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Intervenciones para la prevención de la infección urinaria recurrente durante el embarazo

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Resumen

Antecedentes

Las infecciones urinarias recurrentes (IUR) son frecuentes en las embarazadas y pueden causar resultados adversos graves del embarazo tanto para la madre como para el niño incluido el parto prematuro y recién nacidos pequeños para la edad gestacional. Las intervenciones utilizadas para prevenir la IUR en las embarazadas pueden ser farmacológicas (antibióticos) o no farmacológicas (productos de arándanos, acupuntura, probióticos y modificaciones conductuales). Hasta el presente se conoce poco acerca de la mejor forma de prevenir la IUR en las embarazadas.

Objetivos

Evaluar los efectos de las intervenciones para la prevención de la IUR en las embarazadas.

Los resultados maternos primarios fueron la IUR antes del parto (definida de varias maneras) y el parto prematuro (antes de las 37 semanas). Los resultados primarios del recién nacido fueron el tamaño pequeño para la edad gestacional y la mortalidad total.

Métodos de búsqueda

Se hicieron búsquedas en el registro de ensayos del Grupo Cochrane de Embarazo y Parto (Cochrane Pregnancy and Childbirth Group) (20 de mayo 2015) y en las listas de referencias de los estudios recuperados.

Criterios de selección

Ensayos controlados aleatorizados (ECA) publicados, no publicados y en curso, ensayos controlados cuasialeatorizados, ensayos aleatorizados grupales y resúmenes de cualquier intervención (farmacológica y no farmacológica) para la prevención de la IUR durante el embarazo (en comparación con otra intervención, placebo o atención habitual).

Obtención y análisis de los datos

Dos autores de la revisión de forma independiente evaluaron los ensayos para la inclusión y el riesgo de sesgo, extrajeron los datos y verificaron su exactitud.

Resultados principales

La revisión incluyó un ensayo con 200 mujeres y tuvo un riesgo de sesgo de moderado a alto. El ensayo comparó una dosis diaria de nitrofurantoína y la vigilancia estrecha (visita clínica regular, cultivos de orina y antibióticos cuando se encontró un cultivo positivo), con la vigilancia estrecha solamente. No se encontraron diferencias significativas para los resultados primarios: pielonefritis recurrente (riesgo relativo [RR] 0,89; intervalo de confianza [IC] del 95%: 0,31 a 2,53; un estudio, 167 mujeres), IUR antes del parto (CR 0,30; IC del 95%: 0,06 a 1,38; un estudio, 167 mujeres) y parto prematuro (antes de las 37 semanas) (RR 1,18; IC del 95%: 0,42 a 3,35; un estudio, 147 mujeres). La calidad general de la evidencia de estos resultados, evaluadas mediante los criterios GRADE, fue muy baja. No hubo diferencias significativas entre los dos grupos de comparación para los siguientes resultados secundarios, peso al nacer inferior a 2500 (g) (RR 2,03, IC del 95%: 0,53 a 7,80; un estudio, 147 lactantes), peso al nacer (diferencia de medias [DM] ‐113.00, IC del 95%: ‐327,20 a 101,20; un estudio, 147 recién nacidos), puntuación de Apgar a los cinco minutos menor de siete (RR 2,03, IC del 95%: 0,19 a 21,87; un estudio, 147 lactantes) y abortos espontáneos (RR 3,11, IC del 95%: 0,33 a 29,29; un estudio, 167 mujeres). La evidencia para estos resultados secundarios también fue de calidad muy baja. La incidencia de bacteriuria asintomática (BSA) (al menos 103 colonias por ml) (resultado secundario), solo se informó en mujeres con una tasa de asistencia al consultorio superior al 90% (RR 0,55; IC del 95%: 0,34 a 0,89; un estudio, 102 mujeres), y se redujo significativamente en las mujeres que recibieron nitrofurantoína y una vigilancia estrecha. No se informaron datos sobre la mortalidad total y los recién nacidos pequeños para la edad gestacional.

Conclusiones de los autores

No se ha demostrado que una dosis diaria de nitrofurantoína y el control estricto prevengan la IUR, en comparación con el control estricto solo. Se encontró una reducción significativa de la BAS en las pacientes con una tasa alta de asistencia al consultorio y que recibieron nitrofurantoína y control estricto. Hubo un informe limitado de los resultados primarios y secundarios para las mujeres y para los recién nacidos. No es posible establecer conclusiones con respecto a la intervención óptima para prevenir la IUR en las embarazadas. Se necesitan ensayos controlados aleatorizados que comparen diferentes intervenciones farmacológicas y no farmacológicas con el objetivo de examinar las intervenciones potencialmente efectivas para prevenir la IUR en embarazadas.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Resumen en términos sencillos

Intervenciones para la prevención de las infecciones urinarias recurrentes durante el embarazo

