desmopressin withdrawal strategy for pediatric enuresis: a ...2015, and an updated search was...

REVIEW ARTICLEPEDIATRICS Volume 138 , number 1 , July 2016 :e 20160495

Desmopressin Withdrawal Strategy for Pediatric Enuresis: A Meta-analysisMichael E. Chua, MD, DPBU, a, b, c Jan Michael Silangcruz, MD, a Shang-Jen Chang, MD, MsCE, b Katharine Williams, BSN, RN, c Megan Saunders, BSN, RN, c Roberto Iglesias Lopes, MD, PhD, c Walid A. Farhat, MD, FRCS, FAAP, c Stephen S. Yang, MD, PhDb

abstractCONTEXT: A high relapse rate after discontinuation of desmopressin treatment of pediatric

enuresis is consistently reported. Structured withdrawal strategies have been used to

prevent relapse.

OBJECTIVE: To assess the efficacy of a structured withdrawal strategy of desmopressin on the

relapse-free rate for desmopressin responder pediatric enuresis.

DATA SOURCES: Systematic literature search up to November 2015 on Medline, Embase, Ovid,

Science Direct, Google Scholar, Wiley Online Library databases, and related references

without language restriction.

STUDY SELECTION: Related clinical trials were summarized for systematic review. Randomized

controlled trials on the efficacy of structured versus abrupt withdrawal of desmopressin in

sustaining relapse-free status in pediatric enuresis were included for meta-analysis.

DATA EXTRACTION: Eligible studies were evaluated according to Cochrane Collaboration

recommendations. Relapse-free rate was extracted for relative risk (RR) and 95%

confidence interval (CI). Effect estimates were pooled via the Mantel–Haenszel method with

random effect model.

RESULTS: Six hundred one abstracts were reviewed. Four randomized controlled trials

(total 500 subjects) of adequate methodological quality were included for meta-analysis.

Pooled effect estimates compared with the abrupt withdrawal, structured withdrawal

results to a significantly better relapse-free rate (pooled RR: 1.38; 95% CI, 1.17–1.63; P =

.0001). Subgroup analysis for a dose-dependent structured withdrawal regimen showed a

significantly better relapse-free rate (pooled RR: 1.48; 95% CI, 1.21–1.80; P = .0001).

LIMITATIONS: The small number of studies included in meta-analysis represents a major

limitation.

CONCLUSIONS: Structured withdrawal of desmopressin results in better relapse-free rates.

Specifically, the dose-dependent structured withdrawal regimen showed significantly better

outcomes.

aInstitute of Urology, St Luke’s Medical Center, National Capital Region, Philippines; bDivision of Urology, Taipei Tzu Chi Hospital, Medical Foundation, New Taipei, Taiwan and Buddhist Tzu Chi

University, Hualien, Taiwan; cDivision of Urology, Department of Surgery, The Hospital for Sick Children, Toronto, Canada

Drs Chua and Silangcruz conceptualized and designed the study, data collection, and analysis and drafted the original manuscript; Dr Chang conceptualized and

designed the study and data analysis; Ms Williams and Ms Saunders performed data analysis and reviewed the manuscript; Dr Lopes performed data collection and

reviewed the manuscript; Dr Farhat carried out the initial analyses and reviewed and revised the manuscript; Dr Yang designed the data collection instruments,

coordinated and supervised data collection, and critically reviewed the manuscript; and all authors approved the fi nal manuscript as submitted.

This trial has been registered at the PROSPERO registry for systematic reviews (http:// www. crd. york. ac. uk/ PROSPERO) (identifi er CRD42015017895).

