significant urological concern prevalent

Introduction
Nocturnal enuresis [NE], commonly known as bedwetting, is a significant urological concern
prevalent among children (Keten et al., 2020). NE is defined as the inappropriate repeated
voiding of urine during periods of sleep at least twice a week, for periods longer than three
consecutive months in children of chronological age five years or over (American Psychiatric
Association [APA], 2022). Monosymptomatic NE (MNE) is a term used clinically to
differentiate children presenting with nocturnal incontinence without lower urinary tract
symptoms, such as diurnal incontinence and polyuria (APA, 2022; Keten et al., 2020).
Prevalence of MNE varies; decreasing with age, it affects 15% of children at age five, 5% at
age ten and 1 to 2% at ages 15 years and older. Most concerningly, 7% of children diagnosed
with MNE will remain nocturnally incontinent into adulthood (Keten et al., 2020; Tu & Baskin,
2020). The uncontrollable nature of MNE means the elimination disorder is strongly
associated with adverse psychosocial childhood development as the symptoms foster feelings
of shame and embarrassment, significantly impacting psychological, social, and emotional
well-being. Thus, prompt treatment and intervention are essential in preventing and reducing
the impact of this significant health concern (Keten et al., 2020; Pedersen et al., 2020; Perrin
et al., 2015). The preferred first-line treatment modalities include non-pharmacological
bedwetting alarm therapy and pharmacological therapy using the synthetic vasopressin
analogue drug desmopressin (Tu & Baskin, 2020). The comparable efficacy of each modality
for successful MNE treatment is unclear (Peng et al., 2018). Therefore, this annotated
bibliography will evaluate four research articles discussing the two first-line treatment
modalities to answer the research question “
In children diagnosed with MNE, will alarm
therapy, compared to desmopressin, be more effective in producing a treatment response and
reducing symptoms?”
.
Annotated Bibliography
Keten, T., Aslan, Y., Balci, M., Erkan, A., Senel, C., Oguz, U., Kayali, M., Guzel, O., Karabulut, E.,
& Tuncel, A. (2020). Comparison of the efficacy of desmopressin fast-melting formulation and
enuretic alarm in the treatment of monosymptomatic nocturnal enuresis.
Journal of Paediatric
Urology, 16
, 645.e1 – 645.e7. https://doi.org/10.1016/j.jpurol.2020.07.018
Keten et al. (2020) undertook a quantitative study design to compare the efficacy of
desmopressin and alarm therapy amongst patients with MNE. A small sample size of 130
mixed-sex patients with primary MNE from sixty-eight boys and sixty-two girls within an
outpatient clinic was sourced. A detailed history and physical examination were completed
for each participant to exclude those with a previous history of treatment or other forms of
enuresis. Two randomised control groups were established from the sample using the flip of
a coin, group 1 using desmopressin MELT with a mean age of 11.2, and group 2 using an
enuresis alarm with a mean age of 10.2. A follow-up during the trial’s fourth, 12th and 24th
week measured each participant for efficacy and progress.
Results quantified a <50% reduction of wet nights as no response to treatment, a 50 to 99%
reduction as a partial response, and no wet nights as a complete response. Statistical analysis
compared the categorical values with a P-value of <0.05, considered statistically significant.
Overall response rates were evaluated in the 24
th week, finding that the alarm group had a
statistically significantly higher success rate than the desmopressin group with a P-value of
0.035, which answers the researcher’s question. However, concluded with only 120
participants as exclusions occurred due to lack of follow-up.
There are several strengths to this study; it is highly relevant as it compares the efficacy and
treatment response of the two modalities and is of currency, thus is beneficial for inclusion in
determining evidence-based practice. Furthermore, it includes a statistical analysis, which
ascertains the homogeneity of the participants and the rigour and quality of the overall result.
However, the limitations outweighed the strengths. The selection of the sample participants
was not blind nor randomised, which significantly increases the risk of selection bias within
this research. Secondly, the lower hierarchy of evidence and small sample size reduces the
applicability for generalisation amongst the MNE population. Other limitations included
attrition bias, with 14.3% exclusion occurring within only one of the control groups and the
monitoring method of participants not being addressed, meaning the adherence of each
control group is unknown. Overall, the research is of some benefit to clinical practice, but it
does not provide enough weight alone to develop an evidence-based answer for the posed
research question.

