Abstract
Introduction
Nocturnal enuresis affects 15−20% of 5-year-old children, 5% of 10 year-old-children and 1−2% of people aged 15 years and over. Without treatment, 15% of affected children will become dry each year. Nocturnal enuresis is not diagnosed in children younger than 5 years, and treatment may be inappropriate for children younger than 7 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of interventions for relief of symptoms? We searched: Medline, Embase, The Cochrane Library and other important databases up to March 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, anticholinergics (oxybutynin, tolterodine, hyoscyamine), desmopression, dry bed training, enuresis alarm, hypnotherapy, standard home alarm clock, tricyclics (imipramine, desipramine).
Key Points
Nocturnal enuresis affects 15−20% of 5-year-old children, 5% of 10-year-old children, and 1−2% of people aged 15 years and over. Without treatment, 15% of affected children will become dry each year.
Nocturnal enuresis is not diagnosed in children younger than 5 years, and treatment may be inappropriate for children younger than 7 years.
Enuresis alarms increase the number of dry nights compared with no treatment, and may be more effective than tricyclic drugs at reducing treatment failure and relapse.
Combining the use of alarms with dry bed training may increase the number of dry nights, but we don't know whether adding tricyclic drugs to alarms is also beneficial.
We don't know whether using an alarm clock set to wake the child before the time of likely enuresis is more likely to lead to dry nights compared with waking every 3 hours.
Desmopressin and tricyclic drugs reduce the number of wet nights compared with placebo, but they seem not to be effective once treatment is discontinued, and they can cause adverse effects which, in the case of tricyclic drugs, include potentially fatal overdose.
We don't know whether desmopressin is more or less effective at reducing wet nights than tricyclic drugs or enuresis alarms.
An alert has been issued in the UK regarding rare but serious adverse effects including hyponatraemia, water intoxication, and convulsions associated with desmopressin nasal spray, and the primary nocturnal enuresis indication has been withdrawn from the nasal spray in the UK.
We don't know whether dry bed training, anticholinergic drugs,acupuncture or laser acupuncture,or hypnotherapy are effective at increasing dry nights, or how they compare with other treatments.
About this condition
Definition
Nocturnal enuresis is the involuntary discharge of urine at night in a child aged 5 years or older in the absence of congenital or acquired defects of the central nervous system or urinary tract. Disorders that have bedwetting as a symptom (termed "nocturnal incontinence") can be excluded by a thorough history, examination, and urinalysis. "Monosymptomatic" nocturnal enuresis is characterised by night time symptoms only and accounts for 85% of cases. Nocturnal enuresis is defined as primary if the child has not been dry for a period of more than 6 months, and secondary if such a period of dryness preceded the onset of wetting. Most management strategies are aimed at children aged 7 years and older.
Incidence/ Prevalence
Between 15% and 20% of 5-year-olds, 7% of 7-year-olds, 5% of 10-year-olds, 2-3% of 12-14-year-olds, and 1-2% of people aged 15 years and over wet the bed twice a week on average.
Aetiology/ Risk factors
Nocturnal enuresis is associated with several factors, including small functional bladder capacity, nocturnal polyuria, and, most commonly, arousal dysfunction. Linkage studies have identified associated genetic loci on chromosomes 8q, 12q, 13q, and 22q11.
Prognosis
Nocturnal enuresis has widely differing outcomes, from spontaneous resolution to complete resistance to all current treatments. About 1% of children remain enuretic until adulthood. Without treatment, about 15% of children with enuresis become dry each year. We found no RCTs on the best age at which to start treatment in children with nocturnal enuresis. Anecdotal experience suggests that reassurance is sufficient below the age of 7 years. Behavioural treatments, such as moisture or wetting alarms, require motivation and commitment from the child and a parent. Anecdotal experience suggests that children under the age of 7 years may not exhibit the commitment needed.
Aims of intervention
To stay dry on particular occasions (e.g. when visiting friends); to reduce the number of wet nights; to reduce the impact of the enuresis on the child's lifestyle; to initiate successful continence; to avoid relapse, with minimal adverse effects.
Outcomes
Rate of initial success (defined as 14 consecutive dry nights); average number of wet nights a week; number of relapses after initial success; average number of wet nights after treatment has ceased.
