MEDICAL COMPLICATIONSOF PREGNANCY

0889-8545/01 $15.00 i .OO

URINARY TRACT INFECTIONS DURING PREGNANCY

Larry C . Gilstrap 111, MD, and Susan M. Ramin, MD

Urinary tract infections as a group are the most common medical complication of pregnancy. Although pregnancy, per se, does not predispose a woman to the acquisition of bacteria in the bladder (i.e., asymptomatic bacteriuria), it does predispose her to acute upper urinary tract infection or pyelonephritis. As discussed herein, the latter infection is associated with significant morbidity for the gravida and fetus. Urinary tract infections are relatively common in women when compared with men. The major reason for this difference is probably anatomic. The female urethra is only 3 to 4 cm in length and lies in close proximity to the vagina, anus, and rectum, all of which are areas colonized with enteric flora (the Enterobacteriaceae)." The pathogenesis of urinary tract infections is schematically illustrated in Figure 1.
MICROBIOLOGY OF URINARY TRACT INFECTIONS

Most cases of urinary tract infections are caused by the Enterobacteriaceae, especially Escherichia coli and Klebsiella and Enferobacfer spp. These organisms account for approximately 90% of all urinary tract 11, infections encountered during pregnan~y.~, Other commonly isolated uropathogens include Profeus, Pseudomonas, Cifrobacter, Staphylococcus, and group B streptococcus. Group B streptococcal bacteriuria may be associated with early-onset neonatal sepsis. In a prospective study of

From the Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Maternal-Fetal Medicine, University of Texas-Houston Medical School, Houston, Texas

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA

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FEMALE URETHRA Short Close proximity to vagina, anus, rectum

1

H
PREGNANCY Stasis (hormonal and mechanical) Glucosuria Proteinuria
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' I

FETAL

MATERNAL

Figure 1. Pathogenesis of urinary tract infections in pregnant women.

group B streptococcal bacteriuria, Wood and Dil10n~~ found a significant number of pregnant women colonized with this organism. Women with group B streptococcal bacteriuria should receive intrapartum antibiotic prophylaxis as well as therapy for the bacteriuria at time of diagnosis.'
RISK FACTORS FOR URINARY TRACT INFECTIONS

Socioeconomic status is the most significant risk factor, with medically indigent women having a fivefold greater incidence of bacteriuria than nonindigent populations.n, 29 When sickle cell status and socioeconomic status are controlled for, race, per se, does not seem to be associated with urinary tract infections in pregnancy. In a study of more than 8000 women receiving prenatal care, Pastore and colleagues24reported

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that the presence of sickle cell hemoglobin almost doubled the risk [prevalence odds ratio (POR), 1.9; 95% confidence interval (95% CI), 1.o-3.51 for having bacteriuria among African-Americans. AfricanAmericans with normal hemoglobins actually had a lower prevalence odds of bacteriuria when compared with whites (POR, 0.6; 95% CI, 0.4-0.9). Other risk factors for bacteriuria identified in this study included a prepregnancy history of urinary tract infections and antepartum urinary tract infection before prenatal care. Whalley and colleague^^^ were among the first researchers to describe an association of sickle cell trait and bacteriuria. Diabetes, including gestational diabetes, is also associated with an increased risk of urinary tract infections.23 The more commonly reported risk factors for urinary tract infection during pregnancy are a medically indigent status, sickle cell hemoglobin, diabetes, a history of urinary tract infection, and a neurogenic bladder.
ASYMPTOMATIC BACTERIURIA

