Urinary Tract Infections in Pregnancy Overview of UTIs in Pregnancy

Pregnancy causes numerous changes in the woman’s body. Hormonal and mechanical changes increase the risk of urinary stasis and vesicoureteral reflux. These changes, along with an already short urethra (approximately 3-4 cm in females) and difficulty with hygiene due to a distended pregnant belly, increase the frequency of urinary tract infections (UTIs) in pregnant women. Indeed, UTIs are one of the most common bacterial infections during pregnancy.

In general, pregnant patients are considered immunocompromised UTI hosts because of the physiologic changes associated with pregnancy (see Pathophysiology). These changes increase the risk of serious infectious complications from symptomatic and asymptomatic urinary infections even in healthy pregnant women.

For more information, see Urinary Tract Infection in Females.

Definition of UTI

UTI is defined as the presence of at least 100,000 organisms per milliliter of urine in an asymptomatic patient, or as more than 100 organisms/mL of urine with accompanying pyuria (>7 WBCs/mL) in a symptomatic patient. Particularly in asymptomatic patients, a diagnosis of UTI should be supported by a positive culture for a uropathogen. UTIs are associated with risks to both the fetus and the mother, including pyelonephritis, preterm birth, low birth weight, and increased perinatal mortality.

Asymptomatic bacteriuria

Asymptomatic bacteriuria (ASB) is commonly defined as the presence of more than 100,000 organisms/mL in 2 consecutive urine samples in the absence of declared symptoms. Untreated ASB is a risk factor for acute cystitis (40%) and pyelonephritis (25-30%) in pregnancy. These cases account for 70% of all cases of symptomatic UTI among unscreened pregnant women.

Acute cystitis

Acute cystitis involves only the lower urinary tract; it is characterized by inflammation of the bladder due to bacterial or nonbacterial causes (ie, radiation, viral). Acute cystitis develops in approximately 1% of pregnant patients, of whom 60% have a negative result on initial screening. Signs and symptoms include hematuria, dysuria, suprapubic discomfort, frequency, urgency, and nocturia. These symptoms are often difficult to distinguish from those due to pregnancy itself.

Acute cystitis is complicated by upper urinary tract disease (ie, pyelonephritis) in 15-50% of cases.

Acute pyelonephritis

Pyelonephritis is the most common urinary tract complication in pregnant women, occurring in approximately 2% of all pregnancies. Acute pyelonephritis is characterized by fever, flank pain, and tenderness in addition to significant bacteriuria. Other symptoms may include nausea, vomiting, frequency, urgency, and dysuria. Furthermore, women with additional risk factors (eg, immunosuppression, diabetes, sickle cell anemia, neurogenic bladder, recurrent or persistent UTIs prior to pregnancy) are at an increased risk for a complicated UTI.

Vaginal infections

Vaginal infections can cause or mimic UTIs, which are common in women in their reproductive years, affecting 25-35% of women aged 20-40 years. Discriminating between the 2 depends on the results of vaginal and urinary cultures (see Urine Studies).

Treatments

Oral antibiotics are the treatment of choice for asymptomatic bacteriuria and cystitis. The standard course of treatment for pyelonephritis is hospital admission and intravenous antibiotics. Antibiotic prophylaxis is indicated in some cases. (See Treatment of UTI in Pregnancy.)

Morbidity and mortality concerns

The primary complication of bacteriuria during pregnancy is cystitis, although the primary morbidity is due to pyelonephritis. Septic shock and death have been reported, although these outcomes are rare. Hypoxic fetal events can occur because of maternal complications of infection that lead to hypoperfusion of the placenta. See Complications in Clinical Presentation for further discussion.

Impact

Annual health costs for UTI exceed $1 billion. Although the condition-specific cost of asymptomatic bacteriuria or UTI in pregnancy is unknown, screening for these conditions in pregnant women has been shown to be cost-effective compared with treating UTI and pyelonephritis without screening.

For more information, see the following topics:

• Urinary Tract Infection in Females
• Urethral Catheterization in Women

The physiologic changes of pregnancy predispose to bacteriuria. These changes include urinary retention caused by the weight of the enlarging uterus and urinary stasis due to progesterone-induced ureteral smooth muscle relaxation. Blood-volume expansion is accompanied by increases in the glomerular filtration rate (GFR) and urinary output.

Loss of ureteral tone combined with increased urinary tract volume results in urinary stasis, which can lead to dilatation of the ureters, renal pelvis, and calyces. Urinary stasis and the presence of vesicoureteral reflux predispose some women to upper tract UTIs and acute pyelonephritis.

Although the influence of progesterone causes relative dilatation of the ureters, ureteral tone progressively increases above the pelvic brim during pregnancy. However, whether bladder pressure increases or decreases during pregnancy is controversial. In addition, glucosuria and aminoaciduria during pregnancy provide an excellent culture medium for bacteria in areas of urine stasis.

Causes of infection

Escherichia coli infection is the most common cause of UTI, accounting for approximately 80-90% of cases. It originates from fecal floras that colonize the periurethral area, causing an ascending infection. Klebsiella, Enterobacter, and Proteus species cause most of the remaining cases.

Gram-positive organisms, particularly Enterococcus faecalis and group B Streptococcus (GBS), are also clinically important pathogens. Infection with Staphylococcus saprophyticus, an aggressive community-acquired organism, can cause upper urinary tract disease, and this infection is more likely to be persistent or recurrent.

