The Voided Urinary, Perineal, and Faecal Microbiota Among Children and Adolescents - the PpUF-study.

Official title

The Voided Urinary, Perineal, and Faecal Microbiota Among Children and Adolescents With Overactive Bladder and Daytime Urinary Incontinence and Healthy Children and Adolescents - the PpUF-study.

Overview

The aim of this study is to investigate whether the voided urinary, perineal/preputial, and the fecal microbiota are different between children suffering from Overactive Bladder (OAB) and Daytime Urinary Incontinence (DUI) compared to age- and gender-matched healthy children without bladder symptoms. Moreover, the study aims to investigate if the microbiota is different according to the severity of DUI and if the microbiota is changed throughout treatment of DUI. A follow-up study will as well be performed on healthy children to investigate how the microbiota evolves with increasing age and pubertal stage. Children with OAB and DUI will be recruited from involved pediatric departments, and specimen in the form of urine, perineal/preputial swabs, and feces will be collected according to the protocol.

Detailed description

In Denmark, Daytime Urinary Incontinence (DUI) affects up to 22 % of children aged 5-7 years and 4.5 % of children aged 11-15 years. The most common cause of DUI is an idiopathic overactive bladder (OAB), leading to urgency (sudden desire to void) and frequency (frequent urinations). The cause of OAB among children and adolescents is not yet fully understood, however, studies among adults suggest dysbiosis of the voided and fecal microbiota as a possible explanation of OAB and DUI. This possible explanation is strengthen by the overlap in the symptomatology of OAB and urinary tract infections. Whether a different bacterial composition of the voided urinary, the perineal/preputial, and the fecal microbiota is evident for children with OAB and DUI compared to healthy children without bladder symptoms is yet to be elucidated.

The objectives of the present study are to investigate

1. if the bacterial composition of the voided urinary, the perineal/preputial, and the fecal microbiota differs between children with OAB and DUI and healthy children without bladder symptoms. 2. if the bacterial composition of the voided urinary, the perineal/preputial, and the fecal microbiota differs according to the severity of DUI. 3. if the bacterial composition of the voided urinary, the perineal/preputial, and the fecal microbiota alters concurrently with the treatment of DUI.

Moreover the objective of the study is to investigate how the microbiota changes with increasing age and pubertal stage.

Methods:

The study consists of three sub-studies. Sub-study one is a cross-sectional study comparing the microbiota of children with OAB and DUI and healthy children. The two other sub-studies are cohort follow-up-studies investigating the microbiota of children with OAB and DUI and healthy children without bladder symptoms, respectively. Seventy children with OAB and DUI and 40 healthy children without bladder symptoms will be recruited. Besides specimen collection (urine, swabs from the perineum (girls) and preputium (boys), and feces), the study participants and/or their parents are asked to fill in questionnaires, frequency and volume charts, and Dry Pies.

All children participating in the first sub-study are invited to enter the cohort follow-up-study. From participants with OAB and DUI willing to enter the follow-up-study, urine samples, swabs from the perineum/preputium, and fecal samples will be collected before initiating a new treatment modality of daytime urinary incontinence, and healthy children will be invited to a follow-up every 6 months until adulthood.

Primary outcome measures

• Differences in the voided urinary microbiota between children with overactive bladder and daytime urinary incontinence and healthy children without bladder symptoms. [Time frame: Baseline]
• Differences in the perineal/preputial microbiota between children with overactive bladder and daytime urinary incontinence and healthy children without bladder symptoms. [Time frame: Baseline]
• Differences in the fecal microbiota between children with overactive bladder and daytime urinary incontinence and healthy children without bladder symptoms. [Time frame: Baseline]
• Differences in the voided urinary microbiota depending on severity of daytime urinary incontinence. [Time frame: Baseline]
• Change in the voided urinary microbiota concurrently with non-pharmacological and pharmacological treatment of daytime urinary incontinence. [Time frame: Baseline AND 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after enrolment.]
• Change in the perineal/preputial microbiota concurrently with non-pharmacological and pharmacological treatment of daytime urinary incontinence. [Time frame: Baseline AND 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after enrolment.]
• Change in the fecal microbiota concurrently with non-pharmacological and pharmacological treatment of daytime urinary incontinence. [Time frame: Baseline AND 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after enrolment.]
• Change in the voided urinary microbiota among healthy children with increasing age and puberty stage. [Time frame: Baseline AND 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after enrolment.]
• Change in the perineal/preputial microbiota among healthy children with increasing age and puberty stage. [Time frame: Baseline AND 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after enrolment.]
• Change in the fecal microbiota among healthy children with increasing age and puberty stage. [Time frame: Baseline AND 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months after enrolment.]

