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doi:10.1111/jpc.12383
COCHRANE COMMENTARIES
Edited by Katrina Williams ([email protected])
Written by Evi V Nagler ([email protected]),
Clinical perspective from Mike South ([email protected])
Primary vesicoureteric reflux grade I to V:
No compelling evidence for routine antibiotics
or surgical intervention
What Is This Review About?
What are the benefits and risks of antibiotic and surgical treatment options for children with vesicoureteric reflux (VUR)?
What Are the Findings?
Long-term low-dose antibiotic prophylaxis showed a nonsignificant trend to reduced repeat symptomatic urinary tract infection
(UTI) (846 children; risk ratio (RR) 0.68, 95% confidence interval (CI) 0.39 to 1.17) and febrile UTI in children with VUR (946
children; RR 0.77, 95% CI 0.47 to 1.24) when compared with
placebo and surveillance (Fig. 1). These findings are largely consistent with those of a related review in children unselected for
the presence of VUR.1
Children treated with long-term low-dose antibiotic prophylaxis had fewer events of progressive renal damage measured by
dimercaptosuccinic acid (DMSA) scan (446 children; RR 0.35,
95% CI 0.15 to 0.80; number needed to treat = 33). The tradeoff was a threefold increase in resistance to the prophylactic
antibiotics in subsequent UTIs (132 urine cultures; RR 2.94,
95% CI 1.39 to 6.25); otherwise there were few and only mild
side effects (Fig. 1). In the trials comparing antibiotic prophylaxis in combination with surgical or endoscopic VUR correction
against antibiotic prophylaxis alone, surgical correction resulted
in a 57% reduction in febrile UTI at 5 years (429 children; RR
0.43, 95% CI 0.27 to 0.70), but not at 1–2 years, and did not
alter the risk of new or progressive renal damage (468 children;
RR 1.05, 95% CI 0.85 to 1.29) (Fig. 2).
What Are the Findings Based On?
Although 20 trials were included in the review, not every study
assessed every outcome at every time-point; hence, not every
study contributed to the meta-analyses presented here, but
every study was included in at least one outcome meta-analysis
of one comparison (antibiotics vs. no antibiotics, anatomical
correction vs. no anatomical correction).
Eight studies, including 1039 children, mostly children
with lower grades of VUR (I to III), compared antibiotic treatment with surveillance or placebo. Although combined
trimethoprim–sulfamethoxazole was the most commonly used
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antibiotic (seven studies), nitrofurantoin and amoxycillin–
clavulanic acid were alternatives to trimethoprim–
sulfamethoxazole in one trial each, and one study did not
specify the antibiotics used. The age range of children included
in the studies varied, with four studies recruiting children
under three, three studies recruiting children into school age,
and one study in which age was not provided. Ten trials
including 1141 children evaluated the value added by longterm antibiotics to surgical or endoscopic correction of VUR,
including mostly children with higher grades of VUR (III to V).
Trimethoprim–sulfamethoxazole and nitrofurantoin were the
most commonly specified antibiotics used, but the antibiotic
was not specified for four studies. Age of participants was
under 3 years for one study, not specified in one study, and
included school-age children for eight studies. For the six
studies that assessed renal damage, either DMSA, intravenous
pyelography (IVP), or ultrasound was used. At entry the proportion of children with renal abnormalities in the surgical
trials was much higher (56–100%) than in the antibiotic trials
(25–40%), and in the surgical intervention studies almost one
in two children had a progressive renal defect on IVP after 4 to
5 years, compared with 1 in 10 on DMSA at 1 to 3 years in
the antibiotic trials.
Definitions and criteria for diagnosis of the initial or recurrent
UTI (based on cultures or requiring symptoms and/or fever) and
renal abnormalities (based on DMSA or IVP) differed greatly
among the various studies. Trials were largely reported inadequately and without sufficient detail of design to permit judgement about risk of bias. Only four studies described blinding
of objective and subjective outcomes; only three described
adequate blinding of all involved in the study. Seven studies
addressed incomplete outcome data and were analysed on an
intention-to-treat basis.
Clinical Perspective
Primary VUR is thought to be a maturational defect, potentially
predisposing children to UTI, renal involvement during UTI, and
subsequent renal damage. It is also now recognised that some of
the renal cortical defects found in children who have had a UTI
are in fact pre-existing developmental abnormalities and not the
consequence of infection, as was historically thought to be the
Journal of Paediatrics and Child Health 49 (2013) 876–879
© 2013 The Author
Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Cochrane Commentaries
Fig. 1
Long-term low-dose antibiotic prophylaxis versus surveillance for vesicoureteric reflux: main outcomes and adverse events. M-H, Mantel-Haenszel.
case. What proportion of renal defects are pre-existing as
opposed to secondary to infection remains unknown and
controversial. The same applies to the long-term significance
of these renal cortical defects for future renal function and
hypertension.
