research in a well-defined NE population is needed to establish the role of standard urotherapy in first-line treatment of children with NE or as an add-on to other first line treatments. We conclude that at present there is insufficient evidence for recommending standard urotherapy to children with PNE as a first line treatment modality.

      Keywords

      Introduction

      Nocturnal enuresis (NE) is defined as intermittent incontinence during sleep after the age of five years [
      • Nevéus T.
      • Fonseca E.
      • Franco I.
      • Kawauchi A.
      • Kovacevic L.
      • Nieuwhof-Leppink A.
      • et al.
      Management and treatment of nocturnal enuresis-an updated standardization document from the International Children's Continence Society.
      ], and is a very common childhood condition seen in 10–16% of seven-year-old children [
      • von Gontard A.
      • Heron J.
      • Joinson C.
      Family history of nocturnal enuresis and urinary incontinence: results from a large epidemiological study.
      ,
      • Yeung C.K.
      • Sreedhar B.
      • Sihoe J.D.
      • Sit F.K.
      • Lau J.
      Differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study.
      ]. NE can negatively impact the child's social and psychological well-being [
      • Redsell S.A.
      • Collier J.
      Bedwetting, behaviour and self-esteem: a review of the literature.
      ]. During the previous years, a variety of different interventions have been suggested as first line treatment for NE. In 1974, Azrin et al. introduced the term “Dry-bed Training” (DBT) [
      • Azrin N.H.
      • Sneed T.J.
      • Foxx R.M.
      Dry-bed training: rapid elimination of childhood enuresis.
      ]. Originally, the DBT included inhibiting urination, positive reinforcement, training in rapid awakening, increased fluid intake, increased social motivation, self-correction of accidents and practice in toileting, combined with the use of a bedwetting-alarm device. However, over the years, many variants of the concept with or without an alarm have been described with different terminology such as “behavior modification”, “behavior therapy”, “bladder training”, “basic bladder advice”, and more. In 2014, the International Children's Continence Society (ICCS) [
      • Austin P.F.
      • Bauer S.B.
      • Bower W.
      • Chase J.
      • Franco I.
      • Hoebeke P.
      • et al.
      The standardization of terminology of lower urinary tract function in children and adolescents: update report from the Standardization Committee of the International Children's Continence Society.
      ] defined the concept of “urotherapy” in their guidelines as the conservative-based approach to lower urinary tract symptoms (LUTS). The treatment approach is divided into “standard therapy” and “specific interventions” (such as pelvic floor muscle retraining, neuromodulation, or intermittent catheterization). According to the ICCS [
      • Austin P.F.
      • Bauer S.B.
      • Bower W.
      • Chase J.
      • Franco I.
      • Hoebeke P.
      • et al.
      The standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the International Children's Continence Society.
      ], standard urotherapy includes 1) information and demystification, 2) instruction in how to resolve LUT dysfunction, 3) lifestyle advice, 4) registration of symptoms and voiding habits, and 5) support and encouragement. Even though LUTS are not always present in children with NE, aspects of urotherapy are widely used before starting treatment with an enuresis alarm or desmopressin (DDAVP) [
      • Nevéus T.
      • Fonseca E.
      • Franco I.
      • Kawauchi A.
      • Kovacevic L.
      • Nieuwhof-Leppink A.
      • et al.
      Management and treatment of nocturnal enuresis-an updated standardization document from the International Children's Continence Society.
      ]. Since initiation of standard urotherapy may lead to significant postponement of other more efficient therapies while awaiting improvement, and interventions like fluid restrictions and retention control training can be very demanding for a child, it is imperative to evaluate whether this approach is indeed evidence based. The aim of this review was to identify and present available literature on urotherapy for NE and test the hypothesis that there is evidence to support the use of standard urotherapy in the treatment of children with primary NE (PNE).

      Materials and methods

      The systematic review protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) checklist for study protocols [
      • Research S.M.C.
      Methods used in developing and applying quality indicators in primary care.
      ], and was registered in the PROSPERO database (CRD42020185611).

      Search methods for identification and selection of studies

      A systematic literature search was conducted in MEDLINE (via PubMed Interface), Embase (via embase.com Interface), and CENTRAL based on the key concepts of standard urotherapy and NE (Appendix 1 presents the search string). Our search strategy was a combination of subject terms (Mesh/Emtree) and free-text terms. Additionally, we identified relevant studies by using the reference lists and citations from included articles. We included both interventional (pre-post study designs, non-randomized trials, and randomized controlled trials) and observational designs (cohort, case-control, and cross-sectional designs). Both prospective and retrospective studies were included. We excluded study protocols, meta-analyses, literature reviews, conference abstracts without sufficient information, and studies with a single-case design.
      The Covidence tool (Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at www.covidence.org) was used for screening and data extraction. Two reviewers (CSJ and LD) independently screened all titles and abstracts of all identified studies. On a second step, the same two authors screened full-text articles of potentially relevant studies, or studies for which the abstracts did not provide sufficient information. Any discrepancy was discussed with a third party (KK). For the initial search, there were no language restrictions. However, for the study selection, only articles in English, German, Danish, French and Dutch, were considered.

      Selection criteria of studies and outcome measures

      The study population was defined as children (age 5–18 years) suffering from PNE, who were neurologically normal and otherwise healthy. To be included, the studies had to evaluate the efficacy of standard urotherapy as defined by the ICCS [
      • Austin P.F.
      • Bauer S.B.
      • Bower W.
      • Chase J.
      • Franco I.
      • Hoebeke P.
      • et al.
      The standardization of terminology of lower urinary tract function in children and adolescents: update report from the Standardization Committee of the International Children's Continence Society.
      ], 1) standard urotherapy vs. no active treatment, 2) one type of standard urotherapy vs. another type of standard urotherapy, 3) standard urotherapy vs. alarm treatment and/or other specific interventions, and 4) standard urotherapy vs. drug treatment (including placebo).
      As primary outcomes, we evaluated the reduction in mean number of wet nights per week as well as the number of children who achieved complete dryness (complete responders). As secondary outcomes, we evaluated relapse rate, reduction in LUTS, adverse events, and adherence regarding treatment.

