Abstract: Thirty four studies involving 4001 children were included. Interventions included; long-term low-dose antibiotics, surgical reimplantation of ureters, endoscopic injection treatment, probiotics, cranberry products, circumcision, and oxybutynin. Interventions were used alone and in combinations. The quality of conduct and reporting of these studies was variable, with many studies omitting crucial methodological information used to assess the risk of bias. Only four of the 34 studies were considered at low risk of bias across all fields of study quality. The majority of studies had many areas of uncertainty in the risk of bias fields, reflecting missing detail rather than stated poor design. Low-dose antibiotic prophylaxis compared to no treatment/placebo may make little or no difference to the risk of repeat symptomatic UTI (9 studies, 1667 children: RR 0.77, 95% CI 0.54 to 1.09; low certainty evidence) and febrile UTI (RR 0.83, 95% CI 0.56 to 1.21; low certainty evidence) at one to two years. At one to three years, antibiotic prophylaxis made little or no difference to the risk of new or progressive renal damage on DMSA scan (8 studies, 1503 children: RR 0.73, 95% CI 0.33 to 1.61; low certainty evidence). Adverse events were reported in four studies with little or no difference between treatment groups (1056 children: RR 0.94, 95% CI 0.81 to 1.08; ), but antibiotics increased the likelihood of bacterial drug resistance threefold (187 UTIs: RR 2.97, 95% CI 1.54 to 5.74; moderate certainty evidence). Seven studies compared long-term antibiotic prophylaxis alone with surgical reimplantation of ureters plus antibiotics, but only two reported the outcome febrile UTI (429 children). Surgery plus antibiotic treatment may reduce the risk of repeat febrile UTI by 57% (RR 0.43, 95% CI 0.27 to 0.70; moderate certainty evidence). There was little or no difference in the risk of new kidney defects detected using intravenous pyelogram at 4 to 5 years (4 studies, 572 children, RR 1.09, 95% CI 0.79 to 1.49; moderate certainty evidence) Four studies compared endoscopic injection with antibiotics alone and three reported the outcome febrile UTI. This analysis showed little or no difference in the risk of febrile UTI with endoscopic injection compared to antibiotics (RR 0.74, 95% CI 0.31 to 1.78; low certainty evidence). Four studies involving 425 children compared two different materials for endoscopic injection under the ureters (polydimethylsiloxane (Macroplastique) versus dextranomer/hyaluronic acid polymer (Deflux), glutaraldehyde cross-linked (GAX) collagen (GAX) 35 versus GAX 65 and Deflux versus polyacrylate polyalcohol copolymer (VANTRIS)) but only one study (255 children, low certainty evidence) had the outcome of febrile UTI and it reported no difference between the materials. All four studies reported rates of resolution of VUR, and the two studies comparing Macroplastique with Deflux showed that Macroplastique was probably superior to dextranomer/hyaluronic acid polymer (3 months: RR 0.50, 95% CI 0.33 to 0.78; 12 months: RR 0.54 95% CI 0.35 to 0.83; low certainty evidence) Two studies compared probiotic treatment with antibiotics and showed little or no difference in risk of repeat symptomatic UTI (RR 0.82 95% CI 0.56 to 1.21; low certainty evidence) Single studies compared circumcision with antibiotics, cranberry products with no treatment, oxybutynin with placebo, two different surgical techniques and endoscopic injection with no treatment. Compared with no treatment, the use of long-term, low-dose antibiotics may make little or no difference to the number of repeat symptomatic and febrile UTIs in children with VUR (low certainty evidence). Considerable variation in the study designs and subsequent findings prevented drawing firm conclusions on efficacy of antibiotic treatment. The added benefit of surgical or endoscopic correction of VUR over antibiotic treatment alone remains unclear since few studies comparing the same treatment and with relevant clinical outcomes were available for analysis.

Plain-language summary: A total of 34 randomised studies, involving 4001 children were identified and underwent data extraction and analysis. The most frequent comparisons were for long-term, low-dose antibiotics with no treatment (8 studies) or placebo (4 studies) and antibiotics versus surgical reimplantation of ureters plus antibiotics (7 studies). Other treatments looked at endoscopic correction by injection compared with antibiotics (3 studies), different materials for endoscopic correction (2 studies) circumcision (1 study), probiotics (1 study), cranberry product (1 study), and oxybutynin (2 studies). Meta-analysis of similar studies found that long-term low-dose antibiotic treatment compared with no treatment may lead to little or no difference in the risk for repeat UTIs in children with VUR. Associated side effects were infrequent and minor, but prophylaxis was associated with a threefold increased risk of bacterial resistance to the treatment drug in later infections. Surgery decreased the number of repeat UTIs with fever, but did not change the number of children developing UTI with illness or kidney damage. Many studies did not contribute to the meta-analysis as they failed to report relevant outcomes or were single studies examining a treatment option not used by other studies or combinations of treatments. Long-term low-dose antibiotic treatment in children with VUR makes little or no difference to the risk of repeat UTI causing a person to be unwell. Surgery may reduce the risk of repeat UTI with fever however this is based on two studies of 429 children who may not represent the majority and may not bear true in a more general group of children with VUR. Complementary therapies such as probiotics and cranberry were trialled in single or two studies and do not provide evidence of sufficient certainty to support or deny their use.