Las infecciones urinarias recurrentes (IUR) son frecuentes en las mujeres en general y en particular en las embarazadas. Una infección urinaria (IU) es una infección del tracto urinario (vejiga, riñones) debido a la presencia de bacterias en la orina (bacteriuria). Durante el embarazo la IU puede ser una complicación grave que se asocia con resultados adversos del embarazo para la madre y para el niño, incluido el parto prematuro y recién nacidos pequeños para la edad gestacional. Por lo tanto, es importante definir la intervención óptima para la prevención de la IUR durante el embarazo con el objetivo de mejorar los resultados del embarazo. Las intervenciones utilizadas para prevenir la IUR en las embarazadas pueden ser farmacológicas (antibióticos) o no farmacológicas (productos de arándano, acupuntura, probióticos y modificaciones conductuales). Hasta el presente se conoce poco acerca de la mejor forma de prevenir la IUR en las embarazadas.

Esta revisión identificó un estudio que incluyó a 200 embarazadas que recibieron nitrofurantoína (antibióticos) y control estricto (visitas regulares al consultorio, urocultivos y antibióticos al encontrar un cultivo positivo), o control estricto solo. No se demostró que el tratamiento de supresión con una dosis diaria de nitrofurantoína y una vigilancia estrecha impidiera la IUR en comparación con la vigilancia estrecha sola, pero la evidencia fue de calidad muy baja. Se encontró una reducción significativa de la bacteriuria asintomática (presencia de bacterias en la orina sin síntomas de IU) en las pacientes con una tasa alta de asistencia al consultorio que recibieron nitrofurantoína y control estricto. No es posible establecer conclusiones debido a la falta de evidencia. Se necesitan ensayos controlados aleatorizados futuros que comparen diferentes intervenciones farmacológicas y no farmacológicas para evaluar la intervención óptima para prevenir la IUR en las embarazadas. Dichos ensayos deben informar una amplia variedad de resultados para las mujeres y para los recién nacidos.

Authors' conclusions

Implications for practice

This review found that daily dose of nitrofurantoin and close surveillance was not more likely to prevent RUTI compared with close surveillance alone. However, a significant reduction in asymptomatic bacteriuria was found in women with a clinic attendance rate of more than 90% and who received nitrofurantoin and close surveillance. It is important to note that the results of this review were based on only one small trial with limited reporting of primary and secondary outcomes in both mother and child. Due to the lack of randomised controlled trials no conclusions can be drawn.

Implications for research

It is important to have a standard definition for RUTI in women who are pregnant. Since pregnancy is a limited period during which a UTI may be associated with increased risks for both mother and baby, the definition for RUTI should be adapted for pregnant women. A possible definition of RUTI in pregnant women may be: at least one UTI during the current pregnancy or either three UTI in the 12 months or two in six months before onset of pregnancy.

Further large trials (with sufficient power) comparing different pharmacological and non‐pharmacological interventions are needed to assess the optimal intervention to prevent RUTI in women who are pregnant. Such trials should report on a broad range outcomes for both women and infants. Given the significant differences found in the greater than 90% follow‐up group, future trials should further asses the effects of close surveillance on preventing RUTI in pregnant women

Summary of findings

Open in table viewer
Summary of findings for the main comparison. Nitrofurantoin and close surveillance compared with close surveillance alone for preventing recurrent urinary tract infection during pregnancy

Nitrofurantoin and close surveillance compared with close surveillance alone for preventing recurrent urinary tract infection during pregnancy

Patient or population: pregnant women with a history of one or more UTI before or during pregnancy
Settings: Los Angeles, USA.
Intervention: nitrofurantoin and close surveillance
Comparison: close surveillance alone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Close surveillance alone

Nitrofurantoin and close surveillance

Recurrent pyelonephritis

Study population

RR 0.89
(0.31 to 2.53)

167
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

82 per 1000

73 per 1000
(26 to 208)

Moderate

82 per 1000

73 per 1000
(26 to 208)

Recurrent UTI (cystitis)

Study population

RR 0.30
(0.06 to 1.38)

167
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

82 per 1000

25 per 1000
(5 to 114)

Moderate

82 per 1000

25 per 1000
(5 to 114)

Preterm birth (< 37 weeks)

Study population

RR 1.18
(0.42 to 3.35)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

81 per 1000

96 per 1000
(34 to 272)

Moderate

81 per 1000

96 per 1000
(34 to 272)

Birthweight < 2500 (g)

Study population

RR 2.03
(0.53 to 7.80)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

41 per 1000

82 per 1000
(21 to 316)

Moderate

41 per 1000

82 per 1000
(21 to 316)

Birthweight (g)

The mean birthweight (g) in the control group was 0

The mean birthweight (g) in the intervention group was 113 lower (327.2 lower to 101.2 higher)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

Five‐minute Apgar score < seven

Study population

RR 2.03
(0.19 to 21.87)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,4

14 per 1000

27 per 1000
(3 to 296)

Moderate

14 per 1000

27 per 1000
(3 to 295)