Urea-splitting bacteria, including Proteus, Klebsiella, Pseudomonas, and coagulase-negative Staphylococcus, alkalinize the urine and may be associated with struvite stones. Chlamydial infections are associated with sterile pyuria and account for more than 30% of nonbacterial UTIs.

GBS colonization has important implications during pregnancy. Intrapartum transmission that leads to neonatal GBS infection can cause pneumonia, meningitis, sepsis, and death. Current guidelines recommend universal vaginal and rectal screening in all pregnant women at 35-37 weeks' gestation rather than treatment based on risk factors.

United States statistics

The frequency of UTI in pregnant women (0.3-1.3%) is similar to that in nonpregnant women.^[1] Changes in coital patterns (eg, position, frequency, postcoital antibiotics) can offset recurrence in at-risk individuals.

Overall, UTIs are 14 times more frequent in women than in men. This difference is attributed to the following factors:

• The urethra is shorter in women
• In women, the lower third of the urethra is continually contaminated with pathogens from the vagina and the rectum
• Women tend not to empty their bladders as completely as men
• The female urogenital system is exposed to bacteria during intercourse

A difference between pregnant and nonpregnant women is that the prevalence of asymptomatic bacteriuria in pregnant women is 2.5-11%, as opposed to 3-8% in nonpregnant women. In up to 40% of these cases, bacteriuria may progress to symptomatic upper tract UTI or pyelonephritis, significantly more than in nonpregnant women.^[2]

Several patient-level factors are associated with an increased frequency of bacteriuria during pregnancy. Indigent patients have a 5-fold increased incidence of bacteriuria compared with nonindigent patients. The risk is doubled in women with sickle cell trait. Other risk factors for bacteriuria include diabetes mellitus,^[3] neurogenic bladder retention, history of vesicoureteral reflux (treated or untreated),^[4] previous renal transplantation,^[5] and a history of previous urinary tract infections.

International statistics

Versi and colleagues described a higher prevalence of bacteriuria in pregnant white women (6.3%) than in pregnant Bangladeshi women (2%).^[6] Pregnancies that resulted in preterm deliveries were strongly associated with bacteriuria in white women; this was not observed Bangladeshi women. The authors hypothesized that the difference could be due to differences in hygiene practices and clothing.

A large, population-based Israeli study of nearly 200,000 pregnant Israeli women demonstrated a 2.5% rate of ASB^[7] and 2.3% rate of symptomatic UTI.^[8] In this population, asymptomatic bacteriuria was found to have an association with multiple pregnancy complications including hypertension, diabetes, intrauterine growth retardation, prolonged hospitalization, and preterm labor. Sheiner and colleagues suggested that these findings may be a marker for intensity of prenatal care rather than a specific causal effect of the urinary infection. Additionally, their follow-up study examining women with symptomatic UTI showed a clear association between UTI and low birth weight and preterm delivery, a finding consistent with multiple previous investigations.

Race, age, and UTI in Pregnancy

A retrospective analysis of 24,000 births indicates that the prevalence of UTI during pregnancy is 28.7% in whites and Asians, 30.1% in blacks, and 41.1% in Hispanics. When socioeconomic status is controlled, no significance difference among the races seems to exist. An additional survey-based analysis of self-reported UTI showed similar racial trends. This study also examined trends among Native American women and found the highest prevalence of UTI in this population (24.2%) compared with Asian (10.3%), white (16.6%), Hispanic (18.3%), and black (20.3%) women.^[9]

UTI is associated with preterm delivery in persons of all races. The adjusted odds ratio in infants with very low birth weight is 2.8 in blacks and 5.6 in whites, adjusted for parity, body mass index (BMI), maternal age, marital status, cigarette smoking, education, and prenatal care. The overall relative risk of bacteriuria in blacks or whites is estimated at 1.5-5, and the relative risk of preterm birth in women with bacteriuria is 1.8-2.3.

The prevalence of UTI during pregnancy increases with maternal age.

Patient history

The presentation varies depending on whether the patient has asymptomatic bacteriuria, a lower tract UTI (cystitis), or an upper tract UTI (pyelonephritis).

Burning with urination (dysuria) is the most significant symptom in pregnant women with symptomatic cystitis. Other symptoms include frequency, urgency, suprapubic pain, and hematuria in the absence of systemic symptoms. The usual complaints of increased frequency, nocturia, and suprapubic pressure are not particularly helpful, because most pregnant women experience these as a result of increased pressure from the growing uterus, expanding blood volume, increased glomerular filtration rate, and increased renal blood flow.

Pyelonephritis symptoms on presentation vary. Symptoms often include fever (>38°C), shaking chills, costovertebral angle tenderness, anorexia, nausea, and vomiting. Right-sided flank pain is more common than left or bilateral flank pain. Patients may also present with hypothermia (as low as 34°C). Lower UTI symptoms are common, but not universal.

Physical examination

During the physical examination, the findings should be considered in relation to the duration of pregnancy. The differential diagnoses may change in each trimester, and the increasing size of the gravid uterus may mask or mimic disease findings. A thorough physical examination is recommended, with particular attention to the abdomen. Suprapubic and/or costovertebral tenderness may be present.

