Impact of continuous low-dose antibiotic prophylaxis on growth in children with vesicoureteral reflux

Impact of continuous low-dose antibiotic prophylaxis on growth in children with vesicoureteral reflux

Accepted Manuscript Impact of Continuous Low-Dose Antibiotic Prophylaxis on Growth in Children with Vesicoureteral Reflux P. Joseph Guidos, Angela M. ...

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Accepted Manuscript Impact of Continuous Low-Dose Antibiotic Prophylaxis on Growth in Children with Vesicoureteral Reflux P. Joseph Guidos, Angela M. Arlen, Traci Leong, Megan A. Bonnett, Christopher S. Cooper PII:

S1477-5131(18)30376-0

DOI:

10.1016/j.jpurol.2018.07.007

Reference:

JPUROL 2913

To appear in:

Journal of Pediatric Urology

Received Date: 26 February 2018 Accepted Date: 12 July 2018

Please cite this article as: Guidos PJ, Arlen AM, Leong T, Bonnett MA, Cooper CS, Impact of Continuous Low-Dose Antibiotic Prophylaxis on Growth in Children with Vesicoureteral Reflux, Journal of Pediatric Urology (2018), doi: 10.1016/j.jpurol.2018.07.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Impact of Continuous Low-Dose Antibiotic Prophylaxis on Growth in Children with Vesicoureteral Reflux

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P. Joseph Guidos1, Angela M. Arlen2, Traci Leong3, Megan A. Bonnett1, and Christopher S. Cooper1

Please address all correspondence to:

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From the Departments of Urology and Pediatrics, University of Iowa Hospitals and Clinics1, Iowa City, IA, Department of Urology, Yale University2, New Haven, CT and Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University School of Medicine3, Atlanta, GA

Ethical Approval

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Christopher S. Cooper, MD University of Iowa Department of Urology 200 Hawkins Drive, 3RCP Iowa City, IA 52242-1089, USA Telephone: (319) 353-8673 Fax: (319) 356-3900 Email address: [email protected]

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Approved under University of Iowa Hospitals & Clinics IRB 200301092.

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Running Title: Impact of Continuous Antibiotics on Growth

Summary

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Background

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Impact of Continuous Low-Dose Antibiotic Prophylaxis on Growth in Children with Vesicoureteral Reflux

Continuous antibiotic prophylaxis (CAP) is a mainstay of treatment for children with vesicoureteral re-

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flux (VUR). There has been an increasing focus on the effect of antibiotics on gut microbiota and subsequent repercussions on growth. CAP is generally considered safe however its impact on growth in children with VUR remains unknown. Objective

with VUR. Study design

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We sought to determine whether CAP altered height, weight, or body mass index (BMI) in children

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Children diagnosed with primary VUR were identified. Demographics including weight and height percentiles, BMI and BMI percentiles, age, gender, antibiotic class, prior antibiotic use, urinary tract in-

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fection (UTI) history, and breakthrough infections were tested in uni-and multivariate analyses. Primary outcome was change in BMI, as well as weight, height, and BMI percentiles. Results

One hundred and eighty patients (146 girls, 34 boys) were prescribed CAP at mean age of 29.2 ± 26.2 months. Mean follow-up on CAP was 4.1 ± 3.3 years, with median follow-up of 3.08 years. Mean increase in weight percentile was 1.49 (2.02 males, 1.37 females; p = 0.46). Mean decrease in height per-

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centile was -4.44 (-2.18 males, -4.95 females; p = 0.51). Age at diagnosis (p = 0.004) and history of prior treatment courses of antibiotics (p = 0.007) were associated with a significant BMI increase (Figure 1). BMI percentile increased from 58.4 to 66.5, however, this increase was only significant in chil-

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dren over 1 year of age (p<0.0001). Of note, children over 1 year of age were significantly more likely to have a history of prior treatment courses of antibiotics (58% vs. 32%; p<0.0001), and when controlling for prior antibiotic use, the increase in BMI percentile in those over 1 year of age

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did not reach significance.

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Discussion

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Figure 1. Prior antibiotic use and younger age at start of daily antibiotics are associated with increasing BMI.

