Neonatal sepsis occurs when there is a serious bacterial or viral infection manifesting in the first 28 days of life (National Institute for Health and Care Excellence (NICE) 2012). A systematic review with meta-analysis by Fleischmann-Struzek et al (2018) involving 23 studies estimated that it carries a mortality rate of 11–19*. The same study estimated that, globally, 3 million neonates are affected each year; the non-specific and varied nature of presentation may result in late diagnosis and delayed treatment. It is important that health professionals are aware of the condition and suspect sepsis at an early stage. This article details the clinical features of neonatal sepsis and includes two illustrative case studies to provide context.
Epidemiology
Neonatal infections are divided into early-onset sepsis (EOS) occurring within the first 48 hours of birth, and late-onset sepsis (LOS) occurring between 2 and 28 days after birth (Cailes et al, 2018). The neonatal infection surveillance network (NeonIN) study involving 12 neonatal units in England over a 10-year period recorded a total of 541 bacterial infections in 443 infants; it recorded an infection rate of 8/1000 live births, and 71/1000 in those admitted to the neonatal unit; sepsis was most common among male infants (56*) born prematurely (<37 weeks) and/or had a low birth weight <2500 g (Vergnano et al, 2011).
In another UK study, the incidence of EOS was 0.9/1000 live births and 9/1000 neonatal admissions; the majority (76*) of cases were diagnosed on the first day of life (Cailes et al, 2018). EOS had a weak association with gestational age and birth weight. Infants were premature in 58* of EOS cases, and 50* had a low birth weight (weighing <2.50 kg). Most EOS cases in the UK are caused by Gram-positive organisms (74*), notably group B Streptococcus (GBS); Gram-negative organisms account for 25* of cases and Candida 1*. Bacteria causing neonatal sepsis are usually found in the maternal genital tract; GBS and Escherichia coli account for around 70* of EOS infections, but other causative organisms should always be considered (Simonsen et al, 2014).
In a study by Vergnano et al (2011), LOS was more common than EOS, with an incidence of 7/1000 live births, and accounting for 61/1000 neonatal admissions. LOS occurred at a median age of 20 days and had a stronger correlation with prematurity; 92* of cases occurred in those born at <32 weeks and 90* of cases had a low birth weight (<2500 g) (Vergnano et al, 2011). Coagulase negative Staphylococci (CoNS) was regarded as a pathogen only if there were central lines in situ or if the neonate was very unwell and CoNS was the only organism cultured; it is mostly associated with prematurity. Bacterial growth identified in LOS were Gram-positive in 49* of cases and Gram-negative organisms in 42* fungi were responsible for the remaining 9* (Vergnano et al, 2011).
A prospective cohort study conducted in Northern Ireland involving 93 episodes of LOS in 61 babies found a 13* incidence of human parechovirus infection, and 54.4* of these tested positive for a concomitant bacterial infection (Davis et al, 2015). These findings reiterate the importance of awareness that neonatal sepsis may be caused not only by bacteria, and that viral causes should also be considered. A negative bacterial culture does not eliminate the possibility of sepsis.
Pathophysiology
In bacterial or viral infection the innate immune system is the first line of protection and mounts an immune response involving the release of a wide range of inflammatory mediators that possess anti-infective qualities (Wynn and Levy, 2010). These mediators include tumour necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8), all of which are all pro-inflammatory cytokines released in response to infection (Machado et al, 2014). These inflammatory mediators promote activation of immune cells, leading to the release of polymorphonuclear leukocytes, histiocytes, platelets and endothelial cells (Bayston and Cohen, 1990). This in turn results in a cascade that produces more pro-inflammatory mediators such as platelet-activating factor (PAF), arachidonic acid metabolites and histamine. Severe sepsis in neonates can be defined by the presence of these pro-inflammatory cytokines beyond the third day following diagnosis. The complex pathogenesis and imbalance, in neonatal sepsis, of interactions between pro-inflammatory and anti-inflammatory mediators is still not fully understood (Machado et al, 2014).
Neonates are highly susceptible to infection due to their poorly developed skin barrier and generally immature immune system (Satar and Özlü, 2012). Babies born before 30 weeks' gestation are particularly at risk because transfer of maternal antibodies mostly occur after this time. Decreased levels of complement protein and reduced monocyte function further compromise innate immunity, resulting in reduced ability to produce pro-inflammatory cytokines. These factors result in increased susceptibility, incidence and severity of infection in the newborn (Satar and Özlü, 2012).
