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Urinary tract infections and asymptomatic bacteriuria in pregnancy

Urinary tract infections and asymptomatic bacteriuria in pregnancy
Authors:
Thomas M Hooton, MD
Kalpana Gupta, MD, MPH
Section Editors:
Stephen B Calderwood, MD
Charles J Lockwood, MD, MHCM
Deputy Editor:
Allyson Bloom, MD
Literature review current through: Sep 2021. | This topic last updated: Jul 14, 2021.

INTRODUCTION — Urinary tract infections (UTIs) are common in pregnant women. By convention, UTI is defined either as a lower tract (acute cystitis) or upper tract (acute pyelonephritis) infection. UTIs (acute cystitis and pyelonephritis) and asymptomatic bacteriuria in pregnant women will be reviewed here.

Issues related to UTIs or asymptomatic bacteriuria in other populations are discussed in detail elsewhere. (See "Acute simple cystitis in women" and "Acute simple cystitis in men" and "Acute complicated urinary tract infection (including pyelonephritis) in adults" and "Asymptomatic bacteriuria in adults" and "Catheter-associated urinary tract infection in adults".)

EPIDEMIOLOGY

Incidence and risk factors — The incidence of bacteriuria in pregnant women is approximately the same as that in nonpregnant women, however, recurrent bacteriuria is more common during pregnancy. Additionally, the incidence of pyelonephritis is higher than in the general population, likely as a result of physiologic changes in the urinary tract during pregnancy. (See 'Pathogenesis' below.)

Asymptomatic bacteriuria occurs in 2 to 7 percent of pregnant women [1,2]. It typically occurs during early pregnancy, with only approximately a quarter of cases identified in the second and third trimesters [3]. Factors that have been associated with a higher risk of bacteriuria include a history of prior urinary tract infection, pre-existing diabetes mellitus, increased parity, and low socioeconomic status [4-6].

Without treatment, as many as 20 to 35 percent of pregnant women with asymptomatic bacteriuria will develop a symptomatic urinary tract infection (UTI), including pyelonephritis, during pregnancy [7,8]. This risk is reduced by 70 to 80 percent if bacteriuria is eradicated (see 'Rationale for treatment' below). Although a study from the Netherlands suggested a low rate of pyelonephritis among 208 women with untreated asymptomatic bacteriuria (2.4 percent versus 0.6 percent among 4035 women without bacteriuria), this study included only low-risk women with uncomplicated singleton pregnancies without diabetes mellitus or urinary tract abnormalities, and it is uncertain whether these results are generalizable [9].

Acute cystitis occurs in approximately 1 to 2 percent of pregnant women, and the estimated incidence of acute pyelonephritis during pregnancy is 0.5 to 2 percent [10-13]. Most cases of pyelonephritis occur during the second and third trimesters. As an example, the incidence of acute pyelonephritis in pregnancy in the setting of routine prenatal screening for asymptomatic bacteriuria was examined in a prospective study of a general obstetric population [12]. During the two year study period, 440 cases of acute pyelonephritis were identified in 32,282 pregnant women (14 per 1000 deliveries). The majority of cases occurred in the second trimester (53 percent). In addition to prior untreated bacteriuria, other clinical characteristics that have been associated with acute pyelonephritis during pregnancy include age <20 years, nulliparity, smoking, late presentation to care, sickle cell trait, and pre-existing (not gestational) diabetes [12-14]

Pregnancy outcomes — Many studies have described a correlation between maternal urinary tract infection, particularly asymptomatic bacteriuria, and adverse pregnancy outcomes. Studies have also suggested that acute pyelonephritis has a similar association, but there are several variables that potentially confound this association, such as socioeconomic status and previous preterm delivery.

Untreated bacteriuria has been associated with an increased risk of preterm birth, low birth weight, and perinatal mortality in most [1,7,15-20], but not all [9,21], studies. As an example, in a meta-analysis of 19 studies, among women without bacteriuria, the risks of preterm birth and a low birth weight infant were one-half and two-thirds the risks among women with asymptomatic bacteriuria [20]. Other pregnancy complications have also been associated with bacteriuria. As an example, a case control study of over 15,000 pregnant women found an increased risk of preeclampsia with either asymptomatic bacteriuria or symptomatic UTI [22].

No correlation has been clearly established between acute cystitis of pregnancy and increased risk of low birth weight, preterm delivery, or pyelonephritis [17], perhaps because pregnant women with symptomatic lower UTI usually receive treatment.

Pyelonephritis, however, has been associated with adverse pregnancy outcomes. In an 18-year retrospective study of over 500,000 singleton pregnancies followed at a large health care system in the United States, the rate of preterm birth, primarily between weeks 33 and 36, was higher among the 2894 women who had pyelonephritis during pregnancy (10.3 versus 7.9 percent among those who did not, OR 1.3, 95% CI 1.2-1.5) [13]. There were no differences in stillbirth or neonatal death. Other complications of pyelonephritis include anemia, sepsis, and respiratory distress [12]. Maternal morbidity and obstetric outcomes with pyelonephritis do not appear to differ by trimester [23].

PATHOGENESIS — The organisms that cause bacteriuria and urinary tract infections (UTI) in pregnant women are of the same species and have similar virulence factors as in nonpregnant women. Thus, the basic mechanism of entry of bacteria into the urinary tract is likely to be the same for both groups [24]. However, the smooth muscle relaxation and subsequent ureteral dilatation that accompany pregnancy are thought to facilitate the ascent of bacteria from the bladder to the kidney, resulting in the greater propensity for bacteriuria to progress to pyelonephritis during pregnancy [15,25]. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)

Pressure on the bladder and ureters from the enlarging uterus may also increase the risk of progression to pyelonephritis. In addition, the immunosuppression of pregnancy may contribute. As an example, mucosal interleukin-6 levels and serum antibody responses to Escherichia coli antigens appear to be lower in pregnant women [26].