In asymptomatic bacteriuria, no physical findings are typically present. Symptoms may arise intermittently, only to be overlooked because of lack of persistence or severity.

Pelvic examination is recommended in all symptomatic patients (with the exception of the third-trimester patient with bleeding) to rule out vaginitis or cervicitis. In patients with cystitis, tenderness can often be elicited with isolation of the bladder on pelvic examination.

Patients with pyelonephritis have fever (usually >38°C), flank tenderness upon palpation, and an ill appearance. Flank tenderness is right-sided in more than half of patients, bilateral in one fourth of patients, and left-sided in one fourth of patients. Pain may also be found suprapubically with palpation.

Based on gestational age, include fetal heart rate as part of the evaluation. Often, owing to maternal fever, the fetal heart rate is elevated to more than 160 beats per minute.

Complications

Complications may include the following:

• Perinephric cellulitis and abscess
• Septic shock
• Renal dysfunction (usually transient, but as many as 25% of pregnant women with pyelonephritis have a decreased GFR)
• Hematologic dysfunction (common but seldom of clinical importance)
• Hypoxic fetal events due to decreased placental perfusion
• Premature delivery leading to increased infant morbidity and mortality

Pulmonary injury may also complicate UTI in pregnancy. Approximately 1 in 50 women with severe pyelonephritis during pregnancy have evidence of pulmonary injury due to systemic inflammatory response syndrome and respiratory insufficiency. Endotoxins that alter alveolar-capillary membrane permeability are produced; subsequently, pulmonary edema and acute respiratory distress syndrome develop.

The most common uropathogen in the pregnant patient is E coli. This organism is isolated in approximately 80% of cultures.

Other pathogens include the following:

• Klebsiella pneumoniae (5%)
• Proteus mirabilis (5%)
• Enterobacter species (3%)
• S saprophyticus (2%)
• Group B beta-hemolytic Streptococcus (1%)
• Proteus species (2%)^[10]

Infections result from ascending colonization of the urinary tract. The primary source of organisms is existing vaginal, perineal, and fecal flora.

Various maternal physiologic and anatomic factors predispose to ascending infection. The smooth-muscle–relaxation properties of progesterone and mechanical obstruction by an enlarging uterus cause dilatation of the renal calices, pelves, and ureters, leading to urinary stasis and potentiating infection. Calyceal and ureteral dilatation are more common on the right side; in 86% of cases, the dilatation is localized on the right side. The degree of calyceal dilatation is also more pronounced on the right than the left (15 mm vs 5 mm).

This dilatation appears to begin by about 10 weeks' gestation and worsens throughout pregnancy (see the images below). This is underscored by the percentage of cases of pyelonephritis during pregnancy: 2% during the first trimester, 52% during the second trimester, and 46% in the third trimester.

Glucosuria and an increase in levels of urinary amino acids during pregnancy are additional factors that lead to UTI. Glucose excretion increases in pregnancy by 100-fold over nonpregnant values of 100 mg/d. Glycosuria is due to impaired resorption by the collecting tubule and loop of Henle of the 5% of the filtered glucose, which escapes proximal convoluted tubular resorption.

The fractional excretion of alanine, glycine, histidine, serine, and threonine is increased throughout pregnancy. Levels of cystine, leucine, lysine, phenylalanine, taurine, and tyrosine are elevated in the first half of pregnancy but return to reference range levels by the second half. The mechanism of selective aminoaciduria is unknown, although its presence has been postulated to affect the adherence of E coli to the urothelium.

Preeclampsia

Women who develop preeclampsia during pregnancy seem to be predisposed to UTI. A retrospective review of the perinatal database at a major tertiary center revealed a UTI rate of 16.2% in normotensive patients, but this increased to 27.3% in women with mild preeclampsia and 35.9% in women with severe preeclampsia. The authors hypothesize that underlying renal damage weakens the patients' systemic defense mechanisms against ascending infection.

Cesarean delivery

Cesarean delivery is associated with UTI (2.7 times more likely), but this association may be confounded by bladder catheterization or prolonged rupture of membranes (PROM). The incidence of symptomatic UTI is 9.3% and of asymptomatic bacteriuria is 7.6%.

Orthotopic continent urinary diversion

Many women who, in the past, would have been counseled against pregnancy are now attempting pregnancy. In orthotopic continent diversion (OCD), an ileal-ascending colon conduit is made (OCD, Kock pouch) and reattached to the in situ urethra (OCD) or a continent abdominal stoma (Kock pouch).

Typical candidates are patients born with congenital exstrophy of the bladder in whom primary reconstruction has failed. Recurrent UTI and hydronephrosis are common because of outflow obstruction of the orthotopic stoma secondary to uterine compression or uterine prolapse. Indwelling catheterization of the urethra or continent stoma may be necessary, particularly during the later stages of pregnancy. In rare cases, a percutaneous nephrostomy tube or antegrade passage of a ureteral stent may be indicated.

Beta streptococci

Beta streptococci are important pathogens in pregnancy because early and late complications of neonatal beta-streptococcal infection are well documented. Incidental documentation of beta-streptococcal bacteriuria suggests a higher colonization count than revealed by a screening vaginal or rectal culture. Beta-streptococcal colonization in the urine warrants immediate treatment and antibiotic prophylaxis when the patient presents in labor.

