Obstetrics and Gynecology

Asymptomatic Bacteriuria

Asymptomatic bacteriuria in pregnancy

1. What every clinician should know

Epidemiology

“Asymptomatic bacteriuria” is the presence of significant bacteriuria in a person without symptoms or signs of urinary tract infection. Urinary tract infection (UTI) is the most common bacterial infection to inflict a pregnant woman.

The prevalence of asymptomatic bacteriuria (ASB) in nonpregnant and pregnant women is 2% to 10% and depends on race, parity, and socioeconomic status. The incidence of pyelonephritis in pregnant woman with untreated bacteriuria is significantly increased: 20 to 30 fold. The incidence of symptomatic UTI in pregnancy is 7.4% and pyelonephritis in pregnancy is 0.5% to 2%. The risk factors associated with ASB includes low socioeconomic status, diabetes, sickle cell disease or traits, multiparity, history of UTI, and anatomic or functional urinary tract abnormalities.

The anatomic and physiologic changes during pregnancy increase a woman’s susceptibility to UTI and pyelonephritis. The progesterone induces dilation of the renal pelvis and ureter, the decreased peristalsis of the ureters, the mechanical obstruction from the enlarging uterus, and the increased bladder capacity resulted in urinary stasis. Along with the change in urine pH and osmolality, glucosuria and aminoaciduria also facilitate bacterial growth and thus progression to pyelonephritis. A review of 20 descriptive studies from the 1960s found 30% of untreated ASB resulted in symptomatic UTIs as compared to 1.8% of nonbacteriuric controls. In a recent prospective longitudinal study from 2000 to 2001, the incidence of hospitalization for acute pyelonephritis was 1.4% as compared to 3% to 4% rate in the early 1970s, prior to routine ASB screening.

Kass, in his 1959 randomized, placebo-controlled trial, demonstrated treatment of bacteriuric pregnant women prevented pyelonephritis and decreased preterm delivery by 20%. Subsequent series of studies and Cochrane review also support the benefits of detection and early treatment of ASB with antibiotics by significantly reducing the incidence of symptomatic UTI, preterm births, and low birth weight. Thus the screening for ASB in pregnancy and treatment to prevent UTI became the standard of obstetrical care.

National guidelines

The U.S. preventive service task force and American Congress of Obstetricians and Gynecologists most strongly recommend screening and treating for asymptomatic bacteriuria (ASB) in pregnant women. A midstream clean catch urine specimen should be collected for screening culture at 12 to 16 weeks’ gestation or at the first prenatal visit, if later. The presence of at least 105 colony-forming units per mL (CFU/mL) of urine with a single uropathogen is considered a positive test result. Internationally other organizations such as Infectious Disease Society of America, the National Institute for Clinical Excellence, the European Association of Urology, the Canadian Task Force on Preventive Care, and the Scottish Intercollegiate Guidelines Network also developed similar recommendations. The benefits of early detection and treatment of ASB with antibiotics significantly reduce the incidence of symptomatic UTI and low birth weight.

There is an ongoing debate on the value of routine screening where the prevalence of ASB is low, given the limited role of ASB on perinatal outcome, the effective management of symptomatic UTI, the recent identification of other subclinical infections associated with prematurity, and the improvement in prematurity management.

2. Diagnosis and differential diagnosis

Screening and Diagnosis

Significant bacteriuria is defined as >105 colony-forming units of a single uropathogen/mL in two consecutive midstream urine specimens or >102 CFU/mL in a catheterized urine specimen. The original criteria of two consecutive clean-catch urine specimens have 96% sensitivity for bacteriuria. However, the detection of >105 CFU/mL in a single-voided midstream specimen is a more practical alternative with positive predictive value of 80%.

A prospective study of 3,254 pregnant women to identify the optimal time for screening found a single urine specimen obtained at 12 to 16 weeks gestation identified 80% of women with ASB. Most national guidelines recommend a single urine culture in the first prenatal visit. However, some authors recommend culture in each trimester of pregnancy. Approximately 1% to 2% of pregnant women who tested negative for ASB in the first trimester will develop UTIs in late pregnancy.

Since the pregnant woman is without symptom, the gold standard for ASB screening in pregnancy is the urine culture. Even though Escherichia coli is responsible for 70% to 80% of ASB, there are other Enterobacteriaceae spp., gram-negative and gram-positive uropathogens. In the current environment of increasing antibiotic-resistant microorganisms, the urine cultures can identify the specific uropathogen and their antibiotic resistance pattern. Thus allow the physician to select the treatment with more efficacy and low resistance.

A urine culture is more expensive, requires trained personnel, and requires 24 to 48 hours for results. Multiple studies have evaluated several rapid screening tests, and none performs adequately to replace the semiqualitative culture for diagnosis of ASB. Urine microscopy and pyuria have low sensitivity (25%) and high specificity (99%).