MICROBIOLOGY — As in nonpregnant women, E. coli is the predominant uropathogen found in both asymptomatic bacteriuria and urinary tract infection (UTI) in pregnant women. As an example, in a study of over 400 cases of pyelonephritis, E. coli accounted for approximately 70 percent of cases [12]. Other organisms responsible for infection included Klebsiella and Enterobacter species (3 percent each), Proteus (2 percent), and gram-positive organisms, including group B Streptococcus (10 percent). Group B Streptococcus in pregnancy is discussed in detail elsewhere. (See "Group B streptococcal infection in pregnant women", section on 'Urinary tract'.)

As in other community-acquired infections, antimicrobial resistance is an increasing concern. Infections caused by extended-spectrum beta-lactamase (ESBL)-producing strains are increasing in number [27,28]. In India, ESBL-producing uropathogens is a particular problem, even in pregnant women [29].

Isolation of more than one species or the presence of Lactobacillus or Cutibacterium (formerly Propionibacterium) acnes may indicate a specimen contaminated by vaginal or skin flora. However, repeated isolation of Lactobacillus with high colony counts and without other organisms in consecutive urine cultures may not represent simple contamination, although the significance of this finding in pregnancy is not known.

ASYMPTOMATIC BACTERIURIA

Diagnosis — The diagnosis of asymptomatic bacteriuria is made by finding high-level bacterial growth on urine culture in the absence of symptoms consistent with urinary tract infection (UTI). Details on the timing of screening, specimen collection, and diagnostic criteria are discussed below.

Screening — We agree with the guidelines from the Infectious Diseases Society of America that recommend screening all pregnant women for asymptomatic bacteriuria at least once in early pregnancy [2]. Other expert groups make a similar recommendation [30,31]. The rationale for screening is the same as for treatment of bacteriuria and is discussed elsewhere. (See 'Rationale for treatment' below.)

Screening for asymptomatic bacteriuria is performed at the first prenatal visit with a urine culture [2,32]. Rescreening among those who did not have bacteriuria on the initial test is generally not performed in low-risk women. It is reasonable to rescreen women at high risk for infection (eg, history of UTI or presence of urinary tract anomalies, diabetes mellitus, hemoglobin S, or preterm labor), however the optimal target populations for this is uncertain. There is minimal evidence informing the benefits and harms of repeat screening following an initial negative culture.(See "Prenatal care: Initial assessment".)

Specimen collection — The diagnosis of asymptomatic bacteriuria should be based on culture of a urine specimen collected in a manner that minimizes contamination. Although the optimal method for collecting voided urine is uncertain, instructing women to spread their labia and collect a midstream urine (without requiring a clean-catch) seems most reasonable. Routine catheterization to screen for bacteriuria is not warranted due to the risk of introducing infection. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults".)

In order to minimize contamination of the voided specimen, it is often recommended that the patient collect a clean-catch (after local cleansing of the urethral meatus and surrounding mucosa) midstream (collection of the second portion of the voided urine after discarding the initial stream) specimen. However, it is not clear that these measures reduce contamination. In a study of 113 asymptomatic pregnant women, each was instructed to collect a sample from the first concentrated morning urine, a midstream sample, and a clean-catch midstream sample, in that order, over the course of a day [33]. Rates of mixed growth and growth of skin flora on culture in midstream urine were comparable with those observed in the morning and clean-catch samples. Overall rates of contamination were high in all three samples, and the women were tested at a mean of 32 weeks of gestation as opposed to the recommended period of 16 weeks. Findings from this and other studies suggest that collection of a clean-catch voided urine specimen is of little value [34,35].

Proper handling and processing of the specimen is crucial to avoid false-positive results. (See "Microbiology specimen collection and transport".)

Diagnostic criteria — For asymptomatic women, bacteriuria is formally defined as two consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts of ≥105 colony-forming units (cfu)/mL or a single catheterized urine specimen with one bacterial species isolated in a quantitative count of ≥102 cfu/mL [2]. In clinical practice, however, only one voided urine specimen is typically obtained, and diagnosis (and treatment initiation) is made in women with ≥105 cfu/mL without obtaining a confirmatory repeat culture. The diagnosis (and treatment) of asymptomatic bacteriuria due to group B streptococcus during pregnancy is discussed in detail elsewhere. (See "Group B streptococcal infection in pregnant women", section on 'Asymptomatic bacteriuria'.)

If bacteria that are not typical uropathogens (such as lactobacillus) are isolated, treatment should be reserved for patients in whom the organism grows as a single isolate on consecutive cultures.

Rapid screening tests, such as dipstick, enzymatic screen, reagent strip, or interleukin-8 testing, do not come close to urine culture in terms of sensitivity and specificity for detecting asymptomatic bacteriuria in pregnant women and should not be used [36-38]. In addition, cultures are useful in guiding therapy. This can be particularly important in pregnancy, during which the number of safe treatment alternatives is reduced.

Management — Management of asymptomatic bacteriuria in pregnant women includes antibiotic therapy tailored to culture results and follow-up cultures to confirm sterilization of the urine.

Rationale for treatment — Asymptomatic bacteriuria during pregnancy increases the risk of pyelonephritis and has been associated with adverse pregnancy outcomes, such as preterm birth and low birth weight infants (see 'Epidemiology' above). Antimicrobial treatment reduces the risk of subsequent development of pyelonephritis and is associated with improved pregnancy outcomes [7,39-44]. This was illustrated in a meta-analysis of 15 randomized trials of antibiotic treatment versus placebo or no treatment for pregnant women with asymptomatic bacteriuria [7]. Antibiotic therapy was more likely to clear asymptomatic bacteriuria (odds ratio [OR] 0.30, 95% CI 0.18-0.53) and to lower the incidence of pyelonephritis (OR 0.24, 95% CI 0.13-0.41). There was also a reduction in the incidence of low birth weight infants with antibiotic treatment. However, the included studies that evaluated these outcomes were deemed to be of poor quality.

