mvjrMedical Herald of the South of Russia2219-80752618-7876The Rostov State Medical University10.21886/2219-8075-2021-12-3-22-31Research ArticleREVIEWОБЗОРЫAsymptomatic bacteriuria and pyelonephritis during pregnancyБессимптомная бактериурия и пиелонефрит при беременностиhttps://orcid.org/0000-0002-0937-4573NabokaY. L.Yulia L. Naboka, Dr. Sci. (Med.), Professor, head of Department of microbiology and virology №1
Rostov-on-Don
nagu22@mail.ruRymashevskyA. N.Alexander N. Rymashevsky, Dr. Sci. (Med.), professor, Head of the Department of Obstetrics and Gynecology No. 1
Rostov-on-Don
rymashevskyan@mail.ruKoganO. M.Olga M. Kogan, Cand. Sci. (Med.), head gynecology division, leader «Women’s Health» centre, chief gynecologist
Rostov-on-Don
olga.kogan.71@mail.ruhttps://orcid.org/0000-0003-0995-7848GudimaI. A.Irina A. Gudima, Dr. Sci. (Med.), associate professor, professor of the Department of microbiology and virology №1
Rostov-on-Don
naguirina22@gmail.comVorobyevaN. V.Natalia V. Vorobyeva, obstetrician gynecologist the scientifi c research institute for obstetrics and pediatrics
Rostov-on-Don
nensi71@mail.ruAlkinaA. K.Anna K. Alkina
Rostovon-on-Don
alkinann@yandex.ruRostov State Medical UniversityRostov State Medical UniversityRostov Clinical Hospital of the Southern District Medical CenterRostov State Medical University, Rostov-on-DonRostov State Medical UniversityRostov State Medical University2021300920211232231Copyright © The Rostov State Medical University, 20212021This work is licensed under a Creative Commons Attribution 4.0 License.The most common extragenital pathology during pregnancy is urinary tract infection (UTI) of various localization. In some cases, untreated UTI can contribute to the development of obstetric, urological, and perinatal pathologies. Factors predisposing to the UTI manifestation may include increased progesterone, delayed peristalsis, urine retention in the ureters, uterine growth, bladder displacement, and increased residual urine volume. Asymptomatic bacteriuria (ASB) during pregnancy can increase the risk of pyelonephritis and subsequent maternal and fetal complications. Pregnant women should be screened for ASB at least once at the beginning of pregnancy (aft er 14 weeks). E.coli is the dominant uropathogen in 70 – 95% of UTI cases in pregnant women. The main treatment for ABT and pyelonephritis in pregnancy (PiP) is antibiotic therapy (ABT), which is prescribed empirically in most cases. There is currently no consensus on the choice of ABT and the duration of treatment for UTI in pregnant women. In the case of ineff ective drug therapy of PiP, it is necessary to raise the issue of the upper urinary tract drainage promptly.
К наиболее распространённой экстрагенитальной патологии во время беременности относят инфекции мочевых путей (ИМП) различной локализации, которые при отсутствии лечения могут приводить в некоторых случаях к развитию акушерской, урологической и перинатальной патологий. Предрасполагающими факторами к манифестации ИМП могут являться повышенный прогестерон, замедленная перистальтика, застой мочи в мочеточниках, рост матки, смещение мочевого пузыря и увеличение объема остаточной мочи. Во время беременности бессимптомная бактериурия (ББ) может повышать риск развития пиелонефрита и последующих осложнений со стороны матери и плода. Беременные должны проходить обследование на ББ минимум один раз в начале беременности (после 14 недель). В 70 – 95% эпизодов ИМП у беременных, E.coli является доминирующим уропатогеном. Основным методом лечения ББ и гестационного пиелонефрита (ГП) у беременных является антибиотикотерапия (АБТ), которая в большинстве случаев назначается эмпирически. В настоящее время отсутствует консенсус как в отношении выбора антимикробного препарата (АМП), так и продолжительности лечения при ИМП у беременных. При отсутствии эффекта от проводимой консервативной терапии при обструктивном пиелонефрите у беременных необходимо своевременно решать вопрос о дендрировании верхних мочевых путей (ВМП).
pregnancyurinary tract infectionsasymptomatic bacteriuriapyelonephritisantibiotic therapyE.coliIntroductionUrinary tract infection (UTI) is the main extragenital infectious pathology in obstetrical practice [1]. It comprises a range of diseases associated with bacteriuria > 10,000 microorganism colonies in 1 ml of urine and/or microbial invasion with the development of the infectious process in some regions of the urinary tract from the urethral orifice to the renal cortex [2].