To cite: Chua ME, Silangcruz JM, Chang S, et al. Desmopressin Withdrawal Strategy for Pediatric Enuresis: A Meta-analysis. Pediatrics. 2016;138(1):e20160495

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CHUA et al

The International Children’s

Continence Society defines pediatric

enuresis as a symptom and condition

of incontinence among children ages

≥5 years that occurs exclusively

during sleeping periods, with >1

episode per month, and a frequency

of 3 episodes over 3 months.1 Based

on the previous literature, the

prevalence of enuresis in the general

pediatric population is 8% to 15%

in children age 6 years and ~2%

in adolescents.2–5 Desmopressin,

a vasopressin analog that reduces

urine production, is currently the

first-line pharmacologic agent

recommended for the treatment

of pediatric nocturnal enuresis.5

Treatment results with desmopressin

are favorable, with acceptable

adverse effects; however, as reported

by several studies, the relapse rate

is high.5, 6 Therefore, a structured

withdrawal (time dependent and

dose dependent) of desmopressin

therapy was being studied in

several retrospective studies.

Although these results showed that

structured withdrawal is more time

consuming and costly, a higher

clinical success rate was achieved.7–9

Despite its popularity, available

literature showed inconsistent

results when compared with abrupt

discontinuation of desmopressin.10–13

Therefore, there is an imminent need

to assess the clinical applicability

of structured desmopressin

withdrawal compared with abrupt

discontinuation. Our aim is to assess

the efficacy of different structured

withdrawal strategies and an abrupt

withdrawal strategy to prevent

relapse and sustain dry nights for

desmopressin-responsive patients

with pediatric nocturnal enuresis.

METHODS

The protocol of this meta-analysis

was made in consultation with a

topic expert and methodologist; it

was also registered in the PROSPERO

registry (CRD42015017895) and

complies with the recommendations

of Preferred Reporting Items for

Systematic Reviews and Meta-

Analyses statement.14 Meta-analysis

and risk of bias assessment were

performed according to the Cochrane

Collaboration recommendations.15

Identifi cation of the Literature

Two independent reviewers (M.E.C.

and J.M.S.) identified published

medical literature of human studies

about desmopressin in the treatment

of pediatric nocturnal enuresis. This

search was carried out in March

2015, and an updated search was

conducted in November 2015, for

the following electronic databases:

Medline, Embase, Science Direct,

Ovid, Google Scholar, and Wiley

Online Library. The reviewers

searched the clinicaltrial.gov Web site

for possible unpublished trials, and

inquiries were sent to the authors

about the incomplete data. The

search strategy used was as follows:

(desmopressin AND enuresis). No

restriction on language was imposed.

A comprehensive search for eligible

studies was carried out to minimize

reporting bias, publication bias,

within-trial reporting bias, and their

potential impact. Hand-searching

of review articles and cross-

references of reference lists that

met our inclusion criteria were also

performed for potentially relevant

titles. External peer reviewers were

asked to identify additional relevant

studies that were not included in the

draft.

This meta-analysis includes only

randomized controlled trials

(RCTs) that compare the efficacy of

structured versus abrupt withdrawal

(as control) of desmopressin

among desmopressin-responsive

patients with pediatric nocturnal

enuresis. Clinical trials (ie, non-

RCTs, comparisons of desmopressin

therapy with other medical agents or

behavioral therapy, and clinical trials

with no control group) were excluded

for meta-analysis but included in the

systematic review, with assessment

of the outcome of relapse-free rate,

tabulated in a supplemental table.

The primary outcome measure

determined in this meta-analysis

was the rate of sustained response

at ≥1 month after withdrawal from

desmopressin therapy. We applied

intention to treat analysis with all

randomly assigned subjects included

for analysis of effect estimate. The

dropout cases for all treatment

groups were considered relapses.

The subgroup analysis divided the

structured withdrawal therapies into

dose dependent and time dependent.

Dose dependent is described as

decreasing the effective dosage until

the cessation of medication. Time

dependent is described as sustaining

the effective dosage while increasing

the time interval of taking the

medication until complete cessation

of medication.