This meta-analysis included a trial of pregnant women in the Netherlands (where screening for asymptomatic bacteriuria is not performed routinely), which suggested generally similar effects of treatment [9]. Women with asymptomatic bacteriuria between 16 and 22 weeks gestation who were not treated or received placebo treatment had a higher rate of pyelonephritis (2.4 percent of 208 women) compared with both those who received nitrofurantoin treatment for asymptomatic bacteriuria (0 percent of 40 women) and those who did not have asymptomatic bacteriuria (0.6 percent of 4035 women). Likewise, low birth weight occurred in 17 of 208 untreated or placebo-treated women with asymptomatic bacteriuria (8 percent) compared with 1 of 40 of nitrofurantoin-treated women (2.5 percent). While this difference was not statistically significant, the study was under-powered for this outcome. Preterm birth did not differ between these two groups. Notably, the study included only women who were at low risk for UTI, pre-term birth, or other complications, and the pyelonephritis rate was lower than in previous studies of pregnant women with asymptomatic bacteriuria [21].

Antimicrobial treatment — Asymptomatic bacteriuria is treated with an antibiotic tailored to the susceptibility pattern of the isolated organism, which is generally available at the time of diagnosis. Potential options include beta-lactams, nitrofurantoin, and fosfomycin (table 1). The choice of antimicrobial agent should also take into account safety during pregnancy (including the particular stage of pregnancy). (See 'Antibiotic safety in pregnancy' below.)

The optimal duration of antibiotics for asymptomatic bacteruria is uncertain. Short courses of antibiotics are preferred to minimize the antimicrobial exposure to the fetus. Short course antibiotic therapy is usually effective in eradicating asymptomatic bacteriuria of pregnancy, although single-dose regimens may not be as effective as slightly longer regimens [45-47]. As an example, in a meta-analysis of 13 studies comparing single-dose treatment with four to seven day treatments, there was a trend towards lower rates of bacteriuria clearance with the single-dose regimen [47].

An exception is single-dose fosfomycin, which successfully treats bacteriuria. In three trials comparing this drug with other therapies administered for a longer time, eradication of the organism was comparable (77 to 94 percent versus 68 to 94 percent with other agents) [48].

Follow-up — Up to 30 percent of women fail to clear asymptomatic bacteriuria following a short course of therapy [1]. Thus, a repeat culture is generally recommended as a test of cure, which can be performed a week after completion of therapy for asymptomatic bacteriuria [49]. However, there are insufficient data informing the utility of repeat testing following an initial episode of asymptomatic bacteriuria, and it is not known whether retreatment of recurrent or persistent bacteriuria improves outcomes [2]. Thus, our approach is based primarily on expert opinion:

If repeat culture has no growth, there is no indication for further testing for bacteriuria in the absence of symptoms suggestive of urinary tract infection.

If repeat culture is positive for bacterial growth (≥105 cfu/mL), optimal management is uncertain. We generally repeat antibiotic treatment tailored to antimicrobial susceptibility testing (table 1); if the repeat culture yielded the same species as the first culture, we give either the same antimicrobial as administered the first time for a longer course (eg, seven days, if a three-day regimen was used previously) or a different antimicrobial for a typical duration. However, we do not continue testing for asymptomatic bacteriuria following this second treatment course.

There are insufficient data to support the use of suppressive or prophylactic antibiotics for persistent or recurrent asymptomatic bacteriuria, and we do not do this.

ACUTE CYSTITIS

Clinical manifestations — Cystitis is a symptomatic infection of the bladder. The typical symptoms of acute cystitis in the pregnant woman are the same as in nonpregnant women and include the sudden onset of dysuria and urinary urgency and frequency. Hematuria and pyuria are also frequently seen on urinalysis.

Systemic symptoms, such as fevers and chills, are absent in simple cystitis.

Diagnosis — Acute cystitis should be suspected in pregnant women who complain about dysuria. Although urinary frequency and urgency are typical findings of acute cystitis, they are also frequently a normal physiologic change of pregnancy and reported by pregnant women without cystitis or bacteriuria [50,51]. The presence of fever and chills, flank pain, and costovertebral angle tenderness should raise suspicion for pyelonephritis (see 'Acute pyelonephritis' below). A urinalysis and urine culture should be performed in pregnant women who have new onset dysuria. Specimen collection is the same as for asymptomatic bacteriuria. (See 'Specimen collection' above.)

The diagnosis of acute cystitis is confirmed by finding of bacterial growth on urine culture. Prior to confirming the diagnosis, empiric treatment is typically initiated in a patient with consistent symptoms and pyuria on urinalysis (see 'Management' below). As in nonpregnant women, pyuria is usually present in almost all pregnant women with symptomatic urinary tract infection, and its absence strongly suggests an alternative diagnosis. (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults", section on 'Interpretation of pyuria'.)

Studies defining the threshold of bacterial growth on voided urine that represents significant bacteriuria in pregnant women have not been performed, but based on studies in nonpregnant women, relatively low colony counts can reflect true bacteriuria in the presence of symptoms. In nonpregnant women with acute simple cystitis, coliform colony counts in voided urine as low as 102 colony-forming units (cfu)/mL have been noted to reflect bladder infection [52-54]. As most clinical laboratories do not routinely quantify urine isolates to 102 cfu/mL, it is reasonable to use a quantitative count ≥103 cfu/mL in a symptomatic pregnant woman as an indicator of symptomatic UTI. If bacteria that are not typical uropathogens (such as lactobacillus) are isolated, the diagnosis of cystitis is typically made only if they are isolated in high bacterial counts (≥105 cfu/mL). (See "Sampling and evaluation of voided urine in the diagnosis of urinary tract infection in adults", section on 'Definition of a positive culture'.)

Differential diagnosis — As in nonpregnant women, dysuria in pregnant women can be a result of other infectious and noninfectious processes, such as vaginitis or urethritis. Similarly, urinary frequency and urgency may be symptoms of normal pregnancy in the absence of urinary tract infection. However, true bacteriuria is typically not present in these settings and thus distinguishes acute cystitis. If not already performed, testing for sexually transmitted infections (such as chlamydia and gonorrhea) is warranted for pregnant women with dysuria without bacteriuria or women who have persistent dysuria despite successful treatment of bacteriuria. (See "Acute simple cystitis in women", section on 'Differential diagnosis'.)

