Nicola Austin1, Brian A Darlow2, William McGuire3
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1NICU, Christchurch Womens Hospital, Christchurch, New Zealand
2Department of Paediatrics, Christchurch School of Medicine, CHRISTCHURCH, New Zealand
3Centre for Reviews and Dissemination, Hull York Medical School, York, UK
Citation example: Austin N, Darlow BA, McGuire W. Prophylactic oral/topical non-absorbed antifungal agents to prevent invasive fungal infection in very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD003478. DOI: 10.1002/14651858.CD003478.pub3.
NICU
Christchurch Womens Hospital
Christchurch
New Zealand
E-mail: nicola.austin@cdhb.govt.nz
| Assessed as Up-to-date: | 14 July 2009 |
|---|---|
| Date of Search: | 30 April 2009 |
| Next Stage Expected: | 14 July 2011 |
| Protocol First Published: | Issue 1, 2002 |
| Review First Published: | Issue 1, 2004 |
| Last Citation Issue: | Issue 4, 2009 |
| Date / Event | Description |
|---|---|
| 04 June 2009 Updated | This updates the review "Prophylactic oral antifungal agents to prevent systemic candida infection in preterm infants" published in the Cochrane Database of Systematic Reviews, Issue 1, 2004 (Austin 2004). Updated search identified one new study for inclusion (Ozturk 2006).Total number of participants included in evaluation of primary outcomes increased from 667 to 1646. |
| 04 June 2009 New citation: conclusions changed | Substantive update. |
| Date / Event | Description |
|---|---|
| 04 November 2008 Amended | Converted to new review format. |
| 14 October 2007 New citation: conclusions changed | Substantive amendment |
Invasive fungal infection is an important cause of mortality and morbidity in very preterm (< 32 weeks gestation) or very low birth weight (VLBW) infants. Clinical uncertainly exists about the effect of prophylactic oral/topical non-absorbed antifungals to reduce mucocutaneous colonisation and so limit the risk of invasive fungal infection in this population.
To assess the effect of prophylactic oral/topical non-absorbed antifungal therapy on the incidence of invasive fungal infection, mortality and morbidity in VLBW infants.
The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 - May 2009), EMBASE (1980 - May 2009), conference proceedings, and previous reviews.
Randomised controlled trials that compared the effect of prophylactic oral/topical non-absorbed antifungal therapy versus placebo or no drug or another antifungal agent or dose regimen in very preterm or VLBW infants.
Data were extracted using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and data extraction by each review author and synthesis of data using relative risk (RR) and risk difference (RD) and weighted mean difference (WMD).
Three trials, in which a total of 1625 infants participated, have compared oral/topical non-absorbed antifungal prophylaxis (nystatin or miconazole) with placebo or no drug. These trials had various methodological weaknesses including quasi-randomisation, lack of allocation concealment, and lack of blinding of intervention and outcomes assessment. The incidence of invasive fungal infection was very high in the control groups of two of the included trials. Meta-analysis found a statistically significant reduction in the incidence of invasive fungal infection [typical RR 0.19 (95% confidence interval (CI) 0.14, 0.27); typical RD -0.19 (95% CI -0.22,-0.16)] but substantial statistical heterogeneity was detected. A statistically significant effect on mortality was not found [typical RR 0.88 (95% CI 0.72, 1.06); typical RD -0.02 (95% CI -0.06, 0.01)]. Long-term outcomes were not assessed by any of the trials.
One small trial (N = 21) that assessed the effect of oral/topical non-absorbed antifungal prophylaxis (nystatin) compared with systemic antifungal (fluconazole) prophylaxis was underpowered to exclude important clinical effects.
The finding of a reduction in risk of invasive fungal infection in infants treated with oral/topical non-absorbed antifungal prophylaxis should be interpreted cautiously because of methodological weaknesses in the included trials. Further large randomised controlled trials in current neonatal practice settings are needed to resolve this uncertainty. These trials might compare oral/topical non-absorbed antifungal agents with placebo, with each other, or with systemic antifungal agents and should include an assessment of effect on long-term neurodevelopmental outcomes.