Risk factors
The various risk factors associated with EOS and LOS are presented in Box 1 and Box 2. Premature birth, low birth weight and suspected/confirmed maternal sepsis carry a particularly high risk for neonatal sepsis. Mothers with a history of confirmed GBS on high vaginal swabs in the current or a previous pregnancy should be offered antibiotic prophylaxis during labour.
Box 1.Risk factors for early-onset sepsis
- Invasive group B streptococcal infection in a previous sibling in the neonatal period
- Maternal group B streptococcal colonisation, bacteriuria or infection in the current pregnancy
- Prelabour rupture of membranes
- Preterm birth following spontaneous labour (<37 weeks' gestation)
- Suspected or confirmed rupture of membranes for >18 hours in a preterm birth
- Intrapartum fever higher than 38°C, or confirmed or suspected chorioamnionitis
- Parenteral antibiotic treatment given to the pregnant woman for confirmed or suspected invasive bacterial infection (such as septicaemia) at any time during labour, or in the 24-hour periods before and after the birth [This does not refer to intrapartum antibiotic prophylaxis]
- Suspected or confirmed infection in another baby in the case of a multiple pregnancy
Source: adapted from National Institute for Health and Care Excellence, 2012
Box 2.Risk factors for late-onset sepsis
- Low birth weight
- Prematurity
- Long-term use of invasive interventions (for example, mechanical ventilation, indwelling catheters and central lines)
- Need for parenteral nutrition
- Absence of breastfeeding
- Prolonged period of hospitalisation
- Previous surgery
- Underlying respiratory or cardiovascular diseases
- Prolonged period of nil by mouth
- Low Apgar score
- Male sex
- Maternal exposure to antibiotics
Sources: National Institute for Health and Care Excellence, 2012; Simonsen et al, 2014; Fenton-Jones et al, 2017
Differential diagnoses
The three main diagnoses to consider in an acutely unwell neonate are sepsis, congenital heart disease and metabolic disorders. Other less likely diagnoses include, but are not limited to, acute surgical diagnoses, seizures, endocrine crises, enteric emergencies and trauma. Table 1 outlines the differential diagnoses to consider in an infant presenting with suspected sepsis.
Table 1. Differential diagnoses to consider
| Cardiac abnormalities | Commonly involve duct-dependent cardiac lesions such as transposition of the great arteries, pulmonary atresia, hypoplastic left heart, coarction of aorta etc (Gandhi, 2016). These neonates commonly have severe haemodynamic compromise and require time-critical appropriate management, eg prostaglandin analogues (to keep the ductus arteriosus open), fluid resuscitation, defibrillation etc, followed by transfer to specialist cardiology centres |
| Inborn errors of metabolism | Most commonly present between the 2nd and 7th day of life. Metabolic acidosis, hyper-ammonaemia, persistent hypoglycaemia and a positive family history should increase the suspicion. The newborn heel-prick test, conducted on day 5, screens for many of these congenital conditions, for example hypothyroidism, phenylketonuria, medium-chain acyl-CoA dehydrogenase deficiency, maple syrup urine disease and homocystinuria |
| Seizures | Commonly present with subtle motor automatisms, with the classic tonic-clonic movements being less common. Causes include intracranial haemorrhages, intracranial infections, electrolyte abnormalities, drug withdrawal |
| Endocrine crisis | Including hypoglycaemia, hypocalcaemia, congenital adrenal hyperplasia and thyrotoxicosis. These can present as late as 6 weeks of life |
| Enteric emergencies | Suggestive physical findings: bilious vomiting, abdominal distention and constipation may be present. Malrotation (with or without volvulus), necrotising enterocolitis and Hirschsprung's disease (delay in passage of meconium for >48 hours after birth) should be considered differentials to late-onset sepsis |
| Trauma | Both accidental injuries and non-accidental injuries should be considered. Differentials include in-hospital newborn falls, accidental falls at home (Paul et al, 2011; Gray et al, 2018), and iatrogenic birth injuries sustained during or after the delivery |
Management
History
The neonate presenting with suspected sepsis needs consideration of a number of different aspects including maternal history and perinatal history (included in risk factors for EOS and LOS and red flags, Box 3). We have suggested below a framework for health professionals to consider when obtaining a history of the baby's presentation (NICE, 2012; Fenton-Jones et al, 2017); most of these would be relevant in LOS, but would be useful to ask in neonates whose parents may have chosen to take an early discharge from the hospital and subsequently presented to the emergency department (ED):
- Gestational age and birth weight
- Method of delivery: normal delivery, instrumental or Caesarean section
- How long has the infant being unwell and what is his or her response to handling?