Urine dipstick for leukocyte esterase and nitrites consistently have low sensitivity and high specificity. A meta-analysis of accuracy of the urine dipstick found poor sensitivity of 0.46 (95% CI 0.38 to 0.56) and specificity of 0.98 (95% CI 0.97 to 1.00). The accuracy of nitrite was high (diagnostic odds ratio of 165) and that negative test results for both leukocyte esterase and nitrite could rule out UTI. In a study comparing various test results and a prospective observational study, the gram-staining of uncentrifuged urine have very low positive predictive value of 7.3% to16%. Systematic review of eight prospective studies on diagnostic tests for ASB in pregnancy involving any one or a combination of rapid urine tests did not support their use other than for urine cultures.

Dipslide culture consists of 2 x 5 cm plastic paddle coated on one side with MacConkey medium (red) for gram-negative bacteria and other side with cysteine lactose electrolyte deficient medium (green) for all known uropathogenic bacteria. The dipslide is inoculated by dipping the agar-coated slides into urine and then placing in an incubator at 37° C for 24 hours. The microbial density on the slide is compared to a model chart and a positive result is designated when the colony concentration was 105 CFU/mL or higher of a single microorganism. A positive dipslide increases the probability of ASB to 98% and a negative dipslide reduces the probability to less than 1%. A positive dipslide can then be cultured to identify the microorganism and the antibiotic resistance pattern.

Using a decision analytical model, first trimester urine culture screening and treatment of ASB to prevent pyelonephritis was cost beneficial over a wide range of estimates with an ASB rate >2%. Using baseline probability and cost estimates for cohorts of 1,000 patients, no screening resulted in 23.2 cases of pyelonephritis, versus 16.2 cases with the dipstick strategy and 11.2 cases with the culture strategy. Both screening strategies and treatment of ASB were more cost beneficial than no screening. The culture strategy was most cost beneficial, but not significantly better than the dipstick strategy. Currently, the Netherlands ASB study group is conducting a cost and effects study using the dipslide culture strategy.

Microbiology

Enterobacteriaceae (90%) – E. coli, Klebsiella, Enterobacter. E. coli causes 70% to 80% of symptomatic and asymptomatic bacteriuria. Uropathogenic strains of E. coli with virulence determinants such as toxins, adhesins, pili, or fimbriae that can adhere to uroepithelial cells and in turn, progress to symptomatic infection. Only 22% of strains of E. coli from women with ASB as compared to 75% from women with pyelonephritis have these virulence determinants.

Other gram-negative microorganisms include Proteus mirabilis, Pseudomonas, and Citrobacter. Proteus are resistant to nitrofurantoin treatment.Gram-positive microorganisms include Staphylococcus saprophyticus andEnterococcusspp. Staphylococcus saprophyticus can cause a symptomatic UTI in nonpregnant women, but is infrequently reported in ASB during pregnancy. Staphylococcus aureus is not a typical uropathogen, except in a study of pregnant women from the low-income population in Nigeria.

Group B streptococci (Streptococccus agalactiae) is commonly found in the vagina and in the urine of 2% to 7% of pregnant women. Its isolation in the urine during pregnancy is a marker for heavy colonization and association with preterm rupture of membranes, preterm delivery, and early onset of neonatal sepsis. A randomized trial of treatment with penicillin for any colony count of GBS isolates in urine did reduced preterm rupture membranes and preterm delivery. Center for Disease Control recommends all pregnant women with GBS bacteriuria should be treated for UTI during pregnancy and should receive intrapartum antibiotic prophylaxis to prevent neonatal infection.

Other bacteria – up to 15% isolates from urine – includes Ureaplasma urealyticum and Gardnerella vaginalis. Women with urologic device are at risk for polymicrobial bacteriuria includes Pseudomonas aeruginosa, Proteus mirabilis, Providencia stuartii, and Morganella morganii. A large percentage of pregnant women also have anaerobic and other fastidious microorganisms in their urine. The significance of these organisms and their association to perinatal outcome is unknown. There is no evidence to support routine examination for these organisms.

3. Management

In treating pregnant women for urinary tract infection, the antibiotic must be safe for mother and fetus. Most antibiotics do cross the placenta, and therefore the treating physician needs to consider the agents and the gestational age of the pregnancy. Drugs with known adverse fetal effects include fluoroquinolones, chloramphenicol, and tetracycline. The physiologic changes of pregnancy include increase in maternal vascular volume by 40% to 50% and increased renal blood flow and glomerular filtration by 30% to 50%. Thus the serum and tissue drug concentration may be lower. Both of these considerations should play a role in the physicians’ selection of the antibiotics, doses, and duration of therapy.