Fungi such as candida (the organism that causes thrush) can cause severe infections in very low birth weight (VLBW) infants (birth weight less than 1.5 kilograms). These infections are often difficult to diagnose and frequently cause death or disability. Therefore, it may be appropriate to attempt to prevent such infections by giving VLBW infants antifungal drugs as a routine part of their care. This review assessed the effect of giving VLBW infants antifungal drugs that reduce skin and gut carriage of fungi to minimise the chances of a severe infection developing. The trials that were identified suggested that this treatment might reduce severe infection rates but there was no evidence that death rates were reduced. Larger and higher quality trials are needed to resolve this uncertainty.
Invasive fungal infection accounts for 10% of all cases of nosocomial sepsis in very preterm or very low birth weight (VLBW) infants (Stoll 2002). The reported mortality rates of greater than 25% are higher than those attributed to nosocomial bacterial infection in VLBW infants (Benjamin 2003; Makhoul 2002; Saiman 2000; Stoll 2002). Invasive fungal infection is also associated with short and long-term morbidity, including adverse neurodevelopmental outcomes (Benjamin 2006; Lee 1998; Friedman 2000; Saiman 2000).
The overall incidence of invasive fungal infection in VLBW infants is between about 1% and 4% but the risk of infection is inversely related to gestational age and birth weight. In extremely preterm or extremely low birth weight (ELBW) infants, reported incidences are between about 2% and 8%. Much higher incidences, up to 20%, have been reported for infants of birth weight less than 750 grams or gestational age at birth less than 26 weeks (Clerihew 2006; Horbar 2002; Karlowicz 2002; Makhoul 2002; Saiman 2000).
Observational studies suggest that mucocutaneous or endotracheal fungal colonisation is a risk factor for invasive infection (Faix 1989; Huang 1998; Pappu-Katikaneni 1990; Rowen 1994). However, multivariate analyses that account for potential confounding variables, particularly ELBW, have not confirmed this association (Saiman 2000). Other putative risk factors for invasive fungal infection in VLBW infants include severity of illness at birth, the use of multiple courses of antibiotics (particularly third-generation cephalosporins), the use of parenteral nutrition, the presence of a central venous catheter, and exposure to histamine receptor subtype 2 antagonists (Rowen 1994; Benjamin 2006; Cotton 2006; Manzoni 2006).
The clinical presentation of invasive fungal infection in VLBW infants is similar to that of bacterial sepsis and this may cause delays in diagnosis and treatment. The diagnosis may be further delayed due to an inability to recover the organism from microbiological culture of blood, cerebrospinal fluid, or urine. A high index of suspicion and the use of additional laboratory and clinical tests may be needed to confirm the suspected diagnosis (Benjamin 2003).
Given the difficulty in establishing an early diagnosis and the high level of associated morbidity and mortality, there is a need to assess the effect of strategies to prevent invasive fungal infection in VLBW infants (Brecht 2009). In addition to generic infection control practices and avoidance of modifiable risk factors, two broad chemoprophylactic strategies are employed in current clinical practice (Burwell 2006; Clerihew 2008; Ganesan 2008; Howell 2009):
This review focusses on randomised comparisons of oral/topical non-absorbed antifungal prophylaxis compared with no antifungal prophylaxis or compared with systemic antifungal prophylaxis. The effect of systemic antifungal prophylaxis compared with no prophylaxis is addressed in another Cochrane review (Clerihew 2007).
To assess the effect of prophylactic oral/topical non-absorbed antifungal therapy on the incidence of invasive fungal infection, mortality and adverse neurodevelopmental outcomes in very preterm or VLBW infants.
The effects of the following interventions were examined:
The following subgroup analyses were pre-specified:
Randomised or quasi-randomised controlled trials, including cluster randomised trials.
VLBW infants (< 1500 grams) or very preterm infants (< 32 weeks' gestation at birth).
Antifungal prophylaxis with oral/topical non-absorbed drugs vs. placebo/nothing or another oral/topical antifungal regimen.
