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Clinical Reviews


UTI in pregnancy: 6 questions to guide therapy

Crucial are treatment, test of cure, frequent screening until delivery, and antibiotic suppression, when indicated.

November 2004 · Vol. 16, No. 11

THE CASE: SIGNS AND SYMPTOMS

A 29–year–old nullipara at 18 weeks’ gestation complains of fevers and back pain. She had a diagnosis of urinary tract infection with sulfonamide-resistant Escherichia coli at 9 weeks of gestation, which was treated with nitrofurantoin, 100 mg by mouth twice a day for 7 days. A test of cure by urine culture was negative.

Now her temperature is 101°F and she has right costovertebral angle tenderness.

How should you proceed?

Anatomy is destiny, in the case of susceptibility to urinary tract infection (UTI). The female urethra is only 3 cm to 4 cm long, and its proximity to the vagina, anus, and rectum facilitates colonization of normal gastrointestinal flora in the bladder.1

Sexual activity also facilitates migration of normal gastrointestinal flora to the female urethra.2

Anatomical features of pregnancy exacerbate the female predisposition to urinary tract infection. In pregnancy, hormonal and mechanical changes that occur in the urinary tract lead to urinary stasis and ureterovesical reflux—setting the stage for urinary tract infection (FIGURE 1).

Who should be screened?

All pregnant women should be screened for UTI early in pregnancy, according to the American College of Obstetricians and Gynecologists.3

I recommend a urine culture screening for all pregnant women at their first prenatal visit.

Screen often if she has risk factors

I recommend frequent screening (at least every trimester) by urine culture, in pregnant women with any of these risk factors:

  • diabetes mellitus, including gestational diabetes4;
  • urologic abnormalities—specifically, neurogenic bladder;
  • prepregnancy (for example, 2 to 3 infections per year) and antepartum history of UTI prior to initiation of prenatal care5;
  • sickle cell hemoglobinopathy.5

Which test is best?

The gold standard for detecting bacteria in urine is by culture.

Which threshold to use?

The standard definition of a positive urine culture from a clean-catch, midstream, voided specimen is ≥100,000 colony forming units (CFU) per mL of a single organism. However, in symptomatic patients, the test’s sensitivity is increased by lowering the cut-off to 100 CFU/mL of a single organism.6 In women with urinary symptoms, only 50% of patients had 100,000 CFU/mL by urine culture collected from clean-catch, midstream, voided specimens, though all of them had positive cultures from suprapubic taps.

The clean-catch, midstream, voided specimen is the specimen of choice for practical purposes, since it is noninvasive and easily obtained in the office setting.

For the record: The presence of any organism represents UTI in specimens obtained via suprapubic aspiration of the bladder; 100 CFU/mL of a single organism is positive for specimens obtained by urethral catheterization.

I recommend that, when obtaining urine cultures via clean-catch, midstream, voided specimens:

  • for asymptomatic patients, use ≥100,000 CFU/mL of a single organism.
  • in symptomatic patients, use ≥100 CFU/mL of a single organism.

What about rapid tests?

Urinary sediment analysis and urine dipstick testing offer speed and low cost, but with lower accuracy than urine cultures, which require 24 to 48 hours for results and cost more.

Urinary sediment analysis can diagnose pyuria, defined as a clean-catch, midstream, voided specimen, which is spun and which has >10 leukocytes per high-power field.

Pyuria can occur without infection due to:

  • previous treatment with antibiotics,
  • contamination of urine sample by sterilizing solution,
  • contamination of urine sample with vaginal leukocytes,
  • chronic interstitial nephritis (such as analgesic abuse),
  • uroepithelial tumor, and
  • nephrolithiasis.

Pyuria on urinalysis has low sensitivity (25%) but high specificity (99%).

Bacteria visualized on microscopic examination is more sensitive (75%) but less specific (60%).7

Urinary dipstick testing—fast, convenient, and low in cost—is considered positive if it identifies either leukocyte esterase or nitrite. Positive leukocyte esterase signifies pyuria. Positive nitrite indicates the presence of enteric organisms that convert urinary nitrate to nitrite.

With either finding, dipstick sensitivity is only 50%, although specificity is 97%.7

I recommend:

  • If a symptomatic patient’s rapid test is positive, obtain a urine culture, empirically treat for UTI, and then use urine culture results to decide whether to continue treatment.
  • If an asymptomatic patient’s rapid test is positive, obtain a urine culture and treat only if the culture is positive.