      Data extraction, risk bias and quality assessment, and data synthesis

      The reviewers independently performed structured data extraction from the original reports. Information was extracted on study design, method of recruitment, inclusion and exclusion criteria, the number and characteristics of participants, the intervention(s) and follow-up, outcomes, and power calculations.
      To assess the quality of the studies, the QualSyst Checklist was used (Table 1) [
      • Kmet L.M.L.R.C.
      • Cook L.S.
      Standard quality assessment criteria for evaluating primary research papers from a variety of fields.
      ]. The QualSyst tool is developed by the Effective Public Health Practice Project (EPHPP, Canada) for Public Health purposes and can be used to assess studies with varying study designs. It is a 14 items scale, and the final score is defined by the sum of the scores obtained across rated items (“yes” = 2, “partial” = 1, “no” = 0) divided by the total possible score (i.e. excluding “n/a” questions) resulting in a range 0–1. Different cut-off points have been suggested to decide whether to include a paper or not. Since the number of publications was limited, we have chosen not to exclude manuscripts based on score but display for each article our quality assessment (Table 1). To summarize the studies, we performed a descriptive narrative synthesis, since it provides an overview of relevant information through a textual approach, which is appropriate when studies are too heterogeneous to allow for a quantitative summary [
      • Ioannidis J.P.
      • Patsopoulos N.A.
      • Rothstein H.R.
      Reasons or excuses for avoiding meta-analysis in forest plots.
      ].
      Table 1Quality assessment of all included studies using the QualSyst checklist (QualSyst Tool) [
      • Kmet L.M.L.R.C.
      • Cook L.S.
      Standard quality assessment criteria for evaluating primary research papers from a variety of fields.
      ] Y = yes, N = no, P = partial, N/A = not applicable. The total score ranges from 0 to 1.
      StudyQuestion/objective sufficiently described?Study design evident and appropriate?Method of subject/comparison group selection or source of information/input variables described and appropriate?Subject (and comparison group, if applicable) characteristics sufficiently described?If interventional and random allocation was possible, was it described?If interventional and blinding of investigators was possible, was it reported?If interventional and blinding of subjects was possible, was it reported?Outcome and (if applicable) exposure measure(s) well defined and robust to measurement/misclassification bias? Means of assessment reported?Sample size appropriate?Analytic methods described/justified and appropriate?Some estimate of variance is reported for the main results?Controlled for confounding?Results reported in sufficient detail?Conclusions supported by the results?Total score
      Randomized controlled studiesBollard 1977 [
      • Bollard R.J.
      • Woodroffe P.
      The effect of parent-administered Dry-Bed training on nocturnal enuresis in children.
      ]
      YYPPNN/AN/AYPPNNYY0.58
      Doleys 1977 [
      • Doleys D.M.
      • Ciminero A.R.
      • Tollison J.W.
      Dry-bed training and retention control training: a comparison.
      ]
      YPNYNN/AN/AYPYNNPP0.50
      Harris 1977 [
      • Harris L.S.
      • Purohit A.P.
      Bladder training and enuresis: a controlled trial.
      ]
      YYYYPN/AN/APPPNNPY0.63
      Azrin 1978 [
      • Azrin N.H.
      • Thienes P.M.
      Rapid elimination of enuresis by intensive learning without a conditioning apparatus.
      ]
      YYYPNN/AN/AYYPNNYY0.67
      Nettelbeck 1979 [
      • Nettelbeck T.
      • Langeluddecke P.
      Dry-bed training without an enuresis machine.
      ]
      YYPPNN/ANPNNNNPY0.38
      Mehrotra 1980 [
      • Mehrotra S.N.
      • Liu L.
      • Srivastava J.R.
      • Singh S.B.
      Evaluation of various methods in treatment of enuresis.
      ]
      PPNNNN/AN/APYNNNNP0.25
      Fava 1981 [
      • Fava G.A.
      • Cracco L.
      • Facco L.
      Positive reinforcement and enuresis.
      ]
      YYPNPN/AN/APPPNNNP0.42
      Bollard 1982 [
      • Bollard J.
      • Nettelbeck T.
      • Roxbee L.
      Dry-bed training for childhood bedwetting: a comparison of group with individually administered parent instruction.
      ]
      YYYPPN/AN/AYPPNNYY0.67
      Keating 1983 [
      • Keating J.C.
      • Butz R.A.
      • Burke E.
      • Heimberg R.G.
      Dry bed training without a urine alarm: lack of effect of setting and therapist contact with child.
      ]
      YYPPNN/AN/APNPNNPP0.42
      Lester 1991 [
      • Iester A.
      • Marchesi A.
      • Cohen A.
      • Iester M.
      • Bagnasco F.
      • Bonelli R.
      Functional enuresis: pharmacological versus behavioral treatment.
      ]
      YPPNPN/AN/ANPNNNPP0.33
      Ronen 1995 [
      • Ronen T.
      • Rahav G.
      • Wozner Y.
      Self-control and enuresis.
      ]
      YYPPNN/AN/APPYYPPY0.67
      Kahan 1998 [
      • Kahan E.
      • Morel D.
      • Amir J.
      • Zelcer C.
      A controlled trial of desmopressin and behavioral therapy for nocturnal enuresis.
      ]
      YYYPYN/APYYYNNYY0.77
      Kruse 1999 [
      • Kruse S.
      • Hellström A.L.
      • Hjälmås K.
      Daytime bladder dysfunction in therapy-resistant nocturnal enuresis. A pilot study in urotherapy.
      ]
      YPPPNN/AN/AYPNNNPP0.42
      Hamano 2000 [
      • Hamano S.
      • Yamanishi T.
      • Igarashi T.
      • Ito H.
      • Murakami S.
