Duración del tratamiento para la bacteriuria asintomática durante el embarazo
Resumen
Antecedentes
Una revisión sistemática Cochrane ha demostrado que el tratamiento farmacológico de la bacteriuria asintomática en las embarazadas disminuye significativamente el riesgo de pielonefritis y reduce el riesgo de parto prematuro. Sin embargo, no está claro si el tratamiento con dosis única es tan efectivo como el tratamiento convencional de mayor duración con antibióticos.
Objetivos
Evaluar los efectos de diferentes duraciones del tratamiento para la bacteriuria asintomática durante el embarazo.
Métodos de búsqueda
Se hicieron búsquedas en el Registro de ensayos del Grupo Cochrane de Embarazo y Parto (Cochrane Pregnancy and Childbirth Group) (31 de agosto 2015) y en las listas de referencias de los artículos identificados.
Criterios de selección
Ensayos aleatorizados y cuasialeatorizados que compararon regímenes terapéuticos antimicrobianos de diferente duración (especialmente regímenes con dosis únicas comparados con regímenes de mayor duración) en embarazadas con diagnóstico de bacteriuria asintomática.
Obtención y análisis de los datos
Dos autores de la revisión evaluaron de forma independiente los ensayos para la inclusión y el riesgo de sesgo, extrajeron los datos y verificaron su exactitud. La calidad de la evidencia se evaluó con los criterios GRADE.
Resultados principales
Se incluyeron 13 estudios con 1622 mujeres. Todas las comparaciones incluyeron tratamiento con dosis única versus tratamientos de cuatro a siete días. El riesgo de sesgo de los ensayos incluidos en esta revisión fue en gran medida incierto, y en su mayoría los ensayos tuvieron alto riesgo de sesgo de realización. La calidad de la evidencia se evaluó mediante el enfoque GRADE. Cuando se utilizó cualquier agente antibiótico, la tasa de "no curación" de la bacteriuria asintomática en las embarazadas fue ligeramente inferior para el tratamiento de corta duración en comparación con el tratamiento de dosis única, aunque hubo evidencia de heterogeneidad estadística (riesgo relativo [RR] promedio 1,28, intervalo de confianza [IC] del 95%: 0,87 a 1,88; 1502 mujeres, 13 estudios; I² = 56%; evidencia de calidad muy baja). Los datos de los ensayos de buena calidad también mostraron mejores tasas de curación con regímenes cortos (de cuatro a siete días) del mismo agente microbiano (RR promedio 1,72, IC del 95%: 1,27 a 2,33; 803 mujeres, dos estudios; I² = 0%; evidencia de calidad alta). No hubo diferencias claras en la tasa de recurrencia de la bacteriuria asintomática entre los grupos de tratamiento y control si se utilizaron los mismos agentes microbianos, o si fueron diferentes (RR 1,13; IC del 95%: 0,77 a 1,66; 445 mujeres, ocho estudios; I² = 0%; evidencia de calidad muy baja). Se detectaron diferencias para los recién nacidos con bajo peso al nacer que favorecieron el tratamiento corto (de cuatro a siete días) del mismo agente microbiano, aunque los datos provienen de un solo ensayo (RR 1,65; IC del 95%: 1,06 a 2).57; 714 mujeres; evidencia de calidad alta), pero no se observaron diferencias para el parto prematuro (RR 1,17, IC del 95%: 0,77 a 1,78; 804 mujeres; tres estudios; I² = 23%; calidad moderada) o la pielonefritis (RR 3,09, IC del 95%: 0,54 a 17,55; 102 mujeres; dos estudios; I² = 0%; evidencia de calidad muy baja). Por último, el tratamiento de dosis única de cualquier agente microbiano se asoció con una disminución de los informes de "cualquier efecto secundario" (RR 0,70; IC del 95%: 0,56 a 0,88; 1460 mujeres, 12 estudios; I² = 9%; evidencia de calidad baja). La calidad de la evidencia se disminuyó debido a las preocupaciones con el riesgo de sesgo en los ensayos que aportaron datos, y a las estimaciones imprecisas del efecto (intervalos de confianza amplios que cruzan la línea de ningún efecto y, en algunos casos, estudios pequeños con pocos eventos).
Conclusiones de los autores
Un régimen de una sola dosis de antibióticos puede ser menos efectivo que un régimen de corta duración (de cuatro a siete días), pero se necesita más evidencia de ensayos amplios que midan resultados importantes, como la tasa de curación. Las mujeres con bacteriuria asintomática durante el embarazo se deben tratar con el régimen estándar de antibióticos hasta que haya más datos disponibles que prueben los regímenes de siete días en comparación con los de tres o cinco días.
PICO
Resumen en términos sencillos
Duración del tratamiento para la bacteriuria asintomática durante el embarazo
La bacteriuria asintomática es una infección urinaria (sin síntomas) frecuente en el embarazo. Si no se trata puede provocar pielonefritis (infección del riñón). Se recomienda el tratamiento con antibióticos. Esta revisión intentó identificar si los tratamientos antibióticos con dosis única son tan efectivos como los tratamientos más prolongados para los resultados maternos y neonatales. En general, el riesgo de sesgo de los ensayos incluidos en esta revisión fue en gran medida incierto. La calidad general de la evidencia se evaluó mediante los criterios GRADE. La revisión de 13 estudios, en los que participaron más de 1622 mujeres, encontró que un régimen de siete días es más efectivo que un ciclo de un día, especialmente para el resultado del bajo peso al nacer (evidencia de calidad alta), pero este resultado se basa en un solo estudio. No hubo diferencias claras entre una dosis única y un ciclo corto de antibióticos de cuatro a siete días para otros resultados de la revisión, incluida la infección renal (evidencia de calidad muy baja) y el parto prematuro (evidencia de calidad moderada). Las mujeres con un régimen de dosis única informaron menos efectos secundarios (evidencia de calidad baja). Se necesitan más ensayos para confirmar cuál es la mejor duración del tratamiento para las mujeres y los recién nacidos.