Miscarriages

Study population

RR 3.11
(0.33 to 29.29)

167
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,4

12 per 1000

37 per 1000
(4 to 345)

Moderate

12 per 1000

37 per 1000
(4 to 346)

*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).
CI: Confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1One study with design limitations (‐1)

2One study of small sample size and few events. Wide CI crossing the line of no effect (‐2)

3One study of small sample size. Wide CI (‐1)

4One study of small sample size. Wide CI crossing the line of no effect (‐2)

Background

Description of the condition

Recurrent urinary tract infections (RUTI) are a common healthcare problem in women generally and particularly in pregnant women. Up to 30% of women who are not pregnant experience at least one recurrence within a year after the initial infection (Foxman 1990; Hooton 2001; Mabeck 1972; Scholes 2000). A urinary tract infection (UTI) is an infection of the urinary tract which can be divided in lower and upper UTI based on the location of the infection. A lower UTI is an infection of the bladder and results in a combination of significant bacteriuria and symptoms such as dysuria (painful urination) and frequency. In practice the diagnosis of UTI is often based on clinical symptoms alone. An upper UTI or pyelonephritis is an infection of the kidney accompanied by symptoms such as fever and renal tenderness. Asymptomatic bacteriuria (ASB) is significant bacteriuria without symptoms of a UTI (Schnarr 2008; Sobel 2014).

A UTI during pregnancy may be a serious complication as it is associated with adverse pregnancy outcomes for both mother and child (Anderson 2007; Bánhidy 2007; Dimetry 2007; Savage 1967; Schieve 1994; Sheiner 2009; Vazquez 2011). Important complications include preterm birth and small‐for‐gestational‐age babies (Dimetry 2007; Lang 1996; Mazor‐Dray 2009), although an association between UTI and preterm birth and small‐for‐gestational‐age babies has not been clearly established (Bánhidy 2007; Chen 2010; Dimetry 2007; Mann 2009; Mazor‐Dray 2009). Associations seen between UTI and adverse pregnancy outcomes in older studies (before the 1970s) may no longer be as evident with the advent of more antibiotic prescriptions (Bánhidy 2007; Savage 1967). While causal mechanisms remain unknown, there is evidence supporting the important role that prostaglandins, stimulated by bacterial and host signals following an infection, play in inducing preterm labour (Olson 2003; Romero 1988).

The exact incidence of symptomatic UTI in women who are pregnant is unknown (Gilstrap 2001). Two studies report an incidence between 1% to 2.3% during pregnancy for their particular population (Harris 1981; Mazor‐Dray 2009). Pyelonephritis (infection of the kidney) occurs in 2% of pregnancies, with a recurrence rate up to 23% within the same pregnancy or soon after the birth (Gilstrap 1981; McCormick 2008).

Some international guidelines recommend screening and treating ASB in women who are pregnant to prevent UTI and possible adverse pregnancy outcomes (U.S. Preventive Services Task Force 2008). This policy is followed by many countries and might have had an impact on the recently described incidences of both UTI and RUTI during pregnancy.

Varying definitions of RUTI exist, especially in pregnant women. In non‐pregnant women RUTI is frequently defined as three episodes of UTI in the previous 12 months, or two episodes in the last six months (Epp 2010; Foster 2008; Gopal 2007). For this review we used the following criteria for RUTI: pregnant women with a history of one or more UTI before or during pregnancy. We decided to include women with only one UTI as well because one UTI during pregnancy can be a reason to start prophylaxis during pregnancy both in practice and for research trials. Most UTI recurrences occur in the first three months following the initial infection (Foxman 1990). In studies on RUTI in pregnant women, one episode of UTI during pregnancy is often an indication to start prophylaxis to prevent RUTI (Harris 1974; Pfau 1992).

Uropathogens, generally originating in the rectal flora, may cause a UTI when they ascend to the bladder after they colonise the urethra and the periurethral area. The pathogenesis of a UTI in women who are suffering from RUTI is considered comparable with a single infection in women without a history of RUTI (Hooton 2010; Kodner 2010). In RUTI, uropathogens possibly recolonise the bladder after treatment because they are not eliminated from the rectal flora (Hooton 2001). E. coli is the most common UTI uropathogen (Kodner 2010; Sobel 2014). Particularly in the presence of structural abnormalities of the urinary tract, the following organisms are associated with RUTI: Proteus, Pseudomonas, Klebsiella and by Enterobacter spp. and enterococci and staphylococci (Sobel 2014).

There are four patterns of response of bacteriuria to therapy: cure, bacteriologic persistence, bacteriologic relapse or reinfection. Bacteriologic persistence is persistence of bacteriuria with the same microorganism after 48 hours of treatment (Sobel 2014). Relapse is an infection with the same microorganism that caused initial infection and usually occurs within one to two weeks after the cessation of treatment. A relapse indicates that the infecting organism has persisted in the urinary tract. Reinfection is an infection after sterilisation of the urine. Most of the time there is a change in bacterial species. Reinfection can be defined as a 'true' recurrence. Both persistence and relapse may be related to inadequate treatment (Hooton 2010; Sobel 2014). Although relapse and reinfection are two distinct outcomes, they both can be grouped under the wider outcome of recurrence.