The national guidelines suggest recommendations for the common uropathogen antimicrobial agents. Since the diagnosis of ASB is based on urine culture with sensitivity, the choice of antibiotics should be based on this result and on the local microbial resistance patterns for excellent efficacy and low resistance rates, rather than on evidence from clinical trials.

A variety of oral antimicrobial regimens for the treatment of pregnant women with ASB has been recommended:

  • Single-dose treatments include amoxicillin 3 g, ampicillin 2 g, cephalosporin 2 g, nitrofurantoin 200 mg, trimethoprim-sulfamethoxazole 320/1600 mg.

  • The 3-day course treatments include amoxicillin 500 mg TID, ampicillin 250 mg QID, cephalosporin 250 mg QID, ciprofloxacin 250 mg BID, levofloxacin 250 mg Q day, nitrofurantoin 50 to 100 mg QID, trimethoprim-sulfamethoxazole 160/800 BID.

  • Other regimens include nitrofurantoin 100 mg QID for 10 days, nitrofurantoin 100 mg BID for 7 days, nitrofurantoin 100 mg QHS for 10 days.

  • The treatment failure regimen is nitrofurantoin 100 mg QID for 21 days.

A multicenter, double-blind, randomized, placebo-controlled noninferiority trial compared 1-day to 7-day course of twice daily 100 mg capsules of nitrofurantoin. The 1-day course had lower bacteriologic cure rates at treatment day 14 (75.7% vs. 86.2%; cure rate difference was -10.5% [95% CI -16.1% to -4.9%]). There was lower mean birth weight and mean gestational age at delivery in the 1-day treatment group. However, there were no statistical differences in preterm deliveries (11.0% vs. 8.9%) or in the rate of low birth weight (13.2% vs. 8.0%). The number of patients with ASB needed to treat in order to prevent one episode of pyelonephritis was seven (95% CI 6, 9). Early dx and treatment of ASB resulted in a 75% reduction in pyelonephritis.

Three recent Cochrane reviews have addressed the different antibiotic regimens and the duration of therapy for ASB in pregnancy. The 2009 Cochrane review included 14 studies that compared antibiotic treatment to placebo or no treatment. Antibiotic therapy was effective in clearing ASB (RR 0.25, 95% CI 0.14 to 0.48), reduce the incidence of pyelonephritis (RR 0.23, 95% CI 0.13 to 0.41), and reduce the incidence of low birth weight babies (RR 0.66, 95% CI 0.49 to 0.89), but there was no difference in preterm delivery.

The 2010 Cochrane review included five studies, involving 1,140 women with ASB, that could not identify the most effective and safest initial treatment. The 1-day course of nitrofurantoin had more persistent infection than the 7-day course (RR 1.76, 95%CI 1.29 to 2.40). Ampicillin was better tolerated than pivmecillinam.

The 2011 Cochrane review included 13 studies involving 1622 women compared single-dose treatment versus 4- to 7-day treatments. The "no cure rate" was slightly higher for the single-dose; however, the results were not statistically significant from heterogeneity of the studies (different agents: RR 1.43, 95% CI 0.87 to 2.34) and (same agents: RR 0.98, 95% CI 0.49 to 1.95). There were slight differences for preterm births (different agents: RR 1.09, 95% CI 0.52 to 2.26) and pyelonephritis (different agents: RR2.97, 95% CI 0.51 to 17.28). Single-dose treatment was associated with less side effects (same agents: RR 0.77, 95% CI 0.61 to 0.97) and (different agents: RR 0.16, 95% CI 0.04 to 0.58).

Recurrent UTI/ASB

Regardless of the antibiotic regimen given, the recurrence rate is approximately 30%. This may reflect a covert upper tract infection and the need for 21 days therapy and/or suppressive therapy. See Table I. Antibiotics treatment of asymptomatic bacteriuria during pregnancy.

Table 1

Antibiotics treatment of asymptomatic bacteriuria during pregnancy

4. Complications

Significance of bacteriuria in pregnancy

Adverse pregnancy outcome

Pyelonephritis – the benefit of screening and treating ASB is outlined in Screening/diagnosis and Management sections. In a recent prospective longitudinal study from 2000 to 2001, the incidence of hospitalization for acute pyelonephritis was 1.4%. Acute pyelonephritis occurred more often in the second trimester (53%). Complications from pyelonephritis in pregnancy include anemia (23%), septicemia (17%), transient renal dysfunction (2%), pulmonary insufficiency (7%), preterm birth (5%), and low birth weight (7%).

Preterm delivery studies have found consistent association with ASB but the interpretation remains controversial. The Cardiff birth survey – 25,844 births – found ASB was not associated with preterm delivery (OR 1.2; 95% CI 0.9 to 1.5). Meis et al. found significant association between bacteriuria and medically indicated preterm births (OR 2.03; 95% CI 1.5 to 2.8) but not to spontaneous preterm births (OR 1.07; 95% CI 0.78 to 1.46).

