Asymptomatic Bacteriuria in Pregnancy

Introduction

Urinary tract infections (UTIs) are a common problem in women at all stages of life, and assume greater importance particularly during pregnancy. UTIs can be divided into two types – lower tract infections and upper tract infections (Figure 1).

Upper tract infections: These involve the ureters and kidneys, leading to pyelonephritis. Upper urinary tract infections usually occur because bacteria travel up from the bladder into the kidney. Sometimes, they occur when bacteria travel from other areas of the body through the bloodstream and settle in the kidney.

Lower tract infections: These infections involve the bladder (cystitis) or urethra (urethritis). Bacteria normally found in the intestine are the main cause of lower urinary tract infections. These bacteria spread from the anus to the urethra and bladder, where they grow, invade the tissue and cause infection.

Women are anatomically predisposed to UTIs because of their shorter urethra and proximity of the urethra to the anus and vagina. Hence, the urinary tract can be easily contaminated with fecal flora and pathogens from other sources (Figure 2).¹

UTIs are a common problem in pregnancy due to the morphological and physiological changes that takes place in the genitourinary tract during pregnancy. UTI may be either symptomatic or asymptomatic. Asymptomatic bacteriuria (ASB) is defined as the presence of actively multiplying bacteria within the urinary tract, excluding the distal urethra, at a time when the patient has no urinary symptoms.²

Significant bacteriuria may exist in 6% of pregnant, asymptomatic women. Significant bacteriuria is traditionally defined as >10⁵   colony forming units or bacteria/ml of urine, as at this level the chance of contamination from distal urethra is less than 1%. At concentrations of 10³  -10⁴   bacteria/ml, there is a 50% chance that contamination is responsible for a positive culture, warranting a repeat testing with a midstream sample of urine. Isolation of the same organism in the second sample is more indicative of significant bacteriuria.³

Pathogenesis

Beginning in week 6 and peaking during weeks 22 to 24, approximately 90% of pregnant women develop ureteral dilatation, which persists until delivery (hydronephrosis of pregnancy). Increases in urinary progestins and estrogens cause relaxation of the ureteric smooth muscle, leading to dilatation of ureters, which is further aggravated by pressure from the expanding uterus. This, along with increased bladder volume and decreased bladder tone, contributes to increased urinary stasis and ureterovesical reflux, facilitating bacterial colonization and ascending infection.

In addition, the physiologic increase in plasma volume during pregnancy decreases urine concentration. Moreover, glycosuria, which develops in up to 70% of pregnant women, encourages bacterial growth in the urine.⁴

During pregnancy, the content of amino acids, vitamins and other nutrients is also increased in the urine, which further favors growth of bacteria.⁵

Maternal immunity is modified during pregnancy and may have a role in facilitating infection by uropathogens. Diabetes mellitus, gestational diabetes and prepregnancy UTI are other risk factors that predispose to UTI during pregnancy.

Other factors that can predispose to UTI are increasing age, low socioeconomic status and medical interventions, such as catheterization.³

Microbiology

The organisms that cause UTIs during pregnancy are the same as those found in nonpregnant patients. Escherichia coli accounts for 80% to 90% of infections. Other gram-negative rods, such as Proteus mirabilis and Klebsiella pneumoniae, are also common. Gram-positive organisms, such as group B streptococcus and Staphylococcus saprophyticus, are less common causes of UTI. Group B streptococcus has important implications in the management of pregnancy. Less common organisms that may cause UTI include enterococci, Gardnerella vaginalis and Ureaplasma ureolyticum.⁴

Forty percent of asymptomatic bacteriuria cases develop into acute symptomatic UTI. Hence, early detection and treatment are of considerable importance not only to prevent acute pyelonephritis and chronic renal failure in the mother, but also to reduce prematurity and fetal mortality in the offspring.²