In the structure of lower UTIs, acute cystitis is observed in 20–40% of cases and is diagnosed in 1–2% of pregnant women [3]. The prevalence of asymptomatic bacteriuria (ASB) among pregnant women varies from 2% to 15% of all pregnancies (on average, 7–8%) [4]. In 11–40% of pregnant women with ASB, gestational pyelonephritis (GP) develops. Its rate can reach 15–33.8% of young pregnant women. In 10–30% of them, recurrent pathology is observed. Acute pyelonephritis can develop at any period of pregnancy. Primarily, it sets on during the 2nd or at the beginning of the 3rd trimester (22–28 weeks) [5][6].
Materials and MethodsInitially, the authors searched in the Scopus database the publications dated from 1961 to 2021. They searched for the keywords “asymptomatic bacteriuria” and “pregnancy” using a logical operator SQL. Further, the authors additionally searched for relevant scientific publications in the databases PubMed Database, Web of Science Core Collection, eLIBRARY, The Cochrane Database, and The Lancet for keywords “UTI”, “pyelonephritis”, “uncomplicated UTI”, and “complicated UTI”. A total of 56 publications were included in the review (Russian and foreign systematic reviews, meta-analyses, original studies) that described different aspects of ASB and GP in pregnant women.
ClassificationClassification of UTIs during pregnancy primarily corresponds to the classification in non-pregnant women. UTIs are classified by the localization: infection of the lower urinary tract (cystitis, urethritis), infection of the upper urinary tract (UUT) (pyelonephritis), ASB; by the etiology – community-acquired and hospital-acquired infections; by the development: non-complicated and complicated [7][8][9].
An uncomplicated development of the infection is characterized by the lack of disturbances of urine outflow from kidneys or bladder associated with functional and structural alterations in the kidneys or ureters. Complicated infections develop in patients with obstructive uropathy and after invasive methods of examination and treatment of associated diseases (diabetes mellitus, renal insufficiency, immune suppression, etc.) [10].
UTI during pregnancy is a complicated infection that can persist throughout pregnancy. It can be associated with elements of obstructive uropathy such as ureter stones, ureter stenosis, neurogenic bladder, and immune suppressive conditions. These factors should be taken into account when choosing adequate tactics of treatment. In the majority of cases, dilation of ureters during pregnancy should be considered a functional and adaptive condition.
EtiologyThe spectrum of infectious agents of uncomplicated and complicated infections of the upper and lower urinary tract is similar: uropathogenic E. coli (70–95% of cases), P. mirabilis, Klebsiella spp., and other enterobacteria, as well as S. saprophyticus (5–10%). Complicated UTI, including in pregnant women, is caused by a wider spectrum of microorganisms than uncomplicated: Enterobacteriaceae, in particular, E. coli, prevail. In the etiological structure, the specific weight of gram-negative non-fermenting bacteria (Pseudomonas spp., etc) and gram-positive cocci (Staphylococcus spp., Enterococcus spp.) increase [11][12][13]. UTI infectious agents in pregnant women can include symbiotic microbiota that colonizes periurethral and perianal areas, vaginal vestibule, intestine, etc.
Pathogenesis. Predisposing factorOne of the oldest principles of the pathogenesis of UTI is an ascending pathway of the urinary system infection that is considered to be the main one. Another pathway for pathogens to kidneys and urinary tract is hematogenic [1][5].
However, there is another view on this issue, which indicates that microorganisms of normal microflora that are present in the urine and bladder can initiate an inflammatory process [14]. The endogenous pathway is logical and possible with the translocation of microorganisms from other biotopes, including intestine [15][16].
During pregnancy, the urinary tract undergoes intensive physiological and anatomical alternations that can become predisposing factors for the development of UTI. In particular, the length of kidneys (approximately by 1 cm) and their volume (up to 30%) increase, as well as glomerular filtration rate (by 30–50%). Moderate hydroureteronephrosis can be observed at the early stages of pregnancy. This dilation has a functional character. During pregnancy, the bladder gradually moves upwards and anterior to increase its capacity, which can lead to urine stagnation [7][13]. A physiological increase in the plasma volume during pregnancy reduces urine concentration to 70%, which can lead to glycosuria that contributes to the growth and development of bacteria in the urine [15].
The role of urethrovaginal reflux was identified in the development of combined urogenital pathology. It was established that the inflammation of the urinary and genital tracts was rarely isolated. More frequently, both systems are involved in the infectious process. Similar to the principles of the interconnected vessels, if an infection is revealed in one of the systems, it is necessary to perform a cross-check screening control of the condition of the urinary or genital tract [3]. Besides, the associated infectious gynecological diseases, renal and urogenital pathology, and earlier episodes of UTI are considered to be predisposing risk factors for the development of the infection.