The use of antibiotics has been associated with alterations in pediatric growth parameters in both animal models and clinical studies. However, little information exists on the impact of prophylactic dosed antibiotics on growth. While our study is limited by the retrospective analysis and small sample size, we found that the use of CAP did impact growth parameters, with a stronger effect seen in children who had received prior treatment courses of antibiotics before the infection leading to the initiation of CAP. Conclusion 2

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Continuous antibiotic prophylaxis was correlated with significant increase in BMI in children with prior antibiotic usage and a significant increase in BMI percentile in children over 1 year of age. CAP was also associated with decreased height percentiles, particularly in patients less than 1 year of age,

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though it did not reach statistical significance. Further analysis is needed to investigate whether these effects on weight, height, and BMI are persistent and clinically significant.

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Key Words

Vesicoureteral Reflux (VUR); Continuous antibiotic prophylaxis (CAP); weight percentile; height per-

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centile; body mass index (BMI)

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Introduction Prophylactic antibiotics have traditionally been considered a non-specific approach for prevention of recurrent urinary tract infection (UTI) in children with vesicoureteral reflux (VUR). Daily admin-

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istration of low-dose antibiotics is based on the knowledge that new reflux-associated renal scarring appears to occur exclusively in the setting of infected urine and that most pediatric cases of VUR will spontaneously resolve. Antibiotic prophylaxis in children with VUR has been widely employed to main-

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tain sterile urine, and a reduction in UTIs in those patients receiving prophylaxis has been confirmed by the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) and Swedish Reflux

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studies [1,2]. While continuous antibiotic prophylaxis (CAP) is considered safe and well-tolerated in general, the emergence of bacteria with high rates of resistance has been reported [3]. In addition to resistance, early-life antibiotic exposure has been associated with increased adiposity in animal models and observational studies in children have reported associations between antibiotic

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exposure and increased body mass [4-7]. Antibiotics affect the gut microbiota, and the link between altered gut microbiota and human metabolism is becoming increasingly apparent [8]. In addition, alterations to the gut microbiota have been noted to impact and impair bone growth and development [9-11].

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The full impact of antimicrobials, whether at therapeutic or prophylactic dosing, on the human gut, metabolism, height, weight, as well as other potential side effects remain unknown [12]. We hypothesized

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that the use of CAP could impact growth by decreasing linear growth and increasing weight, and evaluated this by examining weight, height, and BMI in patients with VUR on CAP and compared them to their individual baseline growth parameters.

Materials and methods

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Study Design

Institutional review board approval was obtained. Children from a single institution with primary VUR diagnosed between 1984 and 2003, with detailed height/weight data at presentation and follow-up

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were identified. Height and weight were routinely measured in a consistent fashion and all data points were collected from a single hospital facility. Growth percentiles were calculated using standardized reference values from the World Health Organization (WHO) and Centers for Disease Control and Preven-

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tion (CDC) growth charts. For children ages 0 to 24 months of age, the WHO growth standards were utilized, which are based on the WHO Multicentre Growth Reference Study [13]. For children age 2

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years and older, the CDC growth charts, developed based on the National Health Examination Surveys (NHES) and National Health and Nutrition Examination Survey (NHANES) were employed [14]. Body mass index (BMI) and BMI percentiles were calculated from the CDC BMI-for-age growth tables. Other variables that were explored as confounders were gender, age, antibiotic class, maximum VUR

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grade on initial VCUG, laterality, breakthrough urinary tract infections, history of multiple UTIs (afebrile and/or febrile) prior to the diagnosis of VUR and the beginning of CAP, and treatment courses of

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antibiotics prior to treatment of the UTI that led to the diagnosis of VUR and the beginning of CAP.

Study Population

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All children were placed on prophylactic antibiotics and followed with subsequent cystograms on an annual basis until reflux resolution or operative repair. Children with secondary VUR, ectopic ureters, complete ureteral duplication, ureterocele, concomitant ureteropelvic junction or ureterovesical junction obstruction, or unknown clinical outcomes/no follow-up growth parameters were excluded from study, as were those not prescribed continuous antibiotic prophylaxis and those who did not comply with antibiotic regimen. Children on CAP for less than 12 months were also excluded from study. In

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addition, children with major medical illnesses that could impact their growth such as prematurity, severe lung disease, or gastrointestinal maladies were excluded.