Authors' conclusions
Summary of findings
| Single dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria during pregnancy | ||||||
| Patient or population: patients with asymptomatic bacteriuria during pregnancy Comparison: short‐course (four‐ to seven‐day) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Single‐dose antibiotic versus short‐course (4‐ to 7‐day) antibiotic for asymptomatic bacteriuria | |||||
| No cure ‐ all trials | Study population | RR 1.28 | 1502 | ⊕⊝⊝⊝ | ||
| 166 per 1000 | 212 per 1000 | |||||
| Moderate | ||||||
| 138 per 1000 | 177 per 1000 | |||||
| Recurrent asymptomatic bacteriuria ‐ all trials | Study population | RR 1.13 | 445 | ⊕⊝⊝⊝ | ||
| 169 per 1000 | 191 per 1000 | |||||
| Moderate | ||||||
| 139 per 1000 | 157 per 1000 | |||||
| Pyelonephritis ‐ Same antimicrobial agent only4 | Study population | RR 3.09 | 102 | ⊕⊝⊝⊝ | ||
| 21 per 1000 | 64 per 1000 | |||||
| Moderate | ||||||
| 28 per 1000 | 87 per 1000 | |||||
| Low birthweight ‐ Same antimicrobial agent only | Study population | RR 1.65 | 714 | ⊕⊕⊕⊕ | ||
| 80 per 1000 | 132 per 1000 | |||||
| Preterm delivery ‐ Same antimicrobial agent only | Study population | RR 1.17 | 804 | ⊕⊕⊕⊝ | ||
| 91 per 1000 | 99 per 1000 | |||||
| Moderate | ||||||
| 89 per 1000 | 97 per 1000 | |||||
| Side effects ‐ all trials | Study population | RR 0.70 | 1460 | ⊕⊕⊝⊝ | ||
| 194 per 1000 | 136 per 1000 | |||||
| Moderate | ||||||
| 182 per 1000 | 127 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded twice due to serious risk of bias concerns. Most of the pooled effect provided by studies “B” or “C” (as specified by WHO criteria)* with a substantial proportion (i.e. > 40%) from studies “C” (‐2). 4 All data available for this outcome came from trials testing the same microbial agents. * "A" studies are of low risk of bias; "B" studies (‐1) are those with serious design limitations, including lack of allocation concealment, blinding (where relevant) or other problems with the conduct of the study; and "C" studies (‐2) have the same problems as B studies but to a greater degree. | ||||||
| Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria during pregnancy (subgrouped by trial quality) | ||||||
| Patient or population: patients with asymptomatic bacteriuria during pregnancy Comparison: short‐course (4‐7 day) antibiotic | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Single‐dose antibiotic versus short‐course (4‐ to 7‐day) antibiotic for asymptomatic bacteriuria (subgrouped by trial quality) | |||||
| Same antimicrobial agent ‐ No cure (good quality studies) | Study population | RR 1.72 | 803 | ⊕⊕⊕⊕ | ||
| 137 per 1000 | 236 per 1000 | |||||
| Moderate | ||||||
| 134 per 1000 | 230 per 1000 | |||||
| Different antimicrobial agents ‐ No cure (good quality studies) | Study population | RR 1.36 | 84 | ⊕⊕⊝⊝ | ||
| 50 per 1000 | 68 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded once for imprecision. Wide confidence interval crossing the line of no effect (‐1). | ||||||
Background
Description of the condition
Asymptomatic bacteriuria, defined as bacterial colonization of the urinary tract without symptomatology, is a common and potentially serious medical complication when it occurs during pregnancy. The incidence of asymptomatic bacteriuria during pregnancy has been reported to be between 2% and 10% (Andrews 1992; Sweet 1977). Escherichia coli is the most common causative organism followed by organisms such as Staphylococcus saprophyticus, Klebsiella spp, Enterobacter spp, Proteus spp, Enterococcus spp, and others. Between 15% and 45% of pregnant women with asymptomatic bacteriuria, if left untreated, will develop pyelonephritis (Wang 1989). Pyelonephritis is associated with an increase in maternal and fetal morbidity.
Description of the intervention
There is evidence to show that screening (and treatment) of all pregnant women for asymptomatic bacteriuria is both effective and cost‐beneficial when compared to no treatment in reducing the risk of pyelonephritis. A meta‐analysis of 11 randomized controlled trials (RCTs) found that treatment of asymptomatic bacteriuria reduced the risk of the development of pyelonephritis when compared to no treatment (Smaill 2015). Using decision analysis modeling to compare 'no screening' to 'screening' for asymptomatic bacteriuria, pyelonephritis was shown to decrease from 23.2 cases per 1000 among unscreened pregnant women to 16.20 cases per 1000 in those screened with leukocyte esterase‐nitrite dipstick, to 11.2 cases per 1000 among those screened with the more sensitive test of urine culture (Rouse 1995). In addition, both dipstick and culture screening were shown to be more cost‐beneficial when compared to no screening, and had a high level of agreement in the diagnosis of asymptomatic bacteriuria (Rouse 1995).
The association between asymptomatic bacteriuria and preterm delivery has also been studied. Findings from the Cardiff Birth Survey, which prospectively studied 25,844 births, reported that asymptomatic bacteriuria, adjusted for demographic and social factors, was not associated with preterm delivery (odds ratio (OR) 1.20, 95% confidence intervals (CI) 0.90 to 1.50) (Meis 1995a). However, when preterm births were categorized into 'indicated' or 'spontaneous' preterm births (Meis 1995b), a significant association between bacteriuria and indicated preterm birth was found (OR 2.03, 95% CI 1.50 to 2.80). In an overview of antimicrobial interventions to prevent preterm birth (Villar 1997), risk of preterm delivery/low birthweight was found to be significantly decreased for pregnant women who had received antibiotic treatment for asymptomatic bacteriuria when compared to women who did not receive treatment (risk ratio (RR) 0.67, 95% CI 0.52 to 0.85). There was an even greater decrease in risk when the only three trials which had categorized preterm delivery separately from low birthweight were considered (RR 0.53, 95% CI 0.33 to 0.86). An earlier meta‐analysis of eight RCTs showed that antibiotic treatment significantly reduced the risk of low birthweight (RR 0.56, 95% CI 0.43 to 0.73); however, preterm delivery was not reported independently (Romero 1989). Another meta‐analysis of six RCTs found that antibiotic treatment was associated with a reduction in the incidence of low birthweight babies (RR 0.64, 95% CI 0.45 to 0.93), and also a difference in preterm delivery (Smaill 2015). These findings have the limitations that the antibiotic regimens varied, and that many of the antimicrobials may no longer be prescribed in routine clinical practice. Nonetheless, we think that the evidence supports the view that all pregnant women with asymptomatic bacteriuria should be treated to prevent the development of acute pyelonephritis and reduce the risk of preterm delivery.
