Rationale and impact
- Information and support
- Intrapartum antibiotics
- Women with prolonged prelabour rupture of membranes who have group B streptococcal colonisation, bacteriuria or infection
- Risk factors for and clinical indicators of possible early-onset neonatal infection
- Antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection
- Risk factors for and clinical indicators of possible late-onset neonatal infection
- Investigations for late-onset neonatal infection
- Antibiotics for late-onset neonatal infection
- Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection
- Early- and late-onset meningitis (babies in neonatal units)
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
The committee decided that some of the information and support recommendations in the previous version of the NICE guideline on neonatal infection for the families of babies with early-onset infection were also applicable to the families of babies who may develop late-onset infection.
The previous version of the guideline on early-onset infection recommended that parents and carers of babies with risk factors for early-onset infection should be given verbal and written information on the signs and symptoms of infection. This is particularly important when the baby already has risk factors that indicate they may develop infection. However, the committee noted that any baby can develop an infection, even if they are not identified as high risk at the time of discharge. The committee therefore thought it was important that all parents and carers should be given information about the signs and symptoms of neonatal infection before their baby is discharged from hospital.
The committee also wanted to ensure that the signs of infection listed in the recommendations were written in simple language that families could understand, rather than using clinical terminology. Therefore, examples of the most common breathing problems experienced by babies with neonatal infection were added to the recommendation on signs and symptoms.
The committee thought it was important that information was given in accessible formats, including different languages where appropriate to ensure that information was equally accessible to all. They noted these principles are outlined in the NICE guideline on patient experience in adult NHS services and so cross-referred to this guideline.
These recommendations have been adapted from the existing guidelines for early-onset neonatal infection, reflecting standard practice. As such, they are not expected to have a substantial impact on practice. Expanding the recommendation on signs and symptoms so that advice is given to all parents and carers will mean that more families will be aware of the signs of infection and will know to seek medical help if their baby develops any of them.
No new evidence was identified since 2012, when the previous version of the guideline was published. The committee extended the 2012 recommendation on antibiotics for group B streptococcus to cover women who had colonisation in a previous pregnancy. This was because group B streptococcus colonisation in a previous pregnancy greatly increases the chance of being colonised in future pregnancies. The committee were concerned about a woman not receiving treatment because of a false negative test result, and so they decided to specify that a negative test should be from enrichment culture or PCR on rectovaginal swab samples. Although some tests may have higher false positive rates, all women with positive tests should be treated as if they have GBS so that no babies who are at higher risk of infection are missed.
For women in pre-term labour and women with a clinical diagnosis of chorioamnionitis, there was no evidence identified on the effects on intrapartum antibiotics on the number of neonatal infections. However, antibiotics did reduce the number of maternal infections in women in pre-term labour. The committee also agreed that pre-term labour and chorioamnionitis are important risk factors for neonatal infection, so intrapartum antibiotics are very likely to reduce the risk to the baby. Chorioamnionitis is a serious infection that needs to be treated with antibiotics to prevent harm to the mother. The committee thought that it was important to make recommendations for antibiotic treatment that would simultaneously treat infection in the mother and prevent early-onset group B streptococcal infection in the baby to make the best use of antibiotics.
The committee retained the recommendations on using benzylpenicillin as first-choice antibiotic from the 2012 guideline. Based on their knowledge and experience, gentamicin and metronidazole are also now recommended for women with chorioamnionitis, because chorioamnionitis can be caused by Gram positive or negative aerobic and anaerobic bacteria, so clinicians need to use broad-spectrum antibiotics that are effective against both. Once-daily dosing for gentamicin was recommended based on the knowledge and experience of the committee because 8 hourly dosing has additional monitoring requirements and would need additional nursing time for administration.