      Functional bladder capacity as predictor of response to desmopressin and retention control training in monosymptomatic nocturnal enuresis.
      ]
      YYPYPN/AN/AYPYYNYY0.79
      Van Hoeck 2007 [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ]
      YYYPYN/APYPYYYYY0.88
      Van Dommelen 2009 [
      • van Dommelen P.
      • Kamphuis M.
      • van Leerdam F.J.
      • de Wilde J.A.
      • Rijpstra A.
      • Campagne A.E.
      • et al.
      The short- and long-term effects of simple behavioral interventions for nocturnal enuresis in young children: a randomized controlled trial.
      ]
      YYYPYN/AN/AYPYNNPY0.71
      Oliveira 2012 [
      • Oliveira L.F.
      • Oliveira D.M.
      • Paula L.I.S.
      • Chaoubah A.
      • Figueiredo A.A.
      • Barroso U.O.
      • et al.
      Para-sacral transcutaneous electrical neural stimulation (PSTENS) in children with monosymptomatic enuresis.
      ]
      YYYPYN/AN/APPYYNYY0.79
      Cederblad 2015 [
      • Cederblad M.
      • Sarkadi A.
      • Engvall G.
      • Nevéus T.
      No effect of basic bladder advice in enuresis: a randomized controlled trial.
      ]
      YYYYYN/AN/AYYYYNYY0.92
      ElBaz 2015 [
      • ElBaz F.
      • Zahra S.
      • Khairy M.
      Assessment of the efficacy of desmopressin in treatment of primary monosymptomatic nocturnal enuresis in Egyptian children.
      ]
      YPPPPN/AN/APPPYPPY0.63
      Kajbafzadeh 2015 [
      • Kajbafzadeh A.M.
      • Sharifi-Rad L.
      • Mozafarpour S.
      • Ladi-Seyedian S.S.
      Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial.
      ]
      YYYYYN/AN/AYYYYNYY0.92
      Ma 2017 [
      • Ma Y.
      • Liu X.
      • Shen Y.
      Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: randomized controlled trial.
      ]
      YPPYPN/AN/APPPNNYP0.54
      Hascicek 2019 [
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ]
      YYYYYN/AN/AYYYYNYY0.92
      Cohort studiesDische 1971 [
      • Dische S.
      Management of enuresis.
      ]
      YYYYN/AN/AN/AYYNNNPY0.68
      Azrin 1979 [
      • Azrin N.H.
      • Thienes Hontos P.
      • Besalel-Azrin V.
      Elimination of enuresis without a conditioning apparatus: an extension by office instruction of the child and parents.
      ]
      YYYPN/AN/AN/AYYNNNYY0.68
      Devlin 1990 [
      • Devlin J.B.
      • O'Cathain C.
      Predicting treatment outcome in nocturnal enuresis.
      ]
      YYYYN/AN/AN/APYPNNPY0.68
      Hirasing 1991 [
      • Hirasing R.A.
      • Reus H.
      Dry bed training in nocturnal enuresis.
      ]
      PNNNN/AN/AN/APPNNNNP0.18
      Spehr 1991 [
      • Spehr C.
      • De Geeter P.
      Faulty voiding and drinking habits--a contribution to the genesis of enuretic syndrome?.
      ]
      YYPPN/AN/AN/APYNNNPY0.55
      Robson 2002 [
      • Robson L.M.
      • Leung A.K.
      Urotherapy recommendations for bedwetting.
      ]
      YPYYN/AN/AN/AYNYYNYY0.77
      Al-Harbi 2004 [
      • Al-Harbi S.M.
      • Needlman R.D.
      • Khan A.S.
      • Patni T.
      Intensive behavioral therapy for primary enuresis.
      ]
      YYYYN/AN/AN/AYPYYNYY0.86
      Marschall-Kehrel 2004 [
      • Marschall-Kehrel A.D.
      • Mürtz G.
      • Kramer G.
      • Jünemann K.P.
      • Madersbacher H.
      • Hjalmas K.
      A suggested treatment algorithm in nocturnal enuresis with emphasis on partial responders.
      ]
      YPYPN/AN/AN/AYYNNNYY0.64
      Pennesi 2004 [
      • Pennesi M.
      • Pitter M.
      • Bordugo A.
      • Minisini S.
      • Peratoner L.
      Behavioral therapy for primary nocturnal enuresis.
      ]
      YYPPN/AN/AN/AYYYNNPP0.64
      Sehgal 2007 [
      • Sehgal R.
      • Paul P.
      • Mohanty N.K.
      Urodynamic evaluation in primary enuresis: an investigative and treatment outcome correlation.
      ]
      YPPPN/AN/AN/APPPYNPP0.55
      Glad Mattsson 2010 [
      • Glad Mattsson G.
      • Brännström M.
      • Eldh M.
      • Mattsson S.
      Voiding school for children with idiopathic urinary incontinence and/or bladder dysfunction.
      ]
      YPPPN/AN/AN/APNPNNPY0.45
      Elsayed 2012 [
      • Elsayed E.R.
      • Abdalla M.M.
      • Eladl M.
      • Gabr A.
      • Siam A.G.
      • Abdelrahman H.M.
      Predictors of severity and treatment response in children with monosymptomatic nocturnal enuresis receiving behavioral therapy.
      ]
      YPPYN/AN/AN/APPNYNPY0.59
      Erol 2016 [
      • Erol M.
      • Özkuvancı Ü.
      • Yiğit Ö.
      • Fucucuoğlu D.
      • Gayret Ö B.
      • Aksu S.
      Motivation therapy in children with primary monosymptomatic nocturnal enuresis.
      ]
      YYYYN/AN/AN/AYPYNNYY0.77
      Tkaczyk 2017 [
      • Tkaczyk M.
      • Maternik M.
      • Krakowska A.
      • Wosiak A.
      • Miklaszewska M.
      • Zachwieja K.
      • et al.
      Evaluation of the effect of 3-month bladder basic advice in children with monosymptomatic nocturnal enuresis.
      ]
      YPPPN/AN/AN/AYPYNPYY0.68
      Im 2018 [
      • Im Y.J.
      • Lee J.K.
      • Park K.
      Time course of treatment for primary enuresis with overactive bladder.
      ]
      YPYYN/AN/AN/AYYYYNYY0.86
      Saarikoski 2018 [
      • Saarikoski A.
      • Koppeli R.
      • Taskinen S.
      • Axelin A.
      Voiding school as a treatment for daytime incontinence or enuresis: assessing the effectiveness of intervention by measuring changes in wetting episodes.
      ]
      YPPPN/AN/AN/APPPNNPP0.45
      Ma 2019 [
      • Ma Y.
      • Shen Y.
      • Liu X.
      Association between enuresis and obesity in children with primary monosymptomatic nocturnal enuresis.
      ]
      YYYYN/AN/AN/AYYYYPYY0.95