- Has there been any reduction/change in activity levels, eg sleepy, drowsy, irritability?
- Duration of rupture of membranes (if >18 hours increased risk of infection)
- Any reduction in fluid intake (and reduced urine output—important markers of dehydration)
- Any abnormality detected during the newborn and infant physical examination (NIPE) (Public Health England, 2013) screening results (in LOS)
- Any symptoms of breathing difficulties, heart racing, vomiting, diarrhoea, abdominal distension, fever, bulging fontanelle (examined with the neonate held in sitting position), appearing pale or mottled etc
- Whether a previous sibling has been affected by GBS sepsis.
Box 3.Red flags: aspects of symptoms to consider in a neonate presenting with suspected sepsis
- Suspected or confirmed infection in another baby in the case of a multiple pregnancy
- Respiratory distress starting >4 hours after birth
- Seizures
- Jaundice <24 hours of life
- Need for mechanical ventilation in a term baby
- Signs of shock
- Other risk factors for early-onset/late-onset sepsis
- Vomiting, excessive gastric aspirates and abdominal distension
- Local signs of infection (for example, affecting the skin or eye)
- Hypothermia (<36°C) or pyrexia (>38°C) which is non-environmental in origin
Sources: National Institute for Health and Care Excellence, 2012; Fenton-Jones et al, 2017
Examination
The features of sepsis, particularly in a neonate, are often non-specific (Fenton-Jones et al, 2017). Baseline observations should include: respiratory rate, heart rate, saturations, temperature, central capillary refill time and an AVPU (alert, voice response, pain response, unresponsive) score; these should be recorded for every infant. These observations should be plotted on a neonatal early warning score (NEWS) because neonates have specific reference ranges that will be different from those for adults and children. Paediatric early warning scores (PEWS) may be used because the neonate may be cared for in settings other than neonatal units or when presenting to the ED with LOS. It may be useful to consider some red flags while assessing the neonate as highlighted in Box 3.
Nurses working in an advanced neonatal nurse practitioner (ANNP) or enhanced neonatal nurse practitioner role may be expected to perform a neonatal examination, observing and recording skin colour, activity, response to handling, wakefulness and tone, and monitoring the baby's condition.
The absence of a fever does not rule out the possibility of sepsis because many neonates, especially those born prematurely, may not become pyrexial in response to an infection, a reflection of the immature function of the newborn physiology. An analytical study from Pakistan looking at culture-proven and probable neonatal sepsis cases admitted to the neonatal intensive care unit found that 28.9* of neonates had mild or moderate hypothermia, while 13.1* had hyperthermia (Ahmad et al, 2016). Likewise, photophobia and neck stiffness are frequently not elicited in neonates with confirmed meningitis; instead, they may show non-specific signs such as poor feeding, intolerance to handling, covering their eyes by moving their forearm and arching of their back (NICE, 2012; 2016).
Investigations
Once the clinical suspicion of EOS/LOS has been raised, a set of essential investigations, including a blood culture, should be carried out before administering antibiotics. Table 2 shows a list of investigations to consider. Special investigations such as cranial ultrasound scans and lumbar punctures may need to be delayed until the baby is stable.
Table 2. Investigations to aid diagnosis
| Blood tests (EOS and LOS) | Full blood count, C-reactive protein, urea and electrolytes, creatinine, liver function tests, a clotting screen and a blood gas including glucose and lactate measurements (NICE, 2012; 2016) |
| Blood cultures (EOS and LOS) | A 1.0 mL blood sample is suggested to detect a bacteraemia when a single paediatric blood culture bottle is used. A UK-wide national survey found that 134/139 microbiology laboratories use a single blood culture bottle (Paul et al, 2018) |
| Urine (LOS) | Culture is important in neonates even when urine analysis is normal because infants do not store urine long enough in their bladder to produce nitrites in response to bacteria (Fenton-Jones et al, 2017). Sampling from catheterisation or suprapubic aspiration may be needed |
| Chest X-ray (EOS and LOS) | Indicated in neonates presenting with features of respiratory distress or where the source of the infection has not been identified (Fenton-Jones et al, 2017). Also may indicate cardiac abnormalities |
| CSF analysis (EOS and LOS) | To be delayed in infants who are critically ill, until they are physiologically stable. If there is a clinical suspicion of sepsis, the blood culture is positive or the infant initially worsens while on antimicrobial therapy, a lumbar puncture should be performed to obtain CSF for analysis, microscopy, culture and polymerise chain reaction (NICE, 2012; Polin et al, 2012) A concurrent blood glucose is needed because CSF glucose is normally 60* of blood glucose, but in bacterial meningitis the levels of CSF glucose are greatly reduced |
| Skin/vesicle swabs (LOS) | If herpes or varicella are suspected, then vesicle (viral) swabs should be taken by puncturing the vesicle and scraping the bottom of the lesion (NICE, 2012) |
CSF=cerebrospinal fluid; EOS=early-onset sepsis; LOS=late-onset sepsis
If the infant belongs to a high-risk group or suspicion is high, antibiotics should be started without delay and specialist investigations may need to be carried out afterwards (NICE, 2012).