The committee also provided guidance on alternatives for women with a penicillin allergy, based on their knowledge and experience. The committee amended the 2012 recommendation on antibiotic alternatives for women who are allergic to penicillin. They changed the recommended antibiotic from clindamycin because there is evidence of resistance to group B streptococcus emerging with clindamycin, meaning that this antibiotic should no longer be used routinely. Based on their knowledge and experience, the committee recommended a cephalosporin with activity against group B streptococcus as an alternative for women with a penicillin allergy that was not severe, and vancomycin or an alternative antibiotic with activity against group B streptococcus in the case of severe penicillin allergy. The committee were aware of the possibility of allergic reaction to cephalosporins in women with a history of penicillin allergy. For women with a history of penicillin allergy that was not severe they thought that this risk was small and was outweighed by the benefits of using cephalosporins to treat chorioamnionitis and prevent neonatal infection. They noted that cephalosporins should be used with caution in these women. Cephalosporins were not recommended in the case of severe penicillin allergy because of an increased chance of a severe allergic reaction to cephalosporins. Severe penicillin allergy refers to a history of allergy to penicillin with effects that are clearly likely to be allergic in nature such as anaphylaxis, respiratory distress, angioedema or urticaria.
Many of the recommendations remain the same as in the 2012 guideline. The recommendations on intrapartum antibiotics have been extended to cover women in pre-term labour without prelabour rupture of membranes, women with chorioamnionitis and women with group B streptococcus colonisation in a previous pregnancy. However, these changes reflect current practice, as many of these women already receive intrapartum antibiotics.
The committee expected that the recommendation on intrapartum antibiotics for chorioamnionitis would have the greatest impact on clinical practice. There is currently variation in which antibiotics are given to women with chorioamnionitis, with some units prescribing broad-spectrum antibiotics to treat infection in the mother and benzylpenicillin to prevent infection in the baby. Recommending a combination of narrow-spectrum antibiotics for women without an allergy to penicillin is likely to reduce the use of broad-spectrum antibiotics, which will improve antibiotic stewardship.
Women with prolonged prelabour rupture of membranes who have group B streptococcal colonisation, bacteriuria or infection
The evidence suggested that immediate delivery can result in a reduced risk of a baby developing neonatal infection when a mother is between 34 and 37 weeks' gestation and has prolonged prelabour rupture of membranes and a positive test result for group B streptococcus. The evidence did not indicate any significant harms to the baby from choosing immediate delivery over expectant management. Therefore, the committee decided that, given the potential serious consequences of a baby developing neonatal infection, a recommendation in favour of immediate delivery was important. This was further supported by the economic evidence, which showed not only a clinical benefit to immediate delivery but also lower associated costs in comparison to expectant management, which has increased antenatal costs and higher rates of infections.
The committee made a recommendation for research on examining the health-related quality of life impact on parents or carers when a baby has neonatal infection. This information was not available and would have improved how well the economic model truly reflected the costs and health consequences of neonatal infection.
This recommendation could increase the number of women who are offered immediate delivery when they have both prolonged prelabour rupture of membranes and a positive test for group B streptococcus. This in turn could reduce the number of babies who need to be treated for neonatal infection and also reduce the number of mothers who need to be monitored throughout the expectant management period. The exact impact of these recommendations will vary between those hospitals where group B streptococcus screening and testing is more routinely performed and those where it is not. Recommendations on group B streptococcus screening were outside of the scope of this guideline. An economic model suggested that increasing the number of women offered immediate delivery would reduce costs overall.
No evidence was found that related specifically to this topic, and the committee agreed that the recommendations from the previous version of this guideline still reflected current best practice so did not need to be changed. These recommendations apply to all women with risk factors, including those who decline antibiotics, or those who either do not receive antibiotics or receive their first dose of antibiotics shortly before birth because of precipitate birth. As such, any women with risk factors should be monitored throughout labour, and these factors should be taken into account when assessing the risk of infection in the baby.
The committee based their recommendations on evidence on the accuracy of clinical decision models for early-onset neonatal infection, as well as evidence on individual neonatal and maternal risk factors.
