Urinary Tract Infection in Pregnancy

Etiology

UTIs in pregnancy can arise from a variety of causes, primarily attributed to anatomical and physiological changes that occur during gestation. One significant factor is the hormonal changes, particularly the increase in progesterone levels, which leads to the relaxation of smooth muscle tissue throughout the urinary tract, including the ureters and bladder. This relaxation reduces ureteral tone and alters bladder dynamics, contributing to urinary stasis and making it easier for bacteria to ascend from the urethra to the bladder and, potentially, to the kidneys.[1]

Additionally, the enlarging uterus can mechanically obstruct the ureters and urinary flow, further predisposing pregnant women to UTIs. Hormonal changes also affect the vaginal flora, potentially increasing the colonization of uropathogens. Moreover, physiological changes in the immune system during pregnancy, such as a decrease in cell-mediated immunity, may impair the body's ability to combat bacterial infections effectively. Together, these factors create an environment conducive to the development of UTIs in pregnancy, highlighting the importance of proactive measures to prevent and manage these infections to safeguard maternal and fetal health.[1]

Epidemiology

The classifications of UTIs in pregnancy include the following: [1]                                                                   

Lower urinary tract infections

• Asymptomatic bacteriuria
• Cystitis

Upper urinary tract infection

• Pyelonephritis

According to the World Health Organization (WHO) estimates, various infections during pregnancy account for 10.7% of pregnancy-related maternal deaths worldwide. Recent studies estimate that most of these infections, almost 28%, are located in the urinary tract.[2] The most significant factor predisposing women to cystitis and pyelonephritis in pregnancy may be ASB. ASB is defined as >100,000 organisms/mL on a clean catch urinalysis obtained from an asymptomatic patient.[3] If ASB is untreated in pregnancy, the rate of subsequent UTI has been quoted at approximately 25%.[4]

The rate of ASB in non-pregnant women is 5% to 6%, which compares similarly to estimated rates in pregnancy of 2% to 10%.[5][1] ASB is seen more frequently in parous women and women of low socioeconomic status. Women who are carriers of sickle cell trait also have a higher incidence of ASB.[4]

Due to both the high rate and potential seriousness of pyelonephritis, it is recommended by most all prenatal guidelines that every pregnant person be screened for ASB once early in prenatal care, either in the first or second trimester. This is most often done with a clean catch urine culture. Previously, treatment of ASB was thought to decrease the rate of clinical infection to 3% to 4%.[5] Interestingly, more recent studies do not provide evidence that treatment of ASB decreases rates of preterm birth and low birth weight. Further studies in this area are needed.[6]

Cystitis occurs in 1% to 2% of pregnant individuals.[5][1] Pyelonephritis also occurs in 1% to 2% of pregnant people, most commonly in the second trimester. Pyelonephritis is a common cause of serious infections, including septic shock, in pregnant patients. It is the cause of most medical hospitalizations during pregnancy.[1] In 1 study, 3.5% of antepartum admissions were due to UTI.[7] Risk factors for pyelonephritis in pregnancy include obesity, low socioeconomic status, young age, nulliparity, diabetes, smoking, and a history of recurrent UTIs.[7] As with ASB, some patients may be predisposed to infection and may report a history of having had ASB, cystitis, or pyelonephritis in the past. Pyelonephritis is most often right-sided, but it may be bilateral in up to 25% of cases.

Pathophysiology

Organisms causing UTI in pregnancy are the same uropathogens that commonly cause UTI in non-pregnant patients. Escherichia coli is the most common organism isolated.[1] An 18-year retrospective analysis found E. coli to be the causative agent in 60% to 82.5% of cases of pyelonephritis in pregnant patients.[8] Other bacteria that may be seen include Klebsiella pneumonia (11%), Proteus (5%), Staphylococcus, Streptococcus, and Enterococcus species.

Gardnerella vaginalis and Ureaplasma are uncommon pathogens but may be isolated, especially in women with underlying kidney disease. Group B Streptococcus (GBS) is commonly isolated from urine cultures in the third trimester of pregnancy and may be even more common than E. coli.[5]

History and Physical

Patients with ASB have no symptoms; thus, it is important to screen for the disease early in pregnancy. These patients may have a history of frequent UTIs or may have experienced ASB in a prior pregnancy. It is reasonable to screen patients with sickle cell trait more frequently during pregnancy, although there is no standard recommendation as to the frequency of screening for UTI in pregnancy in these patients. Patients with spinal cord injuries or diabetes should not be screened more frequently, as this can do more harm.[9][10]

Cystitis presents with the same symptoms seen in non-pregnant individuals. Symptoms may include pain or burning with urination (dysuria in 55%), urinary frequency (82%), or urinary urgency. Suprapubic pain (73%) and tenderness may be noted. However, there is a high rate of false positives for these symptoms alone, as only 26% of women with symptoms have a positive urine culture result.[5]

Likewise, patients with pyelonephritis exhibit symptoms seen in non-pregnant patients with the same disease. Symptoms may include flank pain, fever of or above 38.0 °C, and chills. Nonspecific symptoms such as malaise, anorexia, nausea, and vomiting may be reported, thus the differential diagnosis on initial presentation is often broad. Differential diagnosis includes acute intraabdominal processes such as appendicitis, cholecystitis, and pancreatitis, as well as pregnancy-related complications, including preterm labor and placental abruption.

