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Background
Neonatal infection has been recognised as the third most common cause of neonatal death globally.1 In the UK, a retrospective analysis that spanned over 30 neonatal units from 2005 to 2014 found the incidence of neonatal infection was 6.1 per 1000 live births and 48.8 per 1000 neonatal admissions.2 The incidence of early-onset neonatal sepsis (EONS) in the UK was 0.7 per 1000 live births.2
The National Institute for Health and Care Excellence (NICE) published the first guideline (CG149) intended for management of early-onset sepsis in 2012; this has been updated (NG195) in 2021.3 The guideline refers to the use of Kaiser Permanente Sepsis Risk Calculator (KPSRC), which applies a multivariable modelling approach to predict individualised risk of EONS.4 The KPSRC has been used widely across the world; published reports indicate a significant reduction in antibiotic use without missing true cases of EONS.4–6
Information about the current guideline
The current guideline (NG195) provides new recommendations for intrapartum antibiotics and details the risk factors for infection. It refers to the assessment of risk using the KPSRC, lists the clinical indicators of possible infection and recommends management of late-onset neonatal sepsis (LONS).
This guideline should be used in conjunction with existing NICE guidelines on meningitis (bacterial) and meningococcal septicaemia in under 16s (CG102), urinary tract infection (CG54), sepsis (NG51), fever in under 5s (NG143) and specialist neonatal respiratory care for babies born preterm (NG124) (see box 1).
Resources
Neonatal infection: antibiotics for prevention and treatment (National Institute for Health and Care Excellence guideline 2021): https://www.nice.org.uk/guidance/ng195
Fever in under 5s: assessment and initial management (National Institute for Health and Care Excellence guideline 2019): https://www.nice.org.uk/guidance/ng143
Sepsis: recognition, diagnosis and early management (National Institute for Health and Care Excellence guideline 2016): https://www.nice.org.uk/guidance/ng51
Neonatal infection (early onset): antibiotics for prevention and treatment (National Institute for Health and Care Excellence guideline 2012): https://www.nice.org.uk/guidance/cg149
Meningitis (bacterial) and meningococcal septicaemia in under 16s: recognition, diagnosis and management (National Institute for Health and Care Excellence guideline 2010): https://www.nice.org.uk/guidance/cg102
Urinary tract infection in under 16s: diagnosis and management (National Institute for Health and Care Excellence guideline 2007): https://www.nice.org.uk/guidance/cg54
Specialist neonatal respiratory care for babies born preterm (National Institute for Health and Care Excellence guideline 2019): https://www.nice.org.uk/guidance/NG124
This review encompasses recommendations for both EONS and LONS.
Key issues that the guideline addresses
Recognition and management of pregnant women whose unborn baby is at risk of infection.
Prevention of bacterial infection in healthy neonates up to and including 28 days’ corrected gestational age.
Treatment of neonates with suspected or confirmed bacterial infection.
Definitions
EONS refers to an infection occurring before 72 hours after birth.
LONS refers to an infection occurring after 72 hours after birth.
Red flag indicators refer to the highest risk factors that need immediate treatment.
Non-red flag clinical indicators refer to risk factors that can have causes other than neonatal infection and therefore do not always signal the need for immediate treatment with antibiotics.
Assessment
Prevention of EONS before birth
Women in labour should be offered intrapartum antibiotics when any of the following factors are present:
Preterm labour.
Group B streptococcal (GBS) colonisation, bacteriuria or infection in the current pregnancy.
GBS colonisation, bacteriuria or invasive GBS infection herself in a past pregnancy, but does not have a negative high vaginal swab (HVS) result for GBS in the current pregnancy.
Previous baby with an invasive GBS infection.
Clinical diagnosis of chorioamnionitis.
Immediate delivery (induction or caesarean section) should be offered to women who are at 34–37 weeks’ gestational age with prolonged rupture of membranes (PROM) and with GBS colonisation.
Assessment of babies after birth
Babies should have physical examination including recording of vital signs as part of risk assessment when there are risk factors for (see table 1) or clinical indicators of (see table 2) infection.