Asymptomatic bacteriuria is the most common urinary tract infection encountered during pregnancy, occurring in 2% to 79'0 of all pregnant Asymptomatic bacteriuria is defined as the presence of significant bacteriuria in a woman without symptoms of urinary tract infection. Significant bacteriuria, in turn, is defined as 100,000 organisms per mL of urine or greater of a single uropathogen on a clean-voided specimen. Counts of less than 100,000 organisms per mL per specimen with two or more organisms generally represent contamination and not infection. Counts of less than 100,000 per mL may be significant if the specimen was obtained by catheterization." Less than 1%of women actually acquire bacteriuria during pregnancy if their initial screening culture is negative unless they have one of the risk factors listed previo~sly.~~ Other screening techniques that have been used for the detection of bacteriuria during pregnancy include urinalysis, leukocyte esterase activity, the nitrite test, and microscopic examination of a drop of unspun urine for bacteria. It is now generally accepted that routine urinalysis is inaccurate and should not be used as a screening tool for bacteriuria during pregnancy. Many uninfected pregnant women will have white blood cells or pyuria on urinalysis. The sensitivity and specificity of the agent strips that measure leukocyte esterase activity and nitrite vary depending on the source. In a recent survey by Tincello and Richmond,2' the agent strips were used to test for the presence of blood, protein, nitrite, and leukocyte esterase in women attending their first prenatal visit. The results of these four parameters were compared with urine cultures. The maximum sensitivity was 33% when all four tests were used in combination, and the positive predictive value was 69%. It was concluded that urine agent strips were not of sufficient sensitivity to be used for routine screening for asymptomatic bacteriuria during preg-

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nancy. The identification of bacteria in a drop of unspun urine has been shown to correlate with the presence of significant bacteriuria confirmed by urine culture.z0 In the authors' opinion, urine culture remains the gold standard, and all pregnant women should have a screening culture during their early prenatal care.
Significance of Bacteriuria

The most significant adverse effect of bacteriuria is the development of acute upper urinary tract infection or acute pyelonephritis. Acute pyelonephritis will develop in approximately one fourth of all pregnant women with untreated bacteriuria in comparison with 3% to 4% of women who are treated.30 Routine screening may not be cost-effective in all populations (i.e., those at low risk).2Nevertheless, it seems reasonable to continue to offer screening for bacteriuria to pregnant women with a history of urinary tract infection or to those who have significant risk factors. Other adverse effects that have been reported to be associated with bacteriuria in pregnancy include prematurity or low birth weight, maternal anemia, and maternal h~pertensi0n.l~a d 8 was the first invesK tigator to report an association between low birth weight and maternal bacteriuria. Subsequent studies have revealed significant controversy regarding the effects of bacteriuria on birth weight. In a study by Gilstrap and colleagues,1othere was no significant difference in gestational age at birth, delivery at less than 37 weeks, low birth weight, hypertension, or anemia in 114 newborns of mothers with renal bacteriuria versus uninfected controls. In a meta-analysis of 17 studies of bacteriuria, Romero and colleagueszsconcluded that there was an association between untreated asymptomatic bacteriuria and prematurity or low birth weight. In a multivariate analysis of a cohort of more than 25,000 mother-infant pairs, Schieve and associatesz6found an increased risk of low birth weight, preterm delivery, hypertension, and anemia in women with asymptomatic bacteriuria. Whether bacteriuria causes prematurity is probably a moot point because all pregnant women with asymptomatic bacteriuria should be treated."
Treatment

Because the initial antibiotic therapy is empirical, a variety of antimicrobial agents can be used for the treatment of bacteriuria. These drugs include the sulfonamides (500 mg; four times a day), nitrofurantoin (100 mg twice daily), and the cephalosporins (250 mg four times a day). Therapy should generally be given for 3 days for the initial infection. Longer courses of therapy can be used for recurrent infections.

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Another useful regimen is nitrofurantoin, 100 mg at bedtime for 10 days, or for 21 days for recurrences.21Single-dose regimens have also been Some of these regimens are summarized in Table 1.