Methods
BMJ Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this review: Medline 1966 to March 2007, Embase 1980 to March 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for assessment in this chapter were: published systematic reviews and RCTs in any language, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the chapter as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for Nocturnal enuresis
| Important outcomes | Reduction of enuresis, relapse rates, treatment success, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of interventions for relief of symptoms of nocturnal enuresis? | |||||||||
| 23 (1427) | Reduction of enuresis | Desmopressin v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for poor methodology |
| 4 (331) | Reduction of enuresis | Desmopressin v tricyclics | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for poor methodology. Consistency point deducted for conflicting results |
| 4 (320) | Reduction of enuresis | Desmopessin v enuresis alarm | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for poor methodology. Consistency point deducted for conflicting results |
| 10 (771) | Reduction of enuresis | Desmopessin plus enuresis alarm v alarm alone | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results, and methodological flaws. Consistency point deducted for conflicting results |
| 6 (391) | Relapse rate | Desmopressin plus enuresis alarm v alarm alone | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for incomplete reporting of results and methodological flaws. Consistency point deducted for conflicting results |
| 1 (55) | Reduction of enuresis | Desmopressin v conditioning therapy | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 8 (2210) | Reduction of enuresis | Low v high doses of desmopressin | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for poor methodology |
| 4 (?) | Relapse rate | Desmopressin v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for poor methodology |
| 2 (119) | Relapse rate | Desmopessin v enuresis alarm | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for poor methodology and sparse data |
| 3 (144) | Reduction of enuresis | Dry bed training v no treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (144) | Relapse rate | Dry bed training v no treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (?) | Reduction of enuresis | Dry bed training v enuresis alarm | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (40) | Relapse rate | Dry bed training v enuresis alarm | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (144) | Reduction of enuresis | Enuresis alarm plus dry bed training v no treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (80) | Relapse rate | Enuresis alarm plus dry bed training v no treatment | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 7 (277) | Reduction of enuresis | Enuresis alarm plus dry bed training v alarm alone | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (152) | Relapse rate | Enuresis alarm plus dry bed training v alarm alone | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 17 (?) | Reduction of enuresis | Enuresis alarm v no treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 5 (?) | Relapse rate | Enuresis alarm v no treatment | 4 | 0 | 0 | 0 | 0 | High | |
| 3 (?) | Reduction of enuresis | Enuresis alarm v tricyclics | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (24) | Relapse rate | Enuresis alarm v tricyclics | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 2 (145) | Reduction of enuresis | Enuresis alarm plus tricyclic drugs v alarm | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 2 (145) | Relapse rate | Enuresis alarm plus tricyclic drugs v alarm | 4 | –2 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data and incomplete reporting of results. Consistency point deducted for conflicting results |
| 15 (1179) | Reduction of enuresis | Tricyclic v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 4 (392) | Relapse rate | Tricyclic v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (?) | Reduction of enuresis | Tricyclics plus anticholinergic v placebo | 4 | 0 | 0 | 0 | 0 | High | |
| 1 (30) | Reduction of enuresis | Anticholinergic v placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (111) | Reduction of enuresis | Acupuncture v sham acupuncture | 4 | –3 | 0 | 0 | 0 | Very low quality | Quality points deducted for sparse data, allocation and blinding flaws |
| 1 (40) | Reduction of enuresis | Laser acupuncture v desmopressin | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (125) | Reduction of enuresis | Standard home alarm clock v routine waking | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (125) | Relapse rate | Standard home alarm clock v routine waking | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (48) | Reduction of enuresis | Hypnotherapy v no treatment | 4 | –3 | –1 | 0 | 0 | Very low | Quality points deducted for sparse data, baseline differences, incomplete reporting of results and uncertainty about randomisation. Consistency point deducted for conflicting results |
Type of evidence: 4 = RCT; 2 = Observational; 1 = Non-analytical/expert opinion. Consistency: similarity of results across studies. Directness: generalisability of population or outcomes. Effect size: based on relative risk or odds ratio.
Glossary
- Dry bed training
A multicomponent behavioural programme for treatment of nocturnal enuresis in children. Elements of the programme are directed at increasing bladder capacity, strengthening the sphincter, and encouraging rapid movement from bed to toilet.