Management — Management of acute cystitis in pregnant women includes empiric antibiotic therapy that is subsequently tailored to culture results and follow-up cultures to confirm sterilization of the urine. For those women with persistent or recurrent bacteriuria, prophylactic or suppressive antibiotics may be warranted in addition to retreatment.

Antimicrobial treatment — Antibiotic treatment of acute cystitis in pregnant women is often empiric, initiated at the time of complaints of dysuria, and then tailored to the susceptibility pattern of the isolated organism once urine cultures return. Potential options for empiric and directed therapy include beta-lactams, nitrofurantoin, and fosfomycin (table 1). The choice of an antimicrobial agent should also take into account any prior microbiological data and drug safety during pregnancy (including the particular stage of pregnancy). (See 'Antibiotic safety in pregnancy' below.)

For empiric therapy, we typically choose between cefpodoxime, amoxicillin-clavulanate, and fosfomycin, given their safety in pregnancy and the somewhat broader spectrum of activity compared with other agents (such as amoxicillin or cephalexin). Nitrofurantoin is another option during the second or third trimester or if the others cannot be used for some reason (eg, drug allergy). The choice between them should be individualized on the basis of several factors, including patient allergy history, local practice patterns, local community resistance prevalence, availability, and cost [55].

Although there are limited data in pregnant women, a meta-analysis suggested that there are no large differences in outcomes between different antibiotic regimens in terms of cure rates, recurrent infection, incidence of preterm delivery, and the need for a change of antibiotics [56]. All of the antibiotics studied were very effective and complications were rare. There was not enough evidence to recommend a particular treatment scheme.

For women who are thought to be at risk for or have documented infection with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae, nitrofurantoin and fosfomycin are active in vitro against many such strains and are potential oral options [28,57].

The optimal duration of treatment of acute cystitis during pregnancy is uncertain. As with asymptomatic bacteriuria, short courses of antibiotics are preferred, to minimize the antimicrobial exposure to the fetus. We treat acute cystitis with a three to seven day course of antibiotics as long as there are no symptoms suggestive of pyelonephritis (eg, flank pain, nausea/vomiting, fever [>38°C], and/or costovertebral angle tenderness). Based on data among nonpregnant individuals, there appear to be no differences between short antibiotic courses (three to seven days) and longer ones [1,55,58]. Single-dose therapy is generally limited to fosfomycin.

Follow-up — As with asymptomatic bacteriuria, a follow-up culture should be obtained as a test of cure. We typically perform this a week after completion of therapy. As above, if the patient is asymptomatic but has bacteriuria on test of cure, the optimal management is uncertain. (See 'Follow-up' above.)

Management of recurrent cystitis — In women who have three or more episodes of recurrent cystitis during pregnancy, antimicrobial prophylaxis for the duration of pregnancy is a reasonable strategy to prevent additional episodes. Prophylaxis can be postcoital if the cystitis is thought to be sexually related (which it commonly is) or continuous. However, there are no data to guide whether treatment of isolated recurrent episodes or prophylaxis is a better approach in terms of risks versus benefits.

In the setting of other conditions that potentially increase the risk of urinary complications during episodes of cystitis (eg, diabetes or sickle cell trait), prophylaxis following the first episode of cystitis during pregnancy is also reasonable.

The choice of antimicrobial used for prophylaxis should be based on the susceptibility profile of the pathogens causing the cystitis. Ideally, daily or postcoital prophylaxis with low-dose nitrofurantoin (50 to 100 mg orally postcoitally or at bedtime) or cephalexin (250 to 500 mg orally postcoitally or at bedtime) can be used.

ACUTE PYELONEPHRITIS

Clinical manifestations — Acute pyelonephritis is a manifestation of infection of the upper urinary tract and kidneys. The typical symptoms of acute pyelonephritis in the pregnant woman are the same as in nonpregnant women and include fever (>38°C or 100.4°F), flank pain, nausea, vomiting, and/or costovertebral angle tenderness. Symptoms of cystitis (eg, dysuria) are not always present. Pyuria is a typical finding.

Most cases of pyelonephritis occur during the second and third trimesters. (See 'Incidence and risk factors' above.)

Pregnant women may become quite ill and are at risk for both medical and obstetrical complications from pyelonephritis. It has been estimated that as many as 20 percent of women with severe pyelonephritis develop complications that include septic shock syndrome or its variants, such as acute respiratory distress syndrome (ARDS) [59-61]. As an example, in a prospective study of 440 cases of acute pyelonephritis identified among 32,282 pregnant women in a general obstetric population, complications included anemia (23 percent), bacteremia (17 percent in the minority of patients who were tested), respiratory insufficiency (7 percent), and renal dysfunction (2 percent) [12]. The mechanism of anemia is not well understood, but hemolysis, perhaps mediated by endotoxin, may be important [62]. Acute renal failure associated with microabscesses and suppurative pyelonephritis has been described in isolated cases, independent of sepsis [63]. (See "Acute kidney injury in pregnancy".)

Diagnosis and evaluation — Acute pyelonephritis is suggested by the presence of flank pain, nausea/vomiting, fever (>38°C or 100.4°F), and/or costovertebral angle tenderness, with or without the typical symptoms of cystitis, and is confirmed by the finding of bacteriuria in the setting of these symptoms. (See "Acute simple cystitis in women".)

For pregnant women who present with such symptoms, we check a urinalysis and urine culture. Pyuria is present in the majority of women with pyelonephritis, and its absence should prompt consideration of an alternative diagnosis or complete obstruction. However, absence of pyuria does not rule out UTI if symptoms and urine culture are consistent with the diagnosis. Although many pregnant women have back or flank pain without pyelonephritis, we have a low threshold for evaluation for bacteriuria and a diagnosis of pyelonephritis in pregnant women with these symptoms, given the risk of complications and adverse pregnancy outcomes with untreated pyelonephritis. (See 'Pregnancy outcomes' above.)

Some investigators have questioned the value of obtaining routine blood cultures in pregnant women with pyelonephritis [64], and data on the impact of blood cultures on outcomes are limited [65]. Although there is no evidence that bacteremia portends a worse prognosis or requires longer therapy in an otherwise healthy pregnant woman with pyelonephritis, it is reasonable to obtain blood cultures in those with signs of sepsis or serious underlying medical conditions such as diabetes. Other tests, such as a serum lactate level, can also be useful in women with suspected sepsis to inform the severity of disease [66].