Patients may report contractions or demonstrate contractions with uterine monitoring. This uterine activity is often due to smooth muscle irritability caused by infection. If contractions are felt or determined, patients should be assessed for cervical dilation. Patients should be monitored closely, as preterm labor may develop. Signs and symptoms of sepsis may be present, including tachycardia and hypotension. Such patients require prompt evaluation and interventions.

A comprehensive physical examination is essential, focusing particularly on vital signs and assessing the heart and lungs. Additionally, an abdominal examination may uncover tenderness, while costovertebral tenderness is often detectable with pyelonephritis. Conducting a genitourinary examination to check for cervical infection and assess cervical dilation upon admission is important. Even if there are no immediate concerns about pregnancy complications, it is still advisable to monitor for contractions or any other abnormalities throughout the hospitalization period.

Evaluation

The evaluation of a pregnant patient with concerns for UTI will include a clean catch urinalysis and urine culture. A few considerations are noteworthy regarding the collection of urinary specimens during pregnancy. Well-hydrated patients may excrete dilute urine, rendering some assessed parameters less accurate. Hematuria may result from contamination, particularly when specimens are collected from laboring or postpartum patients. Due to reduced protein reabsorption, small amounts of protein may normally be excreted. Contamination, as may occur with mucous vaginal discharge, may also contribute to the presence of proteinaceous material in the urine of pregnant women.

Urine dipstick screening during pregnancy shows a high false positive result for infection and is overall not beneficial. In symptomatic patients, the detection of nitrites showed notable significance, displaying a specificity of 98.6%, a negative predictive value of 81.9%, and a positive predictive value of 86.6%. Additionally, certain historical symptoms such as dysuria (specificity of 88%) and hematuria (specificity of 93%) proved effective in predicting UTIs confirmed by culture but were less reliable in excluding this condition.[11]

There is also a high prevalence of contaminated urine cultures in pregnancy.[1] High BMI is associated with an increased risk of contamination of urine culture.[12] Skin flora is commonly seen growing from urine cultures from pregnant women, and repeating the culture is futile. Interestingly, having the patient perform perineal cleaning, known as a clean catch, does not decrease the contamination compared to collecting a midstream urine specimen without perineal cleaning. After a negative screening urine culture, the risk of pyelonephritis is low.[13]

When pyelonephritis is suspected in pregnancy, laboratory analysis should include a complete blood count (CBC), electrolytes, and serum creatinine. Tailored studies should be included as appropriate to exclude other causes of patients' symptoms, such as amylase and lipase if pancreatitis is considered a diagnosis. If sepsis is suspected, lactic acid and blood cultures should be obtained. All cultures should be obtained as soon as possible and before starting antibiotic therapy.

When the fetus is viable, fetal heart rate and contraction monitoring should occur. Consideration should be given to obtaining cervical and GBS cultures on admission in the event that pregnancy-related complications develop. Infrequently, renal ultrasound may be indicated to assess for a possible renal abscess.

Treatment / Management

ASB and acute cystitis in pregnancy are treated with oral antibiotic therapy. Treatment for UTI in pregnancy should be started when an asymptomatic patient has a single organism bacterial colony count of ≥100,000 (10^5) CFU/mL in a urine culture. Per the American College of Obstetricians and Gynecologists (ACOG), with symptoms present, a UTI is confirmed with colony counts of 100,000 (10^5) CFU/mL of a single organism.[1] Empiric antibiotic therapy may be started if symptoms of UTI are present, including urinary frequency, dysuria, and hematuria. Antibiotic choice can be tailored based on organism sensitivities when available from urine culture results, which should be collected before initiating antibiotics.[14][15] A 5- to 7-day course of antibiotics should be used.(B3)

Amoxicillin and ampicillin should be avoided as empiric therapy, as there is high antibiotic resistance to these antibiotics from E. coli.[1] Antibiotics commonly used include cephalosporins, nitrofurantoin, fosfomycin, and trimethoprim-sulfamethoxazole. Fluoroquinolones are not recommended as a first-line treatment in pregnancy due to conflicting studies regarding teratogenicity.[16][17]