      Results

      Included studies and study population

      The PRISMA flowchart (Fig. 1) illustrates the flow of the literature search. The first systematic search identified 2,476 studies, which were all screened based on title and abstract. Of these, 102 studies were assessed for eligibility, and based on full text screening 39 studies were included in the review. Of these 39 studies, 36 studies were in English, two in German, and one in Dutch. In total, 22 randomized controlled (RCT) and 17 cohort trials were included (Table 2). Assessed by the QualSyst Checklist [
      • Kmet L.M.L.R.C.
      • Cook L.S.
      Standard quality assessment criteria for evaluating primary research papers from a variety of fields.
      ], the quality varied a lot between the different studies (Table 1). Most of the studies scored low in quality due to inappropriate study design, small sample sizes, and lack of sufficient reporting. The number of participants in the included studies varied from 18 to 666 children aged between 3 and 15 years. All studies included both genders.
      Table 2Description of all 39 included studies and main effect parameters.
      Patients characteristicsInterventionDurationOutcome
      StudyCountryStudy design
      RCT = randomized controlled trial, CS = cohort study.
      Number of participants (male)Age (range (mean2 ± SD))NE-type
      DI = daytime incontinence, PNE = primary nocturnal enuresis, SNE = secondary nocturnal enuresis (the child has been dry for more than 6 months [1]), MNE = monosymptomatic nocturnal enuresis (NE without any other LUTS [39]), NMNE = non-monosymptomatic nocturnal enuresis.
      Positive reinforcement/reward systems/avoidance of punishmentEducationFluid restriction in the eveningRequired drinkingIndividual drinking and voiding regimeWaking or lifting (+/-a password)Retention control trainingCleanliness trainingRelaxation and optimal posturePhysical activityAvoid specific diet
      Robson 2002 (caffein); Elsayed 2012 (calcium and sodium); Oliveira 2012 (caffein); Elbaz 2015 (eat food that soften stool); Kafbafzadeh 2015 (caffein, citric fruits, soft drinks, chocolate, irritating foods, increase fiber diet); Erol 2016 (caffein, coke, carbonated beverages and salty food), Ma 2017 (healthy life style); Tkaczyk 2017 (milk products); Im 2018 (lifestyle modifications); Saarikoski 2018 (juice, fruit, soft drinks, increase wholesome food); Hascicek 2019 (fast-food, healthy diet).
      Easy access to toiletsStop use of diapersDry-bed training
      Based on Azrin et al., 1974 [5] including inhibiting urination, positive reinforcement, training in rapid awakening, increased fluid intake, increased social motivation, self-correction of accidents and practice in toileting, however, with different training protocols, different training settings, and different trainers.
      without an alarm
      Duration of interventions (months)Follow-up (months)Number of children undergoing urotherapy with complete response at the end of treatment (%)Reduction in number of wet nights/week at end of treatment (%) for children undergoing urotherapyNumber of children with relapse (%) after urotherapy treatment
      Bollard 1977 [
      • Bollard R.J.
      • Woodroffe P.
      The effect of parent-administered Dry-Bed training on nocturnal enuresis in children.
      ]
      AURCT34 (19)4-13 (8)NE without DIX13 weeks or dry60 (0)4 (57)
      Doleys 1977 [
      • Doleys D.M.
      • Ciminero A.R.
      • Tollison J.W.
      Dry-bed training and retention control training: a comparison.
      ]
      USARCT19 (13)Group 1: 6.6 Group 2: 7.8PNEXXXXX5-12 or dry6–110 (0)8%
      Harris 1977 [
      • Harris L.S.
      • Purohit A.P.
      Bladder training and enuresis: a controlled trial.
      ]
      CARCT18 (12)5–13NEXXXX35 days9 weeks0.6
      Azrin 1978 [
      • Azrin N.H.
      • Thienes P.M.
      Rapid elimination of enuresis by intensive learning without a conditioning apparatus.
      ]
      USARCT55 (41)3-14 (7.1)PNE without DIX12 or dryUp to 1251 (92)98%20%
      Nettelbeck 1979 [
      • Nettelbeck T.
      • Langeluddecke P.
      Dry-bed training without an enuresis machine.
      ]
      AURCT24 (14)4-14 (8.3)PNE without DIX222.8 (48)
      Mehrotra 1980 [
      • Mehrotra S.N.
      • Liu L.
      • Srivastava J.R.
      • Singh S.B.
      Evaluation of various methods in treatment of enuresis.
      ]
      INRCT60PNE without DIXXX5 weeks4–53 (15)
      Fava 1981 [
      • Fava G.A.
      • Cracco L.
      • Facco L.
      Positive reinforcement and enuresis.
      ]
      ITRCT20Group 1: 8.0 ± 1.7NE without DIXX31 year8 (80)0 (0)
      Bollard 1982 [
      • Bollard J.
      • Nettelbeck T.
      • Roxbee L.
      Dry-bed training for childhood bedwetting: a comparison of group with individually administered parent instruction.
      ]
      AURCT30 (18)7-13 (8.9)NEX2 or dry22 (20)2 (40)2 (100)
      Keating 1983 [
      • Keating J.C.
      • Butz R.A.
      • Burke E.
      • Heimberg R.G.
      Dry bed training without a urine alarm: lack of effect of setting and therapist contact with child.
      ]
      USARCT30 (18)4-14 (8.1)PNEXUntill dry818 (78)6 (33)
      Lester 1991 [
      • Iester A.
      • Marchesi A.
      • Cohen A.
      • Iester M.
      • Bagnasco F.
      • Bonelli R.
      Functional enuresis: pharmacological versus behavioral treatment.
      ]
      ITRCT1326–11PNEXXX612105 (80)
      Ronen 1995 [
      • Ronen T.
      • Rahav G.
      • Wozner Y.
      Self-control and enuresis.
      ]
      ILRCT77 (37)7–14NE without DIXX3682%, 95% (two groups)
      Kahan 1998 [
      • Kahan E.
      • Morel D.
      • Amir J.
      • Zelcer C.
      A controlled trial of desmopressin and behavioral therapy for nocturnal enuresis.
      ]
      ILRCT221NEXXXX2212 (16)2.5 (45)6 (50)
      Kruse 1999 [
      • Kruse S.
      • Hellström A.L.
      • Hjälmås K.
      Daytime bladder dysfunction in therapy-resistant nocturnal enuresis. A pilot study in urotherapy.
      ]
      SERCT22 (14)10-16 (12.4)NEXXX125 (38)85%
      Hamano 2000 [
      • Hamano S.
      • Yamanishi T.
      • Igarashi T.
      • Ito H.
      • Murakami S.
      Functional bladder capacity as predictor of response to desmopressin and retention control training in monosymptomatic nocturnal enuresis.
      ]
      JPRCT114 (88)Group 1: 9.2 ±-2.2