There was uncertainty about how well the Kaiser Permanente neonatal sepsis calculator identified true cases of early-onset infection, because the studies included very few cases of infection that were confirmed by blood culture. This was a problem for the framework outlined in the 2012 version of the guideline as well, but the committee believed that the framework is more conservative and would lead to more antibiotics being prescribed than the Kaiser Permanente calculator (both appropriately and inappropriately). Evidence on the Kaiser Permanente neonatal sepsis calculator suggests that it is good at correctly identifying babies without neonatal infection, so reducing the amount of antibiotics that are prescribed unnecessarily. However, given the very serious consequences of missing an infection, the committee preferred the conservative approach from the framework in the 2012 guideline, with some amendments as outlined. However, as the evidence does not clearly show one option to be better and some UK centres currently use the Kaiser Permanente calculator, they also recommended this as an alternative, but only in the context of a research or audit project. By using the Kaiser Permanente calculator as part of an audit, centres will be able to collect detailed data on the use of the tool within NHS practice, including the number of babies who correctly received treatment, those who received antibiotics unnecessarily, and any who were not recommended antibiotics but did have infection. This information will provide a more detailed understanding of the effectiveness and safety of the Kaiser Permanente calculator which can be used to inform decisions on its use in future updates of this guideline.
The committee decided to specify that the Kaiser Permanente calculator should only be used for babies who are being cared for in a neonatal unit (neonatal intensive care units, local neonatal units and special care units), transitional care or a postnatal ward. The committee highlighted how it would be more difficult to collect the information needed for the audit in other settings. They did not think the calculator should be recommended for use in the emergency department, as babies who are brought in from home are likely to already be showing signs of being unwell and therefore need more immediate treatment than babies who are being assessed for risk of infection in a neonatal unit. In these cases, waiting to consult the calculator could instead delay treatment. The committee also thought that the calculator was not appropriate for use in a midwife-led unit or freestanding midwifery unit as there is currently no evidence that has used the calculator in these settings.
As there was only limited new evidence, the framework for assessing and managing risk, involving red flag indicators and other indicators of infection, has been retained from the 2012 guideline. The committee selected the red flag indicators as those that, based on their clinical experience, are the most high risk factors that need immediate treatment. Non-red flag indicators are those that can have causes other than neonatal infection and therefore do not always signal the need for immediate treatment. Many of the clinical indicators matched those in the 2012 guideline, with the following changes.
Parenteral antibiotics are no longer a risk factor. Since the 2012 guideline, awareness of the risks of maternal sepsis has increased and there has been a focus on early treatment with antibiotics. This has led to more babies being prescribed antibiotics even when a maternal infection is not strongly suspected. This rise in antibiotic use can result in babies being unnecessarily exposed to the side effects associated with antibiotics, such as nephrotoxicity, as well as increasing a baby's length of stay in hospital. Increased antibiotic use is also associated with an increase in the development of antibiotic resistance.
Chorioamnionitis and intrapartum fever are now separate risk factors because intrapartum fever has other potential causes. This change means that women with chorioamnionitis and intrapartum fever will have 2 risk factors, so their babies will receive antibiotics.
Invasive group B streptococcal infection in a previous baby and maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy have been combined into a single risk factor, because having a previous baby with invasive group B streptococcal infection increases the risk of future colonisation and infection, but does not confer additional risk if infection, bacteriuria or infection in the current pregnancy is already known about.
Mechanical ventilation, which was previously a red flag risk factor pre-term babies, and a non-red flag risk factor for term babies has been merged into one recommendation. The committee agreed that mechanical ventilation is a risk factor for infection regardless of prematurity, and so they decided to merge these into one red flag risk factor which did not refer to whether a baby was born pre-term or at term.
Confirmed prelabour rupture of membranes was removed from the table because the committee decided that it is now covered by other risk factors in the table (pre-term birth and confirmed rupture of membranes in a pre-term or term birth). Babies born to mothers with prelabour rupture of membranes will therefore still receive treatment when using the updated version of the framework.
To address the limited evidence, the committee recommended further research on the accuracy of the Kaiser Permanente neonatal sepsis calculator and other clinical prediction models.
Many neonatal units use the framework from the 2012 version of the NICE guideline. Removal of parenteral antibiotics as a risk factor is expected to reduce the number of babies given antibiotics unnecessarily.
Some centres use the Kaiser Permanente neonatal sepsis calculator as an alternative, and the recommendations may increase the number of centres who use this calculator in the context of a research or audit project. Current evidence suggests that this may reduce the number of babies who are unnecessarily given antibiotics, but there was substantial uncertainty about how well the calculator identified true cases of infection. If an increase in use of the Kaiser calculator resulted in more cases of infection being missed, this could increase costs associated with treating neonatal infections, as well as the very serious impact on the baby and their families.
