Urinary Tract Infections in Pregnancy

Practice Essentials

Pregnancy causes numerous changes in the woman’s body that increase the likelihood of urinary tract infections (UTIs). Hormonal and mechanical changes can promote 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, help make UTIs the most common bacterial infections during pregnancy.

Untreated bacteruria  during pregnancy is associated with risks to both the fetus and the mother, including pyelonephritis, preterm birth, low birth weight, and increased perinatal mortality. 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. (See Urinary Tract Infection in Females.)

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). Patients treated for three or more episodes of cystitis or one episodes of pyelonephritis during pregnancy should be continued on daily prophylactic antibiotics for the duration of their pregnancy.

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 is cost-effective, compared with treating UTI and pyelonephritis without screening. Goals for future research include targeting low-income groups and women in developing countries for screening and early treatment, as well as determining whether a causal relation exists between maternal UTI and childhood neurologic consequences.

For patient education information, see the following:

• Urinary Tract Infection (UTI): Symptoms, Causes, Diagnosis, Treatment 
• Urinary Tract Infections in Pregnancy
• What If I Get a UTI While I’m Pregnant?

Definitions of key terms

Urinary tract infection

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 white blood cells [WBCs]/mL) in a symptomatic patient. A diagnosis of UTI should be supported by a positive culture for a uropathogen, particularly in patients with vague symptoms.^[1]

Asymptomatic bacteriuria

Asymptomatic bacteriuria 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 asymptomatic bacteriuria is a risk factor for acute cystitis (40%) and pyelonephritis (25-30%) in pregnancy. This usually occurs in early pregnancy. Risk factors include prior UTIs, pre-existing diabetes, increased parity, and low socioeconomic status. 

Cystitis

Acute cystitis involves only the lower urinary tract; it is characterized by inflammation of the bladder as a result of bacterial or nonbacterial causes (eg, radiation or viral infection). Acute cystitis develops in approximately 1- 2% 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 0.5-2% 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. Most cases of pyelonephritis occur in the second and third trimester. 

Additional risk factors for complicated UTI in pregnancy include the following^[2] :

• Immunosuppression
• Pre-existing diabetes
• Sickle cell anemia
• Neurogenic bladder
• Recurrent or persistent UTIs before pregnancy
• Tobacco use
• Age < 20 years
• Late presentation for prenatal care

• References

Pathophysiology

Infections result from ascending colonization of the urinary tract, primarily by existing vaginal, perineal, and fecal flora. Various maternal physiologic and anatomic factors predispose to ascending infection. Such factors include urinary retention caused by the weight of the enlarging uterus on the bladder; urinary stasis due to progesterone-induced ureteral smooth muscle relaxation; and blood-volume expansion, which increases the glomerular filtration rate 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 can serve as a reservoir for bacteria. Urinary stasis and the presence of vesicoureteral reflux predispose some women to acute pyelonephritis.^[3]

Calyceal and ureteral dilatation are more common on the right side; in up to 80% of cases, the dilatation is localized to the right. The degree of calyceal dilatation is also more pronounced on the right than the left (average 15 mm vs 5 mm). This dilatation appears to begin by about 10 weeks’ gestation and increases throughout pregnancy, resolving approximately 6-12 weeks postpartum. This is underscored by the distribution 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 (aminoaciduria) during pregnancy are additional factors that lead to UTI. In many cases, glucose excretion increases during pregnancy over nonpregnant values of 100 mg/day. Glycosuria is due to impaired glucose reabsorption by the proximal collecting tubule and loop of Henle.

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 Escherichia coli to the urothelium.

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Etiology

Pathogens

E coli is the most common cause of UTI, accounting for approximately 70-80% of cases in pregnancy. It originates from fecal flora colonizing the periurethral area, causing an ascending infection. Other pathogens include the following^[4] :

• Klebsiella pneumoniae (5%)
• Proteus mirabilis (5%)
• Enterobacter species (3%)
• Staphylococcus saprophyticus (3%)
• Group B beta-hemolytic Streptococcus (GBS; 2-5%)
• Proteus species (2%)

Gram-positive organisms, particularly Enterococcus faecalis and GBS, are clinically important pathogens. They cause up to 10% of UTIs in pregnant women. Infection with S 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 atypical pathogens.

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.