1. Confirmed invasive fungal infection as determined by
a. culture of fungus from a normally sterile site: cerebrospinal fluid, blood, urine, bone or joint, peritoneum, pleural space. Samples should have been collected using methods to minimise contamination with surface colonising organisms.
b. findings on autopsy examination consistent with invasive fungal infection
c. findings on ophthalmological examination consistent with fungal ophthalmitis or retinitis
d. pathognomonic findings on renal ultrasound examination: "renal fungal balls"
2. Death prior to hospital discharge
3. Neurodevelopmental outcomes during infancy and beyond using validated assessment tools: neurological evaluations, developmental scores, and classifications of disability, including auditory and visual disability
1. Other morbidity: Duration of mechanical ventilation or oxygen administration, incidence of bronchopulmonary dysplasia (oxygen supplementation at 36 weeks' postmenstrual age), incidence of retinopathy, duration of hospital or intensive care unit admission.
2. Adverse events attributed to drug reactions or toxicity sufficient to cease drug administration.
The standard search strategy of the Cochrane Neonatal Review Group was used.
This included electronic searches of the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2009), MEDLINE (1966 - May 2009) and EMBASE (1980 - May 2009). The search strategy used the following text words and MeSH subject headings: Infant-Newborn, Infant-Low Birth Weight, Infant-Premature, infan$, neonat$, newborn, premature, low birth weight, LBW, fungi, fungemia, fungaemia, candidiasis, Candida albicans, antifungal, fluconazole, azoles, amphotericin B, flucytosine, nystatin, nystan, mycostatin, nilstat, nystex, miconazole, daktarin, ketoconazole, clotrimazole. The searches were limited with the relevant filter for clinical trials. No language restriction was applied.
The references in studies identified as potentially relevant were examined. The abstracts from the Society for Pediatric Research (1993 - 2009), the European Society for Pediatric Research (1995 - 2008), and the Royal College of Paediatrics and Child Health Spring Meeting (2000 - 2009) were searched. Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.
The meta-Register of clinical trials (http://www.controlled-trials.com/mrct/search.html) and the US National Institutes of Health registry of clinical trials (http://clinicaltrials.gov/) web sites were searched for completed or ongoing trials.
The title and abstract of all studies identified by the above search strategy were screened and the full articles for all potentially relevant trials obtained. The full text of any potentially eligible reports was reassessed and those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were discussed until consensus was achieved.
A data collection form was used to aid extraction of relevant information from each included study. Each review author extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufficient, the investigators were contacted for further information.
The criteria and standard methods of the Cochrane Neonatal Review Group were used to independently assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to the intervention, and completeness of assessment in all randomised individuals. Additional information from the trial authors was requested to clarify methodology and results as necessary.
This information was added to the Risk of Bias table.
Relative risk (RR) and risk difference (RD) were calculated for dichotomous data and weighted mean difference (WMD) for continuous data, with respective 95% confidence intervals (CI). The number needed to treat (NNT) or harm (NNH) was determined for a statistically significant reduction in the RD.
The treatment effects of individual trials and heterogeneity between trial results was examined by inspecting the forest plots. The impact of heterogeneity in any meta-analysis was assessed using the I2 statistic. If statistical heterogeneity was noted, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using post-hoc subgroup analyses.
ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL PROPHYLAXIS VS. PLACEBO OR NO DRUG (COMPARISON 1):
Three eligible trials that compared oral/topical non-absorbed antifungal prophylaxis with placebo or no drug were identified (Ozturk 2006; Sims 1988; Wainer 1992: see table, Characteristics of Included Studies):
Ozturk 2006 randomly allocated 938 VLBW infants to receive either prophylactic oral nystatin (100000 IU three times daily) or no treatment. Infants in the control group who had oral fungal colonisation detected at trial entry or on surveillance cultures were treated with nystatin (100000 IU orally, 8 hourly).
Sims 1988 quasi-randomly allocated 67 infants of birth weight < 1250 grams to receive either oral nystatin or no treatment until one week after endotracheal extubation (average five weeks). The trial was undertaken in the mid-1980s in North America during a period of over crowding in the intensive care unit; 222 infants with a birthweight < 1250 grams were born during a 12 month period; 55 died within 48 hours, 88 relatively healthy infants were transferred elsewhere and 67 of the remaining 88 infants were recruited to the study.
Wainer 1992 recruited 600 infants of birth weight < 1750 grams. A consensus decision to include the trial was made because most participating infants were < 1500 grams. Participants were randomised to receive either oral miconazole or placebo until discharge. The study was undertaken in the late 1980s in South Africa. Due to limited resources, mechanical ventilation was not offered to ELBW infants (12% of the participants).