Recent evidence has developed suggesting a link between the use of sulfa derivatives and nitrofurantoin and congenital disabilities when these medications are prescribed in the first trimester. These studies have limitations; however, avoiding using these medications in the first trimester is recommended when alternatives are available.[18] Because the potential consequences of untreated UTI in pregnancy are significant, it is reasonable to use these medications when needed as the benefit strongly outweighs the risk of use. Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency should not be prescribed sulfa derivatives or nitrofurantoin, as these medications can precipitate hemolysis. In the late third trimester, trimethoprim-sulfamethoxazole should be avoided if feasible due to the theoretical risk for the development of kernicterus in the infant following delivery.(B3)

If GBS is noted in a urine culture with a colony count >100,000 CFU/mL, the pregnant patient should be treated with antibiotics per recommendations for UTI in pregnancy. However, ACOG advises that colony counts of GBS <100,000 CFU/mL do not need to be treated. Patients with any amount of GBS found in the urine at any time during pregnancy should receive intravenous (IV) antibiotic therapy during labor. This is to prevent the development of early-onset GBS sepsis, which may occur in infants of women who are colonized with GBS.

Pyelonephritis in pregnancy is a serious condition usually requiring hospitalization. Once an evaluation has been completed, treatment consists primarily of directed antibiotic therapy and IV fluids to maintain adequate urine output. Fever should be treated with a cooling blanket and acetaminophen as needed. Second or third-generation cephalosporins are commonly used for initial treatment, with an aminoglycoside being the second line. Some authors prefer to use third-generation cephalosporins as third-line therapy due to the high risk of inducing antibiotic resistance with these medications.[1][15] Ampicillin and gentamicin or other broad-spectrum antibiotics are alternatives. For patients who have had cephalosporin antibiotic-resistant pyelonephritis in the past, carbapenems are considered the first-line therapy. Second and third-line antibiotic choices in these cases include a fourth-generation cephalosporin or an aminoglycoside and piperacillin/tazobactam, respectively.[15](B3)

Antibiotic choices for pyelonephritis in pregnancy may include the following:

1. Ceftriaxone or cefepime 1 g IV every 24 hours

2. Ampicillin 2 g IV every 6 hours PLUS gentamycin 1.5 mg/kg IV every 8 hours (or 5 mg/kg IV every 24 hours)

3. Aztreonam (for use in patients with β-lactam allergy) 1 g IV every 8 hours to 12 hours

Fosfomycin and nitrofurantoin do not achieve adequate tissue levels in the kidney and should not be used to treat pyelonephritis.

Antibiotic therapy may be adjusted once bacterial sensitivities are known. Patients should be monitored closely for the development of worsening sepsis. For pregnant patients admitted for upper UTIs, medical advice indicates transitioning to oral antimicrobial treatment following a minimum of 48 hours once the systemic inflammatory response and clinical indicators of infection have been stabilized and when oral intake tolerance is satisfactory.[1][15] Parenteral antibiotics should continue until clinical symptoms improve, and a total of 7 to 14 days of combined parenteral and oral antibiotics should be completed. Suppressive therapy daily throughout the remainder of pregnancy may be considered.[1][15](B3)

Antibiotic choices for ASB or cystitis in pregnancy may include the following:

• First-line therapy [5]
  • Nitrofurantoin 50 mg orally BID for 5 to 7 days
    • Low bacterial resistance rates
    • Therapeutic tissue levels obtained in the bladder 
    • Use in the first trimester of pregnancy is reasonable if no alternatives are available
    • Not used for treatment of pyelonephritis due to inadequate tissue levels in the kidney
    • Avoid in patients with G6PD deficiency
  • β-lactams
    • E. coli shows a high degree of resistance  
    • Amoxicillin 500 mg orally BID for 5 to 7 days
    • Amoxicillin clavulanate 500/125 mg orally BID for 5 days                                                                 
• Fosfomycin 3 grams orally once
  • Not used for treatment of pyelonephritis due to inadequate tissue levels in the kidney                                
• Cephalexin 250 mg to 500 mg orally BID for 5 to 7 days                                                                                     
• Sulfamethoxazole-trimethoprim 800/160 mg orally every 12 hours for 5 to 7 days
  • Use in the first trimester is avoided due to the folic acid antagonist properties; it is reasonable if no alternatives are available 
  • Avoided in the third trimester due to the theoretical risk of jaundice in the fetus [5]

Cephalosporins are the most common antibiotics used for pregnant patients with UTIs; however, over a quarter of E. coli isolates have known resistance to third-generation cephalosporins. Women from lower-income countries are more commonly treated as outpatients for UTI during pregnancy, possibly because of low resources or fewer diagnoses.[2]

Following the treatment of a UTI during pregnancy, there is limited guidance on the recommended management. It is suggested to consider obtaining a repeat urine culture 1 to 2 weeks after completion of the initial treatment. Alternatively, patients can be observed for symptoms, and a repeat culture may be obtained only if symptoms reappear. There is insufficient evidence supporting the use of daily prophylaxis with antibiotics after an episode of cystitis during pregnancy.