Incidental documentation of GBS bacteriuria suggests a higher colonization count than is 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.  A systemic review and meta-analysis found no association between GBS colonization and preterm delivery. In cases where preterm delivery occurred, however, there was an increased risk of subsequent GBS colonization.^[5]

Patient factors

Several patient-level factors are associated with an increased frequency of bacteriuria during pregnancy. Compared with nonindigent patients, indigent patients have a 5-fold increased incidence of bacteriuria. The risk is doubled in women with sickle cell trait. Other risk factors for bacteriuria include the following:

• Pre-existing diabetes mellitus^[6]
• Neurogenic bladder retention 
• History of vesicoureteral reflux (treated or untreated)^[7]
• Kidney transplantation^[8]
• Increased parity
• History of previous UTIs

A study that compared pregnant women with and without a positive urine culture found that the following factors were associated with increased odds of UTI^[9] :

• Intercourse ≥3x/week (odds ratio [OR] 5.62)
• Recent UTI (OR = 3.27)
• Not washing genitals precoitus (OR = 2.16)
• Not washing genitals postcoitus (OR = 2.89)
• Not urinating postcoitus (OR = 8.62)
• Washing genitals from back to front (OR = 2.96)

Cesarean delivery

Cesarean delivery is associated with UTI (increasing the likelihood 2.7-fold), but this association may be confounded by bladder catheterization or prolonged rupture of membranes (PROM). The incidence of symptomatic UTI is 9.3%, and that 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.

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Epidemiology

United States statistics

The frequency of urinary tract infection (UTI) in pregnant women (0.3-1.3%) is similar to that in non-pregnant women.^[10] However, recurrent bacteruria is more common in pregnant women than non-pregnant women. 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, so perineal and fecal flora have a shorter distance to travel.
• 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 do.
• 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 as many as 35% of these cases, bacteriuria may progress to symptomatic upper UTI or pyelonephritis; this rate is significantly higher than that seen in nonpregnant women^[11]

International statistics

Versi et al described a higher prevalence of bacteriuria in pregnant white women (6.3%) than in pregnant Bangladeshi women (2%).^[12] Pregnancies that resulted in preterm deliveries were strongly associated with bacteriuria in white women; this association was not observed in Bangladeshi women. The authors hypothesized that the difference could be due to variation in hygiene practices and clothing.

A large population-based study of nearly 200,000 pregnant Israeli women demonstrated a 2.5% rate of asymptomatic bacteriuria^[13] and a 2.3% rate of symptomatic UTI.^[14] 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.

The authors suggested that these findings may be a marker for intensity of prenatal care rather than a specific causal effect of the urinary infection.^[13] 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 those of multiple previous investigations.^[14]

Age- and race-related demographics

The prevalence of UTI during pregnancy increases with maternal age.

A retrospective analysis of 24,000 births found the prevalence of UTI during pregnancy to be 28.7% in whites and Asians, 30.1% in blacks, and 41.1% in Hispanics. When socioeconomic status is controlled for, no significant interracial differences seem to exist. A survey-based analysis of self-reported UTI found similar trends. This study also considered Native American women and found the highest prevalence of UTI in this population (24.2%) as compared with Asian (10.3%), white (16.6%), Hispanic (18.3%), and black (20.3%) women.^[15]

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, 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.

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Prognosis

In most cases of bacteriuria and urinary tract infection (UTI) in pregnancy, the prognosis is excellent. The majority of 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 bloodstream infection 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 UTIs are associated with low birth weight, prematurity, premature labor, hypertension, preeclampsia, maternal anemia, and amnionitis.^{[16, 17]} 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.^[13]  

Preeclampsia

 A meta-analysis of 19 studies demonstrated an increased odds (1.31-fold) of preeclampsia in women with any UTI during pregnancy versus those without UTI.^[17]  A multicenter retrospective study found that UTI in pregnancy, particularly in the third trimester, is strongly associated with preeclampsia. Rates of preeclampsia in patients with UTI compared with those without reported UTI were 31.1% vs 7.8%, respectively (P < 0.001). The authors hypothesize that the increased maternal inflammatory burden from UTI enhances the risk of preeclampsia.^[18]

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History

The presentation varies according to whether the patient has asymptomatic bacteriuria, a lower urinary tract infection (UTI; ie, cystitis) or an upper UTI (ie, pyelonephritis).