What urinary tract disorders occur in pregnancy?

First, determine if the patient has urinary tract symptoms and, if so, whether the symptoms are typical of upper or lower urinary tract infections.

Lower urinary tract symptoms:

  • dysuria
  • frequency
  • urgency
  • suprapubic pain
  • hematuria in the absence of fever and systemic symptoms

Frequency, of course, is difficult to ascertain in pregnancy, since most women experience this complication secondary to increased urinary output due to higher fluid intake, increased plasma volume expansion, and increases in renal blood flow and glomerular filtration rate.

Upper urinary tract symptoms:

  • fever
  • chills
  • flank pain
  • nausea and vomiting
  • The patient may or may not have the symptoms of lower urinary tract infection, as well.

Positive culture and no symptoms

This profile is typical of asymptomatic bacteriuria, a lower urinary tract infection that occurs in 2% to 7% of pregnancies.1

Positive culture with symptoms

This profile probably reflects either:

  • Acute cystitis, a lower urinary tract infection affecting 1% to 2% of pregnancies,8 or
  • Acute pyelonephritis, an upper urinary tract infection affecting 2% of pregnancies.9

What are the consequences of UTI in pregnancy?

Maternal complications

Asymptomatic bacteriuria does not plague the patient with bothersome effects, but if left untreated, asymptomatic bacteriuria will progress to symptomatic UTI: 25% will develop acute pyelonephritis, compared to 3% to 4% of treated patients10; 20% of women with severe pyelonephritis develop serious complications,11 including:

  • sepsis and septic shock,
  • hemolysis and thrombocytopenia,12
  • acute respiratory distress syndrome,13
  • renal insufficiency.14

Adverse fetal outcomes

Untreated asymptomatic bacteriuria is associated with preterm delivery and low birthweight.15-17

Acute pyelonephritis is linked to preterm birth.18,19 Kaul et al,20 in an experimental model of pyelonephritis in mice, confirmed that E. coli plays an important role in the pathogenesis of preterm delivery and low birthweight.

What is the best treatment regimen?

Data are insufficient to recommend any specific regimen.21,22 The following strategies are based on evaluation of review articles.3,23

Asymptomatic bacteriuria and acute cystitis

Nitrofurantoin monohydrate macrocrystals is my first-line treatment. Nitrofurantoin has high concentrations in the urinary tract but induces minimal resistance in gram-negative organisms.

If nitrofurantoin is not effective, I change antibiotics based on urine culture antibiotic sensitivity profiles (FIGURE 2).

Keep in mind the current resistance of E. coli to antibiotics: ampicillin, 28% to 39%; trimethoprim-sulfamethoxazole, 31%; and first-generation cephalosporins, 9% to 19%.24

Single-dose treatment for pregnant women with asymptomatic bacteriuria has been evaluated, given its lower cost and better compliance. However, evidence is insufficient to determine whether single-dose or longer-duration regimens are more effective.25

I recommend longer-duration dosages for now, until a large randomized controlled trial can derive conclusive data.

Remember that treatment success is not contingent upon duration of therapy—just be sure that the test-of-cure urine culture is negative 1 to 2 weeks after treatment is completed.

Acute pyelonephritis

Management should include the following:

  • hospitalization
  • urine and blood cultures
  • laboratory studies of complete blood cell count, electrolytes, creatinine, and liver function
  • monitoring of vital signs and urine output
  • intravenous (IV) crystalloid fluid to maintain urine output
  • IV antibiotics (FIGURE 3).

If symptoms persist after 48 hours despite adequate IV antibiotic therapy, consider other causes such as resistant organisms, nephrolithiasis, perinephric abscesses, renal obstruction, or other infections.

Consider imaging by renal ultrasound to assess the presence of nephrolithiasis, perinephric abscess, or obstruction.

I recommend inpatient treatment for pregnant women with acute pyelonephritis at this time, until further studies are available.

