Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Explain criteria for diagnosis, risk factors, and preventive modalities for pyelonephritis in pregnancy.
2. Describe maternal and fetal sequelae of pyelonephritis in pregnancy.
3. Summarize treatment protocols for pyelonephritis in stable and unstable patients.
Acute pyelonephritis is one of the most common nonobstetric causes of antepartum hospitalization; it is estimated to complicate up to 2% of pregnancies. Acute pyelonephritis is associated with adverse pregnancy outcomes including preterm labor and preterm birth. Patients are also at increased risk for sepsis, respiratory distress syndrome, and acute renal failure.1 Although interventions such as screening for asymptomatic bacteriuria are routinely implemented to decrease the incidence of pyelonephritis, studies demonstrate that the annual rate has remained stable for almost 2 decades.1 Pregnancy predisposes women to pyelonephritis secondary to an increased level of progesterone that leads to relaxation of smooth muscle, decreased ureteral peristalsis, and an increased bladder capacity. The gravid uterus leads to physical obstruction of the urinary tract, contributing to urine stasis and potential for ascending infections.2 Preexisting conditions such as a history of urinary tract infection (UTI), diabetes mellitus, anemia, and sickle cell trait increase risks in some women.3 Current management of pyelonephritis is based on clinical evaluation, supported by laboratory assessment. Trends in microbial resistance to antibiotics continue to create challenges for treatment of this disease, especially in pregnant women. This article helps the physician to identify risk factors and provide guidelines for proper diagnosis and management of acute pyelonephritis.
Pyelonephritis in Pregnancy
Pregnant patients who develop pyelonephritis because of untreated UTI are more likely to be Black or Hispanic, young (20-29 years old), nulliparous, late to prenatal care, and to smoke during pregnancy.1 Risk factors that increase the risk of pyelonephritis include asymptomatic bacteriuria, history of UTI, diabetes mellitus, and sickle cell trait.4-9 Pregnant women with pyelonephritis are more likely to have cases complicated by anemia, acute renal dysfunction, and preterm birth compared with those without the disease. Anemia is the most common complication found in 25% of patients, and approximately 15% to 20% of these women will have bacteremia.10-12 Pyelonephritis can lead to severe and ultimately life-threatening complications, such as sepsis (1.9%-17%) and pulmonary insufficiency with respiratory failure (0.5%-7%).13 Before delivery, recurrent pyelonephritis occurs in approximately 20% of women.14 The risk of pyelonephritis is reduced by 70% to 80% if bacteriuria is eradicated.15 Most cases of pyelonephritis occur during the second and third trimesters.1 The incidence of premature delivery ranges in studies from 6% to 50%.10 Untreated bacteriuria has also been associated with low birth weight and perinatal mortality.16,17 However, there were no differences in stillbirth or neonatal death in patients with pyelonephritis compared with those without the disease.1 A recent meta-analysis demonstrated an association between pyelonephritis in pregnancy and the development of preeclampsia.18
Epidemiology
Development of pyelonephritis is typically a result of untreated asymptomatic bacteriuria. All pregnant patients should receive screening for asymptomatic bacteriuria. Diagnosis requires a midstream urine sample, which should be collected for culture as part of routine prenatal care at the first prenatal visit. Asymptomatic bacteriuria has an incidence of 2% to 10% in pregnancy. Lower urinary tract bacteriuria is associated with a 20% to 30% increased risk of developing pyelonephritis in pregnancy.2 Treatment regimens will vary based on the susceptibility of the isolated uropathogen.
Clinical Manifestations
Symptoms may be similar to those of a lower UTI (cystitis), including urinary urgency, frequency, dysuria, hematuria, and suprapubic discomfort. As symptoms of urgency and frequency can be experienced in normal pregnancy, these symptoms cannot be reliably used to rule out acute cystitis. Patients with either asymptomatic bacteriuria or cystitis should have periodic screening for recurrent bacteriuria and consideration for antimicrobial prophylaxis for management of recurrent UTI during their pregnancy. Up to 40% of pregnant women may develop pyelonephritis if asymptomatic bacteriuria is left untreated; therefore, antibiotic treatment guided by sensitivities is warranted to reduce the risk of pyelonephritis. The Infectious Diseases Society of America (IDSA) recommends an antibiotic treatment regimen of 3 to 7 days for both asymptomatic bacteriuria and cystitis.4 In symptomatic patients, a pelvic examination is often required to rule out cervicitis or vaginitis, unless examination is contraindicated.