Babies with any red flag indicators, or with two or more ‘non-red-flag’ risk factors or clinical indicators, should start antibiotic treatment.
The NICE guideline advises the KPSRC may be used as an alternative method for risk assessment for EONS in babies born after 34 weeks’ gestation, but only in the context of a prospective clinical audit recording:
Total number of babies assessed.
Number correctly identified as having culture-positive infection and the number of babies incorrectly identified by the KPSRC who do not develop a culture-confirmed neonatal infection.
Number of babies missed by the calculator who develop a culture-confirmed neonatal infection.
Risk factors for neonatal sepsis
Clinical indicators of neonatal infection
Investigations
Investigations for suspected EONS/LONS are based on risk factors and clinical indicators and are outlined in table 3.
Neonates readmitted from the community with LONS should be investigated as per the NICE sepsis guideline (NG51).7
Investigations for babies under the care of neonatal unit
Management
In all babies, administer antibiotics within 1 hour of the decision to treat (EONS and LONS).
For babies under the care of neonatal units:
Manage suspected neonatal sepsis as outlined in table 4.
Babies with purulent eye discharge should start treatment for possible gonococcal infection (EONS).
In suspected umbilical infection, such as purulent discharge or redness/swelling, perform a blood culture, take umbilical swab and start intravenous flucloxacillin with gentamicin (EONS).
Add anaerobic cover (eg, metronidazole) in addition to flucloxacillin and gentamicin if necrotising enterocolitis is suspected (LONS).
Antibiotic regimen for neonates readmitted from the community should include cefotaxime and amoxicillin (LONS).7
Management of suspected neonatal sepsis in babies under the care of neonatal unit
What do I need to know
What should I stop doing?
For EONS
C reactive protein (CRP) rise of ≥10 mg/L should not be considered as a marker for performing a lumbar puncture.
Suspected or confirmed maternal infection should not be considered as a ‘red flag’; it is an ‘other’ risk factor.
Isolated respiratory distress for >4 hours should not be considered a ‘red flag’ indicator.
What should I start doing for all neonates?
For EONS and LONS
Use clinical judgement, poor response to antibiotics or positive blood culture (excluding coagulase-negative staphylococcus) as an indicator to consider a lumbar puncture.
Consider the possibility of LONS in babies with clinical indicators of infection presenting ≥72 hours after birth.
If continuing antibiotics >36 hours (EONS) or 48 hours (LONS) with negative blood culture, perform daily review and consider stopping antibiotics when the baby appears clinically well and the CRP trend is reassuring.
In babies with positive blood cultures (other than coagulase-negative staphylococcus or a suspected common commensal), antibiotics should be administered for at least 7 days.
What can I continue to do as before?
For EONS
Take blood cultures before administering antibiotics.
Administer antibiotics within 1 hour of the decision to treat.
Monitor CRP trend and repeat levels at 18–24 hours after starting antibiotics.
Perform investigations and start antibiotics in babies with one red flag or two or more ‘non-red flag’ risk factors/clinical indicators.
Suspected/confirmed infection in another baby in a multiple pregnancy should be considered as a ‘red flag’ indicator.
Empirically prescribe benzylpenicillin and gentamicin as first-line antibiotics.
Consider stopping antibiotics at 36 hours if blood cultures are negative, CRP trends are reassuring and the baby appears well.
Consider confirmed (not suspected) prelabour rupture of membranes of >24 hours in a term infant or >18 hours in a preterm infant as a ‘non-red flag’ risk factor.
What should I do differently?
For EONS
Initiate discussion with the obstetrics team focusing on offering immediate delivery (induction or caesarean section) to women who are 34–37 weeks with PROM and who had GBS colonisation at any time during the pregnancy.
Liaise with maternity teams to offer antibiotics during labour to women who have had GBS colonisation in a previous pregnancy, unless a recent negative swab result is available.
Advise women who are GBS-positive that in future pregnancies there is an increased risk of EONS with GBS affecting the new baby. The general practitioner should be informed of this in writing.
Consider apnoea or the need for cardiopulmonary resuscitation as a ‘red flag’ indicator to start antibiotics.