      Group 2: 9.4 ± 2.3
      NEXXX3314 (23)35 (58), more than 50% reduction5 (36))
      Van Hoeck 2007 [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ]
      BERCT149 (108)5-12 (7.5)NEXX3End of treatment1 (3)
      Van Dommelen 2009 [
      • van Dommelen P.
      • Kamphuis M.
      • van Leerdam F.J.
      • de Wilde J.A.
      • Rijpstra A.
      • Campagne A.E.
      • et al.
      The short- and long-term effects of simple behavioral interventions for nocturnal enuresis in young children: a randomized controlled trial.
      ]
      NLRCT5704–5PNEXX6 or dry3 years32% for all interventions
      Oliveira 2012 [
      • Oliveira L.F.
      • Oliveira D.M.
      • Paula L.I.S.
      • Chaoubah A.
      • Figueiredo A.A.
      • Barroso U.O.
      • et al.
      Para-sacral transcutaneous electrical neural stimulation (PSTENS) in children with monosymptomatic enuresis.
      ]
      BRRCT45 (16)6–16MNEXXXX666% (more than 90%)28%
      Cederblad 2015 [
      • Cederblad M.
      • Sarkadi A.
      • Engvall G.
      • Nevéus T.
      No effect of basic bladder advice in enuresis: a randomized controlled trial.
      ]
      SERCT40 (29)6–8PNEXXXX1End of treatment1 (5)12%
      ElBaz 2015 [
      • ElBaz F.
      • Zahra S.
      • Khairy M.
      Assessment of the efficacy of desmopressin in treatment of primary monosymptomatic nocturnal enuresis in Egyptian children.
      ]
      EGRCT406-15, 9.5 ± 2.9PMNEXXXXXX2235%65%39%
      Kajbafzadeh 2015 [
      • Kajbafzadeh A.M.
      • Sharifi-Rad L.
      • Mozafarpour S.
      • Ladi-Seyedian S.S.
      Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial.
      ]
      IRRCT54 (31)6–14NEXXXXXX21 year7 (25)2.1 (39)1 (14)
      Ma 2017 [
      • Ma Y.
      • Liu X.
      • Shen Y.
      Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: randomized controlled trial.
      ]
      CNRCT369 (216)5-15, (8 ± 2.8)PNEXXXXX235 (6)1 (20)
      Hascicek 2019 [
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ]
      TRRCT63 (40)6-12 (8.3 ± 1.4)PNEXXXXXX2233%
      Dische 1971 [
      • Dische S.
      Management of enuresis.
      ]
      UKCS144 (93)4–15PNEXX6 or dryUp to 4.5 y47 (37)1 (2)
      Azrin 1979 [
      • Azrin N.H.
      • Thienes Hontos P.
      • Besalel-Azrin V.
      Elimination of enuresis without a conditioning apparatus: an extension by office instruction of the child and parents.
      ]
      USACS44 (29)3-15 (6.8)PNEX121244 (100)96%3 (7)
      Devlin 1990 [
      • Devlin J.B.
      • O'Cathain C.
      Predicting treatment outcome in nocturnal enuresis.
      ]
      IE/UKCS127 (84)6-17 (8.8)MNEXXXXX21222 (17)1 (5)
      Hirasing 1991 [
      • Hirasing R.A.
      • Reus H.
      Dry bed training in nocturnal enuresis.
      ]
      NLCS36 (23)6–14MNEXUntill dry631 (86)23 (75)
      Spehr 1991 [
      • Spehr C.
      • De Geeter P.
      Faulty voiding and drinking habits--a contribution to the genesis of enuretic syndrome?.
      ]
      DECS122 (37)4–13MNE og NMNEX1–12 weeks1–1.5 year119 (98)6 (5)
      Robson 2002 [
      • Robson L.M.
      • Leung A.K.
      Urotherapy recommendations for bedwetting.
      ]
      CACS23 (14)4-14 (8.7)MNEXXXXX0.5–30.5–35 (22)2 (34)
      Al-Harbi 2004 [
      • Al-Harbi S.M.
      • Needlman R.D.
      • Khan A.S.
      • Patni T.
      Intensive behavioral therapy for primary enuresis.
      ]
      SACS26 (17)6-14, 9.6 ± 2.6PMNEXXXX1-8 visits3–1212 (46)67%
      Marschall-Kehrel 2004 [
      • Marschall-Kehrel A.D.
      • Mürtz G.
      • Kramer G.
      • Jünemann K.P.
      • Madersbacher H.
      • Hjalmas K.
      A suggested treatment algorithm in nocturnal enuresis with emphasis on partial responders.
      ]
      DECS259 (167)5-18 (8.1)NE without DIX2 weeks3–7942 (16)1 (2)
      Pennesi 2004 [
      • Pennesi M.
      • Pitter M.
      • Bordugo A.
      • Minisini S.
      • Peratoner L.
      Behavioral therapy for primary nocturnal enuresis.
      ]
      ITCS250 (159)5-17 (8.1)PNE without DIXXXX42–18111 (60) (>90% dry nights)9 (8)
      Sehgal 2007 [
      • Sehgal R.
      • Paul P.
      • Mohanty N.K.
      Urodynamic evaluation in primary enuresis: an investigative and treatment outcome correlation.
      ]
      INCS116 (64)5–14PNEXXXX4End of treatment51%0 (0)
      Glad Mattsson 2010 [
      • Glad Mattsson G.
      • Brännström M.
      • Eldh M.
      • Mattsson S.
      Voiding school for children with idiopathic urinary incontinence and/or bladder dysfunction.
      ]
      SECS200 (84)3-14 (7.2)MNEXXX2 half-day sessions1264 (35)
      Elsayed 2012 [
      • Elsayed E.R.
      • Abdalla M.M.
      • Eladl M.
      • Gabr A.
      • Siam A.G.
      • Abdelrahman H.M.
      Predictors of severity and treatment response in children with monosymptomatic nocturnal enuresis receiving behavioral therapy.
      ]
      EGCS122 (68)5-9 (6.8)PNEXXX4416 (22)
      Erol 2016 [
      • Erol M.
      • Özkuvancı Ü.
      • Yiğit Ö.
      • Fucucuoğlu D.
      • Gayret Ö B.
      • Aksu S.
      Motivation therapy in children with primary monosymptomatic nocturnal enuresis.
      ]
      TRCS50 (21)5-15, (9.11 ± 2.4)PMNEXXXXXXX121827 (54)4%
      Tkaczyk 2017 [
      • Tkaczyk M.
      • Maternik M.
      • Krakowska A.
      • Wosiak A.
      • Miklaszewska M.
      • Zachwieja K.
      • et al.
      Evaluation of the effect of 3-month bladder basic advice in children with monosymptomatic nocturnal enuresis.
      ]
      TRCS49 (36)5-16 (7.2)PNMNEXXXXX339 (18)34%
      Im 2018 [
      • Im Y.J.
      • Lee J.K.
      • Park K.
      Time course of treatment for primary enuresis with overactive bladder.
      ]
      KPCS111 (76)5-13, (6.8 ± 1.8)NEXXX1120 (0)
      Saarikoski 2018 [
      • Saarikoski A.
      • Koppeli R.
      • Taskinen S.
      • Axelin A.
      Voiding school as a treatment for daytime incontinence or enuresis: assessing the effectiveness of intervention by measuring changes in wetting episodes.
      ]
      FICS58 (24)6-12 (8)MNEXXXXX2–33–650% more than 50% reduction38%
      Ma 2019 [
      • Ma Y.
      • Shen Y.
      • Liu X.
      Association between enuresis and obesity in children with primary monosymptomatic nocturnal enuresis.
      ]
      CNCS666 (349)5-14 (6.5)PNEXXXXXXX3End of treatmentNormal weight: 27%
      a RCT = randomized controlled trial, CS = cohort study.
      b DI = daytime incontinence, PNE = primary nocturnal enuresis, SNE = secondary nocturnal enuresis (the child has been dry for more than 6 months [
      • Nevéus T.
      • Fonseca E.
      • Franco I.
      • Kawauchi A.
      • Kovacevic L.
      • Nieuwhof-Leppink A.
      • et al.
      Management and treatment of nocturnal enuresis-an updated standardization document from the International Children's Continence Society.
      ]), MNE = monosymptomatic nocturnal enuresis (NE without any other LUTS [
      • Neveus T.
      • Eggert P.
      • Evans J.
      • Macedo A.
      • Rittig S.
      • Tekgul S.
      • et al.
      Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children's Continence Society.
      ]), NMNE = non-monosymptomatic nocturnal enuresis.
      c Robson 2002 (caffein); Elsayed 2012 (calcium and sodium); Oliveira 2012 (caffein); Elbaz 2015 (eat food that soften stool); Kafbafzadeh 2015 (caffein, citric fruits, soft drinks, chocolate, irritating foods, increase fiber diet); Erol 2016 (caffein, coke, carbonated beverages and salty food), Ma 2017 (healthy life style); Tkaczyk 2017 (milk products); Im 2018 (lifestyle modifications); Saarikoski 2018 (juice, fruit, soft drinks, increase wholesome food); Hascicek 2019 (fast-food, healthy diet).
      d Based on Azrin et al., 1974 [
      • Azrin N.H.
      • Sneed T.J.
      • Foxx R.M.
      Dry-bed training: rapid elimination of childhood enuresis.
      ] including inhibiting urination, positive reinforcement, training in rapid awakening, increased fluid intake, increased social motivation, self-correction of accidents and practice in toileting, however, with different training protocols, different training settings, and different trainers.

