Clinical trial NCT03275623
Conditions: Cystitis Cystitis;Puerperium Pyelonephritis
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2017-09-15; Completion date: 2019-03-18
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to determine if treatment of pregnant women with urine cultures with a low level of bacteria (less than 100,000 colony forming units (CFU)) may decrease adverse pregnancy outcomes.

Detailed description:

Arms: arm 1: Standard prenatal care with treatment for any urine culture with growth of 1- 100,000 CFU of any organism. arm 2: Standard prenatal care without treatment for any urine culture with growth of 1- 100,000 CFU of any organism.
Interventions: intervention 1: Antibiotic intervention 2: Standard Prenatal Care
Intervention descriptions: intervention 1: Those randomized for treatment will be prescribed the most commonly used antibiotic for urinary tract infections in pregnancy. This includes: Nitrofurantoin, Cephalexin, and Amoxicillin. It is unsure which antibiotic the participant will receive but a majority of the time it will be one of the above named antibiotic. The choice will be determined by the physician, but will accommodate participants' prior medication history and adverse events. intervention 2: Continued surveillance of urinary cultures

Protocol documents:
Prot_SAP_000.pdf: 
IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management of Sub-Clinical Bacteriuria in Pregnancy: A Feasibility Trial 
 
NCT03275623 
 
Version Date: 08/22/2017 
 
 
 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
                 
 
 
Management of Sub-Clinical Bacteriuria in Pregnancy: A Feasibility Trial 
   
Akwugo A. Eziefule, MD 
Jerrie S. Refuerzo, MD 
Joey A. England, MD 
Diana A. Racusin, MD 
 
Background: 
 
Bacterial Colonization in the Urine 
Assessment and treatment of bacterial colonization in the urine during pregnancy is a routine part of 
prenatal care.1 A urinary tract infection (UTI) is defined as urine culture colonization >100,000 (105) 
colony forming units (CFU) of bacteria per ml with signs and symptoms of UTI including dysuria, 
frequency, urgency, suprapubic pain, and/or hematuria.1-3 Asymptomatic bacteriuria (ASB) is defined as 
urine culture colonization > 105 CFU in the absence of signs and symptoms of UTI, and occurs in 2-10% of 
pregnancies.3,4 Pregnant women with a UTI or ASB are routinely prescribed antimicrobial therapy based 
on identified organisms and sensitivities. 
 
Sub-Clinical Bacteriuria 
Sub-clinical bacteriuria (SCB) occurs when urine culture colonization is between 1 - 105 CFU. The 
frequency by which SCB occurs in pregnancy is unknown. It is also unknown the rate of progression from 
SCB to UTI and/or ASB, and subsequently development in to pyelonephritis. Moreover, there are no 
current guidelines that direct management in this particular condition in pregnancy. In current clinical 
practice, there is strong variation in care such that many patients are treated, despite the lack of proven 
benefit while other clinicians do not treat. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Schematic of potential progression of bacterial colonization in the urine. 
 
Clinical Importance 
Bacterial colonization in the urine during pregnancy can lead to adverse maternal and neonatal 
outcomes. Pyelonephritis is the primary concern in pregnancy due to its association with potential 
urosepsis, renal abscess, decline in renal function, preterm labor and preterm birth.5 Although untreated 
Neg Urine Culture 
UTI 
ASB 
SCB 
Pyelonephritis 
2.0 % 
Unk 
2.4% 
Unk 
Unk 
Unk 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
UTI is the greatest risk factor for developing pyelonephritis, ASB can also lead to pyelonephritis. In a 
recent randomized controlled trial of 4200 women in the Netherlands, they report that the incidence of 
pyelonephritis is only 2.4% when ASB is untreated compared to 0.6% when treated.6 With such a low 
incidence, there is new debate whether to treat or expectantly manage ASB. This same debate also 
pertains SCB. It is unknown whether treatment or expectant management of SCB will lead to difference 
in the rate of progression to UTI and/or SCB, and ultimately pyelonephritis. 
 