Clinical significance

If left untreated, asymptomatic bacteriuria can lead to acute pyelonephritis in 20-30% of cases. Bacteriuria is associated with a 50% increase in the risk of low birthweight and a significant increase in the risk of premature delivery, pre-eclampsia, hypertension, anemia and post-partum endometritis.⁵

Pyelonephritis in the pregnant patient leads to septicemia in 10-20% of cases and acute respiratory distress syndrome in 2%. Fetal risks include fetal growth retardation, stillbirth, mental retardation and developmental delay. It is believed to be due to direct bacterial endotoxin damage.³

Screening and diagnosis

Because asymptomatic bacteriuria is clinically significant in pregnancy, it should be aggressively sought, diagnosed, and treated in all stages. The American College of Obstetrics and Gynecology recommends that a urine culture be obtained at the first prenatal visit.⁶   A repeat urine culture should be obtained during the third trimester, because the urine of treated patients may not remain sterile throughout the pregnancy.

According to the Infectious Diseases Society of America (IDSA)⁷   and the US Preventive Services Task Force,⁸   all pregnant women should undergo screening with urine culture at least once during early pregnancy (12-16 weeks) (Table 1), which is the gold standard for screening of asymptomatic bacteriuria. Non-culture methods are generally not reliable for the identification of bacteriuria in asymptomatic populations, including pregnant women. Routine urinalysis is not appropriate as it may give false negative results in bacteriuria without pyuria and false positive results with contamination from vaginal secretions.

The diagnosis of asymptomatic bacteriuria is confirmed if two consecutive urine specimens are positive. A specimen obtained at 12-16 weeks will

identify 80% of women who will ultimately have asymptomatic bacteriuria during pregnancy.¹⁰

Owing to the limited availability of urine culture, Lumbiganon et al¹¹   evaluated the performance of various other screening tests and effectiveness of antibiotic regimens for ASB, and discovered that a positive dipslide test is very likely to indicate a definitive diagnosis of ASB, whereas a negative result effectively rules out ASB. As for the urine dipstick test, it is currently not appropriate to recommend it for screening ASB in pregnancy due to conflicting results.

Choice of antibiotics should be guided by antimicrobial susceptibility testing whenever possible. The investigators found nitrofurantoin to be the antibiotic of choice for ASB in pregnancy. They recommended that pregnant women with ASB should be treated with a 7-day regimen of antibiotics, although a 1-day regimen might be appropriate in some settings.

Effectiveness of Prevention and Treatment

Prevention of acute pyelonephritis

Diagnosis and treatment of ASB in early pregnancy has been reported to reduce the incidence of acute pyelonephritis later in pregnancy from 20-30% to 2-4%. However, since 0.5%-1.0% of women with initial negative screening urine cultures develop pyelonephritis subsequently in pregnancy, only 50-80% of the burden of pyelonephritis in pregnancy is prevented through screening and treatment. Hence, some workers think that screening is not cost effective, but others, like Wadland and Plante, find screening with a single urine specimen in early pregnancy to be cost effective as long as the prevalence of bacteriuria is over 2% in the population.¹⁰

Prevention of pre-term delivery and low birthweight

A meta-analysis of 8 clinical trials by Romero et al¹²   reported a relative risk of 0.56 (95% confidence interval 0.43-0.73) for antibiotic treatment of asymptomatic bacteriuria in reducing the incidence of low birthweight. The mechanism by which treatment of asymptomatic bacteriuria prevents low birthweight is not clear. It is possible that antibiotic therapy eradicates organisms from the cervix and vagina which may be associated with subclinical chorioamnionitis, rather than a direct effect of treatment of urinary infection.

A Cochrane review¹³   of 13 studies evaluated the effect of antibiotic treatment for asymptomatic bacteriuria on persistent bacteriuria during pregnancy, the risk of preterm delivery and the development of pyelonephritis after delivery. Compared to placebo or no treatment, antibiotic treatment was seen to be effective in clearing asymptomatic bacteriuria and reducing the incidence of pyelonephritis and preterm delivery or low birthweight.