Pyelonephritis is a clinical diagnosis based on symptoms of fever (>38[degrees]C or 100.4[degrees]F) and costovertebral angle (CVA) tenderness, with laboratory confirmation of pyuria or bacteriuria. Patients may also experience chills, anorexia, nausea, vomiting, or flank pain. It is important to note that symptoms of acute cystitis, such as dysuria or increased urinary frequency, may not be present.14-18 Uterine contractions, lower back pain, and/or pelvic pressure may complicate the clinical picture.
Diagnosis of Acute Pyelonephritis
The diagnosis of asymptomatic bacteriuria requires a urine culture. The IDSA defines a positive urine culture as "two consecutive voided cultures with 105 or more colony-forming units (CFUs) of the same bacterium, or a single catheterized urine specimen with 102 or more CFUs of one bacterium." In clinical practice, a single voided urine culture is considered positive if 105 or more CFUs of a single bacterium are present.10 Pyelonephritis is a clinical diagnosis, and the presence of pyuria or leukocyte casts is also consistent with the diagnosis of pyelonephritis. As pyelonephritis is associated with adverse outcomes such as preterm birth, fetal monitoring and assessment for preterm labor should begin once the diagnosis is made.
Due to the risk of introducing uropathogens into the urinary tract, routine catheterization is not recommended. Urethral catheterization or suprapubic aspiration is occasionally used if needed. If a patient is seriously ill, in addition to urine culture, laboratory evaluation may include complete blood cell count and serum chemistry, serum lactate to assess for leukocytosis and hemolysis. A decrease in creatinine clearance may be seen due to transient renal insufficiency. As the infection clears, abnormal renal function is expected to resolve.10
The American College of Obstetricians and Gynecologists (ACOG) recommends hospitalization of pregnant women with pyelonephritis.19 Once the diagnosis of pyelonephritis is suspected, the patient should be hospitalized for treatment with IV antibiotics until afebrile and improvement of symptoms for 24 to 48 hours. An additional 10 to 14 days of oral antibiotics is required after discharge.2
Once pyelonephritis is suspected, the clinician should think of the diagnosis in these categories separated into uncomplicated versus complicated pyelonephritis:
* Stable patient with uncomplicated pyelonephritis;
* Complicated pyelonephritis; and
* Unstable patient with pyelonephritis.
Uncomplicated Pyelonephritis
Patients with acute pyelonephritis are often dehydrated; therefore, IV hydration is typically administered, and urine output monitored closely. Blood cultures are not required for uncomplicated infections.20 Radiologic imaging is not typically performed for the initial diagnosis of uncomplicated acute pyelonephritis as history, physical, and confirmation with laboratory results are sufficient. Imaging can be considered if symptoms do not improve with empiric treatment or if there is recurrent infection. A urine culture should be obtained after completion of the antibiotic course to verify resolution of bacteriuria.
Complicated Pyelonephritis
Patients who fail to improve by 72 hours require further evaluation because acute pyelonephritis may be associated with significant and sometimes severe complications. These include urinary tract obstruction (eg, nephrolithiasis), renal or perinephric abscess formation, atypical or drug-resistant uropathogens, bacteremia, sepsis, or adult respiratory distress syndrome (ARDS). Patients with complications may require escalation of care, and additional assessment including arterial blood gas, metabolic panel, and chest x-ray. In critically ill or septic patients, an ultrasound or abdominal/pelvic CT scan can diagnose underlying structural abnormality or rule out obstructing stone or abscess.10
Diagnostic Testing and Subspecialty Consultation
Patients with urinary obstruction, renal, or perinephric abscess may require interventional radiology and/or urology consultation. Unstable patients will require subsequent blood and urine cultures, antimicrobial susceptibility testing, and a critical care or infectious disease consultation.10 Patients with bacteremia require repeat blood and urine cultures to demonstrate clearance of infection.
As most renal stones are passed spontaneously in pregnancy, the first-line treatment is expectant management. However, one-third of pregnant women will need intervention. Renal stones less than 5 mm are more likely to pass spontaneously than stones that are 5 to 10 mm. Transvaginal ultrasound is the first-line imaging modality when diagnosing renal stones in pregnancy. If ultrasound is inconclusive and the patient has persistent symptoms, magnetic resonance urography, IV urography, or low-dose or noncontrast CT may be considered. Patients may receive hydration to promote stone passage, analgesia, and antimicrobial therapy if infection or pyelonephritis is suspected.21 Data are limited on the use of medical expulsive therapy (MET) use in pregnancy. Use of tamsulosin for MET in pregnancy has been debated. One study in pregnant women suggests that although use of tamsulosin was associated with increased stone passage, it was also associated with sudden infant death syndrome.22 A more recent study demonstrated that short-term utilization of tamsulosin in the second and third trimesters was not associated with adverse maternal or fetal outcomes.23
Complications such as renal or perinephric abscesses should be considered in patients with pyelonephritis who are not improving after 72 hours of antimicrobial treatment. CT is typically the imaging modality of choice to confirm the diagnosis. Definitive antimicrobial therapy will depend on the causative organism.24
Management
Initial treatment for pyelonephritis in pregnancy usually includes the following:
1. Admission to inpatient hospitalization;
2. Assessment of maternal vital signs and stability;
3. Fetal monitoring and labor evaluation depending on gestational age;
4. Evaluation for sepsis and escalation of care as appropriate;
5. Initiate empiric antimicrobial treatment; and
6. Oral antimicrobial therapy after resolution of symptoms.
It is generally accepted that penicillins, cephalosporins, fosfomycin, and aztreonam are safe when used in pregnancy. Table 1 lists the empiric treatment for antepartum pyelonephritis, which includes ampicillin plus gentamycin or a cephalosporin alone. No single treatment has been shown to be significantly better than another. Trimethoprim-sulfamethoxazole and nitrofurantoin are generally avoided during the first trimester. Tetracyclines and quinolones are generally contraindicated.2,10 One study demonstrated that relative to the treatment of UTIs in the periconception period (1 month before conception to 3 months of pregnancy) the use of trimethoprim-sulfamethoxazole, nitrofurantoin, and cephalosporins was associated with a small relative risk of several congenital anomalies when compared with treatment with penicillin alone.25 However, the prevalence of the associated birth defects is exceedingly rare, and the risks of complications of untreated UTIs in pregnancy are common and serious. Therefore, treatment decisions should recognize the low absolute risk of antibiotic usage, and the high risk of perinatal morbidity. Initial empiric antimicrobial therapy should be refined after culture results are obtained.
Suppressive Therapy for Recurrence
After counseling and behavioral modifications, patients with 3 or more episodes of recurrent cystitis should be started on daily antimicrobial prophylaxis of low-dose nitrofurantoin (up to 100 mg nightly or postcoitally) or cephalexin (250 mg nightly or postcoitally), outside the first trimester. Some experts initiate this therapy after one episode of pyelonephritis in at-risk populations. Patients who are immunocompromised can also be considered for suppressive therapy after 1 episode.26
In patients with recurrent pyelonephritis, suppressive therapy with nitrofurantoin 100 mg should be used for the remainder of the pregnancy and for 4 to 6 weeks postpartum. Monthly urine cultures should also be obtained during pregnancy to screen for recurrent bacteriuria.10
Serious Adverse Effects of Acute Pyelonephritis: Sepsis
Escalation of care is advised if the clinical status of a patient with pyelonephritis worsens. Pyelonephritis is a leading cause of antepartum maternal sepsis and can contribute to chorioamnionitis. Pyelonephritis is also a major cause of sepsis in the intrapartum and postpartum periods. Up to 20% of women with pyelonephritis will have bacteremia, which may lead to sepsis. Sepsis is a medical emergency and requires immediate treatment. Signs of worsening sepsis include tachycardia, hypotension, and decreased urine output, which may warrant intensive care unit admission.10
Diagnosis of sepsis in pregnancy or in the postpartum period can be managed with a 2-step approach (Table 2). Step 1 consists of screening, including evaluating vital signs and white blood cell count. Step 2 is confirmation of diagnosis, with laboratory values to evaluate end-organ damage. Blood cultures should be drawn and antibiotics should be administered early, typically within an hour of diagnosis. Regarding the initial sepsis screen, continuous maternal pulse oximetry and fetal monitoring should be implemented as indicated, with intermittent assessment of maternal mental status. Blood pressure, temperature, and urine output should be assessed every 30 minutes. Broad-spectrum empiric antibiotic treatment should be administered within 1 hour of diagnosis of maternal sepsis. If possible, cultures should be drawn before antimicrobial treatment and within 3 hours of a diagnosis of sepsis with end-organ dysfunction. After the initial positive sepsis screen in nonlaboring women, a lactic acid level of more than 2 mmol/L confirms a diagnosis of sepsis. Note that lactic acid levels can be elevated in labor due to increased anaerobic metabolism.20
ARDS is another serious complication of pyelonephritis. The incidence of ARDS in patients with pyelonephritis ranges from 1% to 8%. Patients will present with respiratory compromise including tachypnea, dyspnea, tachycardia, and hypoxia. Chest imaging in patients with ARDS will be significant for evidence of pulmonary edema. Management will require supplemental oxygen and diuresis; a ventilator may be needed. Prompt initiation of antimicrobial treatment and fluid resuscitation is of priority. Obstetric patients who are clinically unstable and at risk for rapid decompensation should immediately be transferred to a critical care unit; this decision should be made with a multidisciplinary team and consultation with a critical care specialist.27
Pyelonephritis is not an independent indication for delivery, and treatment of the infection is the priority. The Society for Maternal-Fetal Medicine (SMFM) states that sepsis by itself is not an indication for immediate delivery (except in cases of chorioamnionitis/intra-amniotic infection). The SMFM also advises that antenatal corticosteroids for fetal lung maturity are not contraindicated in sepsis.28 Expert consultation will further guide decision-making in this situation. Timing of delivery should be individualized based on maternal-fetal status and gestational age. Patients in labor should be concurrently managed with treatment of infection.