Burning with urination (dysuria) is the most significant symptom in pregnant women with symptomatic cystitis. Other symptoms include frequency, urgency, suprapubic pain, hematuria, and pyuria 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 signs and symptoms often include fever (> 38°C), shaking chills, anorexia, nausea, vomiting, and costovertebral angle tenderness. Right-side flank pain is more common than left-side or bilateral flank pain. Pyuria is a common finding. Patients may also present with hypothermia (as low as 34°C). Symptoms of simple cystitis are not always present.

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Physical Examination

Physical examination findings should be considered in relation to the duration of pregnancy. The differential diagnoses may change from one trimester to the next, 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 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 third-trimester patients 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 occurs on the right side more frequently, and is present in more than half of patients. Pain may also be found suprapubically with palpation.

Assessment of the fetal heart rate on the basis of gestational age should be included as part of the evaluation. Often, owing to maternal fever, the fetal heart rate is elevated to more than 160 beats/min.

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Complications

The primary complication of bacteriuria during pregnancy is cystitis, though the primary morbidity is due to pyelonephritis.

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 glomerular filtration rate)
• Hematologic dysfunction, including anemia or thrombocytopenia 
• Hypoxic fetal events due to maternal complications of infection that lead to hypoperfusion of the placenta
• Preeclampsia^[18]
• Preterm labor, and possible subsequent preterm delivery, leading to increased infant morbidity and mortality

Pregnant women with pyelonephritis can become critically ill very quickly. It has been estimated that approximately 20% of pregnant women with severe pyelonephritis develop complications that include septic shock variants.^[19] In a prospective study of cases of pregnant women with acute pyelonephritis, complications included anemia (23%), bacteremia (17%), respiratory insufficiency (7%), and renal dysfunction (2%).^[16]

Pulmonary injury may also complicate UTI in pregnancy. Approximately 2% of 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.

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Approach Considerations

Laboratory studies can include blood studies and urine studies, including culture, urinalysis, dipstick testing, and other tests (eg, urine cytology, sulfosalicylic acid [SSA] testing).

Imaging tests can include ultrasonography and intravenous pyelography.

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Blood Studies

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

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

 In pregnant women who are showing signs of sepsis, it is reasonable to obtain blood cultures and a lactic acid assay.  Although there is no evidence that positive blood cultures are associated with worse prognosis, elevated lactic acid levels have been associated with adverse maternal outcomes in presumed sepsis.^[20]

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Urine Studies

Urine specimen collection

Universal screening is recommended for  all pregnant patients. A urine specimen should be carefully collected for urinalysis and culturing at 12-16 weeks’ gestation, or the first prenatal appointment, whichever comes first.^[21] These tests help to identify patients with asymptomatic bacteriuria, as well as those with other concerning findings such as glucosuria.

For urine collection, a midstream clean catch is adequate, provided that 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 study looking at different methods of specimen collection by pregnant women suggests that the cleansing process does not completely prevent contamination by skin flora. The data showed minimal difference in rates of contamination whether a clean catch was performed or not.^[22] Therefore, it may be reasonable to obtain a midstream (not clean catch) urine sample.

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

The specimen should be sent for evaluation as soon as possible. Specimens that are allowed to sit at room temperature may have falsely elevated colony counts, as bacteria will continue to proliferate in warm urine. Refrigerate the specimen at 4°C if it cannot be transported immediately as this will stop further growth of the bacteria

Urine culture

Urine culture is the standard method for evaluating for urinary tract infection (UTI) during pregnancy. Indications for performing a urine culture include the following:

• New onset of symptoms of cystitis with positive urinalysis or dipstick testing
• Recurrent UTI
• Pyelonephritis
• Failure to respond to initial treatment regimens
• History of recent instrumentation
• Hospital admission

A voided specimen with a bacterial growth of 100,000 colony-forming units (CFUs) per milliliter or higher is the standard definition of a positive urine culture.^[4] Counts lower than 100,000 CFU/mL usually indicate specimen contamination rather than infection. Patients with pyelonephritis often have white blood cell (WBC) casts.

Culture results can be used to identify specific organisms and antibiotic sensitivities, but results are often unavailable at the time of treatment.

Urinalysis by microscopy

Positive results for nitrites, leukocyte esterase, WBCs (pyuria), red blood cells (RBCs), and protein suggest UTI. Pyuria is present in almost all women with cystitis. Bacteria found in the specimen can help with the diagnosis. The presence of bacteria without pyuria usually represents contamination of the urine.

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

Clumping WBCs and WBC casts are indicative of kidney inflammation and are consistent with upper tract infection or pyelonephritis. RBC casts are characteristic of acute glomerulonephritis, which 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.