Evaluation of the Literature

Two reviewers (M.E.C. and

J.M.S.) independently evaluated

the citations and abstracts. The

reviewers flagged article titles that

focused on desmopressin used in

pediatric nocturnal enuresis where

intervention involves withdrawal

of desmopressin and assessment

of sustained response rate after

withdrawal. Articles that either

reviewer flagged were ordered, as

well as articles whose abstracts

and title relevance could not be

determined. Two physician reviewers

then independently reviewed

each full-text article obtained and

determined whether inclusion

criteria were met. Reviewers were

knowledgeable about principles of

critical appraisal. Any discrepancies

were resolved through consensus,

and differences were reviewed by a

senior physician researcher if there

was disagreement.

Data Extraction

Extraction of data on details about

the study characteristics and primary

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PEDIATRICS Volume 138 , number 1 , July 2016

outcome assessment were done. The

risk of bias on quality of the study

design and execution of studies

were assessed independently by

the 2 reviewers according to the

recommendation of the Cochrane

Collaboration; specifically, the

randomization sequence generation;

allocation concealment; blinding of

participants, providers, and outcome

assessors; completeness of outcome

data; selective outcome reporting;

and other potential sources of bias

were assessed. A funnel plot was

generated to explore the possibility

of publication bias.15

Data Synthesis and Data Classifi cation

For both the meta-analysis and

systematic review, details of the

included study trials, such as

study source, study population,

intervention of different structured

desmopressin withdrawal regimens,

study outcome, and data results were

summarized in a table. The RevMan

program, downloaded from www.

cochrane. org, was used for data

analysis, forest plot construction, and

funnel plot construction.

Measures of Treatment Effect

The dichotomous data of sustained

response rates as described

by individual study trials were

expressed as relative risk (RRs)

with 95% confidence intervals (95%

CIs). RR as an effect measure is

appropriate for outcome assessment

among prospective study models,

particularly when sustained

responder and relapse rate are

considered. Effect estimates from

individual studies were then pooled

into the RevMan program for meta-

analysis via the Mantel–Haenszel

method with random effect model.

The number needed to treat (NNT)

to maintain response rate was

calculated for overall effect estimate

and each subgroup analysis.

Assessment of Heterogeneity

We analyzed the heterogeneity

between the treatment effects of

different studies by looking at the

points on the forest plot, the overlap

of CIs (a poor overlap indicates

heterogeneity), and the χ2 statistical

test for heterogeneity. A low P value

(or a large χ2 statistic relative to its

degrees of freedom) shows evidence

of heterogeneity of treatment effects.

A P value of .10 rather than .05 was

used to show heterogeneity because

only a small number of trials with

small sample sizes were included in

this meta-analysis. The I2 statistic

was used to quantify the variations

between the studies. If a value >50%

was found, significant heterogeneity

was assumed, and we determined the

source of heterogeneity among the

study characteristics by considering

the clinical and methodological

characteristics of the included studies

in the meta-analysis.

RESULTS

Figure 1 summarizes the literature

search process from various sources.

Six hundred one titles were available

after duplicates were removed. Vast

numbers of articles were retrieved

that discussed desmopressin for

enuresis; however, the studies

rarely applied and mentioned the

effect of the withdrawal strategies,

so a large percentage of the records

were excluded. Twenty-two eligible

studies remained after screening

based on title and abstract. Eighteen

articles were excluded from meta-

analysis but were included for

systematic review and summarized

in Supplemental Table 3. Four

RCTs10–13 that compare the efficacy

of structured and abrupt withdrawal

of desmopressin after response

to therapy were included for this

meta-analysis. The detailed study

characteristics and risk of bias

assessment of these included studies

are summarized in Table 1 and Table

2, respectively. There were no major

discrepancies between the reviewers

in relation to study inclusion, critical

appraisal, and data extraction.

A Chinese full-text article10 was

included, which was fully evaluated

with no difficulty, because the author

reviewers were fluent in Chinese.

Pooled effect estimates from

the 4 RCTs with no interstudy

heterogeneity (χ2 = 3.82, P = .43;

I2 = 0%) showed that compared

with an abrupt withdrawal regimen,

patients with pediatric nocturnal

enuresis who responded to

desmopressin and managed with

a structured withdrawal approach

had a significantly better sustained

response rate (pooled RR: 1.38;

95% CI, 1.17–1.63; P = .0001)

(Fig 2). The significant difference was

sustained in the subgroup analysis of

studies that applied dose-dependent

structured withdrawal (pooled RR:

1.48; 95% CI, 1.21–1.80; P = .0001),

with no heterogeneity noted between

studies (χ2 = 1.49; P = .47; I2 = 0%).