Whether beta streptococci are associated with preterm labor is controversial. In 1994, McKenzie and colleagues prospectively found no relation of beta-streptococcal bacteriuria to preterm labor, but they describe the use of urinary antibodies to identify at-risk women.^[11] In 2043 consecutive women, those with E coli antibodies at initial visit and at 28 weeks' gestation and women with beta-streptococcal antibodies at 28 weeks' gestation had a significantly higher chance of preterm delivery.

The differential diagnosis of pregnancy includes the following:

• Cervicitis
• Chlamydial Genitourinary Infections
• Cystitis, Nonbacterial
• Ectopic Pregnancy
• Interstitial Cystitis
• Nephrolithiasis
• Trichomoniasis
• Trigonitis
• Urethritis
• Vaginitis

Other disorders to consider include the following:

• Glomerulonephritis
• Group B streptococci colonization
• Sexually transmitted infection (eg, gonorrhea, nongonococcal urethritis)
• Threatened or incomplete miscarriage
• Urge incontinence

Urine specimen collection

In all pregnant patients, a urine specimen should be carefully collected for urinalysis and culturing during the first prenatal visit or at 12-16 weeks' gestation. These tests help to identify patients with asymptomatic bacteriuria as well as those with other specific complaints.

For urine collection, a midstream clean catch is adequate, provided the patient is given careful instructions. The technique is as follows:

• With one hand, spread the labia
• With the other hand, use a Castile soap–moistened towelette to wipe the urethral meatus downward toward the rectum, then discard the towelette
• Void the initial portion of the bladder contents into the toilet
• Catch the middle portion of the bladder contents in the sterile collection container, while keeping the labia spread with the first hand

(Unfortunately, a recent study on pregnant adolescents suggests that the cleansing process does not prevent contamination.)

Collect a catheterized specimen if the patient is unable to void, too ill, extremely obese, or bedridden. Routine catheterization is not recommended because of the risks of introducing bacteria into the urinary tract.

Several methods are available for specimen evaluation; all have benefits and limitations. The clean-catch specimen reduces, but does not eliminate, the possibility of cross-contamination from the urethra and vagina. The presence of more than one organism in a culture usually indicates a contaminated specimen.

Send the specimen for evaluation as soon as possible. Specimens that are allowed to sit at room temperature may have falsely elevated colony counts. Refrigerate the specimen at 4°C if it cannot be transported immediately.

Urine culture

This is the criterion standard for evaluation of a UTI during pregnancy. Indications for performing a urine culture include the following:

• Recurrent UTI
• Pyelonephritis
• Failure to respond to initial treatment regimens
• History of recent instrumentation
• Hospital admission

Two consecutive voided specimens with isolation of the same bacterial strain, at a colony count of 100,000 colony-forming units (CFUs) per milliliter or higher, has historically been used to define a positive culture result. A single catheterized specimen yielding a colony count of at least 100 CFU/mL is also diagnostic.^{[12, 13]} Counts of less than 100,000 CFU/mL, with 2 or more organisms, usually indicate specimen contamination rather than infection. Patients with pyelonephritis often have WBC casts.

Culture results can be used to identify specific organisms and antibiotic sensitivities. Urine culture has an average cost of approximately $40. Results are often unavailable at the time of treatment.

Urinalysis

Positive results for nitrites, leukocyte esterase, WBCs, RBCs, and protein suggest UTI. Bacteria found in the specimen can help with the diagnosis.

Urinalysis has a specificity of 97-100%, but its sensitivity ranges from 25-67% when compared with culture in the diagnosis of asymptomatic bacteriuria.

Millar and Cox indicate that 1-2 bacteria in an unspun catheterized specimen or more than 20 bacteria per high-power field in spun urine correlate closely with more than 100,000 CFUs per milliliter of bacteria on a urine culture.^[14]

Dipstick testing

Several reports describe the use of urine dip for nitrites and leukocyte esterase in the evaluation of asymptomatic bacteriuria. Sensitivities range from 50-92%, and specificity is 86-97% when compared with culture.

In the evaluation of symptomatic patients, dipstick testing is useful and inexpensive. However, the leukocyte esterase test may be unreliable in patients with low-level pyuria (5-20 WBCs per high-power field). The addition of protein and blood increases the sensitivity and specificity of the test in the evaluation of UTI.

As suggested by Kodikara and colleagues, nitrite dipstick testing may be a reasonable and cost-effective screening strategy for women who otherwise may not undergo screening for bacteriuria, such as in developing countries.^[15]

The following blood tests should be ordered at the physician's discretion, although the results do not aid in the diagnosis or change treatment unless they are markedly abnormal:

• Complete blood count
• Serum electrolytes
• Blood urea nitrogen (BUN)
• Serum creatinine

Unless anatomic abnormalities or renal disease is suspected, routine imaging studies are not necessary.

Renal ultrasonography (or limited intravenous pyelography [IVP] if the benefits of a definitive diagnosis outweigh the minor risk of radiation) may be helpful in patients with recurrent UTI or symptoms that suggest nephrolithiasis (see the images below). Confusion about the diagnosis of urolithiasis, pyelonephritis, or both is an indication for obtaining imaging studies.

Urolithiasis and pyelonephritis share many common symptoms (ie, hematuria, flank pain, shaking chills, anorexia). Urolithiasis is usually not associated with fever, except in patients with concomitant pyelonephritis.