During pregnancy, up to 90% of the women develop dilatation of the collecting system (ureters and renal pelvis) and decreased peristalsis of the ureters and bladder, which may facilitate bacterial colonisation and ascending infection due to urinary stasis (Brown 1991; Grenier 2000; McCormick 2008).

The main risk factors for RUTI in premenopausal women are: the age at first UTI (less than 15 years of age indicates a greater risk of RUTI), a family history of UTI in their mother, frequency of sexual intercourse, the use of spermicides and new sexual partners (Hooton 1996; Hooton 2001; Perotta 2008; Scholes 2000). In women who are pregnant, a high parity is a risk factor for UTI (Dwyer 2002; Haider 2010).

Description of the intervention

Interventions used to prevent RUTI in pregnant women can be pharmacological or non‐pharmacological. Pharmacological interventions consist of antibiotics that may be prescribed in different ways to prevent RUTI, continuous prophylaxis, post‐coital prophylaxis and patient‐initiated therapy based on symptoms of a UTI. The non‐pharmacological interventions include cranberries (juice or tablets), probiotics, acupuncture and behavioural modifications such as frequent and complete voiding, voiding after sexual intercourse, liberal fluid intake, and wiping techniques. Other potential interventions, such as vaccines and bacterial interference where one bacterial strain prevents colonisation with another strain and topical application of carbohydrates, are still under development (Epp 2010).

How the intervention might work

Various antibiotic regimens, used as a continuous or as post‐coital prophylaxis, reduce the number of RUTI in women who are not pregnant (Albert 2008; Hooton 2010; Pfau 1992). The effect of post‐coital prophylaxis is related to frequency of sexual intercourse and mostly results in less antibiotic use in comparison with daily prophylaxis (Hooton 2001; Hooton 2010). Antibiotics may cause adverse effects such gastrointestinal symptoms and vaginal and oral candidiasis (Albert 2008; Epp 2010). Furthermore, not all antibiotics used as prophylaxis for RUTI in non‐pregnant women may be safe during pregnancy. Because of this, women who are pregnant often prefer not to use antibiotics during their pregnancy. In addition, the number of drug‐resistant bacteria is increasing, which may influence the potential prophylactic effect of different antibiotics in the future. Different antibiotics such as nitrofurantoin, amoxicillin and fosfomycin have been used to treat primary UTI in women who are pregnant (Vazquez 2011). Antibiotic effect depends on the concentration of the antimicrobial agent achieved in the urine in conjunction with the sensitivity of the organism(s) to that antibiotic (Sobel 2014).

Cranberry products (mainly juice) have been used as an intervention to prevent RUTI for decades. It has been shown in vitro that cranberries prevent bacteria adhering to the uro‐epithelial cells in the bladder (Jepson 2012; Zafiri 1989). Without adhesion the bacteria are unable to cause a UTI (Jepson 2012; Zafiri 1989). In some of the published studies on cranberries in pregnant and non‐pregnant women, there have been significant withdrawals or losses to follow‐up (Jepson 2012). Nausea and vomiting due to physiologic changes in pregnancy can further decrease adherence (Wing 2008). A trial in non‐pregnant premenopausal women showed that antibiotics (trimethoprim‐sulfamethoxazole) once daily is more effective in preventing RUTI than cranberry capsules twice daily, at the expense of emerging antibiotic resistance (Beerepoot 2011). Finally a recent cochrane review on 'Cranberries for preventing urinary tract infections' that included two studies in pregnant women concluded that more studies to assess the effectiveness of cranberry juice need ‘strong justification’ since the benefit is likely to be small especially in combination with poor adherence. Only in women with RUTI more studies of other cranberry products such as tablets and capsules may be useful (Jepson 2012).

Two small randomised controlled trials (with unclear risk of selection bias) have compared acupuncture with no treatment to prevent RUTI in women who are not pregnant. Both showed significant results in preventing RUTI (Alreak 2002; Aune 1998).

It is suggested that some Lactobacillus species prevent uropathogen colonisation of the vagina, a necessary step in ascending infection of the bladder. Studies show that certain Lactobacillus species can be given orally or vaginally and reduce RUTI through colonisation of the vagina and reducing vaginal coliform counts (Czaja 2007; Reid 2003). In postmenopausal women the use of lactobacilli capsules twice daily seems nearly as effective in preventing RUTI as the use of antibiotics once daily, without increase of antibiotic resistance (Beerepoot 2012).