Asymptomatic bacteriuriaThe authors believe that the term asymptomatic bacteriuria (ASB) is outdated because new data were obtained on the microbiome and microbiota of the urine. Urine is not sterile. The long-existing paradigm on the sterility of urine was not proved [17]. The microbiome of healthy women is unique and contains a great number of geni and species of microorganisms [18]. Can pregnant women be an exception? A logical answer would be no. Still, presently, there are no studies on the microbiome of the urine in pregnant women. So far, it is still unknown if there are any changes in the microbiome and/or microbiota of the urine in different periods of gestation in healthy pregnant women and pregnant women with some pathology. Thus, the verification of the diagnosis of ASB is based not only on an old paradigm of urine sterility but also on its routine bacteriological tests that can reveal only a narrow spectrum of uropathogens. The issue of ASB in pregnant women is understudied and remains confusing. At what period of pregnancy do bacteriological urine tests have to be performed, considering that in the majority of cases, the doctors do not know the initial status of the urine microbiota in a certain pregnant woman? Clinical recommendations of the Russian Society of Obstetricians and Gynecologists and the Russian Society of Urology do not provide guidelines for dates of examination of pregnant women for ASB. However, according to the decree of the Ministry of Health of the Russian Federation “Protocol of medical help in obstetrics and gynecology (excluding reproductive-assisted technology)” (2012), all pregnant women are recommended (after 14 weeks of gestation) a single bacteriological culture-based test of the midstream specimen of urine (MSU) to exclude ASB (CFU > 105 in 1 ml MSU) (culture-based tests without clinical symptoms))1. Clinical recommendations of the European Association of Urology (EAU) say that ASB in pregnant women is diagnosed if there are no UTI symptoms and if there are identical microorganisms revealed in the concentration ≥ 105 CFU/ml in two consecutive urine samples obtained during unassisted urination [9].
What guidelines should be used in practice? The decree dated 2012 says that a single bacteriological urine test is enough with the isolation of microorganisms > 105 CFU/ml and EAU recommendations say that two bacteriological tests are required. If the level of bacteriuria is 104 CFU/ml and lower, how should it be interpreted? What shall doctors do with pregnant women that did not have ASB at the early stages of gestation? Shall it be tested for at other periods?
However, there are other points of view on the examination of pregnant women for ASB: American Association for Obstetricians and Gynecologists (2008), European Society of Clinical Microbiology and Infectious Diseases and Infectious Diseases Society of America (2011), and Perinatal Society of Australia and New Zealand (2017) recommend bacteriological urine test for all pregnant women during the first visit to the doctor or not later than 16th week of gestation. The Society of Obstetricians and Gynecologists of Canada (2018) recommend screening for ASB in each trimester [19][20][21][22].
Thus, there is no consensus on the issue of ASB in pregnant women among obstetricians and gynecologists, in particular, on the period of examination and interpretation of the obtained results. The authors believe that it can be explained by a lack of multicenter studies on this issue and an outdated term “asymptomatic bacteriuria”, in other words, ASB is a normal condition of the urine.
These unsolved issues logically lead to the following question. Is it necessary to treat ASB in pregnant women? If so, how should one treat them? There are data that ASB in pregnant women at early stages prevents the development of pyelonephritis in 70–80% of cases and undercarriage – in 5–10% of cases [23][24].
However, in Russian and foreign publications, there is no consensus on the duration of therapy and choice of antimicrobial agents.
The Russian Society of Obstetricians and Gynecologists provides the guidelines for the treatment of ASB and a list of the main drugs for the treatment of this condition in pregnant women. The therapy includes several positions: a short course (3–7 days) of oral ampicillin, amoxicillin/clavulanic acid; a single administration of phosphomycin trometamol (PT); empirical administration of a drug before the urine microbiological test. “If bacteriuria is revealed, the treatment should start with antibiotic therapy within 3 days with a further monthly bacteriological urine test to control possible infection recurrence. In the case of recurrent bacteriuria (16–33%), supportive therapy should be indicated (single administration of drugs after the meal before sleep) before the end of pregnancy and within two weeks after delivery”. “A possible option of management of pregnant women with recurrent bacteriuria is a repeated course of therapy with uroseptics”. The main drugs include amoxicillin and amoxicillin/clavulanic acid. It is recommended to indicate the drugs for three days. Besides, cefixime, cefuroxime, ceftibuten, and cephalexin can be used. The course of therapy should last from three days for cephalexin to seven days for other drugs [24].