How the intervention might work
The relatively higher risk of ascending urinary tract infections and pyelonephritis during pregnancy may result from the decrease of ureteral peristalsis due to a progesterone‐mediated effect on smooth muscle contractility, on one hand, and the ureteral compression of the gravid uterus on the other. The resulting urinary stasis may facilitate the migration of uropathogens to the upper urinary tract. With eradication of the infection by antibiotic treatment, it is expected to prevent ascending urinary tract infections and the development of clinical pyelonephritis (Ramsey 2000).
The relationship of asymptomatic bacteriuria with low birthweight and preterm delivery is controversial and the possible mechanism involved has not been well established yet. Although both, the microbial colonization of the amniotic fluid and the inflammatory process resulting from the presence of bacteria in neighboring organs may induce uterine contractions, the population of women affected by lower urinary or genital tract infections usually have other risk factors for preterm birth and low birthweight (Goldenberg 2000) that may act as confounders. However, if the presence of bacteria predispose to premature uterine contractions, the rationale of antibiotic treatment to treat and clear the infection seems reasonable to prevent these adverse neonatal outcomes.
Why it is important to do this review
The question remains, what is the most effective treatment at the lowest cost, with the fewest side effects? These answers will depend on the pathogen, the choice and duration of antimicrobial, and the available healthcare services. An earlier meta‐analysis of seven RCTs reported that a single dose compared to a four‐ to seven‐day antibiotic treatment for bacteriuria showed no statistically significant difference in effectiveness when measuring outcomes of 'cure' and 'recurrence' (Smaill 1992a). However, these studies lacked a uniform definition for 'cure' and 'recurrence', and lacked consistent protocols for follow‐up of treatment, making comparisons difficult. Nonetheless, the available data do suggest that single‐dose therapy may be as effective as longer, conventional antibiotic treatment. Evidence regarding duration of therapy is especially important because single‐dose therapy offers the benefits of greater compliance of women during pregnancy at lower cost. In under‐resourced settings, the screening and treatment can be done during the same antenatal care visit.
Objectives
The objective of the review is to determine the clinical effectiveness of different durations of treatment for asymptomatic bacteriuria in pregnancy.
Methods
Criteria for considering studies for this review
Types of studies
All randomized controlled trials (RCTs) and quasi‐RCTs comparing treatment regimens for bacteriuria during pregnancy that differ in duration including those that compared different duration of different antimicrobial agents as well as different durations of the same agent. We expected that the majority of trials would attempt to show equivalence between treatments. We have not included trials comparing different therapeutic agents with the same duration of administration in this review, nor those presented only as abstracts.
Types of participants
Women identified during pregnancy as having asymptomatic bacteriuria.
Types of interventions
Antimicrobials of varying duration. Antimicrobial therapy regimens tend to show large variations in duration. For the purposes of this review, we have considered the following interventions distinct and compared to each other:
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single dose (including one‐day treatment with divided doses);
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short course (four to seven days);
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long course (14 days);
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continuous (treatment continued until delivery).
We will group interventions that we identify in future that do not fall into one of the categories listed above in the category that is closest in duration. We will make this allocation without any consideration of the trial results.
Types of outcome measures
Primary outcomes
The primary outcome is maternal cure rate defined as the woman having negative culture (test of cure) following initial treatment for asymptomatic bacteriuria.
Secondary outcomes
(1) Maternal
(a) Recurrent asymptomatic bacteriuria (in this review, recurrence includes relapse (the recurrence of bacteriuria caused by the same organism, usually within six weeks of the initial infection); and reinfection (the recurrence of bacteriuria involving a different strain of bacteria after successful eradication of the initial infection, limited to the bladder, and occurring at least six weeks after therapy (Davison 1992)).
(b) Pyelonephritis.
(2) Newborn
(a) Preterm delivery (gestational age less than 37 weeks).
(b) Low birthweight (birthweight less than 2500 g).
(c) Preterm delivery or low birthweight (if reported together).
(d) Other birth outcomes.
(3) Side effects
Any side effect related to the antibiotic treatment.
Search methods for identification of studies
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Electronic searches
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co‐ordinator (31 August 2015).
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL (EBSCO);
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE, Embase and CINAHL, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
Searching other resources
We searched the reference lists of identified articles.
We did not apply any language or date restrictions.
Data collection and analysis
For methods used in the previous version of this review, seeWidmer 2011.
The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.
Selection of studies
Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted the third review author.
Data extraction and management
We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted the third review author. Data were entered into Review Manager software (RevMan 2014) and checked for accuracy.
When information regarding any of the above was unclear, we planned to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor.
(1) Random sequence generation (checking for possible selection bias)
We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
We assessed the method as:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We assessed the methods as:
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low risk of bias (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed methods used to blind outcome assessment as:
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low, high or unclear risk of bias.
(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)
We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re‐include missing data in the analyses which we undertook.
We assessed methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomization);
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unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
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high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We described for each included study any important concerns we had about other possible sources of bias.
(7) Overall risk of bias
We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. In future updates, we will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
Assessment of the quality of the evidence using the GRADE approach
For this update, we assessed the quality of the evidence using the GRADE approach as outlined in the GRADE Handbook in order to assess the quality of the body of evidence relating to the following outcomes for the comparisons 'Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic', 'Single‐dose antibiotic versus long‐course (14‐day) antibiotic', and 'Single‐dose antibiotic versus continuous (treatment continued until delivery) antibiotic'. However, all included trials were of single‐dose treatments with short‐course (four‐ to seven‐day) treatments and so we were only able to produce 'Summary of findings' tables for this comparison.