      Interventions

      Most studies combined two or more urotherapy elements in a single trial, or in a single arm in a multi-intervention trial. The duration of intervention varied from 1 week to 1 year or until “dry”. The follow-up period varied from 0 to 79 months. The different interventions are described in Table 2. No adverse events because of urotherapy intervention were reported in any study. Adherence was evaluated in 15 studies which reported a significant decrease over time.
      Active comparison interventions were: unstructured play therapy (one study) [
      • Fava G.A.
      • Cracco L.
      • Facco L.
      Positive reinforcement and enuresis.
      ]; placebo (one study) [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ]; controls (seven studies) [
      • Bollard R.J.
      • Woodroffe P.
      The effect of parent-administered Dry-Bed training on nocturnal enuresis in children.
      ,
      • Bollard J.
      • Nettelbeck T.
      • Roxbee L.
      Dry-bed training for childhood bedwetting: a comparison of group with individually administered parent instruction.
      ,
      • Harris L.S.
      • Purohit A.P.
      Bladder training and enuresis: a controlled trial.
      ,
      • Nettelbeck T.
      • Langeluddecke P.
      Dry-bed training without an enuresis machine.
      ,
      • Keating J.C.
      • Butz R.A.
      • Burke E.
      • Heimberg R.G.
      Dry bed training without a urine alarm: lack of effect of setting and therapist contact with child.
      ,
      • Ronen T.
      • Rahav G.
      • Wozner Y.
      Self-control and enuresis.
      ,
      • van Dommelen P.
      • Kamphuis M.
      • van Leerdam F.J.
      • de Wilde J.A.
      • Rijpstra A.
      • Campagne A.E.
      • et al.
      The short- and long-term effects of simple behavioral interventions for nocturnal enuresis in young children: a randomized controlled trial.
      ]; DBT with an alarm (four studies) [
      • Bollard R.J.
      • Woodroffe P.
      The effect of parent-administered Dry-Bed training on nocturnal enuresis in children.
      ,
      • Bollard J.
      • Nettelbeck T.
      • Roxbee L.
      Dry-bed training for childhood bedwetting: a comparison of group with individually administered parent instruction.
      ,
      • Nettelbeck T.
      • Langeluddecke P.
      Dry-bed training without an enuresis machine.
      ,
      • Doleys D.M.
      • Ciminero A.R.
      • Tollison J.W.
      Dry-bed training and retention control training: a comparison.
      ]; alarm alone (five studies) [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ,
      • Ronen T.
      • Rahav G.
      • Wozner Y.
      Self-control and enuresis.
      ,
      • Cederblad M.
      • Sarkadi A.
      • Engvall G.
      • Nevéus T.
      No effect of basic bladder advice in enuresis: a randomized controlled trial.
      ,
      • Kruse S.
      • Hellström A.L.
      • Hjälmås K.
      Daytime bladder dysfunction in therapy-resistant nocturnal enuresis. A pilot study in urotherapy.
      ,
      • Azrin N.H.
      • Thienes P.M.
      Rapid elimination of enuresis by intensive learning without a conditioning apparatus.
      ]; amitryptiline (one study) [
      • Mehrotra S.N.
      • Liu L.
      • Srivastava J.R.
      • Singh S.B.
      Evaluation of various methods in treatment of enuresis.
      ]; imipramine (two studies) [
      • Iester A.
      • Marchesi A.
      • Cohen A.
      • Iester M.
      • Bagnasco F.
      • Bonelli R.
      Functional enuresis: pharmacological versus behavioral treatment.
      ,
      • Sehgal R.
      • Paul P.
      • Mohanty N.K.
      Urodynamic evaluation in primary enuresis: an investigative and treatment outcome correlation.
      ]; DDAVP (six studies) [
      • Kruse S.
      • Hellström A.L.
      • Hjälmås K.
      Daytime bladder dysfunction in therapy-resistant nocturnal enuresis. A pilot study in urotherapy.
      ,
      • Kahan E.
      • Morel D.
      • Amir J.
      • Zelcer C.
      A controlled trial of desmopressin and behavioral therapy for nocturnal enuresis.
      ,
      • Hamano S.
      • Yamanishi T.
      • Igarashi T.
      • Ito H.
      • Murakami S.
      Functional bladder capacity as predictor of response to desmopressin and retention control training in monosymptomatic nocturnal enuresis.
      ,
      • ElBaz F.
      • Zahra S.
      • Khairy M.
      Assessment of the efficacy of desmopressin in treatment of primary monosymptomatic nocturnal enuresis in Egyptian children.
      ,
      • Ma Y.
      • Liu X.
      • Shen Y.
      Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: randomized controlled trial.
      ,
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ]; oxybutynin (two studies) [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ,
      • Sehgal R.
      • Paul P.
      • Mohanty N.K.
      Urodynamic evaluation in primary enuresis: an investigative and treatment outcome correlation.
      ]; flavoxate (one study) [
      • Sehgal R.
      • Paul P.
      • Mohanty N.K.
      Urodynamic evaluation in primary enuresis: an investigative and treatment outcome correlation.
      ]; suoquan (a herbal remedy) (one study) [
      • Ma Y.
      • Liu X.
      • Shen Y.
      Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: randomized controlled trial.
      ]; parasacral transcutaneous electrical neural stimulation (one study) [
      • Oliveira L.F.
      • Oliveira D.M.
      • Paula L.I.S.
      • Chaoubah A.
      • Figueiredo A.A.
      • Barroso U.O.
      • et al.
      Para-sacral transcutaneous electrical neural stimulation (PSTENS) in children with monosymptomatic enuresis.
      ]; and interferential electrical stimulation (one study) [
      • Kajbafzadeh A.M.
      • Sharifi-Rad L.
      • Mozafarpour S.
      • Ladi-Seyedian S.S.
      Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial.
      ].

      Outcome

      The heterogeneity of the studies regarding study design, patient population, interventions, duration of intervention(s), outcome variables, power, and choice of statistical methods makes a meta-analysis and comparisons of the included studies difficult. The number of children with a complete response (became dry) varied from 0 to 100% in the different studies. The number of children with relapse depended on follow-up time and was reported to be between 0 and 100%. Three studies [
      • Pennesi M.
      • Pitter M.
      • Bordugo A.
      • Minisini S.
      • Peratoner L.
      Behavioral therapy for primary nocturnal enuresis.
      ,
      • Glad Mattsson G.
      • Brännström M.
      • Eldh M.
      • Mattsson S.
      Voiding school for children with idiopathic urinary incontinence and/or bladder dysfunction.
      ,
      • Saarikoski A.
      • Koppeli R.
      • Taskinen S.
      • Axelin A.
      Voiding school as a treatment for daytime incontinence or enuresis: assessing the effectiveness of intervention by measuring changes in wetting episodes.
      ] reported reduction in LUTS after urotherapy and reported that daytime symptoms improved or disappeared together with NE.

      Urotherapy evaluated in RCTs

      In this review, 22 RCT studies were included (Table 2). Many of these studies were of poor quality assessed by the QualSyst Checklist (Table 1). The reported number of complete responders at the end of treatment varied from 0 to 92%, and the reduction in number of wet nights varied from 12 to 98%. We want to highlight three RCT studies of higher quality based on the QualSyst score (Table 1) – Cederblad et al., 2015 [
      • Cederblad M.
      • Sarkadi A.
      • Engvall G.
      • Nevéus T.
      No effect of basic bladder advice in enuresis: a randomized controlled trial.
      ]; Kajbafzadeh et al., 2015 [
      • Kajbafzadeh A.M.
      • Sharifi-Rad L.
      • Mozafarpour S.
      • Ladi-Seyedian S.S.
      Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial.
      ]; and Hascicek et al., 2019 [
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ]. They all included an optimization of drinking and voiding during the day together with practicing relaxation and optimal posture, combined with other interventions such as positive reinforcement, education, lifting the child during the night, physical activity, and diet recommendations. Despite different study populations, all three studies reported few children achieving complete response (5%, 25%, and 33%, respectively).
      Kahan et al. found no additional efficacy of positive reinforcement, education, fluid restriction, and retention control to DDAVP treatment in 221 children with monosymptomatic nocturnal enuresis (MNE) when evaluating reduction in number of wet nights [
      • Kahan E.
      • Morel D.
      • Amir J.
      • Zelcer C.
      A controlled trial of desmopressin and behavioral therapy for nocturnal enuresis.
      ]. In contrast, ElBaz et al. found the combination of six behavioral modifications to be as good as DDAVP treatment in reducing the number of wet nights in 40 children with PNE without daytime incontinence (DI) [
      • ElBaz F.
      • Zahra S.
      • Khairy M.
      Assessment of the efficacy of desmopressin in treatment of primary monosymptomatic nocturnal enuresis in Egyptian children.
      ].