A practicing doctor faces the issue of drug choice. If one chooses a single dose of PT or a three-day course drugs, it will be an empirical indication of a drug because a doctor has not received the results of bacteriological urine tests with an individual antibiogram.
However, there are clinical recommendations of the Russian Society of Urology for pregnant women with ASB that include therapy options that are similar to the therapy for cystitis in pregnant women. It is recommended to indicate PT (single uptake of 3 g) or nitrofurantoin for 5–7 days. It is possible to indicate therapy with other antibacterial drugs [25].
Thus, there is another issue, which therapy course is more preferable in pregnant women: single or long-term? There is no consensus on this issue either in the clinical recommendations and current reviews. In particular, Widmer et al. made a review of 10 studies that included more than 500 pregnant women with ASB and compared the effectiveness of a single course of therapy with PT and long-term therapy (5–7 days) with ampicillin, nitrofurantoin, cefalexin, trimethoprim, co-trimoxazol, and amoxicillin. The authors concluded that a single course of therapy resulted in a higher rate of ASB recurrence (p < 0.05) than a long-term therapy [26].
The Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) also recommends 4-7-day schemes of therapy for ASB [27]. However, a systematic review and meta-analysis by Wang et al. (2020) included the review of the effectiveness and safety with a single dose of PT in comparison with other antibacterial drugs in pregnant women with ASB. The data on the safety of therapy were analyzed in 15 studies. It was revealed that a single dose of PT provided equivalent clinical results to other antibiotics from the point of view of clinical and microbiological effectiveness. This meta-analysis suggested that PT was clinically more effective and safe for pregnant women with UTI or ASB [28].
The recommendations of EAU say that “…for the treatment of ASB in pregnant women, standard short-term courses of therapy should be indicated. Still, it should be highlighted that there is little evidence that confirms this recommendation” [9].
Apart from the duration of an antibacterial course of therapy, the issues on the choice of antibacterial drugs indicated to women with ASB are also disputable.
Aminopenicillins (amoxicillin), including inhibitor-protective ones (amoxicillin/clavulanic acid), and cephalosporins of 2nd-3rd generations and PT correspond to the requirements for safety from the FDA and Russian Society of Obstetricians and Gynecologists [8][24][29]. However, according to Asmat et al., E. coli strains isolated from the urine of pregnant women were resistant to amoxicillin [30].
In the USA and Canada, pregnant women with ASB are indicated nitrofurantoin and trimethoprim, and in Great Britain, penicillins and cephalosporins [31][32]. A survey performed among doctors in Northern Europe showed that the majority of practicing doctors followed local recommendations on the indication of pivmecillinam or nitrofurantoin [33].
However, Horrik et al. suggest that the treatment of ASB with antibacterial drugs is not feasible and increases the risk of antibiotic resistance [34].
In some cases, an alternative to antibacterial drugs is phototherapy [35][36].
Thus, there are more questions than answers on the issue of ASB in pregnant women. In other words, in the majority of cases, the doctors indicate the therapy not for some pathological condition but for a bacteriological condition to prevent an infection of the lower urinary tract and/or UUT, in particular, GP.
Gestational pyelonephritisPresently, the occurrence rate of acute pyelonephritis (AP) in pregnant women is 2.5%, which corresponds to 14 out of 1,000 deliveries or 53 out of 10,000 deliveries [37][38]. In 20.0% of cases, this pathology can be recurrent, which increases the risks of different complications for the pregnant woman and the fetus [37]. More frequently, acute GP is diagnosed in the second trimester of pregnancy [39][40]. In some cases (≈20.0%), women with severe GP can develop such complications as renal dysfunction, septic shock, acute respiratory distress syndrome, and disseminated intravascular coagulation (DIC syndrome) [34][39]. In pregnant women with GP, the risk of preterm delivery increases by 10.3%. Besides, there is a risk of spontaneous miscarriage in women and hospitalization to an intensive care unit for neonates because of preterm delivery [37][41]. According to Wing et al., the treatment for ASB decreases the risk of the development of AP in pregnant women from 25.0–30.0% to 1.0–4.0% [38].
It should be mentioned that physiological transformations that are observed during pregnancy can be predisposing factors for pyelonephritis. The dilation of the UUT is an important process that adapts a woman’s organism to changing anatomic peculiarities and normal functioning (accumulation of a larger volume of urine than before pregnancy) [42]. This adaptive mechanism develops after the 12th week; ureters and pelvicalyceal system dilate under the influence of progesterone [43]. In some cases, dilation of the UUT is registered only in the 3rd trimester. Primarily, the right kidney is affected [17][44].