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No cure
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Preterm delivery or low birthweight
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Pyelonephritis
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Recurrent asymptomatic bacteriuria
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Any side effect related to the antibiotic treatment
We used GRADEpro Guideline Development Tool to import data from Review Manager 5.3 (RevMan 2014) in order to create ’Summary of findings’ tables. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
Measures of treatment effect
Dichotomous data
For dichotomous data, we presented results as summary risk ratio with 95% confidence intervals.
Continuous data
No continuous data were analyzed. In future updates, if appropriate, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardized mean difference to combine trials that measure the same outcome, but use different methods.
Unit of analysis issues
The unit of analysis was individual randomized women.
Cluster‐randomized trials
No cluster‐randomized trials were found for this review. If we had identified cluster‐randomized trials, they would have been eligible for inclusion.
In future updates, we will include cluster‐randomized trials in the analyses along with individually‐randomized trials. We will adjust either their sample sizes or standard errors using the methods described in the Handbook [Section 16.3.4 or 16.3.6] using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomized trials and individually‐randomized trials, we plan to synthesize the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomization unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomization unit and perform a sensitivity analysis to investigate the effects of the randomization unit.
Cross‐over trials
Given the objectives of this review, cross‐over trials were not eligible for inclusion.
Other unit of analysis issues
No other units of analyses were used in this review.
Dealing with missing data
For included studies, we noted levels of attrition. In future updates, if more eligible studies are included, we will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, analyses were carried out, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomized to each group in the analyses. The denominator for each outcome in each trial was the number randomized minus any participants whose outcomes were known to be missing. Trials were excluded if it was not possible to enter data on an intention‐to‐treat basis.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either a Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. Had we identified substantial heterogeneity (above 30%) in the primary outcomes, we planned to explore it by pre‐specified subgroup analysis.
Assessment of reporting biases
We investigated reporting biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry visually. If asymmetry was suggested by a visual assessment, we attempted to explain and interpret the finding.
Data synthesis
We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.
If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. If we used random‐effects analyses, the results were presented as the average treatment effect with 95% confidence intervals, and the estimates of Tau² and I².
Subgroup analysis and investigation of heterogeneity
If we identified substantial heterogeneity in the primary outcomes, we investigated it using subgroup analyses and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, we used random‐effects analysis to produce it.
All analyses in the review were set up according to the following clinical subgroups of trials.
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Same antimicrobial agent
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Different antimicrobial agent
Where we had sufficient evidence, we reported a pooled effect estimate. Where there were only data for one of type of antimicrobial, we reported only the evidence we had. We reported positive results of the Test for Subgroup differences where relevant and meaningful. We reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.
Sensitivity analysis
We planned to carry out sensitivity analyses to explore the effect of trial quality assessed by concealment of allocation, high attrition rates, or both, with poor quality studies being excluded from the analyses in order to assess whether this makes any difference to the overall result.
We carried out the following sensitivity analyses according to trial quality, saved as our Comparison 2.
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Good quality studies
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Poor quality studies
Trial quality was assessed according to whether a trial reported taking measures to prevent selection, detection, performance and attrition bias. Trials reporting these domains were considered of high quality.
Results
Description of studies
Results of the search
We identified two new reports from an updated search in 2015 for the same trial (Rafalsky 2013), which we subsequently added to Excluded studies.
Included studies
We included 13 studies, involving 1622 women. For a detailed description of studies, seeCharacteristics of included studies.
Eleven trials included in the review were conducted in high‐income countries (Austria, Belgium, Denmark, Italy, New Zealand, Spain, the United Kingdom, and the United States), and two were conducted in low‐ and middle‐income ones (one multicenter trial conducted in Argentina, Philippines, Thailand, and Viet Nam, and one was conducted in Turkey). The laboratory measurements of selected outcomes required facilities in which urine culture and antibiotic sensitivity testing were possible. Three trials were published recently (Bayrak 2007; Estebanez 2009; Lumbiganon 2009); one of the trials was published in 1990 (Thoumsin 1990); eight of the trials were published in the 1980s; and the remaining trial was published in 1975 (Reeves 1975). The antimicrobial drugs used in the trials included: ampicillin, nitrofurantoin, cephalexin, fosfomycin trometamol, fosfomycin, amoxicillin‐clavulanate, amoxicillin, co‐trimoxazole, trimethoprim, and other sulfonamides. Bayrak 2007 compared a single dose of fosfomycin trometamol with five‐day treatment of cefuroxime axetyl; Thoumsin 1990 compared a single dose of fosfomycin trometamol with seven‐day treatment of nitrofurantoin; and Estebanez 2009 compared a single dose of fosfomycin with seven‐day treatment of amoxicillin‐clavulanate. The remaining 10 trials compared different durations of the same antimicrobial family. The duration of antimicrobial used in the experimental group was either a single dose or one‐day treatment with divided dose, and in the control groups, varied between four and seven days' duration. We included Brumfitt 1982 in spite of inclusion of 24% of symptomatic women in both groups, and Thoumsin 1990 in spite of the state of publication (preliminary results).
Excluded studies
For details of the excluded studies, see table of Characteristics of excluded studies.
Risk of bias in included studies
In general, the trials lacked evidence of sufficient rigor in the design, conduct and analysis of results (Figure 1; Figure 2).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
For detailed information on methods see table of Characteristics of included studies.
Allocation
Generation methods for randomization in six of the 13 trials included computerized process for simple randomization (Masterton 1985), randomized tables (Brumfitt 1982;Estebanez 2009), and blocked randomization (Bayrak 2007; Gerstner 87‐89; Lumbiganon 2009); all assessed as low risk of bias. Two trials described alternate methods (every other woman) and were assessed as of high risk of bias (Anderton 1983; Reeves 1975). The remaining five trials provided no description of the generation method and were assessed as having an unclear risk of bias (Bailey 1983; Bailey 1986; Olsen 1989; Pregazzi 1987; Thoumsin 1990).
Seven trials did not describe the mechanism used for allocation concealment (Brumfitt 1982; Estebanez 2009; Gerstner 87‐89; Masterton 1985; Olsen 1989; Pregazzi 1987; Thoumsin 1990) and were assessed as unclear risk of bias. One trial used numbered treatment bags (Bayrak 2007), another used sealed, opaque treatment boxes numbered sequentially (Lumbiganon 2009) and were considered as low risk of bias; and two described concealment as 'envelopes' only (Bailey 1983; Bailey 1986); these trials were assessed as having an unclear risk of bias. The remaining two trials (Anderton 1983; Reeves 1975) used alternated methods for allocation and were assessed as at high risk of bias.
