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MEDICAL COMPLICATIONSOF PREGNANCY 0889-8545/01 $15.00 iOO

URINARY TRACT INFECTIONSDURING PREGNANCYLarry C . Gilstrap 111, MD, and Susan M. Ramin, MD

Urinary tract infections as a group are the most common medicalcomplication of pregnancy. Although pregnancy, per se, does not predis-pose a woman to the acquisition of bacteria in the bladder (i.e., asymp-tomatic bacteriuria), it does predispose her to acute upper urinary tractinfection or pyelonephritis. As discussed herein, the latter infection isassociated with significant morbidity for the gravida and fetus.Urinary tract infections are relatively common in women whencompared with men. The major reason for this difference is probablyanatomic. The female urethra is only 3 to 4 cm in length and lies in closeproximity to the vagina, anus, and rectum, all of which are areas colo-nized with enteric flora (the Enterobacteriaceae)."The pathogenesis of urinary tract infections is schematically illus-trated in Figure 1.

MICROBIOLOGY OF URINARY TRACT INFECTIONSMost cases of urinary tract infections are caused by the Enterobac-

teriaceae, especially Escherichia coli and Klebsiella and Enferobacfer spp.These organisms account for approximately 90% of all urinary tractinfections encountered during pregnan~y.~,1, Other commonly isolateduropathogens include Profeus, Pseudomonas, Cifrobacter, Staphylococcus,and group B streptococcus. Group B streptococcal bacteriuria may beassociated with early-onset neonatal sepsis. In a prospective study of

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

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA~~

VOLUME 28 * NUMBER 3 * SEPTEMBER 2001 581


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FEMA LE URETHRAShortClose proximity to vagina, anus, rectum

1

FETAL MATERNAL

PREGNANCYStasis (hormonal and mechanical)GlucosuriaHroteinuriaI ' I

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

group B streptococcal bacteriuria, Wood and Dil10n~~ound a significantnumber of pregnant women colonized with this organism. Women withgroup B streptococcal bacteriuria should receive intrapartum antibioticprophylaxis as well as therapy for the bacteriuria at time of diagnosis.'

RISK FACTORS FOR URINARY TRACT INFECTIONSSocioeconomic status is the most significant risk factor, with medi-cally indigent women having a fivefold greater incidence of bacteriuria

than nonindigent populations.n, 29 When sickle cell status and socioeco-nomic status are controlled for, race, per se, does not seem to be associ-ated with urinary tract infections in pregnancy. In a study of more than8000 women receiving prenatal care, Pastore and colleagues24 eported


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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),1o-3.51 for having bacteriuria among African-Americans. African-Americans with normal hemoglobins actually had a lower prevalenceodds of bacteriuria when compared with whites (POR, 0.6; 95% CI,0.4-0.9). Other risk factors for bacteriuria identified in this study in-cluded a prepregnancy history of urinary tract infections and antepar-tum urinary tract infection before prenatal care. Whalley and colleague^^^were among the first researchers to describe an association of sickle celltrait and bacteriuria. Diabetes, including gestational diabetes, is alsoassociated with an increased risk of urinary tract infections.23The morecommonly reported risk factors for urinary tract infection during preg-nancy are a medically indigent status, sickle cell hemoglobin, diabetes,a history of urinary tract infection, and a neurogenic bladder.

ASYMPTOM ATIC BACTERIURIAAsymptomatic bacteriuria is the most common urinary tract infec-tion encountered during pregnancy, occurring in 2% to 79'0 of all preg-nant Asymptomatic bacteriuria is defined as the presence ofsignificant bacteriuria in a woman without symptoms of urinary tractinfection. Significant bacteriuria, in turn, is defined as 100,000 organisms