      Urotherapy vs no treatment (control-group)

      Eight studies compared the efficacy of urotherapy to a control group or to placebo (Table 2). Four of these studies [
      • Bollard R.J.
      • Woodroffe P.
      The effect of parent-administered Dry-Bed training on nocturnal enuresis in children.
      ,
      • Bollard J.
      • Nettelbeck T.
      • Roxbee L.
      Dry-bed training for childhood bedwetting: a comparison of group with individually administered parent instruction.
      ,
      • Nettelbeck T.
      • Langeluddecke P.
      Dry-bed training without an enuresis machine.
      ,
      • Keating J.C.
      • Butz R.A.
      • Burke E.
      • Heimberg R.G.
      Dry bed training without a urine alarm: lack of effect of setting and therapist contact with child.
      ] evaluated the DBT [
      • Azrin N.H.
      • Sneed T.J.
      • Foxx R.M.
      Dry-bed training: rapid elimination of childhood enuresis.
      ]. They reported different results with number of complete responders from 0 to 78%. Harris et al. [
      • Harris L.S.
      • Purohit A.P.
      Bladder training and enuresis: a controlled trial.
      ] evaluated the efficacy of rewards systems, retention control training, physical activity, and required drinking during the day in 18 children with PNE without DI and reported no significant efficacy in reduction of number of wet nights compared to a control group. Ronen et al. [
      • Ronen T.
      • Rahav G.
      • Wozner Y.
      Self-control and enuresis.
      ] combined cognitive treatment to increase self-control of the child and retention control training. It was compared to positive reinforcement in 77 children with PNE and they reported a reduction in number of wet nights of respective 89% (cognitive treatment and retention control training) and 82% (positive reinforcement). Both results were significantly different from a control group. Van Dommelen et al. [
      • van Dommelen P.
      • Kamphuis M.
      • van Leerdam F.J.
      • de Wilde J.A.
      • Rijpstra A.
      • Campagne A.E.
      • et al.
      The short- and long-term effects of simple behavioral interventions for nocturnal enuresis in young children: a randomized controlled trial.
      ] randomized 570 children with MNE into four groups with different interventions which were lifting the child during the nights with and without a password (the child needed to say a password to ensure the child was awake), using a reward system, and a control group. They reported that lifting without a password was the only intervention leading to significant improvement compared to the control group (37% vs. 21% with complete response). Van Hoeck et al. found holding exercises to significantly increase bladder capacity in children with MNE, however, only 3% became dry [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ].