The primary outcomes of all studies were fungal colonisation and invasive fungal infection. All provided data on in-hospital mortality but none assessed any post-discharge outcomes.
ORAL/TOPICAL NON-ABSORBED VS. SYSTEMIC ANTIFUNGAL PROPHYLAXIS (COMPARISON 2):
One trial compared oral/topical antifungal prophylaxis with systemic antifungal prophylaxis (Violaris 1998):
Violaris 1998 randomised 21 VLBW infants to receive either oral nystatin or fluconazole beginning between days five to seven after birth. The trial has been published in abstract form only. Data on invasive fungal infection and mortality were reported.
ONE ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL REGIMEN VS. ANOTHER ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL REGIMEN:
No trials compared different dose regimens of oral/topical non-absorbed antifungal prophylaxis.
Three studies were excluded (Damjanovic 1993; Harris 1960; Herruzo-Cabrera 1994: see Table, Characteristics of Excluded Studies).
Quality assessments are included in the table, Characteristics of Included Studies.
Ozturk 2006: Allocation concealment is likely to have been concealed using random numbered tables by a person not directly involved in the trial. The intervention and assessment was unblinded. 25% of controls received nystatin to treat oral fungal colonisation detected on surveillance cultures. These infants' outcomes have been analysed within the control group (intention to treat). Follow-up was complete.
Sims 1988: Allocation (based on odd or even hospital number) was not concealed, and the intervention and outcome assessment was not blinded. Follow-up was complete.
Wainer 1992: Randomisation, intervention, and outcome assessment were blinded. Follow-up was complete.
Violaris 1998: The randomisation method is not stated. Blinding of the intervention and outcome assessment were not reported. Mortality and systemic fungal infection were assessed in all 21 infants. The study has been published in abstract form only and attempts to obtain further information have been unsuccessful.
ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL PROPHYLAXIS VS. PLACEBO OR NO DRUG (COMPARISON 1):
Primary outcomes:
Incidence of invasive fungal infection (Outcome 1.1):
Ozturk 2006 found a statistically significant reduction RR 0.15 (95% CI 0.10, 0.22); RD -0.31 (95% CI -0.35, -0.26).
Sims 1988 reported a statistically significant reduction RR 0.19 (95% CI 0.04, 0.78); RD -0.26 (95% CI -0.44, -0.09).
Wainer 1992 did not find a statistically significant difference RR 1.32 (95% CI 0.46, 3.75); RD 0.01 (95% CI -0.02, 0.03).
Meta-analysis of data from the three trials found a statistically significant effect but with significant and substantial heterogeneity:
Death prior to hospital discharge (Outcome 1.2):
None of the trials found a statistically significant effect:
Ozturk 2006: RR 0.97 (95% CI 0.61, 1.52); RD -0.00 (95% CI -0.04, 0.03).
Sims 1988: RR 0.59 (95% CI 0.19, 1.82); RD -0.08 (95% CI -0.26, 0.09).
Wainer 1992: RR 0.87 (95% CI 0.70,1.07); RD -0.05 (95% CI -0.13, 0.03)].
Meta-analysis of data from the three trials did not find a statistically significant effect (no statistically significant heterogeneity):
Neurodevelopmental outcomes:
None of the trials reported any neurodevelopmental outcomes.
Secondary outcomes:
Morbidity (Outcomes 1.3, 1.4):
a. Duration of ventilation (two trials: Sims 1988; Wainer 1992).
Neither trial, nor a meta-analysis of data from both, found a statistically significant difference: WMD 0.23 (95% CI -1.11, 1.56) days (I2= 0%).
b. Length of stay in intensive care (two trials: Sims 1988; Wainer 1992).
Neither trial, nor a meta-analysis of data from both, found a statistically significant difference: WMD 0.12 (95% CI -4.46, 4.70) days (I2= 0%).
Subgroup analyses
1. Extremely preterm or ELBW infants
Data were available from one trial (Ozturk 2006).
Invasive fungal infection: Ozturk 2006 found a statistically significant reduction RR 0.12 (95% CI 0.06, 0.26); RD -0.27 (95% CI -0.35, -0.20).