per mL of urine or greater of a single uropathogen on a clean-voidedspecimen. Counts of less than 100,000 organisms per mL per specimenwith two or more organisms generally represent contamination and notinfection. Counts of less than 100,000 per mL may be significant if thespecimen was obtained by catheterization." Less than 1% of womenactually acquire bacteriuria during pregnancy if their initial screeningculture is negative unless they have one of the risk factors listed pre-v i o ~ s l y . ~ ~Other screening techniques that have been used for the detectionof bacteriuria during pregnancy include urinalysis, leukocyte esteraseactivity, the nitrite test, and microscopic examination of a drop of unspunurine for bacteria. It is now generally accepted that routine urinalysis isinaccurate and should not be used as a screening tool for bacteriuriaduring pregnancy. Many uninfected pregnant women will have whiteblood cells or pyuria on urinalysis. The sensitivity and specificity of theagent strips that measure leukocyte esterase activity and nitrite varydepending 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 prenatalvisit. The results of these four parameters were compared with urinecultures. The maximum sensitivity was 33% when all four tests wereused in combination, and the positive predictive value was 69%.It wasconcluded that urine agent strips were not of sufficient sensitivity to beused for routine screening for asymptomatic bacteriuria during preg-


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nancy. The identification of bacteria in a drop of unspun urine has beenshown to correlate with the presence of significant bacteriuria confirmedby urine culture.z0In the authors' opinion, urine culture remains the gold standard,and all pregnant women should have a screening culture during theirearly prenatal care.

Significance of BacteriuriaThe most significant adverse effect of bacteriuria is the developmentof acute upper urinary tract infection or acute pyelonephritis. Acutepyelonephritis will develop in approximately one fourth of all pregnantwomen with untreated bacteriuria in comparison with 3% to 4% ofwomen who are treated.30Routine screening may not be cost-effective in all populations (i.e.,those at low risk).2Nevertheless, it seems reasonable to continue to offerscreening for bacteriuria to pregnant women with a history of urinarytract infection or to those who have significant risk factors.Other adverse effects that have been reported to be associatedwith bacteriuria in pregnancy include prematurity or low birth weight,maternal anemia, and maternal h~pertens i0n. l~a d 8was the first inves-tigator to report an association between low birth weight and maternalbacteriuria. Subsequent studies have revealed significant controversyregarding the effects of bacteriuria on birth weight. In a study byGilstrap and colleagues,1o here was no significant difference in gesta-tional age at birth, delivery at less than 37 weeks, low birth weight,hypertension, or anemia in 114newborns of mothers with renal bacteri-uria versus uninfected controls. In a meta-analysis of 17 studies ofbacteriuria, Romero and colleagueszsconcluded that there was an associ-ation between untreated asymptomatic bacteriuria and prematurity orlow birth weight. In a multivariate analysis of a cohort of more than25,000 mother-infant pairs, Schieve and associatesz6 ound an increased

risk of low birth weight, preterm delivery, hypertension, and anemiain women with asymptomatic bacteriuria. Whether bacteriuria causesprematurity is probably a moot point because all pregnant women withasymptomatic bacteriuria should be treated."

TreatmentBecause the initial antibiotic therapy is empirical, a variety of anti-microbial agents can be used for the treatment of bacteriuria. These

drugs include the sulfonamides (500 mg; four times a day), nitrofuran-toin (100 mg twice daily), and the cephalosporins (250 mg four times aday). Therapy should generally be given for 3 days for the initial infec-tion. Longer courses of therapy can be used for recurrent infections.


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of urinary tract infections may be associated with potential (or at leasttheoretical) risk or adverse outcome. The quinolone group of antibioticshas been reported to be associated with an arthropathy in immatureanimals and is not recommended for routine use during pregnancy. Thisadverse effect has not been described in humans; however, there are nolarge studies regarding the efficacy and safety of this group of antibioticsin pregnant women.The sulfonamides may interfere with bilirubin binding, and pro-tracted use might result in hyperbilirubinemia in the newborn, especiallypremature infants. Nitrofurantoin has been reported to be associatedwith hemolytic anemia in women with glucose-6-phosphate dehydroge-nase deficiency and with a rare form of pneumonitis or pulmonaryreaction.'* Theoretically, it could cause hemolytic anemia in the fetus. Ifthis effect occurs, it is extremely rare.Tetracycline has been associated with yellow-brown discoloration ofthe deciduous teeth, and gentamicin could potentially cause eighth nervedamage in the fetus.The antibiotics listed in Table 1 are relatively safe. In the authors'experience treating hundreds of pregnant women with nitrofurantoinfor bacteriuria, not a single case of obvious hemolytic anemia or pneu-monitis has been encountered.