Follow-Up
One must provide follow-up for women with asymptomatic bacteriuria because approximately one third will experience a recurrent infection during pregnancy. For women with frequent recurrent episodes of bacteriuria or urinary tract infections, continuous antibiotic suppression should be considered. One regimen that the authors prefer is nitrofurantoin macrocrystals, 100 mg orally every night for the remainder of pregnancy. The protracted use of other antibiotics, especially ampicillin and cephalosporins, may interfere with the normal gastrointestinal flora. Prolonged use of these antibiotics may be associated with chronic vulvovaginitis secondary to overgrowth of Cundidu u2bicuns.11 In a 10- to 14-year follow-up of women with bacteriuria during pregnancy, Zinner and K a s P found that approximately one fourth of these women were bacteriuric compared with 5% of the originally nonbacteriuric groups. Moreover, 29% of 41 women with pyelograms had evidence of chronic pyelonephritis on follow-up.
Potential Adverse Outcomes/Risk of Antibiotics

Besides the aforementioned risk associated with the protracted use of ampicillin and cephalosporins, other antibiotics used for the treatment
Table 1. ANTIMICROBIAL AGENTS AND SUGGESTED REGIMENS FOR THE TREATMENT OF ASYMPTOMATIC BACTERIURIA DURING PREGNANCY
~ ~~ ~~ ~ ~

Antimicrobial Agents

Suggested Regimen

Single dose Amoxicillin Ampicillin Cephalosporin* Nitrofurantoin Sulfonamide Trimethoprim/sulfamethoxazole 3-Day course Amoxicillin Ampicillin Cephalosporin* Nitrofurantoin Sulfonamide Other Nitrofurantoin
*First-generation cephalosporin.

3g 2g 2g

200 mg 2g 320/1600 mg

500 mg three times a day 250 mg four times a day 250 mg four times a day 100 mg twice daily 500 mg four times a day

100 mg at bedtime for 10 days

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of urinary tract infections may be associated with potential (or at least theoretical) risk or adverse outcome. The quinolone group of antibiotics has been reported to be associated with an arthropathy in immature animals and is not recommended for routine use during pregnancy. This adverse effect has not been described in humans; however, there are no large studies regarding the efficacy and safety of this group of antibiotics in pregnant women. The sulfonamides may interfere with bilirubin binding, and protracted use might result in hyperbilirubinemia in the newborn, especially premature infants. Nitrofurantoin has been reported to be associated with hemolytic anemia in women with glucose-6-phosphate dehydrogenase deficiency and with a rare form of pneumonitis or pulmonary reaction.'* Theoretically, it could cause hemolytic anemia in the fetus. If this effect occurs, it is extremely rare. Tetracycline has been associated with yellow-brown discoloration of the deciduous teeth, and gentamicin could potentially cause eighth nerve damage in the fetus. The antibiotics listed in Table 1 are relatively safe. In the authors' experience treating hundreds of pregnant women with nitrofurantoin for bacteriuria, not a single case of obvious hemolytic anemia or pneumonitis has been encountered.
ACUTE CYSTITIS

Although the exact incidence of cystitis in pregnancy is unknown, Harris and Gilstrap16reported an incidence of approximately 1% to 2% for their population. The diagnosis of cystitis is based on lower urinary tract symptoms in the presence of significant bacteriuria on culture. The signs and symptoms of acute cystitis in pregnant women are urgency, frequency, dysuria, hematuria, and pyuria. The uropathogens associated with acute cystitis are the same as those causing bacteriuria. Moreover, the treatment of cystitis in pregnancy is the same as the treatment for asymptomatic bacteriuria (Table l),although the authors prefer the 3-day course of therapy. As is true for asymptomatic bacteriuria, cystitis may recur in as many as one third of women, and follow-up is important.
ACUTE PYELONEPHRITIS

Acute symptomatic infection of the upper urinary tract is a major complication of pregnancy that may result in significant maternal and fetal morbidity. It has an incidence of approximately 1%to 2% during pregnancy and, in the presence of untreated bacteriuria, occurs in as many as 25% of pregnant women.Io As previously described (Fig. l),the pathogenesis of acute pyelone-