To evaluate outpatient treatment, Millar and colleagues randomized 120 women under 24 weeks’ gestation either to inpatient IV cefazolin until 48 hours afebrile or to outpatient ceftriaxone intramuscularly. (Both treatment arms completed a course of oral cephalexin.) There were no differences in therapeutic response or birth outcomes, but 6 patients in the outpatient arm required hospitalization for IV therapy and 1 woman developed sepsis.26

The same researchers studied 92 patients of more than 24 weeks’ gestation who received 2 doses of ceftriaxone intramuscularly, then were randomized to either continued inpatient therapy until 48 hours afebrile or discharge with reevaluation as an outpatient in 48 to 72 hours. Again, there were no differences in therapeutic response or birth outcomes; however, almost two-thirds of patients were excluded from the study as they did not meet criteria for outpatient management, due to sepsis, preterm labor, or concurrent medical conditions.27

Adequate antibiotic coverage is crucial

To ensure adequate antibiotic coverage when treating UTI, it is important to understand which organisms cause these infections in pregnancy.

E. coli causes 75% to 90% of UTIs in nonpregnant women.28 Staphylococcus saprophyticus causes 10% to 15% of UTIs in nonpregnant women, but less in pregnant women.

Group B Streptococcus (GBS)—another gram-positive organism—has important implications for pregnant women: Intrapartum prophylaxis is important, to prevent neonatal GBS disease.29

Klebsiella, Enterobacter, Proteus, and Enterococcus species28 infrequently cause UTI in pregnancy.

What about prophylaxis and follow-up cultures?

Expect recurrence

One third of pregnant women diagnosed with UTI will have recurrence.1 Recurrence is either relapse (same strain, within 2 weeks of completing initial treatment for the original infection) or reinfection (different strain or same strain after more than 2 weeks).

2 UTIs or pyelonephritis warrant suppressive therapy

I recommend suppressive therapy if a pregnant woman is diagnosed with 2 lower urinary tract infections or acute pyelonephritis (TABLE).

Nitrofurantoin is the preferred agent, as it has high concentrations in the urinary tract but induces minimal resistance in gram-negative organisms.

Start only after eradication of the acute infection, as evidenced by a negative test-of-cure urine culture at least 1 to 2 weeks after treatment is discontinued.23

Monthly urine cultures until delivery

I recommend monthly follow-up urine cultures until delivery.

Periodic follow-up screening is often recommended, but opinions differ on which test to use or how often to screen.

THE CASE: DIAGNOSIS, TREATMENT, FOLLOW-UP, AND OUTCOME

The patient with upper urinary tract symptoms had a white blood cell count of 15, a urine dipstick positive for leukocyte esterase and nitrites, and a urine sediment analysis indicating pyuria.

She was diagnosed with acute pyelonephritis and started on ampicillin and gentamicin intravenously. Her urine culture drawn upon admission grew >100,000 CFU/mL of sulfonamide-resistant E. coli.

Within 48 hours, she showed clinical improvement and was discharged home with a 10-day course of nitrofurantoin. One week after completing treatment, her test-of-cure urine culture was negative and she was started on nitrofurantoin 50 mg every night at bedtime.

For the rest of pregnancy, she underwent monthly screening urine cultures, which remained negative. She had an uncomplicated delivery at 38 weeks of gestation.

TABLE

Suppressive therapy to prevent UTI recurrence

Suppressive therapy is recommended for any pregnant woman with:

  • 2 lower urinary tract infections or
  • acute pyelonephritis.

Do not initiate suppressive therapy until a negative test-of-cure urine culture confirms eradication of the acute infection.

ANTIBIOTIC

DOSE (ORAL)

Nitrofurantoin monohydrate macrocrystals

50 mg at bedtime

or

 

Cephalexin

250 mg at bedtime

Dr. Chen reports support from a Women’s Reproductive Health Research Career Development Center grant from the National Institutes of Child Health and Human Development.

REFERENCES

1. Gilstrap LC, III, Ramin SM. Urinary tract infections during pregnancy. Obstet Gynecol Clin North Am. 2001;28:581-591.

2. Hooton TM, Scholes D, Hughes JP, et al. A prospective study of risk factors for symptomatic urinary tract infection in young women. N Engl J Med. 1996;335:468-474.

3. American College of Obstetricians and Gynecologists. Antimicrobial therapy for obstetric patients. ACOG Technical Bulletin No. 245. Washington, DC: ACOG; 1998.

4. McMahon MJ, Ananth CV, Liston RM. Gestational diabetes mellitus. Risk factors, obstetric complications and infant outcomes. J Reprod Med. 1998;43:372-378.