Although behavioural modifications are unlikely to be harmful in women who are not pregnant, little information is available that these interventions actually work. Sexually active women who use spermicide while suffering from RUTI are recommended to use an alternative form of contraception (Epp 2010). Spermicide use increases the risk of colonisation of the vaginal and periurethral area with uropathogens and increases the adherence of E. coli to vaginal epithelial cells (Sobel 2014). Behavioural modifications may often be combined with other interventions (Epp 2010).

Why it is important to do this review

There are two Cochrane reviews on prevention of UTI, both in women. (Albert 2008; Jepson 2012). One of these reviews included two studies in pregnant women (Jepson 2012). The results described in the Cochrane review 'Antibiotics for preventing recurrent urinary tract infections in non‐pregnant women' show that continuous antibiotic prophylaxis for six to 12 months reduced the rate of UTI during prophylaxis when compared with placebo. However, women who used antibiotic prophylaxis had more adverse effects (Albert 2008). The results described in the updated Cochrane review 'Cranberries for preventing urinary tract infections' demonstrate that cranberry juice was not as effective as previously indicated and did not decrease the number of symptomatic UTIs over a 12‐month period. Besides, the authors conclude that cranberry juice may not be acceptable over long periods of time because there were large numbers of dropouts (Jepson 2012). A Cochrane protocol on 'Probiotics for preventing urinary tract infections in adults and children' will include studies in women who are pregnant (Schwenger 2010).

Preterm birth, one of the possible serious complications of a UTI during pregnancy, is the main cause of neonatal mortality and morbidity worldwide. The costs of preterm birth are enormous. These costs are mainly associated with intensive care for the neonates (Armstrong 2007; Clements 2007; Gilbert 2003). Prevention of RUTI and UTI will improve maternal and infant health and reduce the risk of preterm birth.

Different approaches have been proposed for prevention of RUTI in women who are not pregnant and include the use of low‐dose antibiotic prophylaxis daily or post‐coitally in sexually active women and non‐pharmacological therapies such as voiding after sexual intercourse or ingestion of cranberry juice (Albert 2008). Little is known about the best way to prevent RUTI in pregnant women, especially as not all approaches used in non‐pregnant women are applicable. Therefore, it is important to define the optimal interventions for preventing RUTI during pregnancy to improve pregnancy outcomes.

Objectives

To assess the effects of interventions for preventing recurrent urinary tract infections in pregnant women.

Methods

Criteria for considering studies for this review

Types of studies

We planned to include all published, unpublished and ongoing randomised controlled trials (RCTs), quasi‐RCTs and clustered‐randomised trials of interventions aimed at preventing recurrent urinary tract infections (RUTI) during pregnancy. In future updates we will also include abstracts where sufficient information is available. Abstracts containing limited information will be classified as 'awaiting assessment' until further information can be obtained.

Types of participants

Pregnant women with a history of one or more urinary tract infections (UTI) before or during pregnancy.

Types of interventions

Any intervention (pharmacological and non‐pharmacological) for preventing recurrent urinary tract infection (RUTI) during pregnancy (compared with another intervention, placebo or with usual care).

Types of outcome measures

Primary outcomes
Maternal

  • RUTI before birth (variously defined e.g. recurrent pyelonephritis, recurrent cystitis)

  • Preterm birth (less than 37 weeks)

Infant

  • Small‐for‐gestational age

  • Total mortality (including stillbirth and babies born alive who die prior to primary hospital discharge)

Secondary outcomes
Recurrences

  • Proportion of pregnant women who experienced at least one UTI, identified using clinical criteria (dysuria)

  • Proportion of pregnant women who experienced at least one UTI, using microbiological criteria

  • Number of UTI per woman during index pregnancy, identified using clinical criteria (e.g. dysuria, fever)

  • Number of UTI per woman during index pregnancy, using microbiological criteria

  • Number of pregnant women who were admitted antenatally because of a UTI

Pregnancy and delivery (complications)

Maternal

  • Maternal death

  • Miscarriage

  • Antenatal pyrexia requiring the use of antibiotics

  • Asymptomatic bacteriuria (ASB) (variously defined)

  • Prelabour rupture of the membranes

  • Eclampsia/pre‐eclampsia (variously defined)

  • Induction of labour

  • Mode of birth (normal vaginal birth, operative vaginal birth, caesarean section)

  • Intrapartum fever requiring the use of antibiotics

  • Postpartum infection requiring the use of antibiotics

  • Postpartum haemorrhage

  • Chorioamnionitis (variously defined)

  • Postpartum fever requiring the use of antibiotics

  • Adverse effects of interventions (nausea, vomiting, diarrhoea)

  • Proportion of women who had severe adverse effects (defined as those requiring withdrawal of treatment)

  • Women's satisfaction with treatment

 Infants

  • Stillbirths (variously defined)

  • Death of liveborn infants prior to hospital discharge

  • Gestational age at birth

  • Preterm birth less than 34 weeks’ gestation

  • Birthweight

  • Birthweight < 2500 (g) (not prespecified)

  • Birth centile (below 10th centile)