Dipstick testing

Several reports describe the use of urine dip for nitrites and leukocyte esterase in the evaluation of asymptomatic bacteriuria. In comparison with culture, sensitivity ranges from 50% to 92% and specificity from 86% to 97%.

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/HPF). The addition of protein and blood increases the sensitivity and specificity of the test in the evaluation of UTI.

A positive nitrite test is reliable for bacteriuria, but a negative test does not exclude bacteriuria. The reason for this is that bacteria converts the dietary metabolite nitrate to nitrite in the urine. As suggested by Kodikara et al, nitrite dipstick testing may be a reasonable and cost-effective screening strategy for women who otherwise may not undergo screening for bacteriuria, as is often the case in developing countries.^[23]

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Renal Ultrasonography and Intravenous Pyelography

Unless an anatomic abnormality or renal disease is suspected, initial routine imaging studies are not necessary. Patients with suspected pyelonephritis who are not responsive to appropriate antibiotic therapy after 48-72 hours should undergo imaging. In pregnant patients, the recommended imaging study to perform first is a renal ultrasound, to avoid contrast and radiation unless necessary.

Renal ultrasound is helpful to visualize kidney or ureteral stones, renal abscess formation, or hydronephrosis. 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 urinary tract infection (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.

View Image

Twenty-nine-year-old pregnant woman with history of reflux uropathy and ureteral reimplantation at age 21 months presents with right-side flank pain a....

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Color-flow Doppler highlights normal flow in right kidney of 29-year-old pregnant woman with history of reflux uropathy and ureteral reimplantation at....

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25-year-old pregnant woman with right lower quadrant pain and hematuria has proximal ureteral obstruction consistent with urolithiasis. After 25 minut....

Urolithiasis and pyelonephritis have many symptoms in common (eg, 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 pregnant women. 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 agents in pregnancy). Anti-inflammatory medications may cause oligohydramnios, premature closure of the patent ductus arteriosus, or both and should therefore be avoided if possible.

If ultrasonography reveals a stone, ultrasound-guided cystoscopic passage of a ureteral stent may relieve ureteral colic. In some cases (eg, pyonephrosis with an obstructing stone), percutaneous nephrostomy can be useful. Cystoscopic extraction of a distal ureteral stone (with fluoroscopic guidance) 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 cGy 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 cGy. Radiation doses greater than 5 cGy have been associated with an increased likelihood of benign and malignant tumors in the child after birth. No patient should receive more than 10-14 cGy.

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

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Histologic Findings

On urine cytology, clumping white blood cells (WBCs) and WBC casts are consistent with pyelonephritis. Red blood cell (RBC) casts are characteristic of acute glomerulonephritis, which should be suspected in patients with 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.

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Approach Considerations

Treatment of bacteriuria and cystitis

Because of the dangers of maternal and fetal complications, acute care should focus on identifying and treating asymptomatic and symptomatic bacteriuria, along with ensuring that an alternate process is not the cause of the symptoms.

Treatment of asymptomatic bacteriuria in pregnant patients is important because of the increased risk of urinary tract infection (UTI) and its associated sequelae, including increased risk of pyelnonephritis, preterm delivery, and low birth weight.^[24]  

Behavioral methods

Any discussion of treatment should be prefaced with a discussion of behavioral methods that may be used to ensure good hygiene and reduce bacterial contamination of the urethral meatus, thereby 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

Antibiotic therapy

Oral antibiotics are the treatment of choice for asymptomatic bacteriuria and cystitis. Treatment is most commonly initiated empirically before culture and susceptibility results return. A meta-analysis concluded that although antibiotic treatment is effective in patients with UTIs, the data are insufficient to recommend any specific regimen for treatment of symptomatic UTIs during pregnancy.^{[25, 26]} All of the antibiotics studied were effective in terms of both increasing cure rates of UTI in pregnancy and decreasing the incidence of associated adverse outcomes. Current oral regimens are summarized in Table 1 below.

Table.

View Table

See Table

Antibiotics most commonly given as empiric therapy are cephalexin, amoxicillin-clavulanate, or fosfomycin, due to their broader spectrum of coverage than the other antibiotic options. The resistance of Escherichia coli to ampicillin and amoxicillin is 20-40%; accordingly, these agents are no longer considered optimal for treatment of UTIs caused by this organism.