Mortality: Ozturk 2006 did not find a statistically significant effect: RR 1.07 (95% CI 0.51, 2.25); RD 0.01 (95% CI -0.05, 0.06).
2. Trials in which participants were infants with fungal colonisation.
None of the trials restricted participation to infants with fungal colonisation at trial entry.
ORAL/TOPICAL NON-ABSORBED VS. SYSTEMIC ANTIFUNGAL PROPHYLAXIS (COMPARISON 2):
Primary outcomes:
Incidence of invasive fungal infection (Outcome 2.1):
Violaris 1998 reported no significant difference in RR [5.79 (95% CI 0.35, 95.07)], but a borderline significantly higher RD [0.31 (95% CI 0.02, 0.59); NNH 3].
Death prior to hospital discharge (Outcome 2.2):
Violaris 1998 reported no significant difference in RR [5.79 (95% CI 0.35, 95.07)], but a borderline significantly higher RD [0.31 (95% CI 0.02, 0.59); NNH 3].
No other outcomes were reported in the Violaris 1998 abstract.
ORAL/TOPICAL NON-ABSORBED ANTIFUNGAL PROPHYLAXIS VS. PLACEBO OR NO DRUG
Meta-analysis of three trials comparing oral/topical non-absorbed antifungal prophylaxis vs. placebo or no drug, in which a total of 1625 infants participated, suggests that oral/topical non-absorbed prophylaxis significantly reduces the risk of invasive fungal infection in VLBW infants. None of the three trials or a meta-analysis of their data found evidence of an effect on mortality. The trials collected limited data on other neonatal morbidities that may be affected by invasive fungal infection. No evidence of an effect on the duration of mechanical ventilation or the length of intensive care admission was found. None of the trials assessed long-term neurodevelopmental outcomes.
The finding of an effect on invasive fungal infection should be interpreted and applied with caution. The existence of substantial statistical heterogeneity in the meta-analysis raises concern that the estimate is not robust. Heterogeneity may be related to various differences between the trials including population characteristics (proportion of ELBW infants), nature of the intervention (miconazole vs. nystatin), methodological quality issues (particularly unblinded allocation and intervention) and the effect of other co-interventions.
The largest trial (N = 948) contributed 91% of the weighted estimate of effect on invasive fungal infection (Ozturk 2006). This trial of nystatin prophylaxis was undertaken in Turkey within the past decade. More than one-third of participants were ELBW infants receiving intensive care interventions. The criteria for diagnosing invasive fungal infection appear to be have been robust. Efforts to limit contamination of microbiological cultures by surface colonising organisms were made: for example, fungal urinary tract infection was based on culture of organisms from two separate supra-pubic bladder aspirates. However, caregivers or assessors were not blinded to the intervention and this may have caused surveillance and ascertainment bias if thresholds for investigation and diagnosis of suspected invasive fungal infection were adjusted according to treatment status. Although 25% of control VLBW infants received nystatin to treat oral fungal colonisation detected at trial entry or during the trial period, this is likely to have reduced the effect size of the primary intervention.
The second largest trial (N = 600) did not detect a statistically significant effect of miconazole prophylaxis on the incidence of invasive fungal infection (Wainer 1992). This trial was placebo-controlled and, therefore, less prone to surveillance bias. The trial was undertaken in South Africa two decades ago in a settling with few intensive care resources. 12% of participants were ELBW and the overall incidence of invasive fungal infection was 2% in the control group. This lower incidence may be related to the fact that because of resource limitations ELBW infants did not receive intensive care interventions. Two-thirds of ELBW infants died. The applicability of the trial's findings to modern neonatal intensive care settings in high-income countries is, therefore, likely to be limited.
The generalisability of the summary finding is also limited by the very high incidence of invasive fungal infection in the control populations in the two trials that found a statistically significant effect on the incidence of invasive fungal infection (Ozturk 2006; Sims 1988). About one-third of infants in the control groups developed invasive fungal infection, much higher than the 1 - 4% incidence estimated in large cohort studies (Clerihew 2006; Horbar 2002; Howell 2009; Karlowicz 2002; Makhoul 2002; Saiman 2000). This limits the applicability of the NNT estimate (five infants) since in clinical settings with lower incidences of invasive fungal infection a much larger number of infants would need treatment to prevent a single extra case of invasive fungal infection.