Reducing the number of babies being given antibiotics may reduce costs for the NHS, both by reducing prescriptions and by reducing the amount of time babies and their mothers spend in hospital.
Antibiotic-impregnated intravascular catheters for reducing the risk of late-onset neonatal infection
There were only 2 studies looking at antimicrobial-impregnated catheters in newborn babies:
One study looked at rifampicin-miconazole-impregnated catheters. These provided no benefit over standard catheters. In addition, they are more expensive than standard catheters.
The other study looked at silver-zeolite-impregnated catheters. They showed some benefit compared with standard catheters, but the study was small and the committee had concerns about its quality. It was also conducted in Italy, and there are differences in clinical practice and infection rates between Italy and the UK.
The committee agreed they could not recommend antimicrobial-impregnated catheters based on the available evidence. The recommendation against the use of rifampicin-miconazole-impregnated catheters was made on the basis of the evidence that they provide no additional benefit over a standard catheter, and not because of any safety concerns over their use. There is a wider range of antimicrobials that can be used to impregnate catheters than have currently been investigated in newborn babies and uncertainty over which type of impregnated catheter is the most effective and whether monotherapy or the use of more than one antimicrobial would provide the most benefits. To address the shortage of evidence they made recommendations for further research.
The recommendation will reduce the use of rifampicin-miconazole-impregnated catheters. However, antimicrobial-impregnated catheters are not commonly used for newborn babies, so this should have a limited impact.
The committee did not feel that there was sufficient, high-quality evidence for any individual model to make a recommendation on clinical prediction models for late‑onset neonatal infection. Instead, they recommended a review of the individual risk factors that may predict a baby's risk of having or developing late-onset neonatal infection.
Although there was evidence on a number of tools aimed at predicting late-onset neonatal infection, the committee did not think that there was sufficient, high quality, evidence including external validation to recommend any of them for use in practice. Most of the evidence was not from recent studies, the models were not readily available as web-based tools or in other formats that could be easily used by clinicians and it was thought that implementing them would have needed considerable changes in clinical practice.
Given the limited evidence currently available for prognostic models for late‑onset infection, the committee decided that they should make a recommendation for research. The recommendation is designed to encourage the development of new models to identify babies at risk of late-onset neonatal infection as well as promoting the validation of these models and evaluation of their effects on practice. This should help to improve the understanding of the factors associated with late-onset neonatal infection so that committees can make recommendations on this area in future guideline updates.
With limited evidence on prognostic models, the committee agreed that it was instead important for clinicians to be aware of the clinical indicators and risk factors for late-onset neonatal infection. There was very limited evidence on maternal risk factors for late-onset infection and so the recommendations were based on the risk factors and signs and symptoms in the baby. The committee decided that the list of high‑risk criteria from the risk stratification tool in the NICE guideline on sepsis (section 1.4, table 3) covered the most important indicators that clinicians in both community and specialist settings should be aware of. They included the recommendation to seek early advice from a paediatrician to highlight the importance of early treatment if any of the main clinical indicators are present. Early specialist advice was thought to be particularly important when caring for babies in the community as they need to be taken to hospital and admitted before treatment can begin, while babies who are on a neonatal unit can be monitored and treated more quickly. It was agreed that in addition to clinical indicators, it was also important to highlight potential risk factors for infection. This will help to ensure that babies who are at greater risk for infection are closely monitored for the presence of any of the clinical indicators. The committee also recommended that clinicians should think about infection in the other babies when one baby from a multiple birth has infection. Evidence was not found on this, but the committee thought that it was in line with current best practice because of the risk that all the babies from the pregnancy will have the same risk of infection.
There was very limited evidence on the signs and symptoms of infection. The committee was aware of existing recommendations on clinical indicators of infection in the NICE guideline on sepsis and so it considered this information when deciding on recommendations. It was agreed that the high-risk indicators listed in the sepsis guideline were an accurate reflection of the committee's experience with babies who develop late-onset infection. Parental or carer concern over changes in behaviour was added to the list of high-risk criteria as this was highlighted as an important indicator of potential infection for babies in the community. Other potential clinical indicators were discussed, but the committee were concerned about the risk of over-treatment if too many clinical indicators were listed in the recommendation, especially if some of those indicators could have causes other than neonatal infection. The committee decided that the signs included in the recommendation were those that were most likely to indicate infection and therefore the most important to consider when assessing whether a baby may need treatment.
