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Review questionWhat is the effectiveness of intrapartum antibiotic prophylaxis in the prevention of early-onset neonatal infection (compared to no treatment)?

DetailsAdditional comments
Review questionWhat is the effectiveness of intrapartum antibiotic prophylaxis in the prevention of early-onset neonatal infection (compared to no treatment)?This question covers all pregnant women, regardless of whether they have risk factors for early-onset neonatal infection in the baby
ObjectivesTo evaluate the effectiveness of intrapartum antibiotic prophylaxis in the prevention of early-onset neonatal infection

Considerations to include:
  • effectiveness of prophylaxis versus no treatment
  • which class of antibiotics (narrow-or broad-spectrum) to use
  • timing of treatment
  • route of administration
  • dosage
The guideline scope excludes term babies whose mothers had prelabour rupture of the membranes (these are covered by the NICE intrapartum care guideline)

The GDG will need to know which bacteria (associated with maternal colonisation or infection) are most commonly associated with early-onset neonatal infection, which antibiotics are most commonly used to treat such infections, and what the antibiotic susceptibilities/sensitivities are; recent UK data will be most important. Bacterial isolates and susceptibilities will vary in the literature depending on whether routine antenatal screening for group B streptococcus (GBS) is performed. While these may not be directly relevant they may be of value by providing data about ‘what if’ scenarios (for example, ‘what if a lot of women are given ampicillin in labour?’)

Antibiotics may be given to the woman during labour for reasons other than prophylaxis of early-onset neonatal infection. These reasons include: suspected or confirmed chorioamnionitis; before caesarean section (as prophylaxis for the woman); suspected infection in the woman (for example, urinary tract infection); intercurrent illness (for example, shortness of breath where the differential needs to include suspected pneumonia); preterm prelabour rupture of membranes. Regimens for these indications may not cover GBS (or the doses given may be much less than the equivalent dose of benzylpenicillin that is given as intrapartum antibiotic prophylaxis against GBS, or the pharmacokinetics of the drugs may be different to those of benzylpenicillin). The GDG needs to determine whether these regimens cover GBS or whether some of the regimens need to add in benzylpenicillin (for example, some regimens for chorioamnionitis or preterm prelabour rupture of the membranes may not cover GBS)

Duration of treatment (course length) will be examined in review question 8

The GDG should be aware that NICE does not normally allow dosages to be included in guideline recommendations (although consideration of once- versus twice-daily administration of antibiotics, for example, is permitted); this rule will be relaxed only when there is direct evidence to support dosages other than those specified in summaries of product characteristics (SPCs)
LanguageEnglish
Study designSystematic reviews

Randomised controlled trials (RCTs)

Pharmacokinetic and pharmacodynamic studies
Restrict to RCTs (or systematic reviews of RCTs) to address effectiveness of antibiotic treatment

Restrict pharmacokinetic and pharmacodynamic studies to RCTs if such studies are available; consider other comparative or non-comparative pharmacokinetic and pharmacodynamic studies for issues that have not been investigated using RCTs; include studies that evaluate loading doses; restrict searches to studies involving the following antibiotics (most relevant choices for UK setting): benzylpenicillin, amoxicillin, ampicillin, co-amoxiclav (augmentin), and clindamycin (for women allergic to benzylpenicillin)

Other antibiotics that may be administered to women in labour for maternal indications include: azithromycin, cephalosporins (and not just third-generation cephalosporins), erythromycin, metronidazole and vancomycin Other antibiotics are likely to be used in special circumstances. The recommendations arising from this question should provide healthcare professionals with a rationale for why women are offered different regimens for different indications and how to ensure GBS cover is included, if it is indicated

Population-based surveillance studies will provide background information about the frequency of different colonising or infecting organisms in the woman and antibiotic susceptibility/sensitivity and resistance (this is background information and no systematic search for evidence will be required); such studies will also provide information about bacteria causing early-onset neonatal infections and antibiotic susceptibility patterns in bacteria causing early-onset neonatal infections
StatusPublished papers
PopulationWomen receiving intrapartum antibiotic prophylaxis because of bacterial infection or colonisation that might cause early-onset neonatal infection or because of perceived risk factors for early-onset neonatal infectionTo include all papers on early-onset infection as the authors define it

Intrapartum prophylaxis covers all women who are going to give birth even without going into labour (that is all women in whom birth is imminent)

Studies will be included only if they are conducted in the European Union, the United States of America, Canada, Australia or New Zealand (pathogens and clinical practice outside these areas are not sufficiently similar to those in the UK to be informative)