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phritis is related to the relative obstruction of pregnancy in association with bacteriuria. This obstruction is the result of hormonal factors (dilation of the ureters secondary to progesterone) and mechanical factors (secondary to the pregnant uterus and its contents)." Most cases of acute pyelonephritis occur after the first trimester. In a review of 656 women with acute pyelonephritis, 73% of cases occurred during the second and third trimesters and 27"/0 during the postpartum period (Table 2)."
Clinical and Laboratory Findings

The clinical diagnosis of acute pyelonephritis during pregnancy is relatively easy and straightforward. The two most common symptoms include fever and flank tenderness. Other signs and symptoms include nausea, vomiting, shaking chills, and costovertebral angle tenderness. The body temperature may be high, with levels reaching 40C or higher in some women." Laboratory findings generally include a positive urine culture (most often, Escherichiu coli) and pyuria on urinalysis. Some women may have a negative urine culture secondary to self-start antibiotic therapy. Many of these women have experienced a previous urinary tract infection and have antibiotics remaining at home. A single dose of oral antibiotics may render the urine culture sterile." In the authors' experience, as many as 10% to 15% of pregnant women with acute pyelonephritis during pregnancy have bacteriuria. Moreover, 1%to 2% of pregnant women with this infection may experience the life-threatening complication of septic shock.a A significant number of pregnant women may also have transient renal dysfunction. In the study by Gilstrap and approximately 20% of women had a serum creatinine level greater than 1 mg/dL. In a study by Whalley and colleagues,31 approximately 25% of pregnant women with acute pyelonephritis had a creatinine clearance of less than 80 mL/ minute. This decrease in creatinine clearance will generally resolve over a few weeks with appropriate antimicrobial therapy.
Table 2. OCCURRENCE OF ACUTE PYELONEPHRITIS IN 656 PREGNANT WOMEN
~

Number of Cases Time Period

(%I
174 482 43 222 217 (27%) (73%) (9%) (46%) (45%)

Postpartum Anteparturn First trimester Second trimester Third trimester

Adapfed from Gilstrap LC, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: An anterospective study Obstet Gynecol57409-413, 1981; with permission.

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Hematologic abnormalities are also relatively common. In one study, two thirds of pregnant women with acute pyelonephritis had a hematocrit of less than 30%, and one third had a drop in hematocrit of 6% or greater.12 The exact cause of this anemia or decrease in hematocrit is unknown, but it has been shown that erythropoietin levels are not decreased in these women.3 The most likely cause of these changes is hemolysis secondary to end~toxin.~, Pregnant women with acute pyelonephritis may have an abnormal chest radiograph consistent with acute respiratory distress syndrome (ARDS). This finding has been reported in approximately 1 in 50 women with acute pyelonephritis.6, These women frequently present with dyspnea, tachypnea, and hypoxia. Chest radiography reveals diffuse infiltrates consistent with ARDS. This syndrome seems to occur more frequently in women with pyelonephritis and premature labor who are given beta-agonist tocolysis.28
Adverse Fetal Effects

Acute pyelonephritis is associated with an increase in premature births. In one study of neonatal outcome in 487 pregnant women with acute pyelonephritis, approximately 15% of the newborns of mothers with this infection had birth weights less than 2500 g.13 The initiation of antibiotics for the treatment of acute pyelonephritis may actually initiate uterine activity.15 Because of the risk of pulmonary failure associated with this infection, magnesium sulfate is probably the tocolytic of choice for premature labor in these women.
Management

Most women with acute pyelonephritis should be hospitalized, at least for the first 24 hours. Many of these women will be dehydrated and are unable to tolerate oral antibiotics. The authors' criteria for the outpatient management of acute pyelonephritis during pregnancy are as follows: Ideally, a 23-hour observation period Tolerance of oral medications No signs or symptoms of sepsis No evidence of organ dysfunction (i.e., hemolysis, ARDS) Availability of home health care follow-up Women who require hospitalization should receive parenteral hydration and antibiotics. Initial antimicrobial therapy is empiric, and the authors usually use a first-generation cephalosporin or ampicillin along with gentamicin. Single-agent therapy with a second- or third-generation cephalosporin or with one of the new penicillin-beta-lactamase inhibi-