Imaging is not routinely used to diagnose pyelonephritis. However, in patients with pyelonephritis who are severely ill or who also have symptoms of renal colic or history of renal stones, diabetes, history of prior urologic surgery, immunosuppression, repeated episodes of pyelonephritis, or urosepsis, imaging of the kidneys can be helpful to evaluate for complications. In pregnant women, renal ultrasound is the preferred imaging modality in order to avoid contrast or radiation exposure.

Differential diagnosis — Nephrolithiasis can present with significant flank or back pain and abnormal findings on the urinalysis, but fever is uncommon with uncomplicated stone disease. This can also be distinguished from pyelonephritis by visualization of the stones on renal ultrasound. (See "Kidney stones in adults: Diagnosis and acute management of suspected nephrolithiasis".)

For pregnant women presenting with fever and/or flank or back pain, certain obstetric complications are important to consider in the differential:

Intraamniotic infection, with or without preterm labor, is an important diagnostic consideration in pregnant women who have fever and abdominal pain. The following features suggest intraamniotic infection over pyelonephritis: presentation with premature rupture of membranes, uterine tenderness and/or foul odor of the amniotic fluid, and the absence of bacteriuria. Other potential causes of fever and back or flank pain in the absence of bacteriuria include other infections (eg, influenza, pneumonia, appendicitis). (See "Intraamniotic infection (clinical chorioamnionitis or triple I)", section on 'Diagnosis'.)

Placental abruption is a key differential diagnosis of acute back or abdominal pain during pregnancy. Back pain is prominent with abruption when the placenta is on the posterior wall of the uterus. Fever is absent and vaginal bleeding is classically present with abruption, in contrast to pyelonephritis. The uterus is often firm, and may be rigid and tender in patients with abruption, but is usually soft in patients with pyelonephritis. Both conditions can be associated with uterine contractions. If present, a retroplacental hematoma on ultrasound supports the diagnosis of abruption. (See "Placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

Management — Management of acute pyelonephritis in pregnant women includes hospital admission for parenteral antibiotics. Antibiotic therapy can be converted to an oral regimen tailored to the susceptibility profile of the isolated organism following clinical improvement. Following the treatment course, suppressive antibiotics are typically used for the remainder of the pregnancy to prevent recurrence.

Site of care — Based upon the higher risk of complications in pregnant women, pyelonephritis has traditionally been treated with hospitalization and intravenous antibiotics until the woman is afebrile for 24 to 48 hours and symptomatically improved [67]. Initial outpatient therapy of pregnant women with pyelonephritis has been attempted in carefully selected populations (eg, no underlying serious medical conditions, renal or urologic abnormalities, pregnancy complications, signs of sepsis, or recent antibiotic use). However, we suggest not initiating therapy of pyelonephritis in pregnant women in the outpatient setting given the limited data evaluating its safety and the need for close monitoring of the patient.

Evidence on the safety of outpatient initiation of pyelonephritis treatment during pregnancy is limited to two trials by the same group [68,69]. Although the studies suggested that outpatient treatment resulted in similar outcomes as inpatient management, several limitations of the studies create uncertainty about the safety and practicality of outpatient management:

In the first trial, 120 pregnant women with pyelonephritis prior to 24 weeks gestation were randomly assigned to receive an outpatient regimen consisting of intramuscular ceftriaxone for 2 days followed by oral cephalexin for 10 days or an inpatient regimen consisting of IV cefazolin followed at discharge by oral cephalexin for 10 days [68]. Clinical responses to therapy and birth outcomes were similar for both outpatients and inpatients. However, six patients initially treated with ceftriaxone were ultimately admitted to the hospital for intravenous therapy, and one woman developed septic shock during the emergency department observation period. Of note, the outpatient regimen included initial parenteral antibiotics, and home health nurses monitored patients assigned to the outpatient strategy.

In the second trial, 92 women who presented after 24 weeks gestation were hospitalized for intramuscular ceftriaxone for 24 hours and then randomly assigned to early discharge on oral cephalexin or continued hospitalization until afebrile for 48 hours [69]. Clinical response and birth outcomes were similar for those who completed the assigned strategy. However, 51 percent of patients either did not qualify for outpatient management based upon study criteria or developed complications, which precluded early discharge from the hospital.

Empiric antibiotics — Parenteral, broad spectrum beta-lactams are the preferred antibiotics for initial empiric therapy of pyelonephritis (table 2). The choice between them should be guided by local microbiology and susceptibility data as well as expected patient tolerance. Fluoroquinolones and aminoglycosides, which are often used for pyelonephritis in nonpregnant individuals, should be avoided in pregnancy if possible. (See 'Antibiotic safety in pregnancy' below.)

The efficacy of beta-lactams was demonstrated in a randomized trial of 179 pregnant women with acute pyelonephritis before the 24th week of gestation: intravenous cefazolin or intramuscular ceftriaxone had equivalent efficacy to intravenous ampicillin plus gentamicin [70]. Although rates of resistance to first generation cephalosporins have generally been less than 10 percent in surveillance studies [71-74], beta-lactams (including first generation cephalosporins) have been less effective than trimethoprim-sulfamethoxazole or the fluoroquinolones for treatment of cystitis in studies of nonpregnant individuals [75]. Given these data and the paucity of data evaluating narrow spectrum cephalosporins in the treatment of pyelonephritis [75], we favor third generation cephalosporins over first or second generation cephalosporins, such as cefazolin, for the empiric treatment of acute pyelonephritis.

For women with a history of infections with extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae (or other risk factors), a carbapenem is an appropriate choice for empiric therapy. Of note, some animal studies have shown adverse fetal effects with imipenem, so meropenem, ertapenem, or doripenem are the preferred carbapenems for use during pregnancy. (See 'Antibiotic safety in pregnancy' below.)