The etiological structure of GP is similar to the one observed in non-pregnant patients with upper and lower UTI with the prevalence of Enterobacteriaceae species, primarily, E. coli. K. pneumoniae, E. aerogenes, C. freundii, P. mirabilis, and E. faecalis are revealed rarer [17][37][40][45][46]. In some cases, Veillonella parvula, Photobacterium damsela, Salmonella typhimurium, Pseudomonas spp., and Staphylococcus saprophyticus are isolated in women’s urine [40]. Based on newly obtained data on the non-sterility of the urine, it can be suggested that GP can be caused by opportunistic pathogenic bacteria represented by symbiotic microbiota of the urine and bladder. Under the effect of different biological processes during pregnancy, a decrease in the ureter motility, development of hypertension of the UUT, hypoxia of the mucous layer, and damage of urothelium are observed, which can lead to bacterial invasion [43].
The main signs of GP include fever, lumbar pain, and leukocyturia [39][47]. Jain et al. reported that patients with asymptomatic pyuria in the anamnesis should be monitored carefully because of a possible risk of GP development [47]. According to the Decree of the Ministry of Health of the Russian Federation No. 572n, the examination of patients with GP should include complete blood count, clinical urine analysis, blood biochemical assay (creatinine, blood urea nitrogen, total protein, uric acid), kidney and ureter ultrasonic investigation, fetal kidney, and ureter ultrasonic investigation at the age of gestation 20–24 weeks, bacteriological MSU test, and vaginal discharge test with the identification of an individual antibiogram. In patients with complicated forms of pyelonephritis, additional biochemical profile tests are recommended that include volumetric tests (triglycerides, electrolytes, albumins, hepatic enzymes), coagulogram, daily proteinuria. If necessary, in the 2nd and 3rd trimesters, radiological methods of diagnostics can be used but magnetic resonance imaging and ultrasonic investigation are preferable because they are the safest ones [48]. One of the severe complications of GP is septic shock. Thus, it is necessary to perform its early diagnostic using an interdisciplinary approach to this issue management [49].
According to EAU Guidelines (2020), patients with uncomplicated pyelonephritis can be treated in outpatient conditions with parenteral antibiotic drugs and monitored regularly. Patients with severe and obstructive cases should be hospitalized for supportive therapy. After the improvement of the clinical picture, it is possible to shift to oral therapy within 7–10 days [9].
In more than 90% of cases, conservative therapy in patients with PG is successful. In the rest cases, ureter draining is performed [50][51].
However, there is no consensus on the draining of ureters in pregnant women for the resolution of obstruction and no precise indications for UUT draining and time when these procedures should be performed. Even though this issue was partially described in scientific publications, in 2019, Levchenko and Morgun published a detailed review on GP and modern draining tactics. The main point in this study was the following: “Since there are no unified standards, each clinician relies on their practical experience that includes a wide range of variable tactical and therapeutic solutions” [52]. This concept does not sound optimistic. Thus, when conservative therapy is not effective, a doctor should choose a method of ureter draining (stenting or percutaneous puncture nephrostomy). Again, there is no consistent opinion on this issue. Several authors insist on the stenting of ureters [53]. Şimşir et al. (2018) showed the effectiveness of percutaneous puncture nephrostomy in patients with symptomatic hydronephrosis in pregnant women [54]. Ngai et al. (2013) successfully applied both methods [55].
Despite some controversy of data on UUT draining in pregnant women, it is indisputable that this approach should be used only in cases when conservative therapy fails. Levchenko et al. say that “drainage-free management of GP and traditional tactics of GP management should be considered not as mutually excluding but as mutually additional approaches to increase the rate of drainage-free cases” [52].
ConclusionDue to newly obtained data on the microbiome and microbiota of urine in healthy people that proved the paradigm of urine sterility to be wrong, the term “asymptomatic bacteriuria” seems to be outdated. To establish normal levels of bacteriuria in pregnant women, multicenter randomized studies should be conducted. Even EAU recommendations on this issue have a low level of evidence because they are based on outdated studies (1950s-1960s).
There is no consensus on the management of patients with GP, especially, on the issues of indications and technique of UUT draining. This condition indicates the necessity of multicenter randomized studies and possible revision of clinical recommendations. This will increase the cohort of patients that receive drainage-free therapy for GP and decrease different stenting-associated complications. The solution to the described issues will provide grounds for personalized management of pregnant women with different variants of UTI.
1. “Protocol of medical help in obstetrics and gynecology (assisted reproductive technology)”. Decree of the Ministry of Healthcare of the Russian Federation dated October 1, 2012, No. 572 n.
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