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tors is also satisfactory for use during pregnancy. Frequent vital signs and urine output measurements are recommended. Most women with acute pyelonephritis are afebrile and asymptomatic within 48 to 72 hours of therapy. In women who are not asymptomatic or who do not respond to initial therapy, other conditions should be considered and include resistant organisms, nephrolithiasis, perinephric abscess, intrarenal cellulitis (alobar nephronia), obstruction, and other infections. Resistant organisms and nephrolithiasis are probably the two most common causes of failure of initial therapy. An unusual complication of intrarenal cellulitis or lobar nephronia has been described by Cox and C~nningham.~ lesion, along with a perinephric This abscess, may be visualized with ultrasound or a CT scan. Rarely, a woman with pyelonephritis will have obstruction from the pregnancy and require a ureteral stent. Because as many as one fourth of women with acute pyelonephritis experience a recurrence of infection, it is of paramount importance to provide follow-up for these patients with either frequent urine cultures or antimicrobial suppression (nitrofurantoin, 100 mg orally once a day at bedtime) for the remainder of pregnancy following an episode of acute pyelonephritis.

Urinary tract infections are relatively common in pregnancy and may result in significant morbidity for the pregnant woman and fetus. The authors recommend that all pregnant women be screened for the presence of bacteriuria at their first prenatal visit. Failure to treat bacteriuria during pregnancy may result in as many as 25% of women experiencing acute pyelonephritis. Women with acute pyelonephritis may sustain significant complications, such as preterm labor, transient renal failure, ARDS, sepsis and shock, and hematologic abnormalities. Pregnant women with urinary tract infections should be followed up closely after treatment because as many as one third will experience a recurrence.

References
1. American College of Obstetricians and Gynecologists Committee on Obstetric Practice: Prevention of early-onset group B streptococcal disease in newborns. ACOG Committee Opinion, No. 173, Washington DC, ACOG, June 1996 2. Campbell-Brown M, McFadyen IR, Seal DV, et al: Is screening for bacteriuria in pregnancy worthwhile? BMJ 2941579, 1987 3. Cavenee MR, Cox SM, Mason R, et al: Erythropoietin in pregnancies complicated by pyelonephritis. Obstet Gynecol 84:252, 1994 4. Cox SM, Cunningham FG: Acute focal pyelonephritis (lobar nephronia) complicating pregnancy. Obstet Gynecol 71:510, 1988