Blinding
In all 13 trials, there was inadequate description to determine whether 'contamination' in the short‐course treatment group, co‐interventions, or protocol deviation occurred. Blinding for outcome assessment was reported in three trials (Bayrak 2007; Lumbiganon 2009; Masterton 1985). No women were blinded to treatment in any of the trials except in the Lumbiganon 2009 trial. Informed consent was mentioned in the majority of trials.
Incomplete outcome data
Loss to follow‐up was described in all trials except Brumfitt 1982, Pregazzi 1987 and Thoumsin 1990; all assessed as of unclear risk of bias. The rates of loss to follow‐up were, as expected given the longer duration, generally higher in the comparison group as compared to the experimental (single‐dose) group. Although the numbers are small, when two treatments produce a different pattern of withdrawal, then this offers evidence that the groups are not entirely comparable (Jones 1996). Several trials had small differences in rates of loss between treatment arms and were assessed as of low risk of bias (Anderton 1983; Bailey 1983; Bailey 1986; Bayrak 2007; Estebanez 2009; Lumbiganon 2009; Masterton 1985; Olsen 1989; Reeves 1975). Gerstner 87‐89, though, we assessed as of high risk due to 13% loss in the treatment arm and 26% loss in the control arm.
Selective reporting
The only trial that reported on the demographics or number of women who met the study eligibility criteria, but were not included in the study and also on compliance with the treatment regimen, was Lumbiganon 2009; this trial was assessed as of low risk of reporting bias. All other trials were assessed as of unclear risk of bias due to lack of information.
Other potential sources of bias
An explanation of the sample size calculation and power calculation was provided in the Bayrak 2007, Lumbiganon 2009 and Masterton 1985 trials; these trials were assessed as of low risk of other sources of bias.
All of the remaining trials were assessed as of unclear risk of bias due to lack of information in the trial report or to specific factors where we were unclear of the impact of potential bias. For example, randomization is less effective in achieving comparable groups in studies with small sample sizes, which many of our studies had. Also, in one trial women in the experimental group were more likely to have a history of urinary tract infection as compared to the control group (50% versus 35%) (Bailey 1983). Disparity in baseline characteristics between treatment groups suggests selection bias due to inadequate randomization or too small a sample size, or both (Villar 1996). We felt there was an increased likelihood of selection bias in most of the trials, but we were unclear of the impact of this bias on results. The total number of women enrolled in these studies ranged from 41 to 778.
Effects of interventions
See: Summary of findings for the main comparison Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria during pregnancy; Summary of findings 2 Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria during pregnancy (subgrouped by trial quality)
Comparison 1: Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria
We included 13 trials, involving 1622 women. After reporting overall results, we report individual results for two groups: (a) trials that compared different duration regimens of the same agent; and (b) trials that compared different duration regimens of different antimicrobial agents.
Comparison 1: overall pooled totals for all trials
Primary outcome
No cure
Cure rates were similar whether women received a single dose or a short course of any antibiotic (average risk ratio (RR) 1.28, 95% confidence interval (CI) 0.87 to 1.88; women = 1502; studies = 13; I² = 56%; Analysis 1.1). There was no evidence of differences in cure rates for our subgroups of same antimicrobial agent or different microbial agent (Test for subgroup differences: Chi² = 0.55, (P = 0.46), I² = 0%) and moderate heterogeneity even with a random‐effects model (Heterogeneity: Tau² = 0.23; Chi² = 27.00, I² = 56%). We graded the evidence for the outcome of no cure as very low quality due to risk of bias in the contributing trials and wide CIs crossing the line of no effect.
When assessing forest plots for publication bias, we found suggested asymmetry in the funnel plot for this outcome (Figure 3). However, the single outlier trial was extremely small, and so the source of asymmetry may well be a small‐study effect rather than publication bias. This trial also contribute very little to the overall pooled effect estimate (1.6%). We have not downgraded evidence for this outcome for publication bias.
Funnel plot of comparison: 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, outcome: 1.6 No cure.
Secondary outcomes
Maternal and newborn outcomes
Recurrent asymptomatic bacteriuria
Rates of recurrence were similar between treatment groups (RR 1.13, 95% CI 0.77 to 1.66; women = 445; studies = eight; I² = 0%), Analysis 1.2. There was no evidence of any difference between subgroups of the same or different agents (Test for subgroup differences: Chi² = 0.03, (P = 0.86), I² = 0%). We graded evidence for recurrence as very low due to risk of bias concerns in the contributing trials and wide CIs crossing the line of no effect.
Results for outcomes (pyelonephritis, preterm delivery and low birthweight) Analysis 1.3; Analysis 1.4; Analysis 1.5 were not pooled due to each outcome only having one subgroup. Results for these outcomes are found below for trials with either the same or different agents.
Side effects
Fewer women who had the single dose experienced side effects (RR 0.70, 95% CI 0.56 to 0.88; women = 1460; studies = 12; I² = 9%), Analysis 1.6. Evidence for side effects was graded to be of low quality due to risk of bias concerns in the trials contributing data. There was evidence of a difference between using the same or different microbial agents noted; however, we would not emphasize this finding due to the small number of trials and events in the different antimicrobial group. The results for both subgroups fall in the same direction with minimal heterogeneity (Test for subgroup differences: Chi² = 5.42, df = 1 (P = 0.02), I² = 81.5%; Heterogeneity: Chi² = 10.93, I² = 9%).
Comparison 1: (a) different duration of the same antimicrobial agent
Primary outcome
No cure
All trials reported bacteriological success of treatment by repeat cultures (Anderton 1983; Bailey 1983; Bailey 1986; Brumfitt 1982; Gerstner 87‐89; Lumbiganon 2009; Masterton 1985; Olsen 1989; Pregazzi 1987; Reeves 1975) The 'no cure' rate was similar for the one‐day and the four‐ to seven‐day treatment (average RR 1.34, 95% CI 0.85 to 2.12; women = 1286; studies = 10; Analysis 1.1). There was moderate heterogeneity for this outcome even with a random‐effects model (Heterogeneity: Tau² = 0.30; Chi² = 25.83, df = 9 (P = 0.002); I² = 65%).