5. Pastore LM, Savitz DA, Thorp JM, Jr. Predictors of urinary tract infection at the first prenatal visit. Epidemiology. 1999;10:282-287.

6. Stamm WE, Counts GW, Running KR, Fihn S, Turck M, Holmes KK. Diagnosis of coliform infection in acutely dysuric women. N Engl J Med. 1982;307:463-468.

7. Bachman JW, Heise RH, Naessens JM, Timmerman MG. A study of various tests to detect asymptomatic urinary tract infections in an obstetric population. JAMA. 1993;270:1971-1974.

8. Harris RE, Gilstrap LC, III. Cystitis during pregnancy: a distinct clinical entity. Obstet Gynecol. 1981;57:578-580.

9. Gilstrap LC, III, Cunningham FG, Whalley PJ. Acute pyelonephritis in pregnancy: an anterospective study. Obstet Gynecol. 1981;57:409-413.

10. Whalley P. Bacteriuria of pregnancy. Am J Obstet Gynecol. 1967;97:723-738.

11. Cunningham FG, Lucas MJ. Urinary tract infections complicating pregnancy. Baillieres Clin Obstet Gynaecol. 1994;8:353-373.

12. Cox SM, Shelburne P, Mason R, Guss S, Cunningham FG. Mechanisms of hemolysis and anemia associated with acute antepartum pyelonephritis. Am J Obstet Gynecol. 1991;164:587-590.

13. Cunningham FG, Lucas MJ, Hankins GD. Pulmonary injury complicating antepartum pyelonephritis. Am J Obstet Gynecol. 1987;156:797-807.

14. Whalley PJ, Cunningham FG, Martin FG. Transient renal dysfunction associated with acute pyelonephritis of pregnancy. Obstet Gynecol. 1975;46:174-177.

15. Romero R, Oyarzun E, Mazor M, Sirtori M, Hobbins JC, Bracken M. Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol. 1989;73:576-582.

16. Schieve LA, Handler A, Hershow R, Persky V, Davis F. Urinary tract infection during pregnancy: its association with maternal morbidity and perinatal outcome. Am J Public Health. 1994;84:405-410.

17. Mittendorf R, Williams MA, Kass EH. Prevention of preterm delivery and low birth weight associated with asymptomatic bacteriuria. Clin Infect Dis. 1992;14:927-932.

18. Gilstrap LC, Leveno KJ, Cunningham FG, Whalley PJ, Roark ML. Renal infection and pregnancy outcome. Am J Obstet Gynecol. 1981;141:709-716.

19. Millar LK, DeBuque L, Wing DA. Uterine contraction frequency during treatment of pyelonephritis in pregnancy and subsequent risk of preterm birth. J Perinatal Med. 2003;31(1):41-46.

20. Kaul AK, Khan S, Martens MG, Crosson JT, Lupo VR, Kaul R. Experimental gestational pyelonephritis induces preterm births and low birth weights in C3H/HeJ mice. Infect Immun. 1999;67:5958-5966.

21. Vazquez JC, Villar J. Treatments for symptomatic urinary tract infections during pregnancy. Cochrane Database Syst Rev. 2003(4);CD002256.-

22. Smaill F. Antibiotics for asymptomatic bacteriuria in pregnancy. Cochrane Database Syst Rev. 2001(2);CD000490.-

23. Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med. 2003;349:259-266.

24. Ovalle A, Levancini M. Urinary tract infections in pregnancy. Curr Opin Urol. 2001;11:55-59.

25. Villar J, Lydon-Rochelle MT, Gulmezoglu AM, Roganti A. Duration of treatment for asymptomatic bacteriuria during pregnancy. Cochrane Database Syst Rev. 2000(2);CD000491.-

26. Millar LK, Wing DA, Paul RH, Grimes DA. Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial. Obstet Gynecol. 1995;86:560-564.

27. Wing DA, Hendershott CM, DeBuque L, Millar LK. Outpatient treatment of acute pyelonephritis in pregnancy after 24 weeks. Obstet Gynecol. 1999;94:683-688.

28. Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Am J Med. 2002;113(suppl 1A):14S-19S.

29. Schrag S, Gorwitz R, Fultz-Butts K, Schuchat A. Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. MMWR Recomm Rep. 2002;51:1-22.

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