ACUTE CYSTITISAlthough the exact incidence of cystitis in pregnancy is unknown,Harris and Gilstrap16 reported an incidence of approximately 1% to 2%for their population. The diagnosis of cystitis is based on lower urinarytract symptoms in the presence of significant bacteriuria on culture. Thesigns and symptoms of acute cystitis in pregnant women are urgency,frequency, dysuria, hematuria, and pyuria.The uropathogens associated with acute cystitis are the same asthose causing bacteriuria. Moreover, the treatment of cystitis in preg-

nancy is the same as the treatment for asymptomatic bacteriuria (Tablel),although the authors prefer the 3-day course of therapy.As is true for asymptomatic bacteriuria, cystitis may recur in asmany as one third of women, and follow-up is important.

ACUTE PY ELONEPHRITISAcute symptomatic infection of the upper urinary tract is a majorcomplication of pregnancy that may result in significant maternal and

fetal morbidity. It has an incidence of approximately 1%to 2% duringpregnancy and, in the presence of untreated bacteriuria, occurs in asmany as 25% of pregnant women.IoAs previously described (Fig. l), he pathogenesis of acute pyelone-


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phritis is related to the relative obstruction of pregnancy in associationwith bacteriuria. This obstruction is the result of hormonal factors (dila-tion 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. Ina review of 656 women with acute pyelonephritis, 73% of cases occurredduring the second and third trimesters and 27"/0during the postpartumperiod (Table 2)."

Clinical and Laboratory FindingsThe clinical diagnosis of acute pyelonephritis during pregnancy isrelatively easy and straightforward. The two most common symptomsinclude fever and flank tenderness. Other signs and symptoms includenausea, vomiting, shaking chills, and costovertebral angle tenderness.The body temperature may be high, with levels reaching 40C or higherin some women."Laboratory findings generally include a positive urine culture (mostoften, Escherichiu coli) and pyuria on urinalysis. Some women may havea negative urine culture secondary to self-start antibiotic therapy. Manyof these women have experienced a previous urinary tract infection andhave 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 pregnantwomen with acute pyelonephritis during pregnancy have bacteriuria.Moreover, 1% o 2% of pregnant women with this infection may experi-ence the life-threatening complication of septic shock.a A significantnumber of pregnant women may also have transient renal dysfunction.In the study by Gilstrap and approximately 20% of womenhad a serum creatinine level greater than 1 mg/dL. In a study byWhalley and colleagues,31 approximately 25% of pregnant women withacute pyelonephritis had a creatinine clearance of less than 80 mL/minute. This decrease in creatinine clearance will generally resolve overa few weeks with appropriate antimicrobial therapy.Table 2. OCCURRENCEOF ACUTE PYELONEPHRITIS IN 656 PREGNANT WOMEN

~

Number of CasesTime Period (%I

Postpartum 174 (27%)Anteparturn 482 (73%)First trimester 43 (9%)Second trimester 222 (46%)Third trimester 217 (45%)

Adapfed from Gilstrap LC, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: Ananterospective 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 hemato-crit of less than 30%, and one third had a drop in hematocrit of 6% orgreater.12 The exact cause of this anemia or decrease in hematocrit isunknown, but it has been shown that erythropoietin levels are notdecreased in these women.3 The most likely cause of these changes ishemolysis secondary to en d~to xin.~ ,Pregnant women with acute pyelonephritis may have an abnormalchest radiograph consistent with acute respiratory distress syndrome(ARDS). This finding has been reported in approximately 1 in 50 womenwith acute pyelonephritis.6, These women frequently present with dys-pnea, tachypnea, and hypoxia. Chest radiography reveals diffuse infil-trates consistent with ARDS. This syndrome seems to occur more fre-quently in women with pyelonephritis and premature labor who aregiven beta-agonist tocolysis.28

Adverse Fetal EffectsAcute pyelonephritis is associated with an increase in prematurebirths. In one study of neonatal outcome in 487 pregnant women withacute pyelonephritis, approximately 15% of the newborns of motherswith this infection had birth weights less than 2500 g.13 The initiation ofantibiotics for the treatment of acute pyelonephritis may actually initiateuterine activity.15 Because of the risk of pulmonary failure associatedwith this infection, magnesium sulfate is probably the tocolytic of choicefor premature labor in these women.