  • Small‐for‐gestational age

  • Five‐minute Apgar score less than seven

  • Chronic lung disease (variously defined)

  • Intraventricular haemorrhage (variously defined)

  • Periventricular leukomalacia

  • Necrotising enterocolitis (variously defined)

  • Respiratory distress syndrome (variously defined)

  • Hyperbilirubinaemia requiring treatment

  • Neonatal convulsions

  • Early neonatal infection requiring antibiotics (less than 48 hours)

  • Hypoxic ischaemic encephalopathy

  • Neonatal encephalopathy

  • Composite of severe neonatal morbidity (variously defined)

Use of resources, e.g. and/or costs utilisation

  • Antenatal admission of the mother

  • Days of antenatal admission of the mother

  • Admission to a neonatal intensive care unit

  • Days of admission to a neonatal intensive care unit

  • Admission to nursery care

  • Costs of interventions

  • Additional visits to clinicians

  • Costs to women and families for extra care

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 (20 May 2015).

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE (Ovid);

  3. weekly searches of Embase (Ovid);

  4. monthly searches of CINAHL (EBSCO);

  5. handsearches of 30 journals and the proceedings of major conferences;

  6. 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

In addition, we searched the reference lists of retrieved articles We did not apply any language or date restrictions to the search and in future updates, we will attempt to obtain translations of papers when necessary.

Data collection and analysis

For methods used in the previous version of this review, seeSchneeberger 2012.

Assessment of the quality of the evidence

For this update, no new reports were identified for assessment but we assessed the quality of evidence of the existing study using the GRADE approach (Schunemann 2009) in order to assess the quality of the body of evidence relating to the following outcomes for the comparison 'nitrofurantoin and close surveillance versus close surveillance alone'.

  1. Recurrent pyelonephritis

  2. Recurrent UTI (cystitis)

  3. Preterm birth (≤ 37 weeks)

  4. Birthweight < 2500 (g)

  5. Birthweight (g)

  6. Five‐minute Apgar score less than seven

  7. Miscarriages

We used GRADEprofiler (GRADEpro 2014) to import data from Review Manager 5.3 (RevMan 2014) in order to create a 'Summary of findings' table. A summary of the intervention effect and a measure of quality for each of the above outcomes has been 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 was 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.

In future updates, if new reports are identified, we will use the methods described in Appendix 1.

Results

Description of studies

Results of the search

The search of the Cochrane Pregnancy and Childbirth Group's Trials Register retrieved two reports relating to one trial eligible for consideration. This trial (involving 200 women) was included in the review (Lenke 1983).

Included studies

Only one trial, performed in Los Angeles, USA with 200 pregnant women was identified that met the inclusion criteria (Lenke 1983). In this study, nitrofurantoin 50 mg three times daily and close surveillance (regular clinic visit, urine cultures and antibiotics when a positive culture was found) was compared with close surveillance only to prevent recurrent urinary tract infections (RUTI) in women who were pregnant and were admitted for pyelonephritis earlier during the index pregnancy. Close surveillance consisted of a visit every two weeks to a special clinic and after 36 weeks, a weekly visit until birth. At each visit a clean‐catch, mid voided urine was obtained for a routine culture and nitrite testing. When necessary, treatment was provided.

Excluded studies

There are no excluded studies.

Risk of bias in included studies

See Figure 1 and Figure 2 for a summary of the 'Risk of bias' assessment.


'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.


'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

In the one included study (Lenke 1983), a random number table was used to generate the sequence, which we considered a low risk of bias. The method of treatment allocation was unclear.

Blinding

No placebos were used and the care providers and the participants were not blinded. The 'Risk of bias' assessment was considered low for the culture results and delivery outcomes. Overall, we considered the risk of bias for performance and detection bias to be unclear.

Incomplete outcome data

There were 18 post‐randomisation losses to follow‐up in the nitrofurantoin and close surveillance group and 15 in close surveillance only group. No data about post randomisation data exclusions were reported. The outcome birthweight of infants was not available for 11 (13.4%) women in the nitrofurantoin group and close surveillance and for nine (10.6%) in the close surveillance only group. The outcomes of birthweight < 2500 (g), preterm birth (before 37 weeks) and five‐minute Apgar score less than seven were not available in nine (11.0%) of the women who received nitrofurantoin and close surveillance and 11 (12.9%) of the women who received close surveillance only.

Selective reporting

No data were reported on the following primary outcomes: total infant mortality and small‐for‐gestational‐age babies. Furthermore, only a small number of secondary outcomes were reported. Overall, we considered this domain to have a high risk of bias.

Other potential sources of bias

No obvious risk of other potential sources of bias for the included studies was apparent.

Effects of interventions

See: Summary of findings for the main comparison Nitrofurantoin and close surveillance compared with close surveillance alone for preventing recurrent urinary tract infection during pregnancy

This review included one trial (Lenke 1983) involving 200 women.