Although 1-, 3-, and 7-day antibiotic courses have been evaluated, 10-14 days of treatment is usually recommended to eradicate the offending bacteria. For example, studies with cephalexin, trimethoprim-sulfamethoxazole, 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%. A systematic review that compared single-dose antibiotic treatment with 4- to 7-day treatments concluded that single-dose regimens may be less effective than a short-course regimen, but until more data become available from large trials, pregnant women with asymptomatic bacteriuria should be treated with the standard regimen.^[26]

Treatment success depends on eradication of the bacteria rather than on the duration of therapy. A test-for-cure urine culture should show negative findings 1-2 weeks after completion of  therapy. A nonnegative culture result is an indication for a 10- to 14-day course of a different antibiotic.

Recurrent Cystitis

Pregnant women who have three or more episodes of cystitis or bacteruria should be started on daily antibiotic prophylaxis for the remainder of pregnancy. Daily antibiotics should also be considered in pregnant women after one episode of pyelonephritis. Regimens for daily prophylaxis includes nitrofurantion 100 mg nightly, or cephalexin 250-500 mg nightly. A Cochrane review in 2015 noted that the rates of recurrent UTI were no different with a daily dose of nitrofurantoin and close surveillance versus close surveillance alone. More research needs to be done to evaluate this, especially due to the increasing prevalence of antibiotic resistance. 

In patients who are immunosuppressed or have medical conditions that would increase the risk of complications from cystitis, it is reasonable to consider antibiotic prophylaxis after one episode of cystitis.

Treatment of pyelonephritis

The standard course of treatment for pyelonephritis consists of hospital admission and intravenous (IV) administration of antibiotics until the patient has been afebrile for 48 hours. The recommended IV antibiotic would be a broad spectrum beta-lactam, such as ceftriaxone. Once culture results with susceptibilities become available and the patient is clinically improved, treatment can be transitioned to an oral antibiotic regimen. For women with a history of extended-spectrum beta-lactamase (ESBL) Enterobacter, carbapenem is recommended. Patients should be discharged with 10-14 days of antibiotic treatment, and then will need daily prophylactic antibiotics for the remainder of pregnancy.  

IV fluids must be administered with caution. Patients with pyelonephritis can become dehydrated because of nausea and vomiting and need IV hydration. However, they are at high risk for the development of pulmonary edema and acute respiratory distress syndrome (ARDS).

Fever should be managed with antipyretics (preferably, acetaminophen) and nausea and vomiting with antiemetics. If fever persists beyond 24 hours, urine and blood cultures should be repeated and a renal ultrasound should be performed.

Preterm labor and delivery are additional risks associated with pyelonephritis. These risks must be evaluated and treated early in the course of admission with tocolysis as necessary per the preterm labor guidelines. If the patient is septic, tocolysis is not recommended.

Inpatient versus outpatient treatment

The prevailing view is that pregnant patients with pyelonephritis require aggressive inpatient hydration and parenteral antibiotics. Pyelonephritis places the patient at risk for spontaneous abortion in early pregnancy and for preterm labor after 24 weeks’ gestation.

However, a randomized, controlled trial of outpatient treatment of pyelonephritis in pregnancy by Millar et al concluded that outpatient therapy is as safe and effective as inpatient care in the treatment of pyelonephritis before 24 weeks’ gestation.^[27] Benefits of outpatient care include cost savings and the psychosocial benefits for the patient. Risks include septic shock and respiratory insufficiency. Consideration of outpatient therapy should be limited to selected patients in their second trimester. More study is necessary before a change in the physician’s practice pattern is considered. 

Antibiotic selection

Antibiotic selection should be based on urine culture sensitivities, if known. Often, therapy must be initiated on an empirical basis, before culture results are available. This requires clinical knowledge of the most common organisms and their practice-specific 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 resistance to first-generation cephalosporins may be as high as 9-19%.

Maternal physiologic changes that influence pharmacokinetics include increased glomerular filtration rate (GFR) 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 the increased GFR.

Some antibiotics should not be used during pregnancy, because of their effects on the fetus. These include the following:

•  Tetracyclines (adverse effects on fetal teeth and bones)
•  Aminoglycosides (ototoxicity following prolonged fetal exposure)
• Fluoroquinolones; avoid during pregnancy and lactation (toxic to developing cartilage)
• Trimethoprim-sulfamethoxazole; avoid during first and third trimester

Fosfomycin does not achieve therapeutic levels in the kidneys and therefore should not be used in cases of pyelonephritis. 