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Statistical Analysis

The primary outcome was change in weight and height percentiles, which were compared to each patient’s initial weight and height percentile at the time of presentation (prior to initiation of antibi-

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otic prophylaxis), as were BMI and BMI percentile. Each child served as his/her own control, minimizing between-individual variability in other factors that could affect growth. Weight and height percentile

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data were used over absolute weight or height gain, as percentiles are more indicative of a child’s growth trajectory over time and normalized their growth on an individual basis. The delta was calculated as the absolute BMI or percentile of weight, height and BMI at the last visit minus the percentile at visit 1 (i.e. diagnosis). Follow-up time was defined as the difference between the first and the last measures

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of growth parameters. The univariate analysis of the delta was only compared with antibiotic type using an ANOVA due to the approximate normality of those data. To achieve the greatest statistical power and efficiency, ANCOVA was employed for remaining statistical analyses, to evaluate whether the means of

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a dependent variable are equal across levels of a categorical independent variable while statistically controlling for the effects of other continuous variables (i.e. covariates). Statistical analysis was performed

Results

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using R 3.1.1, with p<0.05 representing statistical significance.

Six hundred and seventy-four patients with primary VUR were identified, and one hundred and eighty patients (146 girls, 34 boys) met all inclusion criteria and were prescribed CAP for at least 12 months. [Table 1]. Mean age at diagnosis was 29.2 ± 26.2 months, with mean follow-up

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on CAP of 4.1 ± 3.3 years and median (interquartile range) of 3.08 (1.75 to 5.75) years. The average weight, length and BMI percentiles at diagnosis were all at approximately the 60th percentile and mean initial BMI was 16.4. There were no significant differences in the initial growth parameter percentiles at

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baseline between children with documented antibiotic use prior to the initiation of CAP compared to those without prior antibiotic use. The most common reason presentation was febrile UTI in 51.6% of patients, followed by 28.8% with non-febrile UTI, 10.8% with hydronephrosis, 4.3% for sibling screen-

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ing, and 3.8% for other reasons (hematuria, unknown). Female patients tended to be in the older age group (> 12 months), had received prior antibiotics, and had a lower grade of VUR. Sulfamethoxa-

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zole/trimethoprim was the most common antibiotic (66.7%), followed by amoxicillin (10.6%) and nitrofurantoin (10%). Antibiotic type showed no significant impact on change in growth percentiles [Table 2]. Percentile differences by gender

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In Table 3, weight, height, and BMI at last clinical follow-up were considered as the outcome to test the effect of gender controlling for the effects of initial weight, height, and BMI, respectively using an ANCOVA test. Adjusted means (for the effect of baseline weight, height or BMI) and confidence in-

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tervals are given for both males and females and the p-value is listed in the last column. Controlling for the effects of baseline values, there is no statistical difference in outcome by gender. Follow up (mean

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and SD) was compared using a t-test.

Percentile differences by UTI

Of the 180 patients, 41 (26.1%) had a breakthrough UTI which was significantly more likely in girls (p=0.006). There were no significant differences in weight, height or BMI percentile changes at the last visit between those with and without breakthrough UTI. For the breakthrough UTI patients there was a slight, although not statistically significant, decrease in BMI (18.5 [17.5-19.4] versus 17.5 [17-

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18]; p = 0.09). There was a difference in follow-up time indicating that longer length of follow-up (5 vs 3.8 years; p = 0.04) was associated with increased incidence of breakthrough UTI.

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Change in weight, height and BMI percentile as outcome The variables listed in Table 4 were considered in an ANCOVA model with last weight, height and BMI percentile as the outcome and adjusting for initial percentiles. Although the weight and BMI

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percentile increased and the height percentile decreased, no significant difference was able to be demonstrated overall or with respect to the patient characteristics noted in Table 4. However, there was a sig-

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nificant increase found in BMI percentile in children over 1 year of age (p<0.0001). Of note, children over 1 year of age were significantly more likely to have a history of prior treatment courses of antibiotics (58% vs. 32%; p<0.0001), and when controlling for prior antibiotic use, the increase in BMI percentile in those over 1 year of age did not reach significance. One hundred and seventeen children (65%) were initially classified as having a “healthy”

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BMI percentile; at the time of last clinical follow-up, 19 (16.2%) of these children were overweight and 10 (8.5) were obese. This increase in previously healthy BMI children approached but did not

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reach statistical significance (p = 0.06).