Urolithiasis presents a unique problem in the pregnant female. Kidney stones should initially be treated conservatively because 50-67% of stones diagnosed during pregnancy pass spontaneously. Conservative therapy includes appropriate antibiotic coverage, adequate hydration, and systemic analgesics (usually narcotics, which are class C in pregnancy). Anti-inflammatory medications may cause oligohydramnios and/or premature closure of the patent ductus arteriosus and should be avoided, if possible.

If ultrasonography reveals a stone, then ultrasound-guided cystoscopic passage of a ureteral stent may relieve ureteral colic. In some cases (ie, pyonephrosis with an obstructing stone), percutaneous nephrostomy can be useful. Cystoscopic extraction (with fluoroscopic guidance) of a distal ureteral stone should be used sparingly because of the risk of ionizing radiation to the fetus.

The total dosage of ionizing radiation should not exceed 3-5 rads during the course of pregnancy. Of particular concern is radiation delivered during the first trimester, during organogenesis (especially days 11-56). A limited IVP can deliver 0.4-1 rad. Doses of more than 5 rads have been associated with an increase in benign and malignant tumors in the child after birth. No patient should receive more than 10-14 rads.

Renal ultrasonography is often performed initially, but the findings are often inconclusive. A limited IVP (ie, kidneys, ureters, and bladder [KUB] and a 30-min shot following injection of contrast) can be helpful in delineating the site of obstruction.

Urine cytology may be useful in detecting rare upper urinary tract lesions. An antistreptolysin-O (ASO) titer greater than 200 Todd units suggests recent group A streptococcal infection; however, as many as 20% of patients with acute glomerulonephritis have ASO titers within the reference range.

The sulfosalicylic acid (SSA) test measures urine turbidity when a small amount of aspirin is added to the urine specimen. A finding of +2 to +4 suggests bacteriuria.

On urine cytology, clumping WBCs and WBC casts are consistent with pyelonephritis. RBC casts are characteristic of acute glomerulonephritis and should be suspected after a recent or concurrent streptococcal infection.

Renal involvement usually leads to proteinuria. Nephrotic syndrome includes high proteinuria (>3.5 g/24 h), edema, hypercholesterolemia, and hypoalbuminemia; however, this can be confused with preeclampsia. Oval fat bodies and fatty casts can suggest membranous glomerulonephritis.

Treatment of bacteriuria

Because of the dangers of maternal and fetal complications, acute care (eg, in the emergency department [ED]) should focus on identifying and treating asymptomatic and symptomatic bacteriuria, along with ensuring that a more serious process is not the cause of the symptoms.

Treatment of asymptomatic bacteriuria in pregnant patients is important because of the increased risk of UTI and its associated sequelae.^[16] ED care may involve the following:

• Administration of appropriate antibiotics
• Administration of fluid if the patient is dehydrated
• Admission if any indication of UTI exists

Any discussion of treatment should be prefaced with a discussion of behavioral methods to ensure good hygiene and to reduce bacterial contamination of the urethral meatus. This is important in preventing inadequate treatment and recurrent infection.

Behavioral methods include the following:

• Avoid baths
• Wipe front-to-back after urinating or defecating
• Wash hands before using the toilet
• Use washcloths to clean the perineum
• Use liquid soap to prevent colonization from bar soap
• Clean the urethral meatus first when bathing

Antibiotics for bacteriuria and cystitis

Oral antibiotics are the treatment of choice for asymptomatic bacteriuria and cystitis. Appropriate oral regimens include cephalexin 500 mg qid, ampicillin 500 mg qid, nitrofurantoin 100 mg bid, or sulfisoxazole 1 g qid.

The resistance of E coli to ampicillin and amoxicillin is 20-40%; therefore, they are no longer considered an optimal choice for treatment of UTI caused by this organism. Fosfomycin (Monurol), a phosphonic acid derivative, is useful in the treatment of uncomplicated UTIs caused by susceptible strains of E coli and Enterococcus species. Fosfomycin is pregnancy category B (ie, fetal risk is not confirmed in studies in humans but has been shown in some studies in animals).

Although antibiotic courses of 1, 3, and 7 days have been evaluated, 10-14 days of treatment is usually recommended to eradicate the offending bacteria. For example, studies with cephalexin, co-trimoxazole, and amoxicillin have indicated that a single dose is as effective as a 3- to 7-day course of therapy, but the cure rate is only 70%. Data are insufficient to justify abandoning the more traditional long-term regimens.

Treatment success depends on eradication of the bacteria rather than the duration of therapy. A test-for-cure urine culture should show negative findings 1-2 weeks posttherapy. A non-negative culture result is an indication for a 10- to 14-day course of a different antibiotic, followed by suppressive therapy (eg, nitrofurantoin 50 mg qhs) until 6 weeks postpartum.

Mathai and Thomas et al suggest the need for disseminated guidelines for practitioners in developing countries such as India.^[17] In their study, they found inappropriate use of antibiotics in terms of safety, cost, susceptibility, and threat for developing resistance.

Treatment of pyelonephritis

The standard course of treatment for pyelonephritis is hospital admission and intravenous cephalosporins or gentamicin. Administer IV fluids with caution. Patients with pyelonephritis can become dehydrated because of nausea and vomiting and need intravenous hydration. However, patients are at high risk for development of pulmonary edema and adult respiratory distress syndrome (ARDS).