Treatment has traditionally been directed at preventing recurrent UTI, with the idea that this may reduce the risk of symptomatic UTI and possibly the risk of future cortical damage, and
therefore potentially reduce the chance of impaired renal function and hypertension in the future. There are multiple steps
and untested assumptions in this causal pathway, and the effects
of interventions remain unclear.
Long-term, low-dose antibiotics have often been used when
spontaneous resolution of VUR is expected, and surgical or
endoscopic correction of VUR has sometimes been used when
the chances of resolution are deemed slim.
This review provides no compelling evidence that antibiotic
prophylaxis reduces the risk of recurrent UTI in children with
VUR. Antibiotics should generally not be recommended for this
purpose alone.
Antibiotic prophylaxis seems to modestly reduce the risk of
new or progressive renal damage, although the clinical significance of these lesions for long-term prognosis is not clear. Clinical decision making should balance this potential, but uncertain,
Journal of Paediatrics and Child Health 49 (2013) 876–879
© 2013 The Author
Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
877
Cochrane Commentaries
Fig. 2 Anatomic surgical correction plus antibiotic prophylaxis versus antibiotic prophylaxis alone for vesicoureteric reflux: main outcomes. M-H,
Mantel-Haenszel.
benefit with the threefold increase in the risk of developing
antibiotic resistance, the small risk of adverse antibiotic effects,
the cost and inconvenience of daily antibiotic administration
for often prolonged periods, and the potential to increase
community antibiotic resistance not only to the organisms that
cause UTI but also to other pathogenic organisms that would
previously have responded to these drugs.
The incremental value of surgery over low-dose antibiotics
remains uncertain, and the potential very small reduction in
febrile UTI risk should be balanced against the potential risks of
the surgical procedure. Correcting VUR using endoscopic
approaches could theoretically reduce surgical risk, but to date,
the few available randomized study data do not suggest that
surgery confers a systematic reduction in UTI or reduction in
development of renal damage.
Fifteen years ago it was the norm for a child to be intensively
investigated for VUR following a first UTI and very common for
the child, especially if VUR was demonstrated, to be put on
prophylactic antibiotics. Surgical procedures were also common
for those with VUR. In the last decade, clinical practice guidelines from respected bodies and clinical practice itself have
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strongly moved away from this approach – in keeping with
emerging evidence. If we do not need to know if a child has VUR
to guide decision-making, then the value of the investigations
for VUR becomes very limited, and clinicians are ordering them
far less often.2
This useful review increases the confidence of those taking a
less interventional approach to investigation and intervention in
children with VUR.
Implications for Practice
• There is no compelling evidence that antibiotic prophylaxis
reduces the risk of recurrent UTI in children with VUR.
• Antibiotic prophylaxis may reduce the risk of future renal
parenchymal damage, but the number needed to treat is large
(i.e. 33), and the treatment is usually needed over a prolonged period. The long-term benefits of this effect are uncertain, and this needs to be balanced against a number of
measurable and unmeasurable costs and risks.
• Surgery does not provide a systematic reduction in UTI
or reduction in the development of renal damage. It may
Journal of Paediatrics and Child Health 49 (2013) 876–879
© 2013 The Author
Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
Cochrane Commentaries
still have a place in selected cases, but in which remains
unclear.
Interventions for primary vesicoureteric reflux. Nagler EV,
Williams G, Hodson EM, Craig JC. Cochrane Database of Systematic Reviews 2011, Issue 6. Art. No.: CD001532.
DOI: 10.1002/14651858.CD001532.pub4
http://onlinelibrary.wiley.com/doi/10.1002/14651858
.CD001532.pub4/abstract
References
1 Williams G, Craig JC. Long-term antibiotics for preventing recurrent
urinary tract infection in children. Cochrane Database Syst. Rev.
2011; (3): Art. No.: CD001534, doi: 10.1002/14651858.CD001534
.pub3.
2 South M. Radiological investigations following urinary tract
infection: changes in Australian practice. Arch. Dis. Child. 2009; 94:
927–30.
Three owl babies, by Ellie Whatman, from Operation Art 2012.
Journal of Paediatrics and Child Health 49 (2013) 876–879
© 2013 The Author
Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
879