However, subgroup analysis on

homogenous studies (χ2 = 0.80,

P = .37; I2 = 0%) that applied a time-

dependent structured withdrawal

regimen showed no significant

difference between treatment groups

(pooled RR: 1.18; 95% CI, 0.88–1.59;

P = .27). NNT for overall structured

versus abrupt withdrawal is 7; for

dose-dependent withdrawal it is 5,

and for time-dependent withdrawal

it is 12.

On visual inspection, given that

the studies are evenly plotted on

both sides of the average line, the

funnel plot demonstrates a low

probability of publication bias (Fig

3). Common study methodological

limitations included risk of bias for

inadequate information or allocation

concealment, lack of blinding of

both patient and outcome assessor,

and failure to perform an intention

to treat analysis (Table 2). These

prompted downgrading of the overall

quality of evidence from all individual

outcomes. Failure of a study to report

intention to treat analysis raised

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CHUA et al

concerns about reporting bias.11

The overall small sample size of

each study and some inconsistency

across studies led to downgrading for

inconsistency.

No reported adverse events

were noted related to the process

of desmopressin withdrawal

among the treatment groups.

Although, Tang et al10 and Tullus

et al13 described some self-limiting

nonserious symptoms associated

with the desmopressin treatment

(Table 1). In general, desmopressin

was illustrated by most of the

included studies as well tolerated,

with a good safety profile for

pediatric nocturnal enuresis.

DISCUSSION

Desmopressin is a synthetic analog

of human endogenous antidiuretic

hormone, arginine vasopressin;

its major action is to reduce urine

production.16 Nørgaard et al17

postulated that some children with

nocturnal enuresis produce high

volumes of urine with low osmolarity

4

FIGURE 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses fl ow diagram of literature search process and result.


PEDIATRICS Volume 138 , number 1 , July 2016 5

TABLE 1 Summary of Characteristics of Included Studies for Meta-analysis

Study Characteristics

Author (y)

Country

Study Method Population Structured

Withdrawal

Scheme

Treatment

Groups

Outcome Comparison Outcome

Relapse-Free

per Group

Adverse Events

Tullus

(1999)

Sweden

1st phase: open

multicenter;

2nd phase:

RCT

6–12 yo PMNE diagnosed

with ≥2 enuresis per

week observed for

28 d.

Group 1: Gradual

dosage

tapering over

10 wk.

Group 1: 39 Outcome after 1

mo withdrawal

of desmopressin

with defi nition

of no relapse

as sustained

response, defi ned

as no recurrence of

wet night.

Group 1: 9 On desmopressin

12 mo treatment

period: Adverse

event, 82%

reported

≥1 event.

Cold (50%),

fever (27%),

rhinitis (22%),

headache (16%),

gastroenteritis

(13%),

psychological

reaction (10%),

hyponatremia

(1%).

No other comorbidities

and neurologic disease

excluded

Group 2: Abrupt

cessation.

Group 2: 34 Group 2: 3 For withdrawal

period, none

reported.

Treated with 20–40

mcg of intranasal

desmopressin HS) for

12 mo.

Treatment responders

with >90% reduction of

wet nights compared

with baseline enrolled

to withdrawal phase.

Tang (2010)

China

RCT 5–14 yo, PNE diagnosed


night and ≥7 per week.

Group 1: Dose-

dependent

gradual

withdrawal

(gradual

decrease

in effective

dosage of

desmopressin

in half for

2–4 wk until

complete

cessation of

medication).

Group 1: 50

(M31/F19)

Outcome 3 mo after

withdrawal of

desmopressin,

with defi nition

of no relapse

as sustained

response, defi ned

as ≥90% decrease

of enuresis episode

from baseline.