Nitrofurantoin and close surveillance versus close surveillance alone

Primary outcomes

Lenke 1983 found no differences in women who developed recurrent pyelonephritis (upper UTI) (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.31 to 2.53; one study, 167 women) (Analysis 1.1), or RUTI before birth (RR 0.30, 95% CI 0.06 to 1.38; one study, 167 women) (Analysis 1.2), and preterm birth (before 37 weeks) (RR 1.18, 95% CI 0.42 to 3.35; one study, 147 women) (Analysis 1.3) between nitrofurantoin and close surveillance and close surveillance only. Data on total mortality and small‐for‐gestational‐age babies were not reported.

Secondary outcomes

The only secondary outcomes reported were birthweight less than 2500 (g) (RR 2.03, 95% CI 0.53 to 7.80; one study, 147 infants) (Analysis 1.4), birthweight (mean difference (MD) ‐113.00, 95% CI ‐327.20 to 101.20; one study, 147 infants) (Analysis 1.5), five‐minute Apgar score less than seven (RR 2.03, 95% CI 0.19 to 21.87; one study, 147 infants) (Analysis 1.6), and miscarriages (RR 3.11, 95% CI 0.33 to 29.29; one study, 167 women) (Analysis 1.7). There were no significant differences between the two comparison groups for any of these outcomes.

In women who received nitrofurantoin and close surveillance, the incidence of ASB defined as positive cultures with at least 103 colonies per mL is only reported in women with more than 90% clinic attendance rate (RR 0.55, 95% CI 0.34 to 0.89; one study, 102 women) (Analysis 1.8) and showed a significant reduction of asymptomatic positive cultures for women in the nitrofurantoin and close surveillance versus close surveillance alone. No symptomatic recurrences were seen in women with more than 90% clinic attendance rate.

Several secondary outcomes including stillbirth and maternal deaths were not reported.

Discussion

Summary of main results

In this review we found no significant differences between a combination of suppressive therapy with a daily dose of nitrofurantoin and close surveillance and close surveillance alone in preventing recurrent urinary tract infections (RUTI). Only sub‐analyses in women with more than 90% follow‐up show a decreased incidence of asymptomatic bacteriuria (ASB) in women who received nitrofurantoin and close surveillance compared with close surveillance only. Since only one study was included no other interventions to prevent RUTI in pregnant women were assessed.

Overall completeness and applicability of evidence

The evidence for interventions preventing RUTI in pregnant women is incomplete. This review included only one relatively old (1983) trial involving 200 pregnant women with limited reporting of primary and secondary outcomes for both women and infants. Due to lack of randomised controlled trials (RCTs), no conclusions can be drawn regarding the optimal intervention to prevent RUTI in women who are pregnant.

Quality of the evidence

The included trial had moderate to high risk of bias. GradePro software was used to assess the quality of evidence for the main comparison 'nitrofurantoin and close surveillance versus close surveillance alone' for the outcomes listed above.The evidence was of very low quality for all outcomes "recurrent pyelonephritis, RUTI (cystitis), preterm birth (≤ 37 weeks), birthweight < 2500 (g), birthweight (g), five‐minute Apgar score less than seven, and miscarriages". Downgrading of evidence was based on including one small study with design limitations and imprecise results 'wide confidence interval (CI) crossing the line of no effect'.

Potential biases in the review process

Data extraction and assessment of risk of the included study was independently performed by two authors to minimise bias. A third review author was contacted when consensus was not reached. This review only includes one study therefore all conclusions need to be considered with caution. We are not aware of other potential biases in the review process.

Agreements and disagreements with other studies or reviews

Following the results of this review, suppressive therapy with a daily dose of nitrofurantoin and close surveillance has not been shown to prevent RUTI compared with close surveillance alone. These results are not consistent with a Cochrane review on antibiotics to prevent urinary tract infection (UTI) in women who are not pregnant, which showed that continuous antibiotic prophylaxis for six to 12 months reduced the rate of UTI during prophylaxis when compared with placebo (Albert 2008). In the latter review, the authors did not compare antibiotics with non‐pharmacological interventions such as close surveillance. Moreover, more adverse effects were seen in the antibiotic group including vaginal itching and nausea. These side effects are not desirable in pregnant women since both are already more frequent during pregnancy.

Little is known about the effect of close surveillance on preventing RUTI. Lenke 1983 reported that all of the symptomatic recurrences occurred in patients who either had poor clinic attendance and subsequent lack of follow‐up urine cultures or were not treated when gram‐negative organisms (mainly uropathogens) were found in their urine. These results explain that close surveillance itself already may have an effect on preventing RUTI in pregnant women.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 1

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 1 Recurrent pyelonephritis.
Figuras y tablas -
Analysis 1.1

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 1 Recurrent pyelonephritis.

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 2 Recurrent UTI (cystitis).
Figuras y tablas -
Analysis 1.2

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 2 Recurrent UTI (cystitis).

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 3 Preterm birth (< 37 weeks).
Figuras y tablas -
Analysis 1.3

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 3 Preterm birth (< 37 weeks).