The recommendations are consistent with current practice and therefore a large resource impact is not anticipated. The table of clinical indicators may increase awareness of when a baby is at greater risk of late-onset neonatal infection. This may increase the number of babies who receive early treatment in hospital and reduce the negative effects and costs associated with infection.
Clinicians working on a neonatal or paediatric ward are already likely to be aware of the risk factors that were identified in the evidence review. As such, the recommendations are helpful to reinforce the knowledge of these clinicians about the risk factors but may not have a substantial effect on current practice in a hospital setting.
Blood culture is the current 'gold standard' for identifying neonatal infection. However, babies with late-onset infection can still sometimes have a negative blood culture. It can also take hours or days to get the results of blood cultures. These inaccuracies and delays mean that many babies receive treatment before blood culture results are returned, because delaying treatment could lead to complications or death. Having another diagnostic test as an alternative or an addition to blood culture results could therefore reduce unnecessary antibiotic treatment. The committee reviewed the evidence for late-onset infection. Of the other diagnostic tests, only C-reactive protein has enough evidence to recommend it. It is not accurate enough to be used as an alternative to blood culture, but when used in combination it can improve the accuracy of the diagnosis. The committee discussed how a single C-reactive protein measurement is not sufficient to diagnose infection, as this can vary between babies. They therefore decided to recommend that a C‑reactive protein sample is taken when starting antibiotics. This will provide clinicians with a baseline against which to compare future C-reactive protein results, to indicate whether a baby is likely to have infection, whether they are responding to treatment and when to consider stopping antibiotics. Blood culture is still considered the gold standard test for diagnosing neonatal infection but using it in combination with C-reactive protein measurements will allow babies who do not need antibiotics to stop taking them sooner.
As the evidence for late-onset infection lined up with the evidence from the 2012 guideline for early-onset infection, the committee amended the 2012 recommendations to cover all neonatal infection.
There was limited evidence on lumbar puncture specifically for late-onset infection. However, lumbar puncture is the 'gold standard' test for identifying meningitis, and it was recommended in the 2012 guideline for babies with early-onset infection. The committee extended this recommendation to cover both early- and late-onset neonatal infection, as they felt that the benefits of identifying meningitis outweighed the risks of the procedure.
No evidence was identified that supported using urine culture or skin swabs in the neonatal unit. These tests were also not recommended in the 2012 guideline for babies with early-onset infection and so the committee decided to recommend against their use for babies in neonatal units. However, they also discussed how urine culture can be an important test for babies in a paediatric ward if a urinary tract infection is suspected, so included a recommendation which supported its use in babies who are being cared for outside of neonatal units. This is consistent with the recommendations from the NICE guideline on urinary tract infection in under 16s.
The recommendations are not expected to have a major impact on practice as they reflect the procedures currently followed in most hospitals.
There is variation across the country in antibiotic resistance patterns and in which organisms are most likely to cause late-onset neonatal infection. Because of this, local data needs to be used when choosing antibiotics.
Babies in a neonatal unit are likely to have been exposed to different bacteria than babies at home, so the committee made separate recommendations for the 2 groups.
For babies in a neonatal unit, the committee did not believe there was enough evidence to recommend specific antibiotics, and so made a recommendation for research into the best antibiotic regimen to treat late-onset infection. However, the evidence available did show that combinations of narrower‑spectrum antibiotics are as effective as broader-spectrum antibiotics. The committee were aware that using broad-spectrum antibiotics in babies is associated with altered gut flora, increased risk of invasive fungal infection and the development of antibiotic resistance, and so a combination of narrow spectrum antibiotics was recommended as first-line treatment.
For babies who have been admitted from home, there was also limited evidence on which antibiotics to use. The NICE guideline on sepsis recommends treating community-acquired sepsis with ceftriaxone or cefotaxime depending on gestational age. The committee agreed that these antibiotics would be appropriate for late-onset neonatal infection in babies who have been admitted from home, and none of the evidence for this group contradicted it.