Secondary outcomes
(a) Maternal outcomes
The risk of recurrent asymptomatic bacteriuria (Analysis 1.2) in one‐day treatment was not significantly different to that with longer treatment (RR 1.12, 95% CI 0.76 to 1.66; women = 313; studies = six; I² = 0%).
Pyelonephritis (Analysis 1.3) was reported only by Bailey 1983 and Bailey 1986, with 102 women included in the two trials together. There were four more women with pyelonephritis following single‐dose treatment (5/54 versus 1/48; RR 3.09, 95% CI 0.54 to 17.55; women = 102; studies = two; I² = 0%). We graded evidence for this outcome as of very low quality due to risk of bias concerns in the contributing trials, wide CIs and limited data.
(b) Newborn outcomes
Preterm birth
Only three of the 10 trials included in this review reported preterm birth rates (Bailey 1983; Bailey 1986; Lumbiganon 2009). In total, 804 women were studied in these trials (Analysis 1.4), and there is no evidence of a difference between a single‐dose antibiotic and a four‐ to seven‐day course (RR 1.17, 95% CI 0.77 to 1.78; women = 804; studies = three; I² = 23%). We graded evidence for preterm birth to be of moderate quality due to imprecision, or wide CIs crossing the line of no effect.
Low birthweight
Just one trial Lumbiganon 2009 reported low birthweight rates (Analysis 1.5) with 48 cases out of 364 babies in the one‐day arm compared to 28 cases in the 350 babies from the longer‐treatment group (RR 1.65, 95% CI 1.06 to 2.57; women = 714; studies = one; I² = 0%). Evidence for low birthweight was graded as of high quality.
(c) Side effects
The meta‐analysis regarding any side effects (Analysis 1.6) shows a lower incidence of side effects with single‐dose treatment. For those trials that tested the same microbial agent the result is similar (RR 0.77, 95% CI 0.61 to 0.97; women = 1244; studies = nine; I² = 0%). The Reeves 1975 study included in this analysis was stopped prematurely due to the side effects (mainly nausea, vomiting, diarrhea) of sulfadimidine in seven‐day treatment group. A sensitivity analysis including all trials comparing the same antimicrobial but excluding Reeves 1975 also showed higher, yet statistically non‐significant, rates of similar side effects with longer treatment (RR 0.81, 95% CI 0.64 to 1.04).
Comparison 1 (b): different durations of different antimicrobial agents
Primary outcome
No cure
The three trials included in this outcome (216 women) reported bacteriological success of treatment by repeat cultures (Bayrak 2007; Estebanez 2009; Thoumsin 1990). There was no difference in the 'no cure' rate for the single‐dose treatment versus the short‐course treatment, but with wide CIs (RR 0.98, 95% CI 0.49 to 1.95; women = 216; studies = three; I² = 0%), Analysis 1.1.
Secondary outcomes
(a) Maternal outcomes
Recurrent asymptomatic bacteriuria
The incidence of recurrent bacteriuria was reported in two of the three included trials (Estebanez 2009; Thoumsin 1990) (132 women), and there was no significant difference between the two groups, again with wide CIs (RR 1.32, 95% CI 0.23 to 7.46), Analysis 1.2.
Pyelonephritis
No trial included in this subgroup of different agents reported the outcomes of pyelonephritis.
(b) Newborn outcomes
No trial included in this subgroup of different agents reported the outcomes of preterm birth or low birthweight.
(c) Side effects
The three trials (Bayrak 2007; Estebanez 2009; Thoumsin 1990) showed fewer side effects in the single‐dose treatment group than in the short‐course treatment group (RR 0.16, 95% CI 0.04 to 0.58; women = 216; studies = three; I² = 0%), Analysis 1.6.
Comparison 2: Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria
Subgroup analysis by trial quality
Comparison 2 (1): same antimicrobial agent ‐ 'no cure'
When grouped by trial quality (Analysis 2.1), the two trials of good quality (reporting measures to prevent selection, detection, performance and attrition bias) show a significant increase in 'no cure' rates with single‐dose treatment when compared with short‐course (four‐ to seven‐day) treatment (Lumbiganon 2009; Masterton 1985; two trials, 803 women, average RR 1.72, 95% CI 1.27 to 2.33; Heterogeneity: Chi² = 0.35, df = 1 [P = 0.55]; I² = 0%). Heterogeneity remains in the subgroup of poor quality studies (eight trials, 483 women, average RR 1.32, 95% CI 0.73 to 2.42, Heterogeneity: Chi² = 20.84, df = 7 (P = 0.004); I² = 66%). There was some evidence that the intervention worked differently, and better, in trials of higher quality, although the test for subgroup was not significant (Test for subgroup differences: Chi² = 0.58, df = 1 (P = 0.44), I² = 0%). However, there were only two studies in the good quality subgroup and the CIs for both pooled results do overlap.
We have graded the evidence for no cure (good quality studies) as of high quality. See summary of findings Table 2.
Comparison 2 (2): different antimicrobial agent ‐ 'no cure'
When grouped by trial quality, only Bayrak 2007 shows relatively good quality. There was no difference in rates of no cure with a single dose or short‐course doses (one study, RR1.36, 95% CI 0.24 to 7.75), Analysis 2.2. The remaining two trials were ranked as of poor quality; these trials also show no group differences in rates of no cure (two studies, RR 0.93, 95% CI 0.44 to 1.96. Heterogeneity: Chi² = 0.22, df = 1 (P = 0.64); I² = 0%). There was no evidence of a difference between subgroups of high or low quality studies (Test for subgroup differences: Chi² = 0.16, df = 1 (P = 0.69), I² = 0%), but there were too few trials in each subgroup to make this analysis meaningful.
We have graded the evidence for no cure (good quality studies) as of low quality, due to the estimate coming from a single small trial and having wide CIs crossing the line of no effect.
Comparison 3: Single‐dose antibiotic versus long‐course (14 days) antibiotic for asymptomatic bacteriuria
No trials found.
Comparison 4: Single‐dose antibiotic versus continuous (treatment continued until delivery) antibiotic for asymptomatic bacteriuria
No trials found.