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5. Cox SM, Shelbume P, Mason R, et al: Mechanisms of hemolysis and anemia associated with acute antepartum pyelonephritis. Am J Obstet Gynecol 164:587, 1991 6. Cunningham FG, Leveno KJ, Hankins GDV, et al: Respiratory insufficiency associated with pyelonephritis during pregnancy. Obstet Gynecol 63:121,1984 7. Cunningham FG, Lucas MJ, Hankins GDV: Pulmonary injury complicating antepartum pyelonephritis. Am J Obstet Gynecol 156797,1987 8. Cunningham FG, Morris GB, Mickal A Acute pyelonephritis of pregnancy: A clinical review. Obstet Gynecol 42112, 1973 9. Gilstrap LC: Urinary tract infections in women. Curr Opin Obstet Gynecol 1:31, 1989 10. Gilstrap LC, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: An anterospective study. Obstet Gynecol57409, 1981 11. Gilstrap LC, Far0 S Urinary tract infection in pregnancy. In Infections in Pregnancy, ed 2. New York, Wiley-Liss, 1997, p 21 12. Gilstrap LC, Hankins GDV, Snyder RR, et al: Acute pyelonephritis in pregnancy. Compr Ther 1238, 1986 13. Gilstrap LC, Leveno KJ, Cunningham FG, et al: Renal infection and pregnancy outcome. Am J Obstet Gynecol 141:709, 1981 14. Gilstrap LC, Little B B Antimicrobial agents during pregnancy. In Drugs and Pregnancy, ed 2. New York, Chapman and Hall, 1998, p 55 15. Graham JM, Oshiro BT, Blanco JD, et a 1 Uterine contractions after antibiotic therapy for pyelonephritis in pregnancy. Am J Obstet Gynecol 168:577,1993 16. Harris RE, Gilstrap LC III: Cystitis during pregnancy: A distinct clinical entity. Obstet Gynecol57578, 1981 17. Harris RE, Gilstrap LC, Pretty A Single-dose antimicrobial therapy for asymptomatic bacteriuria during pregnancy. Obstet Gynecol59:546, 1982 18. Kass EH. The role of asymptomatic bacteriuric in the pathogenesis of pyelonephritis. In @inn EL, Kass EH (eds): Biology of Pyelonephritis. Boston, Little, Brown, 1960, p 399 19. Kass EH, Savage W, Santamarina BAG: The significance of bacteriuria in preventive medicine. In Kass EH (ed): Progress in Pyelonephritis. Philadelphia, FA Davis, 1965, p 3 20. Kunin CM. Initial significance of bacteriuria visualized in the unstrained urinary sediment. N Engl J Med 265:589, 1961 21. Lucas MJ, Cunningham FG: Urinary tract infection during pregnancy. Clin Obstet Gynecol36:855, 1993 22. Lucas MJ, Cunningham FG: Urinary tract infection complicating pregnancy. In Williams Obstetrics, ed 19, suppl 5. Nonvalk, CT, Appleton-Lange, 1994 23. McMahon MJ, Ananth CV, Lisotn RM: Gestational diabetes mellitus: Risk factors, obstetrics complications and infant outcomes. J Reprod Med 43:372, 1998 24. Pastore LM, Savitz DA, Trhorp JM Jr: Predictors of urinary tract infection at the first prenatal visit. Epidemiology 10282,1999 25. Romero R, Oyarzun E, Mazor M, et al: Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol 73:576, 1989 26. Schieve LA, Handler A, Hershaw R, et al: Urinary tract infection during pregnancy: Its association with maternal morbidity and perinatal outcome. Am J Public Health 84:405, 1994 27. Tincello DG, Richmond D H Evaluation of reagent strips in detecting asymptomatic bacteriuria in early pregnancy: Prospective case series. BMJ 316:435, 1998 28. Towers CV, Kaminskas CM, Garite TJ, et al: Pulmonary injury associated antepartum pyelonephritis: Can patients at risk be identified? Am J Obstet Gynecol 164:974, 1991 29. Turck M, Goff BS, Petersdorf RG: Bacteriuria in pregnancy: Relation to socioeconomic factors. N Engl J Med 266:857, 1962 30. Whalley F: Bacteriuria of pregnancy. Am J Obstet Gynecol 97732, 1967 31. Whalley PJ, Cunningham FG, Martin FG: Transient renal dysfunction associated with acute pyelonephritis of pregnancy. Obstet Gynecol46174, 1974 32. Whalley PJ, Martin RG, Pritchard JA: Sickle cell trait and urinary tract infection during pregnancy. JAMA 189:903,1964

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33. Wood EG, Dillon HC: A prospective study of group B streptococcal bacteriuria i n pregnancy. Am J Obstet Gynecol 140:515, 1981 34. Zinner SH, Kass E H Long-term (10 to 14 years) follow-up of bacteriuria of pregnancy. N Engl J Med 285:820,1971

Address reprint requests to Larry C . Gilstrap 1 1 MD 1, Department of Obstetrics, Gynecology and Reproductive Sciences University of Texas-HoustonMedical School 6431 Fannin, Suite 3.604 Houston, TX 77030