Manage fever with antipyretics (preferably, acetaminophen). Manage nausea and vomiting with antiemetics. Most antiemetics can be used for adverse effects caused by antibiotics, but doxylamine, Emetrol (pregnancy class A), dimenhydrinate, and metoclopramide (class B) are preferred.

Preterm labor and delivery are additional risks associated with pyelonephritis. These risks need to be evaluated and treated early in the course of admission.

Millar and colleagues reported on a randomized, controlled trial of outpatient treatment of pyelonephritis in pregnancy.^[18] They concluded that outpatient therapy is as safe and effective as inpatient care in the treatment of pyelonephritis before 24 weeks' gestation. However, the prevailing attitude still dictates that aggressive inpatient hydration and parenteral antibiotics are necessary. In early pregnancy, pyelonephritis places the patient at risk for spontaneous abortion and, after 24 weeks' gestation, preterm labor.

In their study, Millar et al treated outpatients with 2 doses of intramuscular ceftriaxone and 10 days of oral cephalexin.^[18] Initial outpatient therapy and traditional inpatient therapy failed to cure equal numbers of patients. Benefits include the obvious cost savings and psychosocial benefits for the patient. Risks include septic shock or respiratory insufficiency at home during outpatient therapy.

Strict guidelines for an observation period before emergency department discharge, patient education, and home nursing have been discussed. In addition, approximately two thirds of the outpatient treatment group did not complete the study because the subjects developed one or more complications. If outpatient therapy is considered, only selected patients in their second trimester should be considered. More study is necessary before a change in the physician's practice pattern is considered.

Antibiotic selection

Antibiotic therapy should be based on urine culture sensitivities, if known. Often, therapy is initiated prior to culture-result availability. This requires clinical knowledge of the most common organisms and their practice-specific and/or hospital-specific sensitivities to medications.

Institution-specific drug resistances should also be considered before a treatment antibiotic is chosen. For instance, with E coli infection alone, resistance to ampicillin can be as high as 28-39%. Resistance to trimethoprim-sulfamethoxazole has been described as 31% and, to first-generation cephalosporins, as high as 9-19%.

Maternal physiologic changes that influence pharmacokinetics include increased glomerular filtration rate and renal plasma flow, increased volume of distribution, decreased gastric motility and emptying, and decreased albumin levels. Serum levels of antibiotics are lower in pregnancy because of the gross increase in blood volume and increased glomerular filtration rate.

Some antibiotics should not be used during pregnancy because of their effects on the fetus. These include tetracyclines (adverse effects on fetal teeth and bones, congenital defects), trimethoprim in the first trimester (facial defects, cardiac abnormalities), and chloramphenicol and sulfonamides in the third trimester (Gray syndrome; hemolytic anemia in mothers with glucose-6-phosphate dehydrogenase [G-6-PD] deficiency, jaundice, and kernicterus, respectively).

Fluoroquinolones are contraindicated in pregnancy. Although in utero exposure is not an indication for termination, fetal exposure to fluoroquinolones has resulted in myelomeningocele, hydrocephaly, hypospadias, maldescended testes, inguinal hernia, bilateral hip dysplasia, and atrial septal defects. The anomalies do not seem to follow a particular pattern, which may be reassuring. However, a causal relationship cannot be excluded.

Nitrofurantoin (Macrodantin) is a safe and effective drug; however, its use in pyelonephritis is limited owing to poor tissue penetration. In the past, it was completely avoided in the third trimester because of hemolytic effects on the newborn. More recently, the use of nitrofurantoin has been limited only for women in the last several weeks of pregnancy. The use of nitrofurantoin during this period can cause of hemolytic anemia in the fetus or newborn infant due to their immature erythrocyte enzyme systems (glutathione instability). Nitrofurantoin has also been shown to be safe and effective for once-daily prophylactic therapy during pregnancy.

Macrolides are not first-line agents for UTI in pregnancy. However, they are well tolerated by mother and fetus. A meta-analysis concluded that although antibiotic treatment is effective in patients with UTIs, the data are insufficient to recommend any specific drug regimen for treatment of symptomatic UTIs during pregnancy.^[19] All of the antibiotics studied were shown to be effective in terms of both cure rates of UTI in pregnancy and in decreasing the incidence of associated adverse outcomes.

Surgical treatment

Surgical care is rarely indicated, unless one of the pathologic causes listed in the differential diagnoses is suspected.

In patients with urethral or bladder diverticulum, bladder stones, urethral syndrome, lower urinary tract trauma, interstitial cystitis, or bladder cancer, cystoscopy may aid in establishing the diagnosis.

A retrograde stent or a percutaneous nephrostomy tube should be used to relieve ureteral colic and/or to decompress an obstructed infected collecting system. More invasive procedures, such as ureteroscopic stone extraction, are rarely indicated. Extracorporeal shock wave lithotripsy (ESWL) is contraindicated in pregnancy.

In the rare patient in whom invasive surgical therapy is indicated, the operation should be planned for the second trimester. Surgical intervention during the first trimester is associated with miscarriage; in the third trimester, surgery is associated with preterm labor. Urgent surgical intervention in the third trimester should coincide with delivery of the fetus.