      Discussion

      This systematic review presents available literature regarding the use of standard urotherapy in the treatment of children with PNE. Even though many international guidelines consider urotherapy as first line treatment of NE and urotherapy is widely used, most high-quality studies reported low efficacy rates when evaluating complete response and reduction in number of wet nights. Our findings are in line with the 2013 Cochrane review by Cadwell et al. [
      • Caldwell P.H.
      • Nankivell G.
      • Sureshkumar P.
      Simple behavioural interventions for nocturnal enuresis in children.
      ,
      • Huang T.
      • Shu X.
      • Huang Y.S.
      • Cheuk D.K.
      Complementary and miscellaneous interventions for nocturnal enuresis in children.
      ]. The Cadwell review was performed before the new ICCS standardization [
      • Austin P.F.
      • Bauer S.B.
      • Bower W.
      • Chase J.
      • Franco I.
      • Hoebeke P.
      • et al.
      The standardization of terminology of lower urinary tract function in children and adolescents: update report from the Standardization Committee of the International Children's Continence Society.
      ] thereby using the term “behavioral interventions” and only RCTs were included. The added value of this systematic review is the inclusion of articles published after 2013 (including high quality studies) together with inclusion of both interventional and observational designs. This can be important in a research area where only few high-quality studies are available.
      One possible explanation behind the main finding of low efficacy rates of urotherapy in NE is the large heterogeneity of the study populations. Many of the included studies were published before the ICCS introduced the subdivision of NE into MNE and non-MNE (NMNE) [
      • Neveus T.
      • Eggert P.
      • Evans J.
      • Macedo A.
      • Rittig S.
      • Tekgul S.
      • et al.
      Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children's Continence Society.
      ], and before the general acceptance of targeting therapy towards the underlying pathophysiology, e.g. nocturnal polyuria and reduced functional bladder capacity. Standard urotherapy as defined by the ICCS [
      • Austin P.F.
      • Bauer S.B.
      • Bower W.
      • Chase J.
      • Franco I.
      • Hoebeke P.
      • et al.
      The standardization of terminology of lower urinary tract function in children and adolescents: update report from the standardization committee of the International Children's Continence Society.
      ] includes many different elements. Most of the included studies in this review combined two or more urotherapy modalities, which makes it difficult to ascertain the value of specific elements and which underlying pathophysiologic mechanisms are targeted. Urotherapy has proven efficacy in the treatment of DI and urgency [
      • Schafer S.K.
      • Niemczyk J.
      • von Gontard A.
      • Pospeschill M.
      • Becker N.
      • Equit M.
      Standard urotherapy as first-line intervention for daytime incontinence: a meta-analysis.
      ], and therefore it is hypothesized that urotherapy is more effective in children with NMNE, where bladder dysfunction is part of the pathophysiology. However, other elements of urotherapy such as fluid restriction during the evening could be more effective in the subpopulation of children with underlying nocturnal polyuria [
      • Rittig S.
      • Knudsen U.B.
      • Norgaard J.P.
      • Pedersen E.B.
      • Djurhuus J.C.
      Abnormal diurnal rhythm of plasma vasopressin and urinary output in patients with enuresis.
      ]. If we look into studies including children with LUTS, Im et al. [
      • Im Y.J.
      • Lee J.K.
      • Park K.
      Time course of treatment for primary enuresis with overactive bladder.
      ] treated 111 children with overactive bladder and NE with standard urotherapy according to the ICCS guidelines for one month combined with treatment of constipation. Although none of these children experienced complete response at the end of treatment, urgency improved more quickly than NE. Hamano et al. found daytime functional bladder capacity to be a valuable negative predictor of response to DDAVP, but not of response to urotherapy when combining positive reinforcement, fluid restriction, and retention control training [
      • Hamano S.
      • Yamanishi T.
      • Igarashi T.
      • Ito H.
      • Murakami S.
      Functional bladder capacity as predictor of response to desmopressin and retention control training in monosymptomatic nocturnal enuresis.
      ]. If we then look into studies evaluating urotherapy in the treatment of children without LUTS (MNE according to the ICCS criteria), eight of nine studies reported that less than one third of the children achieved complete response [
      • Van Hoeck K.J.
      • Bael A.
      • Van Dessel E.
      • Van Renthergem D.
      • Bernaerts K.
      • Vandermaelen V.
      • et al.
      Do holding exercises or antimuscarinics increase maximum voided volume in monosymptomatic nocturnal enuresis? A randomized controlled trial in children.
      ,
      • van Dommelen P.
      • Kamphuis M.
      • van Leerdam F.J.
      • de Wilde J.A.
      • Rijpstra A.
      • Campagne A.E.
      • et al.
      The short- and long-term effects of simple behavioral interventions for nocturnal enuresis in young children: a randomized controlled trial.
      ,
      • Kahan E.
      • Morel D.
      • Amir J.
      • Zelcer C.
      A controlled trial of desmopressin and behavioral therapy for nocturnal enuresis.
      ,
      • Hamano S.
      • Yamanishi T.
      • Igarashi T.
      • Ito H.
      • Murakami S.
      Functional bladder capacity as predictor of response to desmopressin and retention control training in monosymptomatic nocturnal enuresis.
      ,
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ,
      • Oliveira L.F.
      • Oliveira D.M.
      • Paula L.I.S.
      • Chaoubah A.
      • Figueiredo A.A.
      • Barroso U.O.
      • et al.
      Para-sacral transcutaneous electrical neural stimulation (PSTENS) in children with monosymptomatic enuresis.
      ,
      • Elsayed E.R.
      • Abdalla M.M.
      • Eladl M.
      • Gabr A.
      • Siam A.G.
      • Abdelrahman H.M.
      Predictors of severity and treatment response in children with monosymptomatic nocturnal enuresis receiving behavioral therapy.
      ,
      • Tkaczyk M.
      • Maternik M.
      • Krakowska A.
      • Wosiak A.
      • Miklaszewska M.
      • Zachwieja K.
      • et al.
      Evaluation of the effect of 3-month bladder basic advice in children with monosymptomatic nocturnal enuresis.
      ]. When evaluating predictive factors for response to urotherapy, studies report gender (males), maternal education level, NE frequency [
      • Ma Y.
      • Liu X.
      • Shen Y.
      Effect of traditional Chinese and Western medicine on nocturnal enuresis in children and indicators of treatment success: randomized controlled trial.
      ], and absence of overweight and obesity [
      • Ma Y.
      • Shen Y.
      • Liu X.
      Association between enuresis and obesity in children with primary monosymptomatic nocturnal enuresis.
      ] to influence response. Lester et al. found the efficacy of urotherapy to be age dependent, and report a higher compliance and a higher response rate in older children [
      • Iester A.
      • Marchesi A.
      • Cohen A.
      • Iester M.
      • Bagnasco F.
      • Bonelli R.
      Functional enuresis: pharmacological versus behavioral treatment.
      ].
      One can argue that the intervention period can have an impact on the outcome. When evaluating the three highlighted RCT studies, the duration of intervention in the study by Cederblad et al. [
      • Cederblad M.
      • Sarkadi A.
      • Engvall G.
      • Nevéus T.
      No effect of basic bladder advice in enuresis: a randomized controlled trial.
      ] was 1 month and the study reported 5% of children achieving complete response, compared to 2 months of intervention in the study by Kajbafzadeh et al. [
      • Kajbafzadeh A.M.
      • Sharifi-Rad L.
      • Mozafarpour S.
      • Ladi-Seyedian S.S.
      Efficacy of transcutaneous interferential electrical stimulation in treatment of children with primary nocturnal enuresis: a randomized clinical trial.
      ] and Hascicek et al. [
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ], who reported 25% and 30% of children obtaining complete response. Also, the intensity of the interventions might affect the response. Hascicek et al. found that complete response to urotherapy was improved significantly to a level comparable with DDAVP treatment if a written checklist of behavioral instructions was offered to the parents of children with PMNE [
      • Hascicek A.M.
      • Kilinc M.F.
      • Yildiz Y.
      • Yuceturk C.N.
      • Doluoglu O.G.
      A new checklist method enhances treatment compliance and response of behavioural therapy for primary monosymptomatic nocturnal enuresis: a prospective randomised controlled trial.
      ], which should intensify the urotherapy treatment. Mattsson et al. invited 200 children with bladder dysfunction and incontinence to participate in voiding schools in small groups, which is a multidisciplinary combined in- and outpatient bladder rehabilitation program for children with urinary incontinence. They reported significant improvement in both DI and NE [
      • Glad Mattsson G.
      • Brännström M.
      • Eldh M.
      • Mattsson S.
      Voiding school for children with idiopathic urinary incontinence and/or bladder dysfunction.
      ]. This might indicate that an intense regimen is needed to experience improvements in symptoms, which could also be the case with DBT where some studies report good results.
      Most of the included studies evaluate urotherapy as an independent treatment. A recently performed RCT including 60 treatment-naïve children with PNE and without DI compared 1) a strict drinking and voiding regimen and optimal toilet posture, 2) an alarm, and 3) a control group. They concluded that standard urotherapy was ineffective as first-line treatment [
      • Borgström M.
      • Bergsten A.
      • Tunebjer M.
      • Hedin Skogman B.
      • Nevéus T.
      Daytime urotherapy in nocturnal enuresis: a randomised, controlled trial.
      ]. Currently, ICCS recommends characterization of the individual child before start of treatment of NE often including diaries of drinking and voiding habits [
      • Neveus T.
      • Eggert P.
      • Evans J.
      • Macedo A.
      • Rittig S.
      • Tekgul S.
      • et al.
      Evaluation of and treatment for monosymptomatic enuresis: a standardization document from the International Children's Continence Society.
      ]. If these diaries show abnormal patterns, one can expect that advice is given together with start of alarm or DDVAP, because of safety regarding DDAVP and with the aim of increasing the efficacy of treatment. Urotherapy as positive reinforcement and education could also be important for the child's experience of treatment and factors such as self-esteem and adherence to treatment. Urotherapy might be more efficient as an add-on to other first line treatments instead of an independent intervention. Furthermore, registration of symptoms can be important for evaluation of response to other treatments. Low cost and no risk for the child are benefits for choosing urotherapy as first treatment.
      Some important limitations of this study are as mentioned the large heterogeneity of included study populations partly due to different terminologies, as well as a variability in combinations of interventions, which makes a comparison of the studies difficult. Furthermore, reporting bias of response is a limitation. According to the QualSyst Checklist (Table 1), many studies are of poor scientific quality. Only studies in English, German, and Dutch were included, which could possibly lead to a certain amount of bias.

      Conclusions

      This systematic review presents available literature in the area and is the first evaluation of evidence since the current ICCS terminology was introduced. Many studies are of poor scientific quality, and the large heterogeneity of included studies made comparisons and conclusions difficult. High quality studies present limited efficacy of urotherapy in the treatment of NE. However, interventions like education, registration of symptoms, and support and encouragement might be important for the efficacy of other treatments.
      We conclude that at present there is insufficient evidence for offering standard urotherapy to children with NE as first line treatment modality. This review highlights the need for high quality RCTs in well-characterized patient populations to clarify whether specific elements of urotherapy are effective in subgroups of children with NE or could play a role as add-on therapy to existing evidence-based treatment options.

      Source of funding

      No grants or financial support has been received.
      Each author listed on the manuscript has seen and approved the submission of this version of the manuscript and takes full responsibility for the manuscript.

      Conflict of interest

      The authors declare that there is no conflict of interests regarding the publication of this paper.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article.

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