Critical appraisal
The latest version of the NICE guideline (NG195) recommends some changes in clinical practice and introduces the KPSRC as a possible option to determine risk of neonatal infection, although with some specific caveats. There remain considerable challenges for clinicians caring for the newborn.
Use of KPSRC in the UK setting
The NICE guidance discusses the KPSRC as an alternative to the NICE criteria for risk assessment in EONS; however, it is highlighted that the KPSRC should only be used as part of a prospective audit. NICE has not suggested using the KPSRC as the main method of risk stratification as there are significant differences in healthcare settings between the US and UK clinical practice. These include the following:
HVS for detecting GBS colonisation, an essential component of the KPSRC, is currently not offered to all pregnant women. However, the KPSRC formula and algorithm take into account ‘unknown’ GBS status as well.
Normal newborn care is midwife-led. Significant workforce and training implications may arise if all babies on the KPSRC pathway have regular observations safely and efficiently.
There are UK data indicating that judicious adaptation of the KPSRC, backed by a robust surveillance programme, enhanced in-hospital observation, and staff and parent education, will be safe in the National Health Service set-up.4 When considering introduction of the KPSRC in their clinical practice, it would be for individual trusts to determine whether the risks relating to diagnosis outweigh the benefits of earlier discharge and better patient flow-through.
Viral sepsis
Management of babies with viral infections would benefit from being addressed in future revisions of the NICE guidance. A Dutch study over 12 years reported the incidence of viral infections as 1% for all admissions to neonatal units, accounting for 5%–6% of LONS.8 A recent prospective cohort study from Ireland showed almost 13% of all preterm infants treated for LONS had human parechovirus.9 Recent advances in molecular diagnostics have made possible rapid diagnosis of viral infections; specific guidance regarding management of viral sepsis would be valuable.
Ideal inflammatory marker for bacterial infection
A definitive one remains elusive. Many studies have shown promising results with novel markers including procalcitonin, interleukin 6, interleukin 8 and CD64 for EONS.10 11 CRP remains the ‘late specific marker’ recommended by the Guideline Development Group (GDG).3 The GDG was unable to advocate a particular cut-off level above which CRP values should trigger concerns. A diagnostic test with greater sensitivity and specificity could lead to shorter duration of antibiotics, especially when blood cultures are negative.9 Multicentre, large-scale studies are needed to establish the benefit of these novel markers in clinical practice.10 11
Need for availability of blood culture results at 36 hours
The revised guideline continues to recommend cessation of antibiotics at 36 hours in suspected EONS following a negative blood culture report. In 2017, a national survey of all microbiology laboratories across the UK identified that at 36 hours blood culture results were available out-of-hours in only 26.6% of centres for a positive result, and 47.5% for a negative result.12 Standardisation of reporting times across the UK would assist successful implementation of the NICE guideline and achieving antimicrobial stewardship.
EONS and respiratory pathology
Respiratory distress can occur in up to 7% of term newborns, with increase in incidence in premature neonates.13 Recommendations regarding use of lung ultrasound to exclude conditions including transient tachypnoea and respiratory distress syndrome may be useful in future guidelines.14 15
Clinical bottom line
Intrapartum antibiotics should be offered to women in labour when appropriate.
Women between 34 and 37 weeks of gestation with PROM together with GBS colonisation/bacteriuria/infection should be offered immediate delivery.
Antibiotics need to be administered within 1 hour of the decision to treat.
The KPSRC may be used for risk assessment for EONS in babies >34 weeks of gestation as part of a prospective audit.
Babies should be reviewed daily and need for continuing/stopping antibiotics should be assessed at each review.
Babies with positive blood culture (other than coagulase-negative staphylococcus or suspected common skin commensal) without meningitis should be treated with antibiotics for 7 days.
Decision for lumbar puncture should not be based on a specific CRP cut-off value.
Parents should be involved in the management of babies with suspected/confirmed sepsis.
Ethics statements
Patient consent for publication
Footnotes
Contributors SPP, HK and PKK planned and wrote the paper and revised the subsequent drafts. PAH and NG provided their expert opinion and helped in editing the manuscript. All authors have approved the final draft.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.