Directed antibiotic therapy and follow-up — As with nonpregnant patients with pyelonephritis, pregnant women generally have definite improvement within 24 to 48 hours of appropriate antibiotic therapy. Once afebrile for 48 hours, pregnant patients can be switched to oral therapy guided by culture susceptibility results and discharged to complete 10 to 14 days of treatment [67]. Oral options are mainly limited to beta-lactams or, if in the second trimester, trimethoprim-sulfamethoxazole. Nitrofurantoin and fosfomycin are not appropriate for treatment of pyelonephritis due to inadequate tissue levels. General principles regarding the safety of antibiotics in pregnancy are discussed elsewhere. (See 'Antibiotic safety in pregnancy' below.)

If symptoms and fever persist beyond the first 24 to 48 hours of treatment, a repeat urine culture and renal ultrasound should be performed to rule out persistent infection and urinary tract pathology.

For women who do not use antimicrobial prophylaxis for the duration of pregnancy following an episode of pyelonephritis (see 'Preventing recurrence' below), we generally check monthly urine cultures to evaluate for recurrent bacteriuria and treat as indicated because of the risk of recurrent pyelonephritis. (See 'Asymptomatic bacteriuria' above.)

Obstetric management — Pyelonephritis is not itself an indication for delivery. If induction of labor or cesarean delivery for standard obstetrical indications is planned in a patient on treatment for pyelonephritis, we favor waiting until the patient is afebrile, as long as delaying the delivery is relatively safe for the mother and fetus.

Since pyelonephritis is associated with preterm birth, an important obstetric consideration is whether tocolysis should be used when pyelonephritis triggers preterm labor at various gestational ages. Tocolysis is typically not administered after 34 weeks gestation. If a woman with pyelonephritis prior to that gestational age experiences preterm labor, administration of tocolysis and steroids is reasonable to attempt to prolong the pregnancy. However, if the patient is septic, tocolysis is generally avoided. Pregnant women with pyelonephritis are at increased risk of pulmonary edema and acute respiratory distress syndrome (ARDS), which may be exacerbated by administration of tocolysis with or without corticosteroids. Detailed discussion of the benefits and risks of tocolysis for acute preterm labor are found elsewhere. (See "Inhibition of acute preterm labor", section on 'Patient selection'.)

Preventing recurrence — Recurrent pyelonephritis during pregnancy occurs in 6 to 8 percent of women [70,76,77]. As a result, after an initial episode of pyelonephritis, low-dose antimicrobial preventive therapy with an agent to which the original organism is susceptible for the remainder of the pregnancy is a reasonable strategy; but there are no randomized trials to inform the optimal approach. If preventive therapy is utilized, reasonable options include nitrofurantoin (50 to 100 mg orally at bedtime) or cephalexin (250 to 500 mg orally at bedtime) [67,78].

Breakthrough bacteriuria can occur during preventive therapy, so we usually perform at least one later culture, such as at the start of the third trimester, to ensure preventive therapy is working. If a follow-up culture is positive (≥105 colony-forming units/mL), then a course of antimicrobial therapy based on susceptibility data should be administered. In addition, the preventive regimen should be reassessed and adjusted if needed.

PREVENTION IN WOMEN WITH HISTORY OF RECURRENT UTI — A separate issue is the management of pregnant women with a history of recurrent urinary tract infections (UTIs) prior to pregnancy, which is often related to sexual intercourse. It is reasonable to use postcoital prophylaxis in pregnant women who have recurrent UTIs that appear to be temporally related to sexual intercourse. The preferred regimen is a single postcoital dose of either cephalexin (250 mg) or nitrofurantoin (50 mg). (See "Recurrent simple cystitis in women", section on 'Initial approach to prevention'.)

The potential efficacy of postcoital prophylaxis to prevent UTIs during pregnancy was evaluated in a report of 33 women with a history of recurrent UTIs who had 39 pregnancies [79]. The women were treated with a single postcoital dose of either cephalexin (250 mg) or nitrofurantoin (50 mg). Only one UTI occurred during pregnancy; this was in sharp contrast to 130 UTIs during a mean observation period of seven months before prophylaxis.

ANTIBIOTIC SAFETY IN PREGNANCY — Much of the information regarding the safe use of antibiotics during pregnancy was obtained decades ago, before pregnant women were excluded from drug studies because of concerns about risk to the fetus. Thus, there is little direct information about the safety of many newer antibiotics in pregnancy, and concern about the use of certain antibiotics generally derives from indirect evidence (eg, animal studies) or observational studies that may have numerous confounders. Overall, the safest course is to use the antibiotics that have well-established safety profiles in pregnancy and limit the use of antibiotics of potential concern to cases in which no safer alternative exists. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

It is generally accepted that penicillins (with or without beta-lactamase inhibitors), cephalosporins, and aztreonam are safe in pregnancy. However, drugs with very high protein binding, such as ceftriaxone, may be inappropriate the day before parturition because of the possibility of bilirubin displacement and subsequent kernicterus. Of the carbapenems, some animal studies have shown adverse fetal effects with imipenem, so meropenem, ertapenem, or doripenem are the preferred carbapenems for use during pregnancy.

Fosfomycin is also generally considered safe in pregnancy [80]. In several studies of single-dose fosfomycin during pregnancy, it was well-tolerated, and adverse fetal effects were not observed.

Nitrofurantoin is frequently used during pregnancy, although some potential concerns exist. Nitrofurantoin has been associated with birth defects in case control studies [81,82], but these findings should be interpreted with caution as multiple comparisons involving small numbers of affected exposed infants may have led by chance to the observed associations. In a prospective study of pregnant women with asymptomatic bacteriuria, there were no congenital birth abnormalities reported among the 40 women who received nitrofurantoin compared with 2 among the 208 women who received placebo or no antimicrobial treatment [9]. The safest course is to avoid using nitrofurantoin in the first trimester if another antibiotic that is safe and effective is available. Nitrofurantoin has also been reported to cause hemolytic anemia in the mother and fetus with G-6PD deficiency [83]. The risk of hemolytic anemia is estimated to be only 0.0004 percent of cases, but its use should be avoided near term for this reason [78,84].