Risk of Antimicrobial Therapy 
The two main risks of empiric antimicrobial therapy include potential for adverse drug effects and 
contribution to drug resistance.  The use of antibiotics is not benign especially during pregnancy. 
Adverse drug effects include masking a diagnosis with empiric treatment of symptoms and no 
identification of an organism. Often times the diagnosis maybe correct, but the antibiotic that was 
chosen for treatment does not have sufficient coverage of the organism that is causing the infection. 
Common side effects to routinely used antibiotics such as nitrofurantoin, sulfa, amoxicillin and 
cephalexin includes rash and diarrhea.9-10 The rise in antibiotic resistance over the past decades is 
evidence to the clinical consequences of unnecessary antimicrobial treatment across the disciplines in 
medicine. Such consequences also have been evident in the field of obstetrics. Nearly 50% of urinary 
isolates are resistant to routine ambulatory antibiotic therapy. Zhanel et al. looked at resistance to 
treatment in the NAUTICA trial. The goal of the North American Urinary Tract Infection Collaborative 
Alliance (NAUTICA) study was to determine antibiotic susceptibility to commonly used agents for urinary 
tract infections against outpatient urinary isolates obtained in various geographic regions in the USA and 
Canada. This study reports higher rates of antibiotic resistance in US versus Canadian outpatient urinary 
isolates and demonstrates the continuing evolution of resistance to antimicrobial agents.7 Thus, if 
antibiotic therapy is not necessary for the management of subclinical cystitis due to low incidence of 
progression to pyelonephritis, it should not be prescribed. 
 
Gap in Knowledge 
The gap in knowledge is whether the risks and benefits of empiric treatment with antimicrobial therapy 
for treatment of SCB outweigh the risk and benefits of developing UTI, ASB or pyelonephritis from 
expectant management or no treatment of SCB. 
 
Rationale for this clinical trial 
The rational for this clinical trial is to determine if treatment of urine cultures with organisms of 1 – 
100,000 CFU are beneficial to pregnancy outcomes when obtained at routine prenatal clinic visits. In 
current clinical practice, there is a strong variation in care such that many patients are treated for urine 
cultures with organisms of <105 CFU despite the lack of proven benefit while other clinicians do not 
treat. 
 
If it is found that treatment of urine cultures with 1 - 105 CFU impact clinical care of a pregnant patient 
by decreasing adverse pregnancy outcome, guidelines will need to be modified to include treatment 
recommendations of urine cultures that do not currently meet criteria of a urinary tract infection. On  
the other hand, if there is no benefit to treatment of urine cultures 1 - 105 CFU, then unnecessary 
antibiotics could be avoided thereby potentially reducing unknown adverse effects to these drugs or 
resistance to antibiotics, which continues to be an alarming health challenge. 
 
Hypothesis: 
We hypothesize that treating urine cultures with organisms between 1- 105 CFU grown in culture media 
in a pregnant population leads to improvement of pregnancy outcomes. 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
 
Objectives: 
To determine the rate of progression from SCB to either UTI or ASB with antimicrobial treatment of 
urine cultures with organisms of 1- 105 CFU compared to no treatment at prenatal care clinic visits. 
 
Study Design: 
For this pilot study, we propose a feasibility trial to determine if a randomized control trial for the 
treatment of subclinical cystitis to prevent pyelonephritis and culture proven cystitis. The trial will 
investigate the effects of treatment or non-treatment of urine cultures obtained during prenatal care 
visits prompted by a positive urinalysis or symptoms, and determine if a randomized control trial is 
needed to further investigate outcomes. 
 
Patients meeting clinical indications will have a urine culture ordered due to two reasons: a) symptoms 
of a UTI or b) positive UA suspicious for infection/inflammation. A negative urine analysis is defined as 
an analysis that is negative for bacteria, leukocyte esterase, nitrites, and protein. A negative urine 
culture is defined as no growth or any amount of skin flora only. 
 
Inclusion Criteria: 
We will include pregnant women who seek prenatal care within the University of Texas Health System 
with UT Physicians. 
 
Exclusion Criteria: 
We will exclude women: 
 
Less than 18 years of age 
 
Risk factors to complicated UTI (including but not limited to: diverticula, urolithiasis, renal cysts, 
indwelling catheter, intermittent catheterization, stent placements, nephrostomy tubes, 
neurogenic bladder, cystocele, vesicoureteral reflux, ileal conduit)8 
 
Use of immunosuppressant drugs 
 
Abnormalities of the urinary tract (including but not limited to: known ureteric or urethral 
strictures, tumors of the urinary tract, pelvicalyceal obstruction, congenital anomalies, history 
of urological procedures) 
 
History of renal disease including renal failure and transplants 
 
Urine culture > 105 CFU of any organism 
 
Those with a urine culture for bacteria but 1 - 105 CFU will be randomized to one of two management 
plans: 
1. Prenatal care with treatment for any urine culture with growth of 1- 105 CFU of any organism 
2. Prenatal care without treatment for any urine culture with growth of 1-105 CFU of any organism 
 
Randomization: 
Randomization will be performed based on a computer-generated list that will be created by a non- 
clinical member of the research team. Randomization will be stratified by clinic site. A permuted block 
randomization with a random fashion will be used to prevent imbalances between sites. At subsequent 
clinic visits, clinic staff will continue to obtain urine culture from symptomatic patients or patients where 
further work up of a urine culture is warranted. ‘Physician to treat urine culture with 1- 100,000 (105) 
CFU” or ‘Physician to NOT treat urine culture with 1-100,000 (105) CFU”, based on the computer- 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
generated list, stored on the RedCap database. The research nurses and team may access the RedCap 
database from any clinical site. 
 