Peng, C. C., Yang, S. S., Austin, P. F., & Chang, S. J. (2018). Systematic Review and Meta-analysis
of Alarm versus Desmopressin Therapy for Pediatric Monosymptomatic Enuresis.
Scientific
Reports, 8
(16755), 1-10. https://doi.org/10.1038/s41598-018-34935-1
Peng et al. (2018) undertook a quantitative study to compare the efficacy of enuresis alarm
versus desmopressin therapy in producing initial long-term response and relapse rates in
managing MNE in children. The study design was conducted by performing multiple database
searches for randomised controlled trial (RCT) studies that compared the efficacy of the two
treatment modalities within MNE. The dates of inclusion were broad, and a total of 15 RCTs
were included within the research after independent evaluation. The pooled participant base
included 1502 children aged 5 to 16 (935 boys, 469 girls). However, three of the included
studies did not include gender.
The results concluded that the desmopressin therapy significantly underperformed in eliciting
a partial response rate when compared to alarm therapy, with a P-value of 0.03 and a 95%
(1.05 to 2.23) confidence interval (CI) for per-protocol (PP) analysis. However, the intentionto-treat (ITT) analysis determined that no significant difference existed in eliciting a complete
response rate. Alarm therapy was also found more efficacious for sustained response rates
and reduced relapse rates, with a CI of 95% (1.38 to 6.0). Although the dropout rates were
much lower for desmopressin therapy (<10%), they were statistically significant with a CI of
95% (3.41 to 4.29). Overall, the results answer the research aim by concluding that alarm
therapy is more effective in managing MNE due to the higher sustained response rate and
lower rate of relapse associated with the treatment.
There are more strengths than limitations within this study; it is of the most robust hierarchal
evidence, as it is a systematic review and meta-analysis, meaning the overall sensitivities of
the sample studies were measured and weighed against each other, increasing the likelihood
of an absolute result. Secondly, it focuses on comparing the two treatment modalities that
are the focus of the research question. The large sample size and homogeneity amongst
included studies make this study suitable for generalisation in the population of children with
MNE. The limitations include the heterogeneity between the inclusion and exclusion criteria.
Heterogeneity increases the risk for allocation, attrition, and sampling bias and reduces the
probability of an accurate comparison. Peng et al. (2018) addressed the heterogeneity, stating
that at least half of the included studies were classified as low risk, the total effect must still

be considered. Overall, it is relevant to the research question posed, providing the answer
that alarm therapy is most effective for MNE, which will help determine the best evidencebased clinical practice.
Perrin, N., Sayer, L., & White, A. (2015). The efficacy of alarm therapy versus desmopressin
therapy in the treatment of primary mono-symptomatic nocturnal enuresis: a systematic
review.
Primary Health Care Research & Development, 16, 21-31.
https://doi.org/10.1017/S146342361300042X
Perrin et al. (2015) completed a quantitative study comparing the efficacy of alarm therapy
and desmopressin therapy in treating primary MNE. The study design involved a stringent
search of five databases for RCTs occurring before 2011 that compared the two treatment
modalities. Strict inclusion/ exclusion criteria were applied; the population of studies must be
children 5-17 years of age, written in English and focused on primary MNE; secondary enuresis
and other treatment comparisons were excluded. The quality assessment further excluded
studies that did not meet the design, data analysis and interpretation criteria. The final pooled
sample of RCTs included eight studies of variable strengths and quality, two of which were
rated weak due to meeting less of the criteria and having a low level of quality; however,
Perrin et al. (2015) noted inclusion was justified by the limited number of studies available
that met the topic requirements.
Several studies had similar findings with no statistical difference in MNE improvement. One
study, however, reported substantial improvement with alarm therapy of statistical
significance (P=0.02). Furthermore, the studies which included follow-up consults reported
statistical significance in improvement between the two groups, with desmopressin
producing more significant rates of relapse (P=<0.01 to P=0.0007). Two studies found alarm
therapy was associated with higher attrition rates (58%) than the desmopressin therapy
groups (44%). Reasons reported for the higher rate of attrition with alarm therapy were
feelings of anxiety, the alarm noise and inconvenience. The study answered the research aim,
with Perrin et al. (2015) concluding that alarm therapy was more effective than desmopressin
in eliciting treatment response for MNE. However, motivated patients and family networks
are required to mitigate the associated treatment attrition rate.