A meta-analysis of 17 cohort studies found strong association between untreated ASB and low birth weight. The cohort studies found the treatment of ASB did reduce low birth weight by two thirds: (RR 0.65; 95% CI 0.75 to 0.74) or a reduction of 3.4%. The randomized trials had lower reduction: (RR 0.56; 95% CI 0.43 to 0.73) or a reduction of 6.4%.The recent Cochrane meta-analysis of antibiotic therapy for ASB found treatment was effective in reducing the incidence of low birth weight babies (RR 0.66, 95%CI 0.49 to 0.89). But no difference in preterm delivery (OR 0.33; 95%CI 0.10 to 1.36).

The mechanism between preterm labor and in trial of symptomatic pyelonephritis is well defined. However, the association between preterm labor and ASB has not been established, but a theoretic role of bacteria producing phospholipase A2 and the subsequent activation of prostaglandin.

The U.S. Physician Consortium for performance improvement and two other groups in Australia and the United Kingdom found poor adherence to screening for ASB, despite the uniform national guideline. This was more common among the low SES population with higher risk for ASB, UTI, low birth weight, and preterm labor.

5. Prognosis and outcome

Urinary tract infection (UTI) is the most common bacterial infection to inflict a pregnant woman. Pyelonephritis (kidney infection) can be a very severe infection with many maternal and obstetrical complications. Complications from pyelonephritis in pregnancy include anemia, bacteria in blood stream or sepsis, temporary partial kidney failure, pulmonary insufficiency, preterm birth, and delivery of low birth weight baby.

“Asymptomatic bacteriuria” is the presence of significant bacteria in urine without symptoms or signs of urinary tract infection and 2% to 10% of pregnant women may have asymptomatic bacteriuria. If undiagnosed and untreated, the risk of pyelonephritis is 20 to 30 times higher. ACOG recommends a urine culture screening test at 12 to 16 weeks gestation or first prenatal care visit. If you should have “asymptomatic bacteriuria,” we will treat you with antibiotic to prevent potential complications of a urinary tract infection, kidney infection, or low birth weight baby.

6. What is the evidence for specific management and treatment recommendations

"US preventive service task screening for asymptomatic bacteria: recommendation statement". Agency for Healthcare Research and Quality (AHRQ ). 2012. pp. 12-3. http://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/guide/index.html.

(US Agency for Healthcare Research and Quality guideline on preventive health care.)

Smaill, F. "Asymptomatic bacteriuria in pregnancy". Best Pract Res Clinl Ob Gyn.. vol. 21. 2007. pp. 439-50.

(Excellent and update review for practicing physicians.)

Nicolle, LE, Bradley, S, Colgan, R. "Infectious Diseases Society of America Guidelines for diagnosis and treatment of asymptomatic bacteriuria in adults". Clin Infect Dis. vol. 40. 2005. pp. 643-54.

(Recent guidelines on ASB in men, women, and pregnant women from the Infectious Diseases Society of America.)

Smaill, FM, Vasquez, JC. "Antibiotics for asymptomatic bacteriuria in pregnancy". Cochrane Database Syst Rev. 2007. pp. CD000490.

Guinto, VT, DeGuia, B, Festin, MR, Dowswell, T. "Different antibiotic regimens for treating asymptomatic bacteriuria in pregnancy". Cochrane Database Syst Rev. 2010. pp. CD 007855.

Widmer, M, Gülmezoglu, AM, Mignini, I, Roganti, A. "Duration of treatment for asymptomatic bacteria in pregnancy". Cochrane Database Syst Rev. 2011. pp. CD000491.

(Series of Cochrane collaboration systematic reviews on ASB in pregnancy.)

Hill, JB, Sheffield, JS, McIntire, DD, Wendel, GD. "Acute pyelonephritis in pregnancy". Obstet Gynecol. vol. 105. 2005. pp. 18-23.

(A recent longitudinal study on prevalence and risk factors associated with pyelonephritis.)

Andrews, WW, Goldenberg, RL, Owen, J. "Screening and treatment of asymptomatic bacteriuria of pregnancy to prevent pyelonephritis: A cost-effectiveness and cost-benefit analysis". Obstet Gynecol. vol. 86. 1995. pp. 119-23.

(Good decision analytical model on cost benefit for screening/treatment strategies.)

Einarson, A, Shuhaiber, S, Koren, G. "Effects of antibacterial on the unborn child: what is known and how should this influence prescribing". Paediatr Drugs. vol. 3. 2001. pp. 803-16.

(Review of antibiotic therapy during pregnancy.)

"AAP and ACOG. Chapter 5: Preconception and antepartum care. In Guidelines for perinatal care". 2012. http://www.acog.org.

(Excellent AAP and ACOG guideline for obstetrical care.)
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