Discussion
Summary of main results
Asymptomatic bacteriuria during pregnancy has serious consequences if it is not treated. Routine screening and antibiotic treatment of positive cases is generally recommended. The optimal duration of the treatment has both cost and practical implications.The standard treatment is a short course of four to seven days. Single‐dose treatment, if effective, could increase compliance (as it can be administered at the healthcare site), and it is likely to be cheaper. These advantages are important in lower‐income countries where women attend antenatal clinics irregularly and where approximately 90% of all preterm deliveries around the world take place (Villar 1994). The objective of this review was to determine the clinical effectiveness of different durations of treatment for asymptomatic bacteriuria in pregnancy. Only trials comparing a single dose with a short course of four to seven days were found for inclusion in this review.
For the outcome of no cure, meta‐analysis of all trials comparing a single dose versus a short course of treatment of the same or different antibiotics showed a wide range of effects (from 50% reduction to a six‐fold increase), with no conclusive difference between treatment groups and moderate heterogeneity between trials. The evidence for no cure was graded as of very low quality due to risk of bias concerns in the contributing trials and the imprecision of treatment effects (wide confidence intervals crossing the line of no effect). Fewer babies of low birthweight were born to women who had treatment with a short course of the same microbial agent than to women receiving a single dose, but this result was based on a single study with 714 women and graded to be of moderate quality. A single course of antibiotics also resulted in fewer side effects in 12 trials (1460 women), regardless of the type of antibiotic used; however, this evidence was graded as of low quality due to serious risk of bias concerns in the contributing trials. There were no clear benefits of either a single dose or a short course of antibiotics for any of the following review outcomes, whether the same antibiotic or different antibiotics were used: recurrence (very low quality evidence), pyelonephritis (very low quality evidence), or preterm delivery (moderate quality evidence). Evidence was downgraded due to risk of bias concerns in contributing trials and to imprecision in effect estimates.
When analysis was restricted to two high quality trials, results from the two trials for the outcome of no cure favored short‐course treatment of the same microbial agent. No conclusions about cure rates can be drawn for different antimicrobial drugs as this analysis included only one small trial.
Overall completeness and applicability of evidence
In general, the trials in this review have several methodological limitations, which makes the interpretation of pooled results difficult. Heterogeneity could presumably be explained by trial design and conduct, but baseline risks of the population studied, differences in the laboratory definition of positive cases (i.e. cultures of > 10,000 or 100,000 CFU/mL), and the different pharmacokinetics and specificities of the antimicrobial agents used could not be ruled out. The Lumbiganon 2009 trial provides about half of the data to the meta‐analysis and is methodologically sound. We therefore think that overall, longer duration of treatment is likely to be more effective. However, there is a drawback that non‐adherence may be higher with treatments of longer duration.
Quality of the evidence
In general, the risk of bias of trials included in this review was largely unclear, with all trials being at high risk of performance bias. Most trials were conducted in the 1980s and 1990s and did not describe methods to avoid selection, detection or performance bias. Only three trials (Lumbiganon 2009; Masterton 1985 in the same agent group, and in Bayrak 2007 in the different agent group) were rated as low risk of bias.
The quality of the evidence was assessed using the GRADE approach, see summary of findings Table for the main comparison; summary of findings Table 2. The evidence was graded as: very low quality for the outcomes no cure rate, recurrence of asymptomatic bacteriuria and pyelonephritis; high quality for the outcome low birthweight; moderate quality for preterm delivery; and low quality for side effects. Evidence was downgraded for risk of bias concerns in trials contributing data and for imprecise effect estimates (wide confidence intervals crossing the line of no effect, and in some cases, small studies with few events).
Potential biases in the review process
We attempted to minimise bias during the review process by having two people assess the eligibility of studies, assess risk of bias and extract data. We attempted to be as inclusive as possible in our search. The asymmetric funnel plot may suggest publication bias (Figure 3) that could result from the small numbers in the included trials. Many trials included in the review were very small. Small trials not only can predispose to publication bias, but also to misleading results as they tend to be conducted and analyzed with less methodological rigor than larger trials and may overestimate the effect of one group. This is of greater concern in equivalence trials where larger sample sizes are required than comparative trials (Jones 1996). Most trials were not blinded and the risk of performance and detection bias was high, especially for clinical outcomes. Morover, few studies reported efforts to blind the outcome assessment, even those performed at the bacteriology lab. Thus, the poor methodological quality of these trials may obscure any important clinical and laboratory differences between duration of treatment regimens. We explored these issues as a plausible source of heterogeneity by analyzing good and poor quality studies separately.
Agreements and disagreements with other studies or reviews
Currently there is a consensus in most settings that asymptomatic bacteriuria during pregnancy should be universally screened and treated (NICE 2008; Nicolle 2005). However, there are increasing concerns about the emergence of resistant bacterial strains due to high rates of antibiotic use in hospitals, the community and agriculture (Laxminarayan 2014). Because of these worries and the lack of convincing evidence for an universal screening and treating policy, some professional associations such as the Dutch Society of Obstetrics and Gynaecology (NVOG 2011), and the Dutch General Practitioners Society (Van Haaren 2005) recommend screening for asymptomatic bacteriuria only in high‐risk women (i.e. women with congenital urinary tract defects, a previous history of urinary tract infections, diabetes mellitus, sickle cell disease or neurological disorders, and reduced immunity). A recently published cohort study from the Netherlands (Kazemier 2015) also questions the universal routine screen‐treat‐policy for asymptomatic bacteriuria in pregnancy as it showed that, if untreated, asymptomatic bacteriuria had low (although significant) absolute risks for pyelonephritis (2.4% in 208 women with untreated asymptomatic bacteriuria versus 0.6% in 4035 women without bacteriuria). An embedded small randomized controlled trial within this cohort (40 women randomly assigned to nitrofurantoin and 45 to placebo) failed to demonstrate significant differences in the rates of low birthweight, preterm birth or pyelonephritis. However, this study is small, included only very low‐risk women and it is uncertain whether these results are generalizable.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Funnel plot of comparison: 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, outcome: 1.6 No cure.
Comparison 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, Outcome 1 No cure.
Comparison 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, Outcome 2 Recurrent asymptomatic bacteriuria.