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Change in Absolute BMI

Controlling for initial absolute BMI, antibiotic use prior to initiation of CAP was associated with a significantly increased final BMI (Table 5). Patients with prior antibiotic use had an average increase of 1.4 ± 0.6 in their BMI (p = 0.007) at their last clinic visit controlling for other variables including initial weight, height, and BMI. A younger age when prophylactic antibiotics were started was also associated with a significant increase in BMI over time. These two variables, age and prior use of antibiotics, were then incorporated in a multivariable model [Figure 1]. Race, gender, laterality, and presentation with

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a history of multiple febrile or non-febrile UTIs prior to starting CAPwere not found to be significantly associated with a change in final BMI (Table 5).

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Discussion Based on prior clinical studies demonstrating increased weight and BMI associated with antibiotic exposure in children, as well as experimental studies demonstrating an adverse impact of antibiotics

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on bone development, we sought to determine whether continuous antibiotic use in children with vesicoureteral reflux could impact growth in an adverse way. Vesicoureteral reflux is one of the most

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common urologic diagnoses affecting children, and low-dose antibiotics are frequently utilized to maintain sterile urine and prevent renal injury from recurrent febrile urinary tract infections [15]. Antibiotics are bactericidal and oral formulations are known to impact the microbiota of the gastrointestinal tract. The microbiota plays a multifunctional role involving enhancement of host digestion, energy turnover, metabolism, absorption of nutrients, barrier against pathogens, and development of the immune and

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nervous systems [16]. The development of resistant bacteria in patients with breakthrough urinary tract infections is widely recognized in the pediatric urology literature, but the role of the microbiota in this

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process remains speculative [3,17]. Reported rates of resistant bacteria in children on CAP range from 3 to 24 times that of children not receiving daily prophylactic antibiotics [1,2,18-20].

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The impact of oral antibiotics on animal growth has been well established for decades [4, 5], with greater increases noted when antibiotics are administered earlier in life [13,21]. More recently, studies have addressed the association between antibiotics and obesity in children. Ajslev et al reported that exposure to antibiotics in the first 6 months of life was associated with a subsequent risk of being overweight in childhood [23]. The impact of early exposure to antibiotics on body mass was also confirmed by Trasande and colleagues [24]. Other studies reported reversible, persistent or progressive effects of antibiotic use on children’s BMI trajectories, with different effects by age, suggesting

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that antibiotic use influenced weight gain throughout childhood [6,25]. An electronic health record review of 64,580 children at the Children's Hospital of Philadelphia demonstrated an increased risk of developing childhood obesity associated with both broad-spectrum antibiotics and cumulative exposure for

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those receiving four or more antibiotic courses [26]. However, a recent retrospective, longitudinal study of more than 38,000 children did not find a statistically significant association between short-term antibiotic use within the first 6 months of life and weight gain [27]. In addition, a secondary analysis of data

cant difference in weight gain compared to controls [12].

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from a randomized clinical trial of 300 children on prophylactic antibiotics failed to show any signifi-

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Antibiotics have been demonstrated to impact bone development and growth in experimental models, however most clinical studies to date focus on weight gain and BMI. A key inclusion in our study was the use of standardized weight and height curves, as well as BMI calculations based on age and gender, which are based on large populations of healthy children. We found a significant increase in

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absolute BMI from baseline in children on CAP that had been treated with antibiotics prior to the UTI that led to the diagnosis of VUR and start of CAP. A significant increase in BMI was also associated with a decreased age when starting CAP. We also demonstrated a significant increase in BMI per-

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centile in those children over 1 year of age, however, these children had significantly more exposure to treatment courses of antibiotics prior to starting CAP than those less than 1 year of age. It

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is possible this prior exposure may have predisposed them to increasing BMI and/or sensitized them to the subsequent impact of CAP. While our study demonstrated a non-significant increase in weight and decrease in height percentiles associated with CAP, it is likely that our study was under powered to demonstrate statistical significance in these growth parameters as other studies demonstrating significant changes in these parameters associated with antibiotics included thousands of children [26]. Since BMI is based on height and weight it is possible that the non-significant increase in weight

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and decrease in height resulted in a change large enough in BMI to demonstrate a significant difference despite our relatively small sample size. Additionally, other reports examined the effect of short-term treatment doses of antibiotics on growth parameters, while our study assessed the effect of continuous

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low-dose prophylaxis. It is possible that the low dosage levels used with antibiotic prophylaxis have a smaller impact on the gut microbiota, especially in antibiotic naïve patients than the impact of treatment doses and may therefore have a smaller impact on growth. Another possibility is that children with

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VUR are at increased risk for recurrent urinary tract infections which may impair growth and it is feasible that our results could be impacted by an overall improvement in the health of children while on

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CAP. However, we did not find a significant change in growth parameters between children with or without breakthrough infections, making this possibility less likely.