There was no evidence on duration of antibiotic treatment for late-onset infection. However, the 2012 guideline made recommendations on this for early-onset infection, and the committee adapted these so that they were applicable to late-onset infection. The duration of initial treatment is recommended to be 48 hours rather than 36 hours as recommended for early-onset infection. This is thought to reflect the different bacteria that cause late-onset infection, which grow more slowly and have a lower load in the bloodstream. This means that it can take longer for a blood culture to become positive for late-onset than early-onset infection and so treatment needs to continue for longer until a negative blood culture result can be confirmed. To help with treatment decisions, the 2012 version of the guideline recommended that healthcare professionals with experience in neonatal infection should be available to provide microbiological or paediatric infection disease advice. The committee decided that this recommendation is also important when making decisions about antibiotic treatment for late-onset infection.
No evidence on treatment duration was identified, and so the committee made recommendations based on their knowledge and experience. The committee recommended a treatment of 7 days for babies with a positive blood culture, consistent with the recommendation on early-onset neonatal infection from the 2012 version of the guideline. The committee recommended that a shorter treatment duration should be used when no pathogen is identified (the blood culture is negative) or the pathogen is a common commensal. In these situations, the committee noted that infection was likely to be less severe and could be safely treated with a shorter treatment duration, which would have the advantage of reducing exposure to antibiotics, which is consistent with the principles of good antibiotic stewardship. The committee also specified situations when a longer treatment duration should be used, such as when there is intra-abdominal co-pathology, necrotising enterocolitis, osteomyelitis or infection of a central venous catheter. There was no evidence for the specific situations where longer treatment would be required, but the committee based their decisions on their knowledge and experience.
These recommendations will help to reduce the use of broad-spectrum antibiotics as first-line treatment for babies in neonatal units, which may help reduce antibiotic resistance. However, use of narrow-spectrum antibiotics is already standard practice in many units, and the costs of antibiotics are low, so there is expected to be very little impact on resource use, especially as most of the affected babies are already receiving intensive care and monitoring.
The recommendation for babies admitted from home may not have a substantial impact on practice, as it refers to an existing recommendation in the NICE sepsis guideline.
The recommendations on duration of treatment are consistent with current practice.
Antifungals to prevent fungal infection during antibiotic treatment for late-onset neonatal infection
Evidence from randomised controlled trials showed that both nystatin and fluconazole can reduce the risk of a baby developing an invasive fungal infection in comparison to placebo or no treatment. Evidence marginally favoured the use of nystatin over fluconazole for reducing the risk of fungal infection and based on the knowledge and experience of the committee, nystatin is better tolerated and there is a lower risk of fungi developing resistance to this antifungal than fluconazole. Economic evidence showed that nystatin was also likely to be the most cost-effective option, and so the committee recommended oral nystatin for antifungal prophylaxis when a baby is being given antibiotics for late-onset neonatal infection. The recommendation for antifungal prophylaxis was limited to babies below 1,500 g or 30 weeks' gestational age because the evidence was from babies in these population groups.
Although oral nystatin was the committee's first choice for antifungal prophylaxis, oral administration of antifungals may not be possible for all babies, particularly those who are very premature. The committee therefore specified that the use of intravenous fluconazole is appropriate when oral administration is not possible.
The committee made a recommendation for research for studies investigating the optimum regimen for giving antifungal prophylaxis when treating a baby with antibiotics for late-onset infection, because evidence was not available to support specific recommendations on the duration and dose of antifungal treatment that should be used.
This recommendation may increase the number of babies who are given nystatin as antifungal prophylaxis when they are prescribed antibiotics for late-onset infection. This should decrease the number of babies who need to be treated for fungal infection which, although rare, can have serious consequences. Economic modelling showed that giving antifungal prophylaxis is likely to be cost saving because of a reduction in costs associated with treating invasive fungal infections and their consequences.
These recommendations were carried forward from the 2012 version of the guideline, but were expanded to cover both early- and late-onset neonatal meningitis for babies in neonatal units based on the knowledge and experience of the committee. Evidence relating to these recommendations was not reviewed for late-onset meningitis, but the committee agreed that the recommendations that were made in 2012 for early-onset infection would also apply to late-onset meningitis for babies treated in neonatal units.