Comparison 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, Outcome 3 Pyelonephritis.
Comparison 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, Outcome 4 Preterm delivery.
Comparison 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, Outcome 5 Low birthweight.
Comparison 1 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria, Outcome 6 Side effects.
Comparison 2 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria (subgrouped by trial quality), Outcome 1 Same antimicrobial agent.
Comparison 2 Single dose versus short‐course (4‐7 day) antibiotic for asymptomatic bacteriuria (subgrouped by trial quality), Outcome 2 Different antimicrobial agents.
| Single dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria during pregnancy | ||||||
| Patient or population: patients with asymptomatic bacteriuria during pregnancy Comparison: short‐course (four‐ to seven‐day) | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Single‐dose antibiotic versus short‐course (4‐ to 7‐day) antibiotic for asymptomatic bacteriuria | |||||
| No cure ‐ all trials | Study population | RR 1.28 | 1502 | ⊕⊝⊝⊝ | ||
| 166 per 1000 | 212 per 1000 | |||||
| Moderate | ||||||
| 138 per 1000 | 177 per 1000 | |||||
| Recurrent asymptomatic bacteriuria ‐ all trials | Study population | RR 1.13 | 445 | ⊕⊝⊝⊝ | ||
| 169 per 1000 | 191 per 1000 | |||||
| Moderate | ||||||
| 139 per 1000 | 157 per 1000 | |||||
| Pyelonephritis ‐ Same antimicrobial agent only4 | Study population | RR 3.09 | 102 | ⊕⊝⊝⊝ | ||
| 21 per 1000 | 64 per 1000 | |||||
| Moderate | ||||||
| 28 per 1000 | 87 per 1000 | |||||
| Low birthweight ‐ Same antimicrobial agent only | Study population | RR 1.65 | 714 | ⊕⊕⊕⊕ | ||
| 80 per 1000 | 132 per 1000 | |||||
| Preterm delivery ‐ Same antimicrobial agent only | Study population | RR 1.17 | 804 | ⊕⊕⊕⊝ | ||
| 91 per 1000 | 99 per 1000 | |||||
| Moderate | ||||||
| 89 per 1000 | 97 per 1000 | |||||
| Side effects ‐ all trials | Study population | RR 0.70 | 1460 | ⊕⊕⊝⊝ | ||
| 194 per 1000 | 136 per 1000 | |||||
| Moderate | ||||||
| 182 per 1000 | 127 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded twice due to serious risk of bias concerns. Most of the pooled effect provided by studies “B” or “C” (as specified by WHO criteria)* with a substantial proportion (i.e. > 40%) from studies “C” (‐2). 4 All data available for this outcome came from trials testing the same microbial agents. * "A" studies are of low risk of bias; "B" studies (‐1) are those with serious design limitations, including lack of allocation concealment, blinding (where relevant) or other problems with the conduct of the study; and "C" studies (‐2) have the same problems as B studies but to a greater degree. | ||||||
| Single‐dose antibiotic versus short‐course (four‐ to seven‐day) antibiotic for asymptomatic bacteriuria during pregnancy (subgrouped by trial quality) | ||||||
| Patient or population: patients with asymptomatic bacteriuria during pregnancy Comparison: short‐course (4‐7 day) antibiotic | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Single‐dose antibiotic versus short‐course (4‐ to 7‐day) antibiotic for asymptomatic bacteriuria (subgrouped by trial quality) | |||||
| Same antimicrobial agent ‐ No cure (good quality studies) | Study population | RR 1.72 | 803 | ⊕⊕⊕⊕ | ||
| 137 per 1000 | 236 per 1000 | |||||
| Moderate | ||||||
| 134 per 1000 | 230 per 1000 | |||||
| Different antimicrobial agents ‐ No cure (good quality studies) | Study population | RR 1.36 | 84 | ⊕⊕⊝⊝ | ||
| 50 per 1000 | 68 per 1000 | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Downgraded once for imprecision. Wide confidence interval crossing the line of no effect (‐1). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 No cure Show forest plot | 13 | 1502 | Risk Ratio (M‐H, Random, 95% CI) | 1.28 [0.87, 1.88] |
| 1.1 Same antimicrobial agent | 10 | 1286 | Risk Ratio (M‐H, Random, 95% CI) | 1.34 [0.85, 2.12] |
| 1.2 Different antimicrobial agents | 3 | 216 | Risk Ratio (M‐H, Random, 95% CI) | 0.98 [0.49, 1.95] |
| 2 Recurrent asymptomatic bacteriuria Show forest plot | 8 | 445 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.13 [0.77, 1.66] |
| 2.1 Same antimicrobial agent | 6 | 313 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.76, 1.66] |
| 2.2 Different antimicrobial agents | 2 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.32 [0.23, 7.46] |
| 3 Pyelonephritis Show forest plot | 2 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.09 [0.54, 17.55] |
| 3.1 Same antimicrobial agent | 2 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.09 [0.54, 17.55] |
| 4 Preterm delivery Show forest plot | 3 | 804 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.77, 1.78] |
| 4.1 Same antimicrobial agent | 3 | 804 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.17 [0.77, 1.78] |
| 5 Low birthweight Show forest plot | 1 | 714 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.65 [1.06, 2.57] |
| 5.1 Same antimicrobial agent | 1 | 714 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.65 [1.06, 2.57] |
| 6 Side effects Show forest plot | 12 | 1460 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.70 [0.56, 0.88] |
| 6.1 Same antimicrobial agent | 9 | 1244 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.77 [0.61, 0.97] |
| 6.2 Different antimicrobial agents | 3 | 216 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.16 [0.04, 0.58] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Same antimicrobial agent Show forest plot | 10 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.1 No cure (good quality studies) | 2 | 803 | Risk Ratio (M‐H, Random, 95% CI) | 1.72 [1.27, 2.33] |
| 1.2 No cure (poor quality studies) | 8 | 483 | Risk Ratio (M‐H, Random, 95% CI) | 1.32 [0.73, 2.42] |
| 2 Different antimicrobial agents Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 No cure (good quality studies) | 1 | 84 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.36 [0.24, 7.75] |
| 2.2 No cure (poor quality studies) | 2 | 132 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.44, 1.96] |