Our study is not without limitations. Aside from the relatively small sample size, data was collected retrospectively through individual medical record review, subjecting it to flaws inherent with such

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study design. Patients were evaluated at a single institution and may not be generalizable to all children with VUR. We only utilized the initial and last follow-up growth parameters in our analysis, and evaluation of additional data points over time would be helpful in order to more fully understand these trends.

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All included patients were treated with CAP; and although we attempted to control for possible confounding variables by comparing individual patients to their own baseline, there was no formal matched

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control group off antibiotics. However, controlling for all variables that can impact growth parameters between individuals would be difficult outside of an animal model. Although exhaustive efforts were made to ascertain and confirm patients’ clinical status, it is possible that some patients were treated previously with antibiotics for conditions that were not detected in our medical record review. The use of BMI as an outcome is controversial as it measures weight adjusted to height and can be affected by multiple other variables and thus has the potential for inter-individual variability. Compliance with antibiotic

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administration was assessed by parental report, and thus is subject to recall bias. Renal scarring is known to affect linear growth, however DMSA (technetium-99m dimercaptosuccinic acid scans) scans were not routinely obtained, therefore the incidence of renal scarring/dysplasia in our patient cohort is

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unknown. Despite these limitations, our study demonstrated a significant independent correlation between CAP and increased BMI in children with a history of a prior use of antibiotics as well as an increase relative to antibiotic exposure with treatment courses prior to starting CAP. Another limita-

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tion is that we do not know the clinical significance of these potential side effects of prolonged antibiotic exposure, nor of the reversibility of these growth parameter changes after CAP is discontinued. Howev-

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er, the potential for such side effects from CAP needs to be considered when weighing the potential risks and benefits of the options for management of VUR on an individual basis.

Conclusions

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Continuous antibiotic prophylaxis was associated with a non-significant increase in weight percentile, decrease in height percentile, and a significant increase in BMI in those children that had prior antibiotic usage. A significant association with increased absolute BMI was also identified relative to

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younger age. Our findings require further analysis with a larger sample size and extended follow-up as part of a multi-institutional study to better define both their statistical and clinical significance. It re-

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mains of utmost importance to balance overtreatment of VUR with its cost and side effects against the potential negative sequelae of undertreatment of VUR [17], and in light of our findings it seems reasonable to also consider impact on growth parameters as potential side effects.

Overall (n=180)

Males (n=34)

Females (n=146)

p-value

22.7 (29.5)

30.7 (25.3)

0.15

Variable Age at diagnosis, M (SD) 29.2 (26.2)

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0.003

Age group, n (%) <1yr 73 (40.6)

22 (64.7)

51 (34.9)

1yr + 107 (59.4)

12 (35.3)

95 (65.1) 0.44

White 124 (68.7)

21 (61.8)

Hispanic 1 (0.6)

Yes 87 (48.3)

7 (20.6)

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Max grade, n (%)

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27 (79.4)

42 (29.0)

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No 93 (51.7)

Bilateral 94 (52.2)

1 (0.7)

13 (38.2)

Prior Abx, n (%)

Unilateral 86 (47.8)

102 (70.3)

0 (0.0)

Other 55 (30.7)

Laterality, n (%)

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Race, n (%)

<0.001

66 (45.2) 80 (54.8)

0.63

18 (52.9)

68 (46.6)

16 (47.1)

78 (53.4)

<0.001

4 (11.8)

16 (11.0)

2 92 (50.8)

15 (44.1)

76 (52.4)

3 54 (30.2)

6 (17.6)

48 (33.1)

4 11 (6.1)

7 (20.6)

4 (2.8)

5 3 (1.7)

2 (5.9)

1 (0.7)

Initial weight %tile, M (SD) 63.0 (27.1)

58.0 (29.0)

64.2 (26.7)

0.27

Initial length %tile, M (SD) 60.7 (30.8)

53.5 (32.8)

62.4 (30.2)

0.17

Initial BMI %tile (SD) 58.0 (29.7)

53.3 (31.0)

59.1 (29.4)

0.34

15.8 (2.1)

16.5 (1.8)

0.08

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1 20 (11.2)

Initial BMI, M (SD) 16.4 (1.9)

0.006

Breakthrough fUTI, n (%) No 133 (73.9) Yes 47 (26.1)

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32 (94.1)

101 (69.2)

2 (5.9)

45 (30.8)

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Table 1. Patient characteristics. Female patients were significantly more likely to be in the older age group (> 1 year at diagnosis), have received prior antibiotics, have lower VUR grade, higher initial BMI, and more breakthrough UTIs.