Group 1: 46 On desmopressin

treatment

period,

decreased

appetite: Control

group 7 patients.

No other comorbidities

and neurologic disease

excluded.

Group 2: Abrupt

cessation

of all

medications.

Group 2: 47

(M27/F20)

Group 2: 28 Experimental

group 8 patients.

Treatment regimen

of 0.2-mg tablet

desmopressin once a

day for 12 wk.

No adverse

event in 3-mo

period after

cessation of

desmopressin.Also, both groups treated

with oxybutynin and

imipramine.


with ≥90% decrease

of enuresis episode

enrolled to withdrawal

study.


CHUA et al

at night, with no associated

increase in secretion of antidiuretic

hormone, hence the applicability of

desmopressin given at bedtime to

supplement antidiuretic hormone

and increase overnight urine

osmolality and decrease urine

volume, leading to dry nights.18–20

According to several literature

reviews, desmopressin treatments

render immediate response;

however, they are associated with

high relapse rates after abrupt

withdrawal.5, 6 Critical care studies

have postulated that suppressed

endogenous vasopressin caused by

vasopressin infusion and sudden

withdrawal may lead to sustained

6

Study Characteristics

Author (y)

Country

Study Method Population Structured

Withdrawal

Scheme

Treatment

Groups

Outcome Comparison Outcome

Relapse-Free

per Group

Adverse Events

Ferrara

(2014)

Italy

RCT >5 yo, MNE diagnosed


week in the last 3 mo.

Group 1: Time-

dependent

structured

withdrawal

(60 mcg/d

for 15 d and

then 60 mcg

every second

evening for

another

15 d until

cessation).

Group 1: 23

(M15/F8)

Outcome 1 mo after

cessation of

desmopressin,

with defi nition of

relapse defi ned

as bedwetting

occurring >2 nights

per month after the

1-mo treatment-

free period.

Group 1: 12 No noted adverse

event associated

with the

treatment

regimen

(according

to author

response).

No other symptoms and

comorbidities.

Group 2: 24

(M17/F7)

Group 2: 13

Treated with 120 mcg

MELT desmopressin

once a day for 3 mo.


with ≥90% decrease

of enuresis episodes

were enrolled for

withdrawal study.

Group 2: Abrupt

cessation.

Gökçe

(2014)

Turkey

Randomized

placebo-

controlled

trial

>5 yo and MNE diagnosed

with enuresis ≥2 per

week in the last 3 mo.

Group 1 Dose

dependent

(gradual

decrease

on half of

the effective

dosage until

cessation after

2 wk).

Group 1: 64

(M41/F23) ITT

(71)

Outcome assessed

at 1 mo, and

nonrelapsing

patients were

scheduled for

control after

12 wk. Relapse

was defi ned

as bedwetting

occurring >2 nights

monthly.

Group 1: 41 (1

mo), 39 (3

mo)

No noted side

effect.

No other associated

symptoms or

comorbidities;

neurologic conditions

excluded.

Group 2 Time

dependent

(effective

dosage every

other day,

then lengthen

interval until

cessation after

2 wk).

Group 2: 66

(M39/F27),

ITT (71)

Group 2: 39 (1

mo), 38 (3

mo)

Treated with 120–240 mcg

MELT desmopressin

once a day for 12 wk.

Group 3:

Immediate

cessation.

Group 3: 65

(M43/F22),

ITT (70)

Group 3: 29 (1

mo), 29 (3

mo)


with no occurrence of

enuresis per week for

4 wk were included for

withdrawal study.

Group 4 received

placebo for

2 wk.

Group 4: 64

(M40/F24),

ITT (71)

Group 4: 32 (1

mo), 30 (3

mo)

F, female; HS, at bedtime; ITT, intention to treat, total number of subjects per treatment group; M, male; MNE, monosymptomatic nocturnal enuresis; PMNE, primary monosymptomatic

nocturnal enuresis; PNE, primary nocturnal enuresis; yo, years old.