Eligibility criteria

Inclusion criteria

• Overactive bladder as per International Children's Continence Society criteria (cases only).
• At least two wet days per week (cases only).
• No prior pharmacological treatment of OAB and DUI (cases only).
• No lower urinary tract symptoms (healthy participants only).
• Negative urine dipstick test

Exclusion criteria

• No known urogenital abnormality affecting the lower urinary tract function.
• No known gastrointestinal or neurological diseases.
• No use of systemic drugs within five half-lives of the drug.
• No use of systemic antibiotics within three months before inclusion
• No current urinary tract infection.
• No urinary tract infection within the last three months prior to inclusion.
• No current constipation.
• Abnormal uroflowmetry (healthy participants only).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Denmark · 4 centers

• Department of Pediatrics, Aalborg University Hospital — Aalborg
• Department of Pediatrics, Aarhus University Hospital — Aarhus
• Department of Pediatrics, Regional Hospital West Jutland — Herning
• Department of Pediatrics, North Denmark Regional Hospital — Hjørring

Publications

• Warner TC, Baandrup U, Jacobsen R, Boggild H, Aunsholt Ostergaard PS, Hagstrom S. Prevalence of nocturia and fecal and urinary incontinence and the association to childhood obesity: a study of 6803 Danish school children. J Pediatr Urol. 2019 May;15(3):225.e1-225.e8. doi: 10.1016/j.jpurol.2019.02.004. Epub 2019 Feb 15. PMID 30930018
• Austin PF, Bauer SB, Bower W, Chase J, Franco I, Hoebeke P, Rittig S, Walle JV, von Gontard A, Wright A, Yang SS, Neveus T. The standardization of terminology of lower urinary tract function in children and adolescents: Update report from the standardization committee of the International Children's Continence Society. Neurourol Urodyn. 2016 Apr;35(4):471-81. doi: 10.1002/nau.22751. Epub 2015 Mar PMID 25772695
• Xing D, Wang YH, Wen YB, Li Q, Feng JJ, Wu JW, Jia ZM, Yang J, Sihoe JD, Song CP, Hu HJ, Franco I, Wen JG. Prevalence and risk factors of overactive bladder in Chinese children: A population-based study. Neurourol Urodyn. 2020 Feb;39(2):688-694. doi: 10.1002/nau.24251. Epub 2019 Dec 5. PMID 31804751
• Chung JM, Lee SD, Kang DI, Kwon DD, Kim KS, Kim SY, Kim HG, Moon du G, Park KH, Park YH, Pai KS, Suh HJ, Lee JW, Cho WY, Ha TS, Han SW; Korean Enuresis Association. Prevalence and associated factors of overactive bladder in Korean children 5-13 years old: a nationwide multicenter study. Urology. 2009 Jan;73(1):63-7; discussion 68-9. doi: 10.1016/j.urology.2008.06.063. Epub 2008 Sep 30. PMID 18829077
• Franco I. Overactive bladder in children. Nat Rev Urol. 2016 Sep;13(9):520-32. doi: 10.1038/nrurol.2016.152. Epub 2016 Aug 17. PMID 27530266
• Pearce MM, Zilliox MJ, Rosenfeld AB, Thomas-White KJ, Richter HE, Nager CW, Visco AG, Nygaard IE, Barber MD, Schaffer J, Moalli P, Sung VW, Smith AL, Rogers R, Nolen TL, Wallace D, Meikle SF, Gai X, Wolfe AJ, Brubaker L; Pelvic Floor Disorders Network. The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol. 2015 Sep;213(3):347.e1-11. doi: 10.1016/j.ajog.2015.07.009. Epu PMID 26210757
• Karstens L, Asquith M, Davin S, Stauffer P, Fair D, Gregory WT, Rosenbaum JT, McWeeney SK, Nardos R. Does the Urinary Microbiome Play a Role in Urgency Urinary Incontinence and Its Severity? Front Cell Infect Microbiol. 2016 Jul 27;6:78. doi: 10.3389/fcimb.2016.00078. eCollection 2016. PMID 27512653
• Okamoto T, Hatakeyama S, Imai A, Yamamoto H, Yoneyama T, Mori K, Yoneyama T, Hashimoto Y, Nakaji S, Ohyama C. Altered gut microbiome associated with overactive bladder and daily urinary urgency. World J Urol. 2021 Mar;39(3):847-853. doi: 10.1007/s00345-020-03243-7. Epub 2020 May 17. PMID 32419054

Identifiers

NCT: NCT07535619 · N-20200070

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