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Percentile differences by Antibiotic Type Overall (n=183)

Bactrim (n=120)

Amoxicillin (n=19)

Keflex (n=9)

Nitrofurantoin (n=18)

Other (n=14)

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Change in weight percentile, M (SD)

1.49 (26.49)

3.01 (27.06)

-1.99 (27.11)

6.27 (25.19)

-1.46 (20.46)

-5.81 (29.64)

0.6 8

Median (Q1-Q3)

0.50 (12.4-16.3)

0.65 (-10.55- -3.95 (-14.318.60) 11.45)

3.5 (-1.00.20 (-15.5-5.83) 8.50)

4.15 (20.2316.48)

0.8 1

Change in height percentile, M (SD)

-4.4 (29.9)

-3.5(28.7)

-5.4 (28.1)

-1.9 (25.8)

1.0 (40.2)

0.6 0

Median (Q1-Q3)

-3.0 (-20.0- -2.1 (-17.311.2) 11.4)

-12.9 (-24.410.5)

2.0 (-7.2-9.2 (-23.9-8.0) 9.4)

-14.0 (20.2-14.3)

0.8 4

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Variable

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-15.4 (34.1)

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Table 2. Percentile differences by antibiotic class; no significant difference was observed.

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Males (n = 34)

Females (n = 146)

P

Last Wt percentile

62.8 (55.1-70.5)

66.1 (62.3- 69.8)

0.457

Last Ht percentile

53.9 (45.0- 62.7)

57.2 (52.9- 61.4)

0.512

Last BMI

17.2 (16.1- 18.3)

17.8 (17.3 -18.4)

0.304

Last BMI percentile

67.3 (10.4-99.1)

66.3 (2.2-99.5)

0.792

Follow up, Years (SD)

3.86 (2.82)

4.15 (3.4)

0.97

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Outcome

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Table 3. No statistical difference in growth parameters by gender.

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Variable

Height %tile p value

BMI %tile p value

Age at diagnosis 0.87

0.75

0.58

Age group (<1yr) 0.57

0.10

0.33

Race 0.66

0.75

0.68

Gender 0.46

0.51

0.79

Abx use prior to initiation 0.16 of CAP

0.57

Weight %tile

VCUG max grade 0.76 High grade 0.97 fUTI 0.92

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0.83

0.75

0.29

0.73

0.92

0.80

0.18

0.29

0.97

0.67

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UTI 0.21

0.91

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Laterality at VCUG 0.34

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p value

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Table 4. Univariate analysis; no variables were associated with a statistically significant increase in weight, height or BMI percentiles.

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Age at diagnosis

0.004

Race

0.89

Gender

0.30

Prior abx

0.007

Laterality at VCUG

0.45

VCUG max grade

0.82

fUTI (<2)

0.65

UTI (<2)

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P value

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Variable

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0.12 0.09

bUTI

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Table 5. Univariate analysis. Age at diagnosis and prior antibiotic use were associated with increased absolute BMI.

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Figure 1. Prior antibiotic use and younger age at start of daily antibiotics are independently associated with increasing absolute BMI over time in a multivariate model.

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Funding Sources None. Conflict of Interest

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The authors declare no relevant financial relationships.

References

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[1] The RIVUR Trial Investigators. Hoberman A, Greenfield SP, Mattoo TK, Keren R, Mathews R, et al. Antimicrobial prophylaxis for children with vesicoureteral reflux. N Engl J Med, 2014;370:2367.

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[2] Brandstrom P, Esbjorner E, Herthelius M, Swerkersson S, Jodal U, Hansson S. The Swedish Reflux Trial in Children: III. Urinary tract infection pattern. J Urol, 2010;184:286. [3] Cheng CH, Tsai MH, Huang YC, Su LH, Tsau YK, Lin CJ, et al. Antibiotic resistance patterns of community-acquired urinary tract infections in children with vesicoureteral reflux receiving prophylactic

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antibiotic therapy. Pediatrics, 2008;122:1212.