Nitrofurantoin is safe and effective; however, poor tissue penetration has limited its use in pyelonephritis. Use near delivery can cause hemolytic anemia in the fetus or neonate as a consequence of their immature erythrocyte enzyme systems (glutathione instability). Nitrofurantoin has also been associated with cardiac birth defects when taken in the first trimester.^[28]  Given this risk profile, use of nitrofurantoin is best limited to the second trimester. However, nitrofurantoin is also safe and effective for once-daily prophylactic therapy during pregnancy.^[29]

Macrolides are not first-line agents for UTI in pregnancy. However, they are well tolerated by mother and fetus

Trimethoprim-sulfamethoxazole is a safe medication to treat UTIs during the second trimester. Trimethoprim is a folic acid antagonist and has been associated with an increased risk of birth defects when taken in the first trimester during organogenesis.^[28]  Sulfonamides are avoided at term because they displace the bilirubin from its binding site in the newborn, which give a theoretical risk of kernicterus. 

Surgical treatment

Surgical care is rarely indicated. Cystoscopy may aid in establishing the diagnosis of urethral or bladder diverticulum, bladder stones, urethral syndrome, lower urinary tract trauma, interstitial cystitis, or bladder cancer.

A retrograde stent or a percutaneous nephrostomy tube should be placed to relieve ureteral colic or decompress an obstructed infected collecting system. More invasive procedures, such as ureteroscopic stone extraction,^[30]  are rarely indicated. Extracorporeal shock wave lithotripsy (ESWL) is contraindicated in pregnancy.

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

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Medication Summary

The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications. Agents used include antibiotics and analgesics.

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Nitrofurantoin (Furadantin, Macrobid, Macrodantin)

• Dosing, Interactions, etc.

Clinical Context:  Nitrofurantoin is a synthetic nitrofuran that interferes with bacterial carbohydrate metabolism by inhibiting acetylcoenzyme A. It is bacteriostatic at low concentrations (5-10 mcg/mL) and bactericidal at higher concentrations. It is bactericidal against uropathogens such as Staphylococcus saprophyticus, Enterococcus faecalis, and Escherichia coli; it possesses no activity against Proteus, Serratia, or Pseudomonas species. It received a “A-I”  rating in the 2011 IDSA guidelines for treating UTIs.

It is manufactured in different forms to facilitate durable urine concentrations: macrocrystals (Macrodantin), microcrystal suspension (Furadantin), and a combined preparation (Macrobid). This agent achieves no appreciable concentrations in the prostate, kidney, or blood. Administer 100 mg orally twice daily for 5-7 days.

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Cephalexin (Keflex)

• Dosing, Interactions, etc.

Clinical Context:  This is a first-generation cephalosporin that inhibits bacterial growth by inhibiting bacterial cell wall synthesis. It is bactericidal and effective against rapidly growing organisms forming cell walls. Administer 500 mg orally every six hours for 5-7 days. 

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Amoxicillin and clavulanate (Augmentin, Amoclan)

• Dosing, Interactions, etc.

Clinical Context:  Amoxicillin interferes with the synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. This drug combination treats bacteria normally resistant to beta-lactam antibiotics. Administer 500/125 mg orally every 8 hours for 5-7 days. An alternative dosing is 875/125 mg twice daily for 5-7 days.

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Amoxicillin (Moxatag)

• Dosing, Interactions, etc.

Clinical Context:  Amoxicillin interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria. Administer 500 mg orally every eight hours for 5-7 days. This should not be used for empiric treatment given its poor efficacy.

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Cefuroxime (Ceftin, Zinacef)

• Dosing, Interactions, etc.

Clinical Context:  Cefuroxime is a second-generation cephalosporin that maintains the gram-positive activity of first-generation cephalosporins; it adds activity against Proteus mirabilis, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Moraxella catarrhalis. Administer 250 mg orally twice daily for 3-7 days

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Fosfomycin (Monurol)

• Dosing, Interactions, etc.

Clinical Context:  Fosfomycin was given a "B, I" rating in the 1999 IDSA guidelines for treating UTIs. Phosphonic acid is a bactericidal agent active against most UTI pathogens, including Escherichia coli and Enterobacter, Klebsiella, and Enterococcus species. Little cross-resistance between fosfomycin and other antibacterial agents exists. It is primarily excreted unchanged in the urine, and concentrations remain high for 24-48 hours after a single dose. It is unique but quite expensive. Administer 3 g orally as single dose with 3-4 oz of water

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