TABLE 1 Continued


7PEDIATRICS Volume 138 , number 1 , July 2016

vasopressin deficiencies.21 Endocrine

withdrawal syndrome is an

established physiologic phenomenon

after discontinuation of hormone

therapy, which results into typical

hormone deficiency syndrome and

a generic withdrawal syndrome;

therefore, it is strongly recommended

to gradually taper the medication

to ease withdrawal symptoms from

the hormonal imbalance state.22

Applying aforementioned clinical

and physiologic principles, one could

elucidate the basis of high relapse

rates after abrupt withdrawal

in pediatric nocturnal enuresis.

Recently, structured gradual

withdrawal of desmopressin has

been examined by several trials as a

method to sustain long-term success

and prevent relapse.7–13, 23, 24

Some studies demonstrated that

desmopressin, when withdrawn

structurally, has a better sustained

response rate when compared with

enuresis alarm alone.8, 25, 26

However, to date no study has

clearly illustrated and explained

the actual biological mechanism

of improved response. A plausible

reason for the better response among

desmopressin structured withdrawal

may be its continuing stimulation and

maturation of the innate production

of antidiuretic hormones from the

posterior pituitary and sustaining

of the circadian rhythm. However,

current literature does not show

sustained urine osmolality levels

among desmopressin responders

after structured withdrawal.18–20 In

contrast, some studies demonstrate

that desmopressin might have >1

mechanism of action in nocturnal

enuresis treatment, such as central

brain signaling, sleep arousability,

circadian rhythm, and renal tubular

proteins; gradual withdrawal

TABLE 2 Risk of Bias Assessment of the Included Studies

Risk of Bias Assessment

Author (y)

Country

Random

Sequence

Generation

Allocation

Concealment

Blinding of

Participant

and Staff

Blinding of

Outcome

Assessment

Incomplete

Outcome

Data

Selective

Reporting

Other Bias

Tullus (1999)

Sweden

Unclear Unclear High risk High risk Low risk Low risk High riska

Tang (2010)

China

Low risk Unclear High risk High risk Unclear Unclear Unclear

Ferrara

(2014) Italy

Low riskb Low riskb High risk High riskb Low risk Low riskb Low riskb

Gökçe (2014)

Turkey

Low risk Low risk Low risk Low risk High risk Unclear High riskc

a Study supported by the drug manufacturer.b Additional information gathered from the corresponding author.c Non–intention to treat analysis.

FIGURE 2Forest plot of comparison by desmopressin withdrawal regimen (structured versus abrupt withdrawal), with an outcome of sustained response (relapse-free rate). M-H, Mantel–Haenszel.


8 CHUA et al

may increase sustainability of the

response.22, 27–31 These concepts

could be a topic for future studies

to explore and explain the efficiency

of structured withdrawal treatment

schemes.

In our study, despite a thorough

literature search, we were able to

gather only 4 RCTs with adequate

methodological quality that

examined the sustained response

and the relapse-free rate of

desmopressin-responsive patients

with pediatric nocturnal enuresis

(Fig 1). Likewise, the pooled studies

included did not have interstudy

heterogeneity (Table 1, Fig 2).

Eighteen non-RCTs were also

identified to summarize the clinical

experience described in the current

literature. However, because of the

low methodological quality with

widely variable withdrawal schemes

and inconsistent results described in

these studies, no definite statement

could be inferred from these studies

(Supplemental Table 3).

Based on the pooled estimates

from the included RCTs for meta-

analysis, we recommend structured

withdrawal for patients with

desmopressin-responsive pediatric

nocturnal enuresis to sustain

long-term success and relapse-

free intervals (Figs 2 and 3). This

recommendation was consistent with

a recent review by Alloussi et al, 6

which summarized 13 retrospective

heterogeneous studies. Despite the

low-level evidence available at that

time, they recommended against

abrupt termination of desmopressin

therapy. Because of insufficient

data, they were unable to clearly

state whether dose-dependent or

time-dependent withdrawal is more

likely to render sustained success.