ManagementMost women with acute pyelonephritis should be hospitalized, atleast for the first 24 hours. Many of these women will be dehydrated

and are unable to tolerate oral antibiotics. The authors' criteria for theoutpatient management of acute pyelonephritis during pregnancy areas follows:Ideally, a 23-hour observation periodTolerance of oral medicationsNo signs or symptoms of sepsisNo evidence of organ dysfunction (i.e., hemolysis, ARDS)Availability of home health care follow-up

Women who require hospitalization should receive parenteral hy-dration and antibiotics. Initial antimicrobial therapy is empiric, and theauthors usually use a first-generation cephalosporin or ampicillin alongwith gentamicin. Single-agent therapy with a second- or third-generationcephalosporin or with one of the new penicillin-beta-lactamase inhibi-


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tors is also satisfactory for use during pregnancy. Frequent vital signsand urine output measurements are recommended.Most women with acute pyelonephritis are afebrile and asympto-matic within 48 o 72 hours of therapy. In women who are not asympto-matic or who do not respond to initial therapy, other conditions shouldbe considered and include resistant organisms, nephrolithiasis, peri-nephric abscess, intrarenal cellulitis (alobar nephronia), obstruction, andother infections. Resistant organisms and nephrolithiasis are probablythe two most common causes of failure of initial therapy. An unusualcomplication of intrarenal cellulitis or lobar nephronia has been de-scribed by Cox and C~ nningham .~his lesion, along with a perinephricabscess, may be visualized with ultrasound or a CT scan. Rarely, awoman with pyelonephritis will have obstruction from the pregnancyand require a ureteral stent.

Because as many as one fourth of women with acute pyelonephritisexperience a recurrence of infection, it is of paramount importance toprovide follow-up for these patients with either frequent urine culturesor antimicrobial suppression (nitrofurantoin, 100 mg orally once a dayat bedtime) for the remainder of pregnancy following an episode ofacute pyelonephritis.

Urinary tract infections are relatively common in pregnancy andmay result in significant morbidity for the pregnant woman and fetus.The authors recommend that all pregnant women be screened for thepresence of bacteriuria at their first prenatal visit. Failure to treat bacteri-uria during pregnancy may result in as many as 25% of women experi-encing acute pyelonephritis. Women with acute pyelonephritis may sus-tain significant complications, such as preterm labor, transient renalfailure, ARDS, sepsis and shock, and hematologic abnormalities.Pregnant women with urinary tract infections should be followedup closely after treatment because as many as one third will experiencea recurrence.

References1. American College of Obstetricians and Gynecologists Committee on Obstetric Practice:Prevention of early-onset group B streptococcal disease in newborns. ACOG Commit-tee Opinion, No. 173, Washington DC, ACOG, June 19962. Campbell-Brown M, McFadyen IR, Seal DV, et al: Is screening for bacteriuria inpregnancy worthwhile? BMJ 2941579, 19873. Cavenee MR, Cox SM, Mason R, et al: Erythropoietin in pregnancies complicated bypyelonephritis. Obstet Gynecol 84:252, 19944. Cox SM, Cunningham FG: Acute focal pyelonephritis (lobar nephronia) complicatingpregnancy. Obstet Gynecol 71:510, 1988