[4] Luckey TD, Moore PR, Elvehjem CA, Hart EB. The activity of synthetic folic acid in purified rations for the chick. Science, 1946;103:682.

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[5] Jukes TH. Antibiotics in animal feeds and animal production. Bioscience 1972;22:526. [6] Schwartz BS, Pollak J, Bailey-Davis L, Hirsch AG, Cosgrove SE, Nau C, et al. Antibiotic use and

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childhood body mass index trajectory. Int J Obes, 2016;40:615. [7] Rasmussen SH, Shrestha S, Bjerregaard LG, Ängquist LH, Baker JL, Jess T, et al. Antibiotic exposure in early life and childhood overweight and obesity: A systematic review and metaanalysis. Diabetes Obes Metab. 2018;20:1508. [8] Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature, 2012;489:242.

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[9] Guss JD, Horsfield MW, Fontenele FF, Sandoval TN, Luna M, Apoorva F, et al. Alterations to the gut microbiome impair bone strength and tissue material properties. J Bone Miner Res, 2017;32(6):1343-53.

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[10] Sjogren K, Engdahl C, Henning P, Lerner UH, Tremaroli V, Lagerquist MK, et al. The gut microbiota regulates bone mass in mice. J Bone Miner Res, 2012;27(6):1357-67.

[11] Yan J, Herzog JW, Tsang K, Brennan CA, Bower MA, Garrett WS, et al. Gut microbiota induce

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IGF-1 and promote bone formation and growth. Proc Natl Acad Sci U S A, 2016;113(47):E7554-e63. [12] Edmonson MB, Eickhoff JC. Weight gain and obesity in infants and young children exposed to

M AN U

prolonged antibiotic prophylaxis. JAMA Pediatr, 2017;171:150.

[13] de Onis M, Garza C, Victora CG, Onyango AW, Frongillo EA, Martines J. The WHO Multicentre Growth Reference Study: planning, study design, and methodology. Food Nutr Bull, 2004;25(1 Suppl):S15.

TE D

[14] Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11, 2002;246:1.

EP

[15] Peters CA, Skoog SJ, Arant BS, Jr., Copp HL, Elder JS, Hudson RG, et al. Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children. J Urol, 2010;184:1134.

AC C

[16] Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol, 2015;11:182. [17] Cooper CS. Fat, demented and stupid: An unrecognized legacy of pediatric urology? J Pediatr Urol, 2017;13:341.

[18] Allen UD, MacDonald N, Fuite L, Chan F, Stephens D. Risk factors for resistance to “first-line” antimicrobials among urinary tract isolates of Escherichia coli in children. CMAJ, 1999;160:1436-1440. [19] Paschke AA, Zaoutis T, Conway PH, Xie D, Keren R. Previous antimicrobial exposure is associat-

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ed with drug-resistant urinary tract infections in children. Pediatrics, 2010;125:664. [20] Craig JC, Simpson JM, Williams GJ, Lowe A, Reynolds GJ, McTaggart SJ, et al. Antibiotic prophylaxis and recurrent urinary tract infection in children. N Engl J Med, 2009;361(18):1748-59.

RI PT

[21] Gaskins HR, Collier CT, Anderson DB. Antibiotics as growth promotants: mode of action. Anim Biotechnol, 2002;13:29.

[23] Ajslev TA, Andersen CS, Gamborg M, Sorensen TI, Jess T. Childhood overweight after establish-

SC

ment of the gut microbiota: the role of delivery mode, pre-pregnancy weight and early administration of antibiotics. Int J Obes, 2011;35:522.

ly-life mass. Int J Obes, 2013;37:16.

M AN U

[24] Trasande L, Blustein J, Liu M, Corwin E, Cox LM, Blaser MJ. Infant antibiotic exposures and ear-

[25] Saari A, Virta LJ, Sankilampi U, Dunkel L, Saxen H. Antibiotic exposure in infancy and risk of being overweight in the first 24 months of life. Pediatrics, 2015;13;617.

TE D

[26] Bailey LC, Forrest CB, Zhang P, Richards TM, Livshits A, DeRusso PA. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr, 2014;168:1063. [27] Gerber JS, Bryan M, Ross RK, Daymont C, Parks EP, Localio AR, et al. Antibiotic exposure during

AC C

EP

the first 6 months of life and weight gain during childhood. JAMA, 2016;315:1258.

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