A subgroup analysis of outcomes for infants colonised with fungi at trial entry was not possible. None of the trials pre-specified fungal colonisation as an entry criterion. Between 25% and 45% of participating infants had fungal colonisation, but subgroup data for these infants were not available in the published reports of the included trials. Even if these data become available for analysis, those from the largest trial would be of limited value since infants in the control group received antifungal treatment if oral fungal colonisation was detected (Ozturk 2006).
ORAL/TOPICAL NON-ABSORBED VS. SYSTEMIC ANTIFUNGAL PROPHYLAXIS
The small trial (N = 21) that assessed the effect of oral/topical non-absorbed antifungal prophylaxis (nystatin) compared with systemic antifungal (fluconazole) prophylaxis was underpowered to exclude important clinical effects (Violaris 1998).
The Cochrane review of systemic antifungal prophylaxis found evidence that fluconazole versus placebo or no drug reduces the incidence of invasive fungal infection in VLBW infants (Clerihew 2007). However, this effect may be partly due to ascertainment bias since systemic antifungal prophylaxis lowers the sensitivity of microbiological culture for detecting fungi in blood, urine, or cerebrospinal fluid. A statistically significant effect on mortality (which is not affected by ascertainment bias) was not found. The major concern with systemic antifungal prophylaxis is the potential to drive the emergence of antifungal resistance (Brion 2007). Because of this concern, and given that oral/topical non-absorbed prophylaxis is inexpensive, simple and safe, current clinical practice tends to favour oral/topical non-absorbed prophylaxis over systemic antifungal agents in at-risk VLBW infants (Burwell 2006; Clerihew 2008; Howell 2009). It has been argued that further trials comparing oral/topical vs. systemic prophylaxis are needed (Isaacs 2008).
The available trial data are insufficient to guide clinical practice. Although meta-analysis of three trials suggests that oral/topical non-absorbed antifungal agents (nystatin or miconazole) reduces the risk of invasive fungal infection, methodological weaknesses limit the validity and applicability of this finding.
Further randomised controlled trials of oral/topical non-absorbed antifungal prophylaxis are needed to provide more valid and precise estimates of effect size. Because most neonatologists who currently use antifungal prophylaxis target infants thought to be at greatest risk, mainly ELBW or extremely preterm infants with additional risk factors, a trial restricted in this population of infants, or perhaps even smaller or lower gestation infants, may be appropriate and acceptable (Burwell 2006; Clerihew 2008; Howell 2009). Oral/topical non-absorbed antifungal prophylaxis may be compared with placebo or with systemic prophylaxis (Clerihew 2007). Any trial should aim to assess long-term outcomes, particularly disability-free survival, as well as the effect on invasive fungal infection.
David Henderson-Smart for his guidance.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Brian Darlow (BD) and Nicola Austin (NA) developed the original protocol and undertook the original review (Austin 2004).
For the 2009 update, William McGuire (WM) screened the title and abstract of all studies identified by the search strategy.
NA and WM screened the full text of the report of each study identified as of potential relevance.
NA and WM extracted the data separately, compared data, and resolved differences by consensus, and with discussion with BD.
NA, BD, and WM completed the final review.