Methods: 
At the initial prenatal care clinic visit all pregnant women will have their urine screened with a UA and 
urine culture. Patients meeting inclusion criteria will be approached for randomization. 
 
Those with a urine culture positive for bacteria 1- 10x5 CFU will be randomized to treatment or no 
treatment. 
 
Those randomized to NO treatment will have a test of cure performed three weeks after initial negative 
urine culture or at next clinical visit thereafter. 
 
Those randomized for treatment will be prescribed the most commonly used antibiotic for urinary tract 
infections in pregnancy. This includes: Nitrofurantoin, Cephalexin, and Amoxicillin. It is unsure which 
antibiotic the participant will receive but a majority of the time it will be one of the above named 
antibiotic. The choice will be determined by the physician, but will accommodate participants’ prior 
medication history and adverse events. 
 
Treatment will continue with a test of cure (urine culture performed after treatment with antibiotics) 
after each round of antibiotic until the urine culture shows no growth of bacteria and/or shows any 
amount of skin flora only. 
 
Written, informed consent will be obtained by a member of our research team, either a physician or 
research assistant. 
 
Once the patient is randomized to their designated arm, urine cultures will continue to be collected 
throughout prenatal care visits as clinically indicated. 
 
 
 
 
 
 
Urine culture 
Prenatal visits 
> 105  CFU= UTI and ASB 
1 - 105  CFU 
0 CFU = negative 
Exclude from study 
RANDOMIZE 
Monitorurine cultures 
Treatment 
N=25 
No treatment 
N=25 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
Figure 2. Flow diagram of study 
 
 
Primary Outcome: 
The incidence of cystitis defined as a urine culture with >105 at any point during antenatal care in this 
pregnancy population and the incidence of pyelonephritis. 
 
Data Collection: 
Data will be collected using standardized forms regarding maternal demographics, pregnancy 
characteristics, laboratory tests ordered in response to clinical signs or symptoms, medications 
prescribed and/or administered, and maternal/fetal adverse effects. Information for these forms will be 
obtained from UTPB and Bellaire clinical schedule, Care4 and AllScripts. The standardized forms that will 
be used during the study have been developed an approved by the Department of Obstetrics, 
Gynecology, and Reproductive Sciences for the purposes of uniform data collection of Internal Review 
Board approved studies being conducted. 
 
Sample Size: 
Because this is a feasibility trial, 50 patients will be recruited from all clinical sites. 25 patients will be 
randomized to prenatal care with treatment for any urine culture with growth between 1-105 CFU of any 
organism and 25 patients will be randomized to prenatal care without treatment for any urine culture 
with growth between 1-105 CFU of any organism. Recruitment will be stopped after recruitment of 50 
randomized patients or a 10-month time period whichever is completed first. 
 
Data Analysis 
Chi-square tests will be used to compare categorical data between the two treatment groups. Student’s 
t-test will be used to compare numerical data. The rate of progression to SCB, UTI, or pyelonephritis will 
be determined by clinical findings, diagnosis if admitted to the hospital and laboratory/urine culture 
results meeting criteria for those mentioned above. 
 
Procedures to Maintain Confidentiality 
All information and data will be kept on paper research charts that will be stored in a locked file cabinet 
within a locked research office of our research team/research coordinator. In addition, an electronic 
database of information and data will be stored on the computer of our research coordinator that is 
password protected, and in a locked office of the research coordinator. We will record subject 
information only by study code number. 
 
Potential Benefits and Risks 
There are potential risks and benefits to either treatment strategy. Since treatment or no treatment are 
currently both generally accepted standard of care options, providers, based on their personal 
preference and practice style, may choose to treat or not. Potential benefits of antibiotic treatment of 
those with 1- 10 5 CFU in urine culture may be decreased development of UTI, pyelonephritis, PTL, and 
preterm birth. Potential risks of treatment may be side effects of the medications as well as potential 
untoward effects of antibiotic therapy that may increase development of resistant organisms in urine 
and other locations (e.g. vaginal, cervix, gut) or may lead to change in flora (e.g. vaginal, cervix, gut) 
which may increase risk of adverse pregnancy outcomes. The benefits of no treatment may be to avoid 
unnecessary and unindicated antibiotic therapy. If evidence shows that treatment of this subset of 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
pregnant patients decreases adverse pregnancy outcome, this can leave a lasting impact on how we 
treat urinary tract infections in pregnancy. 


IRB NUMBER: HSC-MS-17-0294 
IRB APPROVAL DATE: 08/22/2017 
 
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