Use of trimethoprim-sulfamethoxazole is typically limited to mid-pregnancy, avoiding the first trimester and near term. Trimethoprim is generally avoided in the first trimester because it is a folic acid antagonist, has caused abnormal embryo development in experimental animals, and some case control studies have reported a possible association with a variety of birth defects [81,82]. However, it is not a proven teratogen in humans. Women are routinely prescribed folic acid supplementation during pregnancy; this may be particularly important in those who are taking trimethoprim. Sulfonamides should be avoided in the last days before delivery because they can displace bilirubin from plasma binding sites in the newborn, with the theoretical increased risk for kernicterus, although kernicterus related solely to in utero sulfonamide exposure has never been reported. Sulfonamides have also been associated with birth defects in a case control study [81], but the limitations of the study discussed above lead to uncertainty about the association.

Aminoglycosides have been associated with ototoxicity following prolonged fetal exposure [84], and therefore should be avoided unless intolerance or resistance prohibits the use of less toxic agents.

Tetracyclines should not be used, and fluoroquinolones are generally not used during pregnancy. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Antibiotics'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urinary tract infections in adults" and "Society guideline links: Asymptomatic bacteriuria in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Urinary tract infections in pregnancy (The Basics)")

Beyond the Basics topics (see "Patient education: Urinary tract infections in adolescents and adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Bacteriuria occurs commonly in pregnancy, typically during early pregnancy. Without treatment, as many as 30 to 40 percent of pregnant women with asymptomatic bacteriuria will develop a symptomatic urinary tract infection (UTI). The smooth muscle relaxation and subsequent ureteral dilatation that occurs in pregnancy are thought to facilitate the ascent of bacteria from the bladder to the kidney, accounting for the greater risk of pyelonephritis. Additionally, untreated bacteriuria may be associated with an increased risk of preterm birth, low birth weight, and perinatal mortality. (See 'Epidemiology' above and 'Pathogenesis' above.)

As in nonpregnant women, Escherichia coli is the predominant uropathogen found in both asymptomatic bacteriuria and UTI in pregnant women. (See 'Microbiology' above.)

We screen all pregnant women at least once for asymptomatic bacteriuria. Screening for asymptomatic bacteriuria is performed at 12 to 16 weeks gestation with a midstream urine for culture. The diagnosis is made by finding high-level bacterial growth (≥105 colony-forming units [cfu]/mL) on urine culture in the absence of symptoms consistent with UTI. (See 'Diagnosis' above.)

Management of asymptomatic bacteriuria in pregnant women includes antibiotic therapy tailored to culture results, which reduces the risk of subsequent pyelonephritis and is associated with improved pregnancy outcomes. Potential options include beta-lactams, nitrofurantoin, and fosfomycin (table 1). Following treatment, follow-up culture is performed to confirm sterilization of the urine. (See 'Management' above.)

Acute cystitis should be suspected in pregnant women who complain about new onset dysuria, frequency, or urgency. The diagnosis is made by finding of bacterial growth on urine culture in this setting. Management of acute cystitis in pregnant women includes empiric antibiotic therapy that is subsequently tailored to culture results. Potential options for empiric and directed therapy include beta-lactams, nitrofurantoin, and fosfomycin (table 1). As with asymptomatic bacteriuria, follow-up cultures are performed to confirm sterilization of the urine. For those women with recurrent cystitis, prophylactic or suppressive antibiotics may be warranted in addition to retreatment. (See 'Acute cystitis' above.)

Acute pyelonephritis during pregnancy is suggested by the presence of flank pain, nausea/vomiting, fever (>38°C), and/or costovertebral angle tenderness, with or without the typical symptoms of cystitis, and is confirmed by the finding of bacteriuria in the setting of these symptoms. Pregnant women may become quite ill and are at risk for both medical (eg, sepsis, respiratory failure) and obstetrical complications from pyelonephritis. (See 'Clinical manifestations' above and 'Diagnosis and evaluation' above.)

Management of acute pyelonephritis in pregnant women includes hospital admission for parenteral antibiotics, preferably broad spectrum beta-lactams (table 2). Antibiotic therapy can be converted to an oral regimen tailored to the susceptibility profile of the isolated organism following clinical improvement. Oral options are generally limited to beta-lactams or, if in the second trimester, trimethoprim-sulfamethoxazole. Following the treatment course, preventive antibiotics are a reasonable strategy for the remainder of the pregnancy to prevent recurrence. (See 'Management' above.)

It is generally accepted that penicillins (with or without beta-lactamase inhibitors), cephalosporins, aztreonam, and fosfomycin are safe in pregnancy. Because of possible but uncertain associations with adverse birth outcomes, we generally avoid nitrofurantoin during the first trimester and trimethoprim-sulfamethoxazole during the first trimester and near term unless no other options are available. (See 'Antibiotic safety in pregnancy' above.)

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Topic 8065 Version 59.0

References

1 : Detection, significance, and therapy of bacteriuria in pregnancy. Update in the managed health care era.

2 : Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

3 : Clinical Practice Guideline for the Management of Asymptomatic Bacteriuria: 2019 Update by the Infectious Diseases Society of America.

4 : Asymptomatic bacteriuria in pregestational diabetic pregnancies and the role of group B streptococcus.

5 : Asymptomatic bacteriuria and symptomatic urinary tract infections in pregnancy.

6 : Asymptomatic bacteriuria in normal and high-risk pregnancy.

7 : Antibiotics for asymptomatic bacteriuria in pregnancy.

8 : Recommendations on screening for asymptomatic bacteriuria in pregnancy.

9 : Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomised controlled trial.

10 : Urinary tract infections during pregnancy.

11 : Cystitis during pregnancy: a distinct clinical entity.

12 : Acute pyelonephritis in pregnancy.

13 : Acute pyelonephritis in pregnancy: an 18-year retrospective analysis.

14 : Bacteriuria in pregnant women with sickle cell trait.

15 : Bacteriuria and pyelonephritis of pregnancy.

16 : Causes of the excessive rates of perinatal mortality and prematurity in pregnancies complicated by maternal urinary-tract infections.