| Methods | Blinding of allocation: Yes Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measures: No |
|---|---|
| Participants | All neonatal admissions with subgroup analyses of all VLBW (N=938) and only ELBW (N=349) infants. NICU, Division of Neonatology, Erciyes University Hospital, Turkey, 2002-2005. |
| Interventions | Nystatin 100000 IU orally, 8 hourly (N=475) vs. no drug (N=463). 25% of control VLBW infants received nystatin (100000 IU orally, 8 hourly) to treat oral fungal colonisation detected at trial entry or during the trial period. |
| Outcomes | Fungal colonisation and invasive fungal infection. |
| Notes | Randomly assigned using random number tables. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | |
| Allocation concealment? | Yes | Blinding of allocation: Yes |
| Blinding? | No | Blinding of intervention: No Blinding of outcome measures: No |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Unclear |
| Methods | Blinding of allocation: No (quasi-randomised) Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measures: No |
|---|---|
| Participants | 67 infants of birth weight <1250 grams. |
| Interventions | Nystatin 1ml orally, 8 hourly (N=33) vs. no drug (N=34). |
| Outcomes | Fungal colonisation and invasive fungal infection. Duration of mechanical ventilation and duration of intensive care admission. |
| Notes | The study took place during a period of over crowding in the intensive care unit; 222 infants with a birthweight <1250g were born during a 12 month period; 55 died within 48 hours, 88 relatively healthy infants were transferred elsewhere and 67 of the remaining 88 infants were recruited to the study. One infant in the control group had Candida albicans pneumonia supported by postmortem evidence. All the other affected infants had positive urine and blood cultures. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | No | Quasi-randomized |
| Allocation concealment? | Unclear | |
| Blinding? | No | Blinding of intervention: No Blinding of outcome measures: No |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
| Methods | Blinding of randomisation: Can't tell Blinding of intervention: No Complete follow-up: Yes Blinding of outcome measurement: No |
|---|---|
| Participants | 21 VLBW infants. |
| Interventions | Nystatin (100,000 units/kg/day) in each side of the mouth (N=13) vs. fluconazole (4mg/kg) orally (N=8) beginning on day five after birth. Medications were continued until full oral feedings were attained or systemic fungal infection was diagnosed. |
| Outcomes | Invasive fungal infection and mortality. |
| Notes | Published in abstract form only. |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | |
| Allocation concealment? | Unclear | Blinding of randomisation: Can't tell |
| Blinding? | No | Blinding of intervention: No Blinding of outcome measurement: No |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
| Methods | Blinding of randomisation: Yes Blinding of intervention: Yes Complete follow-up: Yes Blinding of outcome measures: Yes |
|---|---|
| Participants | 600 infants of birth weight <1750 grams. |
| Interventions | Miconazole 0.75ml orally 3 times daily (N=302) vs. placebo (N=298). |
| Outcomes | Fungal colonisation and invasive fungal infection. Duration of mechanical ventilation and duration of intensive care admission. |
| Notes | Due to limited resources, mechanical ventilation was not offered to infants <1000 grams. This group made up 12 % (73/600) of the infants and had a high mortality rate (67%). |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | |
| Allocation concealment? | Yes | Blinding of randomisation: Yes |
| Blinding? | Yes | Blinding of intervention: Yes Blinding of outcome measures: Yes |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
| Reason for exclusion | Not a randomised controlled trial, only one third of infants less than 1500g. |
|---|
| Reason for exclusion | The gestational age or birthweight of participants was not reported - assumed to include term and preterm infants. |
|---|
| Reason for exclusion | A prospective cohort study but not a randomised controlled trial. |
|---|
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| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Incidence of invasive fungal infection | 3 | Risk Ratio (M-H, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 All VLBW infants | 3 | 1615 | Risk Ratio (M-H, Fixed, 95% CI) | 0.19 [0.14, 0.27] |
| 1.1.2 Only ELBW infants | 1 | 349 | Risk Ratio (M-H, Fixed, 95% CI) | 0.12 [0.06, 0.26] |
| 1.2 Mortality | 3 | Risk Ratio (M-H, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 All VLBW infants | 3 | 1615 | Risk Ratio (M-H, Fixed, 95% CI) | 0.88 [0.72, 1.06] |
| 1.2.2 Only ELBW infants | 1 | 349 | Risk Ratio (M-H, Fixed, 95% CI) | 1.07 [0.51, 2.25] |
| 1.3 Duration of ventilation | 2 | 667 | Mean Difference (IV, Fixed, 95% CI) | 0.23 [-1.11, 1.56] |
| 1.4 Length of stay in NICU (days) | 2 | 667 | Mean Difference (IV, Fixed, 95% CI) | 0.12 [-4.46, 4.70] |
| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 2.1 Incidence of invasive fungal infection | 1 | 21 | Risk Ratio (M-H, Fixed, 95% CI) | 5.79 [0.35, 95.07] |
| 2.2 Mortality | 1 | 21 | Risk Ratio (M-H, Fixed, 95% CI) | 5.79 [0.35, 95.07] |
This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2009 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review. |
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