- High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
References
- 1.Forsythe WI, Butler R. 50 years of enuretic alarms; a review of the literature. Arch Dis Child 1991;64:879–885. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Blackwell C. A guide to enuresis: a guide to treatment of enuresis for professionals. Bristol: Eric, 1989. [Google Scholar]
- 3.Eiberg H. Total genome scan analysis in a single extended family for primary nocturnal enuresis: evidence for a new locus (ENUR 3) for primary nocturnal enuresis on chromosome 22q11. Eur Urol 1998;33:34–36. [DOI] [PubMed] [Google Scholar]
- 4.Eiberg H. Nocturnal enuresis is linked to a specific gene. Scand J Urol Nephrol 1995;173(suppl):15–17. [PubMed] [Google Scholar]
- 5.Arnell H, Hjalmas M, Jagervall G, et al. The genetics of primary nocturnal enuresis: inheritance and suggestion of a second major gene on chromosome 12q. J Med Genet 1997;34:360–365. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Eiberg H, Berendt I, Mohr J. Assignment of dominant inherited nocturnal enuresis (ENUR 1) to chromosome 13q. Nat Genet 1995;10:354–356. [DOI] [PubMed] [Google Scholar]
- 7.Forsythe WI, Redmond A. Enuresis and spontaneous cure rate of 1129 enuretics. Arch Dis Child 1974;49:259–263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Glazener CMA, Evans JHC. Desmopressin for nocturnal enuresis in children. In: The Cochrane Library, Issue 1, 2007. Chichester, UK: John Wiley & Sons. Search date 2006; primary sources Medline, Embase, Amed, Assia, Bids, Cinahl, Psychlit, Sigle, and Department of Health and Social Services (DHSS) data. [Google Scholar]
- 9.Unüvar T, Sönmez F. The role of urine osmolality and ions in the pathogenesis of primary enuresis nocturna and in the prediction of responses to desmopressin and conditioning therapies. Int Urol Nephrol 2005;37:751–757. [DOI] [PubMed] [Google Scholar]
- 10.Muller D, Roehr CC, Eggert P. Comparative tolerability of drug treatments for nocturnal enuresis in children. Drug Safety 2004;27:717–727. [DOI] [PubMed] [Google Scholar]
- 11.Robson WL, Leung AK. Side effects and complications of treatment with desmopressin for enuresis. J Natl Med Assoc 1994;86:775–778. [PMC free article] [PubMed] [Google Scholar]
- 12.Naitoh Y, Kawauchi A, Yamao Y, et al. Combination therapy with alarm and drugs for monosymptomatic nocturnal enuresis not superior to alarm monotherapy. Urology 2005;66:632–635. [DOI] [PubMed] [Google Scholar]
- 13.Glazener CMA, Evans JHC, Peto RE. Complex behavioural and educational interventions for nocturnal enuresis in children. In: The Cochrane Library, Issue 1, 2007. Chichester, UK: John Wiley & Sons. Search date 2005; primary sources Medline, Cinahl, and Cochrane Central Register of Controlled Trials. [Google Scholar]
- 14.Glazener CMA, Evans JHC, Peto RE. Alarm interventions for nocturnal enuresis in children. In: The Cochrane Library, Issue 1, 2007. Chichester, UK: John Wiley & Sons. Search date 2004; primary sources Medline, Cinahl, and Cochrane Central Register of Controlled Trials. [Google Scholar]
- 15.Glazener CMA, Evans JHC, Peto RE. Tricyclic and related drugs for nocturnal enuresis in children. In: The Cochrane Library, Issue 1, 2007. Chichester, UK: John Wiley & Sons. Search date 2005, primary sources Medline, Cinahl, and Cochrane Central Register of Controlled Trials. [Google Scholar]
- 16.Glazener CMA, Evans JHC, Peto RE. Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics). In: The Cochrane Library, Issue 1, 2007. Chichester, UK: John Wiley & Sons. Search date 2005; primary sources Medline, Cinahl, and Cochrane Central Register of Controlled Trials. [Google Scholar]
- 17.Rushton HG, Belman AB, Zaontz MR, et al. The influence of small functional bladder capacity and other predictors on the response of desmopressin in the management of monosymptomatic nocturnal enuresis. J Urol 1996;156:651–655. [DOI] [PubMed] [Google Scholar]
- 18.Glazener CM, Evans JH, Cheuk DK. Complementary and miscellaneous interventions for nocturnal enuresis in children. In: The Cochrane Library, Issue 1, 2007. Chichester, UK: John Wiley & Sons. Search date 2004; primary sources Medline, Cinahl, and Cochrane Central Register of Controlled Trials. [Google Scholar]
- 19.Radmayr C, Schlager A, Studen M, et al. Prospective randomised trial using laser acupuncture versus desmopressin in the treatment of nocturnal enuresis. Eur Urol 2001;40:201–205. [DOI] [PubMed] [Google Scholar]
- 20.El-Anany FG, Maghraby HA, Shaker SED, et al. Primary nocturnal enuresis: a new approach to conditioning treatment. Urology 1999;53:405–409. [DOI] [PubMed] [Google Scholar]
- 21.Edwards SD, van der Spuy HI. Hypnotherapy as a treatment for enuresis. J Child Psychol Psychiat 1985;26:161–170. [DOI] [PubMed] [Google Scholar]