Antimicrobial Treatment and Considerations for Emerging Infections
Escherichia coli is the most common uropathogen, affecting 85% of patients with UTIs in pregnancy. The less common Gram-negative pathogens include Klebsiella (5%), Enterobacter (3%), and Proteus spp (2%). Group B streptococci and Enterococcus faecalis are the frequently identified Gram-positive organisms causing up to 10% of UTIs in pregnancy.10
Broad-spectrum agents should be used to combat these pathogens in patients at high risk for multidrug-resistant organisms (MDROs). Examples include patients who were recently hospitalized or those who were recently treated with antibiotics. As the prevalence of MDRO increases in the general population, infections with these organisms may increase the risks of complications and mortality in pregnancy. Extended-spectrum [beta]-lactamase-producing organisms such as Enterobacteriaceae (ESBL-E) are a pressing health concern in long-term care facilities and hospitals. The effect of MDROs on the risks of complications and maternal mortality is unknown. This is an important concept in the management of pyelonephritis in pregnancy, as the rates of these uropathogens increase. Antibiotic treatment should be chosen based on the combination of culture results and clinical response.10 A recent case-control study demonstrated that ESBL-E bacteriuria during pregnancy was associated with a history of UTI or asymptomatic bacteriuria, a history of positive ESBL-E urine cultures, and prior antibiotic use. Researchers did not find an association between ESBL-E bacteriuria and severe disease or adverse obstetrical, maternal, neonatal outcomes when compared with pregnant women with non-ESBL-E bacteriuria.29
Conclusion
Pyelonephritis is a leading cause of antepartum maternal sepsis and requires immediate medical attention. Pyelonephritis is associated with adverse maternal outcomes including bacteremia, sepsis, and ARDS; it is also associated with adverse fetal outcomes such as preterm labor and preterm birth. Management includes concurrent assessment for these complications and may require interdisciplinary consultation and management.
Screening and treatment for asymptomatic bacteriuria is crucial in the prevention of disease. Clinical symptoms and laboratory assessment can confirm the diagnosis and direct antimicrobial treatment. Patients should be hospitalized and treated with IV antimicrobial agents until afebrile and improved symptoms for 24 to 48 hours. This treatment should be followed by oral therapy to complete the course. With the emergence of MDROs, it is important for providers to understand prevalent uropathogens in their community and use the results of urine culture and antimicrobial profile to direct treatment.
Practice Pearls
* ACOG endorses the IDSA guidelines for screening of pregnant persons for asymptomatic bacteriuria using urine culture in the first trimester. Criteria for positive urine culture in an asymptomatic person are: (1) at least 100,000 CFUs/mL of urine in 2 voided midstream clean-catch specimens; or (2) at least 100 CFUs/mL of urine from a catheterized specimen.
* Warning signs for patients to recognize frequency, pain/burning with urination, blood-tinged or cloudy urine, low back or pelvic pain, fever, nausea, or vomiting.
* Signs and symptoms of pyelonephritis-fever (>38[degrees]C or 100.4[degrees]F), CVA tenderness, and pyuria or bacteriuria.
* Diagnosis is clinical and confirmed with urine culture. Hospitalize patients if pyelonephritis is suspected.
* Treatment of pyelonephritis is initially with empiric IV antibiotics, later directed by urine culture results, followed by oral antibiotics for 10 to 14 days. Empiric treatment includes ampicillin plus gentamicin or a cephalosporin alone.
* E. coli is the most common uropathogen, in approximately 85% of patients; however, geographic sensitivity should be considered.
* Severe complications: sepsis. Screen with vital signs and white blood cell count: more than 15,000 mm3 or less than 4000 mm3 or more than 10% immature neutrophils (bands). Confirmation with laboratory values to evaluate end-organ damage.
* Antibiotic-resistant organisms: antibiotic treatment to be chosen based off a combination of culture results and clinical response.
REFERENCES