In our subgroup analysis of dose-

dependent structured withdrawal,

we were able to show a significantly

better relapse-free rate over

abrupt withdrawal. Specifically,

an RR of 1.48 (95% CI, 1.21–1.80)

for dose-dependent withdrawal

can be translated as an NNT of 5

to prevent 1 relapse. This finding

strongly justifies its application over

abrupt termination of desmopressin.

However, this significance was not

illustrated in our additional analysis

for the time-dependent structured

withdrawal subgroup, with an RR

of 1.18 (95% CI, 0.88–1.59) and

an NNT of 12 to prevent 1 relapse.

A recent comparative study by

Ohtomo et al24 substantiated our

findings. Their study showed that

gradual dose-dependent and time-


have significantly better outcomes

with lower relapse rates when

compared with only time-dependent

structured withdrawal (17% vs 56%,

respectively; P = .026).24 Overall,

we propose that the structured

withdrawal of desmopressin for

pediatric nocturnal enuresis,

specifically a dose-dependent

withdrawal scheme, should be

recommended by clinicians who treat

patients with complete response to

prevent wet night relapse.

The safety profile of desmopressin in

the treatment of pediatric nocturnal

enuresis was studied in a recent

multinational trial by Van Harzeele et

al, 32 which found that desmopressin

treatment is well tolerated in

children. The same findings were

reported in the 4 studies included in

our meta-analysis (Table 1); likewise,

structured withdrawal is not

associated with any adverse event,

as reported in all 18 clinical studies

included for qualitative analysis

and 4 randomized trials (Table 1,

Supplemental Table 3).

This meta-analysis has the strength of

including only adequate-quality RCTs

with no interstudy heterogeneity.

Likewise, no publication bias was

noted. Subgroup analysis was done

to assess the difference between

dose-dependent and time-dependent

structured versus abrupt withdrawal

to infer comparison. The only

limitation of this meta-analysis is the

small number of studies available

for effect estimation, despite a great

effort by the authors to identify

related trials. We recommend more

high-quality RCTs to assess head-on

comparison of 2 different structured

withdrawal regimens to support

our findings. Moreover, future

studies should explore the biological

mechanism of this improved response,

FIGURE 3Funnel plot of clinical trials on desmopressin-responsive pediatric enuresis, structured versus abrupt withdrawal regimens.


9PEDIATRICS Volume 138 , number 1 , July 2016

as by comparing urine osmolality

between treatment groups.

CONCLUSIONS

The pooled effect estimates in our

meta-analysis showed that structured

withdrawal of desmopressin

results in a better relapse-free rate

compared with abrupt withdrawal of

the medication. Specifically, the dose-


regimen showed significantly better

outcomes.

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ABBREVIATIONS

CI: confidence interval

NNT: number needed to treat

RCT: randomized controlled

trial

RR: relative risk

DOI: 10.1542/peds.2016-0495

Accepted for publication Apr 22, 2016

Address correspondence to Stephen S. Yang, MD, PhD, Division of Urology, Taipei Tzu Chi Hospital, Medical Foundation, New Tapei, Taiwan and Buddhist Tzu Chi

University, Hualien, Taiwan. Email: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2016 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.


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DOI: 10.1542/peds.2016-0495 originally published online June 24, 2016; 2016;138;Pediatrics

Megan Saunders, Roberto Iglesias Lopes, Walid A. Farhat and Stephen S. YangMichael E. Chua, Jan Michael Silangcruz, Shang-Jen Chang, Katharine Williams,Desmopressin Withdrawal Strategy for Pediatric Enuresis: A Meta-analysis

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DOI: 10.1542/peds.2016-0495 originally published online June 24, 2016; 2016;138;Pediatrics

Megan Saunders, Roberto Iglesias Lopes, Walid A. Farhat and Stephen S. YangMichael E. Chua, Jan Michael Silangcruz, Shang-Jen Chang, Katharine Williams,Desmopressin Withdrawal Strategy for Pediatric Enuresis: A Meta-analysis

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