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 4 Birthweight < 2500 (g) (not prespecified).
Figuras y tablas -
Analysis 1.4

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 4 Birthweight < 2500 (g) (not prespecified).

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 5 Birthweight (g).
Figuras y tablas -
Analysis 1.5

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 5 Birthweight (g).

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 6 Five‐minute Apgar score < seven.
Figuras y tablas -
Analysis 1.6

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 6 Five‐minute Apgar score < seven.

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 7 Miscarriages.
Figuras y tablas -
Analysis 1.7

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 7 Miscarriages.

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 8 Asymptomatic bacteriuria in women with 90% clinical attendance.
Figuras y tablas -
Analysis 1.8

Comparison 1 Nitrofurantoin and close surveillance versus close surveillance alone, Outcome 8 Asymptomatic bacteriuria in women with 90% clinical attendance.

Summary of findings for the main comparison. Nitrofurantoin and close surveillance compared with close surveillance alone for preventing recurrent urinary tract infection during pregnancy

Nitrofurantoin and close surveillance compared with close surveillance alone for preventing recurrent urinary tract infection during pregnancy

Patient or population: pregnant women with a history of one or more UTI before or during pregnancy
Settings: Los Angeles, USA.
Intervention: nitrofurantoin and close surveillance
Comparison: close surveillance alone

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Close surveillance alone

Nitrofurantoin and close surveillance

Recurrent pyelonephritis

Study population

RR 0.89
(0.31 to 2.53)

167
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

82 per 1000

73 per 1000
(26 to 208)

Moderate

82 per 1000

73 per 1000
(26 to 208)

Recurrent UTI (cystitis)

Study population

RR 0.30
(0.06 to 1.38)

167
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

82 per 1000

25 per 1000
(5 to 114)

Moderate

82 per 1000

25 per 1000
(5 to 114)

Preterm birth (< 37 weeks)

Study population

RR 1.18
(0.42 to 3.35)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

81 per 1000

96 per 1000
(34 to 272)

Moderate

81 per 1000

96 per 1000
(34 to 272)

Birthweight < 2500 (g)

Study population

RR 2.03
(0.53 to 7.80)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,2

41 per 1000

82 per 1000
(21 to 316)

Moderate

41 per 1000

82 per 1000
(21 to 316)

Birthweight (g)

The mean birthweight (g) in the control group was 0

The mean birthweight (g) in the intervention group was 113 lower (327.2 lower to 101.2 higher)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3

Five‐minute Apgar score < seven

Study population

RR 2.03
(0.19 to 21.87)

147
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,4

14 per 1000

27 per 1000
(3 to 296)

Moderate

14 per 1000

27 per 1000
(3 to 295)

Miscarriages

Study population

RR 3.11
(0.33 to 29.29)

167
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,4

12 per 1000

37 per 1000
(4 to 345)

Moderate

12 per 1000

37 per 1000
(4 to 346)

*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).
CI: Confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1One study with design limitations (‐1)

2One study of small sample size and few events. Wide CI crossing the line of no effect (‐2)

3One study of small sample size. Wide CI (‐1)

4One study of small sample size. Wide CI crossing the line of no effect (‐2)

Figuras y tablas -
Summary of findings for the main comparison. Nitrofurantoin and close surveillance compared with close surveillance alone for preventing recurrent urinary tract infection during pregnancy
Comparison 1. Nitrofurantoin and close surveillance versus close surveillance alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Recurrent pyelonephritis Show forest plot

1

167

Risk Ratio (M‐H, Fixed, 95% CI)

0.89 [0.31, 2.53]

2 Recurrent UTI (cystitis) Show forest plot

1

167

Risk Ratio (M‐H, Fixed, 95% CI)

0.30 [0.06, 1.38]

3 Preterm birth (< 37 weeks) Show forest plot

1

147

Risk Ratio (M‐H, Fixed, 95% CI)

1.18 [0.42, 3.35]

4 Birthweight < 2500 (g) (not prespecified) Show forest plot

1

147

Risk Ratio (M‐H, Fixed, 95% CI)

2.03 [0.53, 7.80]

5 Birthweight (g) Show forest plot

1

147

Mean Difference (IV, Fixed, 95% CI)

‐113.0 [‐327.20, 101.20]

6 Five‐minute Apgar score < seven Show forest plot

1

147

Risk Ratio (M‐H, Fixed, 95% CI)

2.03 [0.19, 21.87]

7 Miscarriages Show forest plot

1

167

Risk Ratio (M‐H, Fixed, 95% CI)

3.11 [0.33, 29.29]

8 Asymptomatic bacteriuria in women with 90% clinical attendance Show forest plot

1

102

Risk Ratio (M‐H, Fixed, 95% CI)

0.55 [0.34, 0.89]

Figuras y tablas -
Comparison 1. Nitrofurantoin and close surveillance versus close surveillance alone