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5. Cox SM, Shelbume P, Mason R, et al: Mechanisms of hemolysis and anemia associated6. Cunningham FG, Leveno KJ, Hankins GDV, et al: Respiratory insufficiency associated7. Cunningham FG, Lucas MJ, Hankins GDV: Pulmonary injury complicating antepartum8. Cunningham FG, Morris GB, Mickal A Acute pyelonephritis of pregnancy: A clinical9. Gilstrap LC: Urinary tract infections in women. Curr Opin Obstet Gynecol 1:31, 198910. Gilstrap LC, Cunningham FG, Whalley PJ: Acute pyelonephritis in pregnancy: Ananterospective study. Obstet Gynecol57409, 198111. Gilstrap LC, Far0 S Urinary tract infection in pregnancy. In Infections in Pregnancy,ed 2. New York, Wiley-Liss, 1997, p 2112. Gilstrap LC, Hankins GDV, Snyder RR, et al: Acute pyelonephritis in pregnancy.Compr Ther 1238, 198613. Gilstrap LC, Leveno KJ, Cunningham FG, et al: Renal infection and pregnancy out-come. 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 5515. Graham JM, Oshiro BT, Blanco JD, et a1 Uterine contractions after antibiotic therapyfor pyelonephritis in pregnancy. Am J Obstet Gynecol 168:577,199316. Harris RE, Gilstrap LC III: Cystitis during pregnancy: A distinct clinical entity. ObstetGynecol57578, 198117. Harris RE, Gilstrap LC, Pretty A Single-dose antimicrobial therapy for asymptomaticbacteriuria during pregnancy. Obstet Gynecol59:546, 198218. 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,

19. Kass EH, Savage W, Santamarina BAG: The significance of bacteriuria in preventivemedicine. In Kass EH (ed): Progress in Pyelonephritis. Philadelphia, FA Davis, 1965, p 320. K u n i n CM. Initial significance of bacteriuria visualized in the unstrained urinarysediment. N Engl J Med 265:589, 196121. Lucas MJ, Cunningham FG: Urinary tract infection during pregnancy. Clin ObstetGynecol36:855, 199322. Lucas MJ, Cunningham FG: Urinary tract infection complicating pregnancy. In Wil-liams Obstetrics, ed 19, suppl 5. Nonvalk, CT, Appleton-Lange, 199423. McMahon MJ, Ananth CV, Lisotn RM: Gestational diabetes mellitus: Risk factors,obstetrics complications and infant outcomes. J Reprod Med 43:372, 199824. Pastore LM, Savitz DA, Trhorp JM Jr: Predictors of urinary tract infection at the firstprenatal visit. Epidemiology 10282,199925. Romero R, Oyarzun E, Mazor M, et al: Meta-analysis of the relationship betweenasymptomatic bacteriuria and preterm delivery/low birth weight. Obstet Gynecol73:576, 198926. Schieve LA, Handler A, Hershaw R, et al: Urinary tract infection during pregnancy:Its association with maternal morbidity and perinatal outcome. Am J Public Health84:405, 199427. Tincello DG, Richmond D H Evaluation of reagent strips in detecting asymptomaticbacteriuria in early pregnancy: Prospective case series. BMJ 316:435, 199828. Towers CV, Kaminskas CM, Garite TJ, et al: Pulmonary injury associated antepartumpyelonephritis: Can patients a t risk be identified? Am J Obstet Gynecol 164:974, 199129. Turck M, Goff BS, Petersdorf RG: Bacteriuria in pregnancy: Relation to socioeconomicfactors. N Engl J Med 266:857, 196230. Whalley F:Bacteriuria of pregnancy. Am J Obstet Gynecol 97732, 1967

31. Whalley PJ, Cunningham FG, Martin FG: Transient renal dysfunction associated with32. Whalley PJ, Martin RG, Pritchard JA: Sickle cell trait and urinary tract infection during

with acute antepartum pyelonephritis. Am J Obstet Gynecol 164:587, 1991with pyelonephritis during pregnancy. Obstet Gynecol 63:121,1984pyelonephritis. Am J Obstet Gynecol 156797,1987review. Obstet Gynecol 42112, 1973

p 399

acute pyelonephritis of pregnancy. Obstet Gynecol46174, 1974pregnancy. JAMA 189:903,1964


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33. Wood EG, Dillon HC: A prospective study of group B streptococcal bacteriuria in34. Zinner SH, Kass E H Long-term (10 to 14 years) follow-up of bacteriuria of pregnancy.pregnancy.Am J Obstet Gynecol 140:515, 1981N Engl J Med 285:820,1971

Address reprint requests toLarry C . Gilstrap 111, MDDepartmentof Obstetrics, Gynecologyand Reproductive SciencesUniversityof Texas-Houston Medical School6431 Fannin, Suite 3.604Houston, TX 77030

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