17 : Urinary tract infections complicating pregnancy.

18 : Urinary tract infections during pregnancy.

19 : Uterine contraction frequency during treatment of pyelonephritis in pregnancy and subsequent risk of preterm birth.

20 : Meta-analysis of the relationship between asymptomatic bacteriuria and preterm delivery/low birth weight.

21 : Management of asymptomatic bacteriuria in pregnant women.

22 : Acute maternal infection and risk of pre-eclampsia: a population-based case-control study.

23 : Impact of trimester on morbidity of acute pyelonephritis in pregnancy.

24 : Virulence factors of Escherichia coli in urinary isolates from pregnant women.

25 : Bacteriuria and pyelonephritis during pregnancy.

26 : Suppressed antibody and interleukin-6 responses to acute pyelonephritis in pregnancy.

27 : The ARESC study: an international survey on the antimicrobial resistance of pathogens involved in uncomplicated urinary tract infections.

28 : Antimicrobial resistance among uropathogens that cause acute uncomplicated cystitis in women in Hong Kong: a prospective multicenter study in 2006 to 2008.

29 : Frequency and factors associated with carriage of multi-drug resistant commensal Escherichia coli among women attending antenatal clinics in central India.

30 : Screening for Asymptomatic Bacteriuria in Adults: US Preventive Services Task Force Recommendation Statement.

31 : Screening for Asymptomatic Bacteriuria in Adults: US Preventive Services Task Force Recommendation Statement.

32 : Screening for asymptomatic bacteriuria in adults: evidence for the U.S. Preventive Services Task Force reaffirmation recommendation statement.

33 : Contamination rates of three urine-sampling methods to assess bacteriuria in pregnant women.

34 : Evaluation of urine sampling technique: bacterial contamination of samples from women students.

35 : Outpatient urine culture: does collection technique matter?

36 : Rapid enzymatic urine screening test to detect bacteriuria in pregnancy.

37 : Evaluation of the centrifuged and Gram-stained smear, urinalysis, and reagent strip testing to detect asymptomatic bacteriuria in obstetric patients.

38 : Urinary interleukin-8 with asymptomatic bacteriuria in pregnancy.

39 : Screening and treatment of asymptomatic bacteriuria of pregnancy to prevent pyelonephritis: a cost-effectiveness and cost-benefit analysis.

40 : Prevention of preterm delivery and low birth weight associated with asymptomatic bacteriuria.

41 : Screening and treatment of asymptomatic bacteriuria in pregnancy prevent pyelonephritis.

42 : Nutritional and antimicrobial interventions to prevent preterm birth: an overview of randomized controlled trials.

43 : Long-term (10 to 14 years) follow-up of bacteriuria of pregnancy.

44 : Screening for Asymptomatic Bacteriuria in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

45 : Treatment of bacteriuria in pregnancy.

46 : Recommended treatment for urinary tract infection in pregnancy.

47 : Duration of treatment for asymptomatic bacteriuria during pregnancy.

48 : Treatment of bacteriuria in pregnancy with single dose fosfomycin trometamol: a review.

49 : Treatment of bacteriuria in pregnancy with single dose fosfomycin trometamol: a review.

50 : Voiding symptoms in pregnancy: an assessment with international prostate symptom score.

51 : Antibiotic Overconsumption in Pregnant Women With Urinary Tract Symptoms in Uganda.

52 : Diagnosis of coliform infection in acutely dysuric women.

53 : Voided midstream urine culture and acute cystitis in premenopausal women.

54 : A reassessment of the importance of "low-count" bacteriuria in young women with acute urinary symptoms.

55 : International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.

56 : Treatments for symptomatic urinary tract infections during pregnancy.

57 : Community infections caused by extended-spectrum beta-lactamase-producing Escherichia coli.

58 : Antibiotic duration for treating uncomplicated, symptomatic lower urinary tract infections in elderly women.

59 : Urinary tract infections complicating pregnancy.

60 : Pulmonary injury complicating antepartum pyelonephritis.

61 : Pulmonary injury associated with antepartum pyelonephritis: can patients at risk be identified?

62 : Mechanisms of hemolysis and anemia associated with acute antepartum pyelonephritis.

63 : Suppurative bacterial pyelonephritis as a cause of acute renal failure.

64 : Limited clinical utility of blood and urine cultures in the treatment of acute pyelonephritis during pregnancy.

65 : Routine blood cultures in the management of pyelonephritis in pregnancy for improving outcomes.

66 : Lactic acid measurement to identify risk of morbidity from sepsis in pregnancy.

67 : Lactic acid measurement to identify risk of morbidity from sepsis in pregnancy.

68 : Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial.

69 : Outpatient treatment of acute pyelonephritis in pregnancy after 24 weeks.

70 : A randomized trial of three antibiotic regimens for the treatment of pyelonephritis in pregnancy.

71 : An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO.SENS Project.

72 : Prevalence and antimicrobial susceptibility of pathogens in uncomplicated cystitis in Europe. The ECO.SENS study.

73 : Surveillance study in Europe and Brazil on clinical aspects and Antimicrobial Resistance Epidemiology in Females with Cystitis (ARESC): implications for empiric therapy.

74 : Antibiotic resistance in Escherichia coli outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA).

75 : Guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women. Infectious Diseases Society of America (IDSA).

76 : Pyelonephritis in pregnancy: a prospective randomized trial to prevent recurrent disease evaluating suppressive therapy with nitrofurantoin and close surveillance.

77 : Prevention of recurrent pyelonephritis during pregnancy.

78 : Efficacy of long-term antimicrobial prophylaxis after acute pyelonephritis in pregnancy.

79 : Effective prophylaxis for recurrent urinary tract infections during pregnancy.

80 : Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria.

81 : Antibacterial medication use during pregnancy and risk of birth defects: National Birth Defects Prevention Study.

82 : Association between antibiotic use among pregnant women with urinary tract infections in the first trimester and birth defects, National Birth Defects Prevention Study 1997 to 2011.

83 : The safety of nitrofurantoin during the first trimester of pregnancy: meta-analysis.

84 : Urinary tract infections during pregnancy.