Treatment

It is well documented that effective treatment of asymptomatic bacteriuria significantly reduces the incidence of pyelonephritis, premature deliveries and low birthweight infants.⁵

The antibiotic chosen (Table 2) should not only address the most common infecting organisms (i.e., gram-negative gastrointestinal organisms), but also be safe for the mother and fetus. Traditionally, ampicillin has been the drug of choice, but in recent years, resistance of E. coli to this drug has progressively increased, with 20 to 30% of these pathogens being found to be ampicillin-resistant. Nitrofurantoin is a good choice because of its high urinary concentration. Other acceptable antibiotics include cephalosporins, fosfomycin, sulfonamides (safe during the first and second trimesters, but carry a risk of kernicterus and hyperbilirubinemia in the newborn when administered during the third trimester). Other common antibiotics (e.g., fluoroquinolones and tetracyclines) should not be prescribed during pregnancy because of possible toxic effects on the fetus.⁴

Pregnancy is associated with a physiological increase (≤ 50%) in the glomerular filtration rate, which increases the elimination rate of drugs excreted via the kidneys. This, together with frequent polyuria in pregnancy, reduces the time for which a drug is present in urine and makes it necessary to increase the dose of some hydrophilic drugs to ensure efficacy.⁵

The duration of therapy required to treat asymptomatic bacteriuria has not been determined. However, a 7-day regimen eradicates bacteriuria in 70-80% of patients and is recommended to treat acute cystitis. Single-dose therapy for asymptomatic bacteriuria is less effective. Recurrent UTIs may warrant postcoital prophylaxis with a single dose of cephalexin or nitrofurantoin.¹

Acute cystitis

Unlike asymptomatic bacteriuria, acute cystitis is characterized by symptoms such as dysuria, urgency and frequency in afebrile patients with no evidence of systemic illness. Up to a third of patients with untreated asymptomatic bacteriuria later develop symptomatic cystitis.⁴

The treatment of cystitis is generally the same as that of asymptomatic bacteriuria, but single-dose regimens are even less likely to be effective here. Since symptoms are present in this condition, treatment can be started without waiting for the urine culture report. Women treated for cystitis should be monitored with monthly urine cultures, as approximately 20% of these women develop another UTI during the course of their pregnancy.¹

Pyelonephritis

Acute pyelonephritis during pregnancy can be serious enough to progress to maternal sepsis, preterm labor and premature delivery. It can be diagnosed by the presence of bacteriuria, accompanied by systemic symptoms or signs such as fever, chills, nausea, vomiting and flank pain. Symptoms of lower UTI (i.e., frequency and dysuria) may or may not be present. Pyelonephritis occurs in 2% of pregnant women, of which up to 23% experience a recurrence during the same pregnancy.⁴

Pyelonephritis in pregnant women is treated the same way as in nonpregnant women, except that certain antibiotics should be avoided during pregnancy. Hospitalization and intravenous antibiotics may be required for most such cases, along with parenteral hydration for nausea, vomiting and dehydration.

Initial antibiotic therapy may be empiric, followed by tailoring to the pathogen grown in the urine. Most patients with cystitis show symptomatic improvement within 1-2 days of beginning therapy; pyelonephritis can take 2-3 days to improve, even with effective therapy. If no improvement is observed, consider resistant organisms, nephrolithiasis, abscess formation and obstruction as causes of therapy failure. Women who have experienced an episode of acute pyelonephritis should be monitored frequently with repeat urine cultures. If close follow-up care is not possible, continuous suppressive therapy can be considered.¹

Role of nitrofurantoin in ASB

Nitrofurantoin has been in clinical use for several decades now for the treatment of UTIs, particularly acute uncomplicated UTIs, recurrent UTIs, asymptomatic bacteriuria of pregnancy and nosocomial infections related to urinary tract instrumentation.¹⁴   Nitrofurantoin’s long record of safety in pregnancy and its bioavailability in urine make it a good choice.¹⁵   Moreover, there is no associated R-factor resistance with nitrofurantoin, compared to recently introduced antimicrobials.¹⁴   Also, it does not affect the normal enteric and vaginal flora.