Consultations

The general obstetrician/gynecologist or family practitioner should be able to manage even a complicated case of pyelonephritis. However, a urologist should be consulted if the patient is not responding to treatment, if the patient has a protracted course, or to rule out other factors such as perinephric abscess or obstruction.

Early after hospital admission for pyelonephritis, consult an obstetrician or other physician familiar with the care of pyelonephritis in pregnancy. Preterm labor and delivery are additional risks associated with pyelonephritis and need to be evaluated and treated early in the course of admission.

Consult a urologist in the case of obstructing urolithiasis or an infected collecting system. Consultation with a urologist should also be strongly considered in patients with anatomic urologic abnormalities and/or a history of previous urologic reconstructive surgery.

Coexisting medical disorders that warrant consultation when found in conjunction with pyelonephritis include the following:

• Preexisting diabetes
• Gestational diabetes
• Cardiac disease
• Autoimmune disease
• Renal disease

Further inpatient care

In addition to appropriate antibiotic and antipyretic therapy, include antepartum management of pyelonephritis through rehydration and tocolytic therapy, if appropriate.

The most important complication of pyelonephritis is respiratory insufficiency due to bacterial endotoxin damage to the alveoli, causing pulmonary edema; therefore, fluid overload (>3 L over outputs in 48 h) must be avoided and tocolytics used sparingly.

Frequent clinical evaluation allows identification of pulmonary injury early. Clinical signs include dyspnea, tachypnea, and hypoxemia and findings on a chest radiograph that are consistent with pulmonary edema ARDS. Prompt recognition can be addressed with oxygen, intubation, and mechanical ventilation, as necessary, to prevent adverse maternal and fetal outcomes. Central hemodynamic monitoring is helpful to guide fluid therapy and oxygen delivery, especially when mechanical ventilation is necessary.

The treatment of pregnant women with acute pyelonephritis may involve the following:

• Hospitalization
• Frequent monitoring of vital signs
• Evaluation of CBC, serum creatinine, and electrolyte levels
• Urine and blood culturing
• Monitoring of urine output (with a catheter, if necessary)
• Administration of intravenous crystalloid fluid to maintain a minimum urinary output of more than 30 mL/h
• Administration of intravenous antimicrobial agent
• Use of antipyretics, if temperature is higher than 39°C

Renal dysfunction typically resolves with hydration; however, nephrotoxic medications should be dose-adjusted for changes in creatinine clearance. Likewise, maternal anemia usually resolves with the infection if iron stores are adequate.

Clinical improvement is usually rapid after the initiation of antimicrobial therapy, although fevers may wax and wane. Most (85%) fevers resolve within the first 48 hours and 90% resolve within 72 hours. Women who do not improve in 72 hours should undergo testing for other sources of infection, including renal ultrasonography to rule out obstructive nephrolithiasis. Continue intravenous antibiotic therapy for 24-48 hours after defervescence.

If conservative treatment fails or if an infected obstructed system is suspected, imaging studies are indicated. Renal ultrasonography is often performed initially, but the findings are often inconclusive. A limited IVP (ie, a kidney, ureters, and bladder [KUB] film and a 30-min shot following injection of contrast) can be helpful in delineating the site of obstruction.

Further outpatient care

Generally, women are discharged with 1-2 weeks of oral antibiotic therapy. Because acute pyelonephritis places the pregnant patient at risk for recurrent antepartum UTI (38%) and recurrent antepartum pyelonephritis (7-8%), continue antibiotic prophylaxis for the remainder of the pregnancy.

Although this approach has not been definitively proven to prevent preterm labor and low birth weight in infants, the significant recurrence of asymptomatic bacteriuria, UTI, and pyelonephritis supports the prudence of prophylaxis. Both continuous (daily) and postcoital prophylaxis regimens are effective. The agents of choice during pregnancy include nitrofurantoin (50-100 mg) and cephalexin (250 mg).

For simple cystitis and bacteriuria, a test-for-cure urine culture should be performed approximately 1-2 weeks after the completion of therapy. Cases that are persistent (positive culture results) or recurrent (positive culture results after 2 wk) should be treated with a sensitive antibiotic and continued on a low-dose suppressive (prophylactic) antibiotic until 6 weeks postpartum.

Possible nonpharmacologic recommendations include early postcoital voiding (type II-3 evidence), pushing fluids (type II-3 evidence), and drinking cranberry juice (type I evidence in elderly women). The patient’s hygiene should be reviewed to determine if certain practices predispose her to infection.

Deterrence/prevention

Untreated asymptomatic bacteriuria progresses to pyelonephritis in 25-30% of cases; therefore, routine screening for bacteriuria is recommended throughout pregnancy. The American College of Obstetricians and Gynecologists and the US Preventive Services Task Force recommend urine culture screening for all pregnant women at their first prenatal visit.^{[20, 21]} The most cost-effective and cost-beneficial screening method depends on the local prevalence of asymptomatic bacteriuria.

Rouse and colleagues described the use of leukocyte esterase-nitrite dipsticks, treating the patients with positive results, and retesting using dipsticks.^[22] A urine culture is unnecessary unless the retest result is positive. If the culture result is positive, the patient is re-treated and placed on suppressive therapy; however, if the prevalence of asymptomatic bacteriuria is high, screening and treatment based on urine culture with reculture (used as test of cure) are also cost-benefit effective.