The guideline scopeexcludes antenatal screening and prophylaxis (because this is already addressed by the NICE antenatal care guideline)
InterventionAntibiotics (and combinations of antibiotics) used for intrapartum prophylaxis, including benzylpenicillin, amoxicillin, ampicillin, co- amoxiclav (augmentin) and clindamycin

Antibiotics (and combinations of antibiotics) used for other indications in women at risk of having a baby with early-onset neonatal infection, including azithromycin, cephalosporins, erythromycin, metronidazole and vancomycin
This list includes some antibiotics that are likely to be first choice for prophylaxis of GBS (benzylpenicillin, with clindamycin for women allergic to benzylpenicillin). The GDG needs to consider how to deal with antibiotics used for other indications

No need to distinguish between bactericidal agents (those that kill bacteria) and bacteriostatic agents (those that inhibit growth or reproduction of bacteria)
ComparatorHead-to-head comparison with any of the interventions listed above

Placebo

No treatment

Dosage, route and frequency of administration (for pharmacokinetic and pharmacodynamic studies)
OutcomesFor clinical effectiveness studies:
  1. Failure of prevention of neonatal infection
  2. Mortality (in the baby)
  3. Duration of hospital stay (in the baby)
  4. Neonatal adverse events
  5. Long-term outcomes (in the baby)
  6. Resistance among neonatal flora (in the baby)
  7. Maternal adverse events
For pharmacokinetic and pharmacodynamic studies:
  • Incidence of toxic concentrations (peaks and troughs, preferably in relation to several cut-off levels, and specifying times measurements taken; continuous data not relevant)
  • Incidence of concentrations in the normal (therapeutic) range, again specifying times measurements taken (categorical data preferred, but continuous data acceptable otherwise)
  • Bias and precision of model prediction (comparison of observed and predicted concentrations, indicating how well a new pharmacokinetic model matches a previous standard; internal comparisons or comparison with historical data may be appropriate if there is no direct comparison between dosing regimens)
Failure of prevention of neonatal infection specified as (in order of importance):
  • documentation of infection/sepsis through bacterial culture positivity
  • clinical presumed infection/sepsis (decision to treat with antibiotics based on clinical suspicion or test findings)
While mortality and long-term outcomes were recognised as being important, the GDG did not formally agree an order of priority. The outcomes listed should be addressed in the same order in similar questions

For pharmacokinetic and pharmacodynamic studies the following parameters should be reported in evidence tables only (that is, as background characteristics to inform interpretation of differences between studies, rather than to guide decisions about effectiveness of different dosing regimens strategies): serum gentamicin half-life, clearance, volume of distribution, and details of dosages actually administered
Other criteria for inclusion/ exclusion of studiesExclude non-human studies

Exclude late-onset neonatal infection (onset of infection after 72 hours of age, except where a specified study includes older babies in its definition of early-onset sepsis) Exclude studies that do not report results specifically for early-onset neonatal infection (however the authors define it)

Exclude results relating to babies with suspected or confirmed non-bacterial infections

Exclude results relating to babies with suspected or confirmed bacterial infection resulting from therapeutic interventions such as surgery

Exclude results relating to babies with suspected or confirmed syphilis

Exclude results relating to babies with suspected or confirmed meningitis who are not receiving care in neonatal units (covered by the NICE guideline on bacterial meningitis and meningococcal septicaemia)

Exclude results for women with pre-labour rupture of membranes at term (covered in the NICE intrapartum care guideline)
This section includes generic exclusions specified in the NICE guidelines manual (for example, non-human studies), exclusions specified in the scope for this guideline (for example, late-onset neonatal infection), and any exclusions specific to this review question
Search strategiesSearches should include all of the antibiotic classes and individual antibiotic drugs listed under interventions

No need to distinguish between bactericidal and bacteriostatic agents
Review strategiesStudies will be assessed for quality according to the process described in the NICE guidelines manual (January 2009)

A list of excluded studies (including reasons for exclusion) will be provided following weeding

Evidence tables and GRADE evidence profiles will be used to summarise the evidence
EqualitiesEqualities issues with be assessed according to the processes described in the NICE guidelines manual (January 2009) and the NICE equality scheme and action plan (2010–2013)

From: Appendix D, Review protocols

Cover of Antibiotics for Early-Onset Neonatal Infection
Antibiotics for Early-Onset Neonatal Infection: Antibiotics for the Prevention and Treatment of Early-Onset Neonatal Infection.
NICE Clinical Guidelines, No. 149.
National Collaborating Centre for Women's and Children's Health (UK).
London: RCOG Press; 2012 Aug.
Copyright © 2012, National Collaborating Centre for Women’s and Children’s Health.

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