Differential Diagnosis

The differential diagnosis of UTIs in pregnancy encompasses various conditions that can present with similar symptoms, necessitating a comprehensive evaluation to ensure accurate diagnosis and appropriate management. Among pregnant individuals, symptoms such as dysuria, frequency, urgency, and suprapubic pain may also be attributed to physiological changes related to pregnancy, such as increased urinary frequency due to pressure on the bladder from the enlarging uterus. Additionally, conditions such as pelvic inflammatory disease, vaginal infections, and sexually transmitted infections may mimic UTI symptoms in pregnancy. More specifically, the differential diagnosis of pyelonephritis in pregnancy includes acute intraabdominal diseases such as appendicitis, pancreatitis, cholecystitis, and kidney stones, as well as pregnancy-related complications such as preterm labor, chorioamnionitis, or placental abruption. 

Prognosis

The prognosis of patients with UTIs in pregnancy largely depends on the promptness and effectiveness of diagnosis and treatment. Untreated or inadequately treated UTIs in pregnancy can lead to serious complications such as pyelonephritis, preterm birth, low birth weight, and maternal sepsis, which can significantly impact maternal and fetal health. However, with appropriate management, including timely administration of antibiotics and close monitoring, the prognosis for most pregnant individuals with UTIs is favorable.

Since the 1960s and 1970s, when asymptomatic bacteria (ASB) began to be routinely tested for, the incidence of pyelonephritis in pregnancy decreased from 20% to 35% to 1% to 4%.[19] However, it is unclear if ASB treatment decreased the rates of preterm birth and low birth weight infants because many of these studies were done more than 30 years ago. Therefore, recent studies have questioned the need for screening and treatment of ASB in pregnancy and found that the incidence of preterm birth and low birth weight infants may not be decreased by treatment of ASB in pregnancy.[6]

Another important aspect to be mindful of is the overuse of antibiotics in pregnant women. This has been noted to be higher in Europe and Asia than in other continents.[20] The frequent use of antibiotics in pregnancy to treat ASB may increase extended-spectrum beta-lactamase-producing (ESBL) bacteria, specifically E. coli and Klebsiella pneumonia.[3]

Complications

Complications due to UTIs in pregnancy include sepsis, anemia, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulopathy, preterm contractions and labor, and renal abscess. Intensive care unit (ICU) admission may be required.[1] Studies indicate that 7.5% of patients with pyelonephritis have bacteria in the blood, 13.3% have sepsis, and 1.9% have septic shock. Preterm premature rupture of membranes (PPROM) is not uncommon (6.3%), while preterm delivery (11%) and birth weight <2800 g (8.2%) are additional complications that may be seen due to UTI in pregnancy. Delivery within 72 hours has been noted in 7% of patients.[21]

Pulmonary complications are not uncommon, occurring in up to 10% of pregnant patients undergoing treatment for pyelonephritis.[14] This is due to endotoxin-mediated alveolar damage and may manifest as pulmonary edema or ARDS. Urine output and oxygen status should be monitored closely, and patients may require ICU admission for respiratory support. Endotoxin release may lead to anemia, which typically resolves spontaneously following treatment. This is the most common complication seen with pyelonephritis, occurring in up to 25% of patients.[8] Endotoxin release may also cause uterine contractions, and patients should be monitored for preterm labor, preterm delivery, and PPROM.

A small number of patients may experience persistent infection. In these cases, consideration should be given to urinary obstruction or renal abscess. Antibiotic choice should be reevaluated, and culture results should be reviewed. In 4% to 5% of pregnancies, 2 or more UTIs occur. This is known as recurrent UTIs in pregnancy. Data are limited regarding the management of recurrent UTIs in pregnancy. Insufficient evidence is available for recommendations after recurrent UTI treatment in pregnancy. Suppressive antibiotic therapy, either once daily or postcoitally with an antibiotic that the bacterial isolate was susceptible to, is commonly recommended in individuals who have had recurrent UTIs in pregnancy. This is typically continued throughout pregnancy.[1] Examples of antibiotics used include nitrofurantoin 100 mg orally daily or cephalexin 250 mg to 500 mg by mouth daily.