Nitrofurantoin concentrations achieve therapeutic levels only in urine, so this drug can only be used to treat infections of the lower urinary tract. Although active against E. coli, nitrofurantoin is not active against Proteus species. Unlike some other antimicrobials, no significant correlation between nitrofurantoin treatment and fetal malformations has been reported.¹⁶   All these qualities make nitrofurantoin a suitable agent for treating bacteriuria in pregnancy.

In a descriptive, cross sectional study,205 participants with a mean age of 30.6 ± 4.3 years and a mean gestational age at booking of 20.9 ±7.0 weeks were surveyed.¹⁷   The prevalence of asymptomatic bacteriuria was 10.7%, and the isolated pathogens were predominantly coliforms (Klebsiella and E. coli) accounting for 45.5% and Staphylococcus saprophyticus (27.3%) (Figure 3). Nitrofurantoin was one of the antibiotics demonstrating high efficacy against these uropathogens with antibiotic sensitivity rates between 72.7% and 81.8%.

A study by Jamie and colleagues¹⁸   tried to determine the antimicrobial susceptibility of gram-negative uropathogens isolated from pregnant women suffering from asymptomatic bacteriuria or cystitis. In the 95 positive cultures identified, isolates were more often susceptible to nitrofurantoin (89%) and trimethoprim-sulfamethoxazole (TMP-SMX) (87%) than to ampicillin (72%). Escherichia coli accounted for 75% cases and was more often susceptible to nitrofurantoin (100%) than to TMP-SMX (87%) (Figure 4).

Thus, nitrofurantoin was superior to TMP-SMX for treatment of infections caused by E. coli, and superior to ampicillin for empiric treatment of lower urinary tract infection in pregnant women.

A multicenter, double-blind, randomized, placebo controlled noninferiority trial¹⁹   was conducted in Thailand, the Philippines, Vietnam and Argentina to evaluate whether a 1-day nitrofurantoin regimen is as effective as a 7-day regimen in eradicating asymptomatic bacteriuria during pregnancy. The study enrolled 778 pregnant women, who were randomly allocated to receive either a 1-day (n=386) or a 7-day (n=392) course of nitrofurantoin in the dose of 100 mg twice daily. The primary outcome was bacteriologic cure on day 14 of treatment.

Escherichia coli was the most common potentially pathogenic organism detected, with prevalence approaching 50%. Bacteriologic cure rates at treatment day 14 were 75.7% and 86.2% for 1-day and 7-day regimens, respectively (Figure 5). The cure rate difference was 10.5% (95% confidence interval 16.1% to 4.9%). Mean birthweight and mean gestational age at delivery were significantly lower in the 1-day regimen group. There were fewer adverse effects in the 1-day regimen group, but the differences were not statistically significant.

Since the 7-day regimen of nitrofurantoin was found to be significantly more effective than the 1-day regimen, the study authors recommended that women with asymptomatic bacteriuria in pregnancy should receive the standard 7-day regimen.

Conclusion

Asymptomatic bacteriuria is now a recognized entity in the spectrum of urinary tract infections. It is more prevalent in women than in men and its occurrence during pregnancy is detrimental to the mother and the fetus due to the various complications it can cause if left untreated. Asymptomatic bacteriuria is mainly caused by E. coli, though Proteus mirabilis and Klebsiella pneumonia may also be involved. The condition can be detected by urine culture, which should be performed at least once during early pregnancy (12-16 weeks). For treatment, nitrofurantoin has been found to be the antibiotic of choice because it achieves therapeutic levels only in the urine and is safe to give during pregnancy.

References

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