This systematic review has several strengths. It is of the highest hierarchical evidence level;
thus, it is of superior rigour and more likely to minimise the effect of bias. Secondly, this study
design incorporated strict selection criteria for research articles, ensuring the sample research
was highly relevant to the researcher’s aim. However, limitations relating to methodological
issues were also paramount. Firstly, the rigour and strengths of each study varied, with some
identified as weak because of their small sample sizing, limited follow-ups, and shorter
intervention periods. Perrin et al. (2015) identified significant heterogeneity as a barrier,
preventing a meta-analysis because each study uses different parameters to define the
success of treatment and significant variation in the randomisation, population, compliance
indicators, and date ranges present. A meta-analysis would have improved the ascertainment
of the results.
Overall, it applies to the research question. However, results must be considered cautiously
due to the limitations and heterogeneity present. Thus, more robust evidence is required to
ascertain the quality of the results and support an evidence-based answer regarding the
efficacy of each treatment choice for clinical practice.
Song, P., Huang, C., Wang, Y., Wang, Q., Zhu, W., Yue, Y., . . . Wen, J. (2019). Comparison of
desmopressin, alarm, desmopressin plus alarm, and desmopressin plus anticholinergic agents
in the management of paediatric monosymptomatic nocturnal enuresis: a network metaanalysis.
BJU International, 123, 388-400. https://doi.org/10.1111/.14539
Song et al. (2019) conducted quantitative research to compare the efficacy of desmopressin
plus alarm therapy against desmopressin plus anticholinergic agents in managing childhood
MNE. Protocol included searches of five databases for RCTs comparing desmopressin, alarm
therapy and combination treatment using anticholinergic agents using Medical Subject
Heading terms and a series of relative synonyms to source articles from inception to 2018.
Two researchers conducted searches independently, verifying eligibility through endnote
software and removing irrelevant articles on review of title and abstracts. The Cochrane
Handbook for Systematic Reviews Interventions and the International Children’s Continence
Society were used to assess methodological quality and define the evaluated outcomes for
meta-analysis. The Cochrane Collaboration tool for risk-of-bias assessment assessed the
included trials’ quality, resulting in the final pooling of eighteen included studies, including
the direct comparisons of desmopressin vs alarm therapy.