Because the prevalence increases with sexual activity, a prudent approach may be to limit activity or use postcoital antibiotic prophylaxis. Investigate untreated pathologies. UTI before pregnancy or antepartum is predictive of bacteriuria at the first prenatal visit. Avoid in-dwelling catheterization during labor and after delivery.

Parkland hospital reported a reduction in cases of acute pyelonephritis (from 4% to 1-2%) after implementing a screening and treatment program for asymptomatic bacteriuria in pregnant women. Residual cases occur in unscreened women (ie, lack of prenatal care) or in women with recurrences. The incidence is increased in the puerperium to approximately 8%.

Women with risk factors have the additional risks of a first, recurrent, or persistent UTI. These women should undergo more frequent screenings. Risk factors include the following:

• Diabetes mellitus, including gestational diabetes
• Urologic abnormalities (eg, neurogenic bladder, duplicated collecting systems)
• History of UTI prepregnancy and antepartum prior to initiation of prenatal care (ie, 2-3 culture-proven UTIs/y)
• Renal transplantation or orthotopic diversion
• Sickle cell hemoglobinopathy

Regarding sickle cell hemoglobinopathy, pyelonephritis was long thought to be more common in sickle cell trait carriers (both pregnant and nonpregnant persons); however, Thurman et al suggested that increased urinary testing did not decrease the incidence of pyelonephritis in pregnant women who carried the sickle cell trait.^[23]

Suppressive antibiotic therapy should be instituted in patients who develop acute cystitis or pyelonephritis during pregnancy. Patients treated for asymptomatic bacteriuria during pregnancy who have recurrent or persistent asymptomatic bacteriuria upon retest should also receive prophylactic antibiotics.

Patients with pyelonephritis, recurrent UTIs, concurrent stone disease, or indwelling ureteral stents should receive prophylactic antibiotics throughout pregnancy and should undergo frequent urine testing.

A recent randomized trial suggests that cranberry juice supplementation may be effective in preventing asymptomatic bacteruria during pregnancy; however, the authors noted significant difficulty with compliance and tolerability of their 3-times-daily regimen.^[24]

Immunization for UTI

Uehling et al reported that repeated immunization with a vaginal mucosal vaccine prolongs the time to reinfection in women susceptible to UTIs.^[25] Women who received 6 doses of a vaginal vaccine remained infection-free significantly longer than patients who received 3 doses or placebo only.

The study was a double-blind phase 2 trial of suppositories containing 10 strains of heat-killed uropathogens. Women who were given the vaccine developed significantly fewer UTIs than those in the control group. Phase 3 clinical trials are ongoing.

Special fetal concerns

In addition to the well-documented consequences of preterm delivery and low birthweight, several recent reports have raised concern for longer-term neurologic consequences in children born to mothers who were diagnosed with UTI in pregnancy.

One population-based study of over 84,000 children demonstrated an adjusted 1.25 odds ratio of an attention-deficit hyperactivity disorder (ADHD) diagnosis for those children born to mothers with UTI compared with those with no prenatal UTI exposure.^[26] Additionally, Sun and colleagues demonstrated a 1.55 times increased odds of epilepsy in children born to mothers with cystitis; the odds ratio was 2.38 for children of mothers diagnosed with pyelonephritis.^[27]

The association of maternal UTI and childhood neurologic difficulties merits further investigation to determine if a specific causative factor exists or if the association exists due to other common factors such as intensity of prenatal care or socioeconomic status in general.

Table: Treatment of Cystitis in Pregnant Patients

Table 1. Treatment Regimens for Pregnant Women with UTI (Open Table in a new window)

In most cases of bacteriuria and UTI in pregnancy, the prognosis is excellent; however, most long-term sequelae are due to complications associated with septic shock, respiratory failure, and hypotensive hypoxia (ie, extremity gangrene).

Maternal UTI has few direct fetal sequelae because fetal septicemia is rare; however, uterine hypoperfusion due to maternal dehydration, maternal anemia, and direct bacterial endotoxin damage to the placental vasculature may cause fetal cerebral hypoperfusion.

Untreated upper tract UTIs are associated with low birth weight, prematurity, premature labor, hypertension, preeclampsia, maternal anemia, and amnionitis.^[28] A retrospective population-based study by Mazor-Dray et al showed that UTI during pregnancy is independently associated with intrauterine growth restriction, preeclampsia, preterm delivery, and cesarean delivery.^[29]

For patient education information, see the Kidneys and Urinary System Center and Pregnancy and Reproduction Center, as well as Urinary Tract Infections, Pregnancy, Bladder Control Problems, and Blood in the Urine.

The physiologic changes of pregnancy predispose women to asymptomatic bacteruria (ASB) and UTI. All pregnant women should be screened for ASB with a urine culture, treated with antibiotics if the culture is positive, and then retested for cure. The goal of treatment of UTI during pregnancy is to prevent negative sequelae to the mother and fetus. Patients treated for symptomatic UTI during pregnancy should be continued on daily prophylactic antibiotics for the duration of their pregnancy. Targets for future research include targeting low-income groups and women in developing countries for screening and early treatment, as well as determining if a causal relationship exists between maternal UTI and childhood neurologic consequences.