Pooled estimates found that success rates for combination therapies were higher than the
two monotherapies: desmopressin (95% CI, 0.11, 0.62) ranking third and alarm ranking fourth
(95% CI, 0.13, 0.61). Rank probabilities were higher for alarm monotherapy for the mean
number of wet nights per week, with alarm ranking second (83.1%). The relapse rates
associated with the two monotherapies were lower than combination therapies. Alarm
therapy is associated with a lower relapse rate than desmopressin groups (95% CI 0.029,
0.53). Song et al. (2019) concluded that the efficacy of alarm therapy is higher than
desmopressin therapy; however, it is associated with poor adherence and higher rates of
attrition. Desmopressin produces a higher response rate but is associated with high relapse
rates. Combination therapy with desmopressin and anticholinergic agents produces higher
success rates; however, it is not statistically significant. Thus, the results answer the aim.
There are several strengths. The evidence hierarchy is superior and is of currency for use in
clinical practice. Study protocol was rigorous, minimising publication and selection bias.
However, several flaws in the protocol also present significant limitations. Firstly, the
exclusion and inclusion criteria are unclear; thus, heterogeneity among included studies and
their methodology is substantial; despite using the random-effects model. High heterogeneity
leads to uncertainty about the quality of the evidence provided. The variability in protocol of
the included samples increases the presence of insufficient statistical power. Further, it did
not solely focus on comparisons between the two treatment modalities; thus, reduced
relevance and increased measurement bias are of concern. The hierarchy, currency and rigour
are strong; however, heterogeneity reduces applicability for clinical practice as the results of
this study are statistically unstable for generalisation in larger population groups.
Literature Evaluation
The substantial body of evidence provided by Keten et al. (2020), Peng et al. (2018), Perrin et
al. (2015) and Song et al. (2019) provide a clear consensus that overall alarm therapy is more
efficacious in producing a sustained treatment response and managing symptoms of MNE
when compared to desmopressin therapy; despite the varied methodologies and aims within
each study.
However, high rates of attrition associated with alarm therapy were poignant within each
study, Peng et al. (2018) and Perrin et al. (2015) each emphasise concerns regarding the

higher rates of attrition associated with alarm therapy. Song et al. (2019) elaborate, stating
that alarm therapy is more effective in producing long-term results, but it is only possible with
adequate support from health professionals. Peng et al. (2018) and Perrin et al. (2015) also
suggest that tolerance assessment of both children and family is crucial in ensuring achieved
benefit. Peng et al. (2018) were superior regarding research rigour and quality; the systematic
review and meta-analysis aimed to address identified flaws within previous studies comparing
the two treatment modalities – it still failed to consider the implications of alarm variety. It is
essential to address the possible implications of alarm brand and quality within future
research, which undoubtedly would have contributed to higher attrition rates in some
instances; identical devices would increase ascertainment of the results. However, it is still
not enough to undermine the efficacy of alarm therapy found in each of the results.
Interestingly, Keten et al. (2020) found that higher relapse rates were associated with the
desmopressin control group. Perrin et al. (2015) concluded that four of the seven evaluated
studies found a statistically significant difference with a P-value range of 0.001 to 0.007, and
Peng et al. (2018) found a strong statistically significant result of P = 0.0001, adding further
weight to this finding. Perrin et al. (2015) raise a point of interest that addresses the
implication of the heterogeneity due to variation between desmopressin formulations used
within each study; whilst Keten et al. (2020) focused on fast-acting MELT formulations,
neither Peng et al. (2018) nor Song et al. (2019) addressed this as a limitation to within their
results.
Another consideration before considering these results for use in clinical practice is the
significant variation in severity of MNE experiences, as well as the age and sex of the individual
children. Song et al. (2019) expressed the point that MNE is a complex and multifactorial
illness; therefore, the same treatment may produce different results due to the diverse
aetiologies and severity of illness. Keten et al. (2020) also believe that urine production data
would elevate the results of future studies and express the lack of data as a limitation within
their research.
Thus, whilst the body of evidence supports alarm therapy has higher associated efficacy than
desmopressin therapy, further studies into the two treatment modalities for MNE are
required, as a homogeneous method that accounts for dosages and formulations of

desmopressin and utilises identical/ similar alarm devices, on samples of similar MNE severity
would substantially elevate and strengthen the ascertainment of these results.
Conclusion
Evidence within each of the annotated studies is clear; alarm therapy should be considered
more effective for clinical practice in treating and managing MNE in children. However,
success is dependent on adherence and motivation. Therefore, desmopressin provides a good
alternative when alarm therapy is deemed unsuitable. Further studies are required in MNE to
ensure evidence-based practice suitable for a broad range of MNE patients is developed.
Recommendations for future studies include incorporating a homogeneous approach with set
formulations of desmopressin and set alarm device type to reduce the heterogeneity and
increase the ascertainment that alarm therapy is, in fact, superior to desmopressin therapy.