Treatment
Infants can present very unwell with sepsis, potentially even in a state of shock. The multidisciplinary team should initiate an ABCDE (airway, breathing, circulation, disability and exposure) approach to achieve stable status. The administration of appropriate antibiotics should remain a priority, ideally administering them within 1 hour from presentation to the hospital.
Antibiotic therapy
For EOS, NICE (2012) advises the administration of an empirical antibiotic combination of intravenous benzylpenicillin and gentamicin. The dose and duration of gentamicin administration may vary depending on hospital policy. A UK-wide survey by Fernando et al (2008), and preceding the publication of the NICE Clinical Guideline 149 (2012), found that only 69* of neonatal units were following the above antibiotic regimen for EOS.
The NICE guideline states that the need for continuation of antibiotic therapy for suspected EOS should be reviewed at 36 hours and then discontinued if the following criteria are fulfilled (NICE, 2012):
- Blood culture remains negative
- Neonate remains clinically well
- C-reactive protein (CRP) levels and trends remain reassuring
- Initial suspicion of EOS was low.
For LOS, NICE (2016) suggests using cefotaxime, with amoxicillin cover for Listeria. The length of antibiotic therapy will depend on the nature of the bacterial growth identified and site of infection. This should be decided through a joint consultation between the paediatrician and microbiologist (NICE, 2012; 2016).
Antiviral therapy
Herpes and varicella zoster infections are usually treated with antiviral agents. Acyclovir is the antiviral of choice for herpes virus infections, with the length of the therapy based on the clinical information. Infants whose mothers develop chickenpox (varicella zoster) between 7 days pre-delivery and 7 days post-delivery should be given varicella zoster immunoglobulin (VZIG) as prophylaxis. This can be given without testing the infant for antibodies (Public Health England, 2019).
Antipyretic therapy
Paracetamol is used to reduce distress and improve hydration and is dosed according to body weight, with doses varying dependent on the corrected gestational age. Ibuprofen is not recommended in infants with a body weight below 5 kg or aged <3 months (Joint Formulary Committee, 2021).
Intravenous fluid support
Fluid resuscitation for neonates should be with 0.9* normal saline, with a bolus of 10 mL/kg given over 10 minutes. A second bolus may be given if there is no improvement (NICE, 2016).
Oxygen support
Oxygen should be administered in cases of suspected sepsis when there are signs of shock or oxygen saturation of less than 92* when breathing on room air (NICE, 2016).
Monitoring
Neonates should be monitored using a NEWS or modified PEWS scoring system, with repeated assessments 2 to 4 hourly. Strict input/output monitoring of fluids is essential (Roland, 2012; Fenton-Jones et al, 2017). A change in score on a NEWS/PEWS scoring system should initiate a medical reassessment.
Role of nurses
Prognosis and outcomes of children presenting with EOS/LOS depends on the cause and the site of infection, eg sepsis, meningitis, urinary tract infection, pneumonia, or a combination of these conditions. However, early recognition and escalation to senior clinicians is likely to make a difference to prognosis and long-term outcomes. It is imperative that nurses remain aware of the common, as well as often non-specific presentations of EOS/LOS, and be familiar with the need for time-critical management. An overview of the different roles of nurses who may encounter children with EOS/LOS is presented in Table 3.
Table 3. Role of nurses in different settings
| Nurse | Role |
|---|---|
| Practice nurse |
|
| Emergency department nurses |
|
| Children's/neonatal nurses |
|
| Health visitors |
|
| Community nurses |
|
EOS=early-onset sepsis; HDU=high-dependency unit; LOS=late-onset sepsis; NEWS/PEWS=neonatal/paediatric early warning score
Case report
Case 1. Early-onset sepsis
History
A term baby is born by normal delivery with maternal premature rupture of membranes for 29 hours. The mother deteriorated in the postpartum period with a sepsis-like-presentation and was admitted to the intensive care unit. The mother also had abnormal liver function tests and she was subsequently transferred to a specialist liver unit. The baby needed resuscitation with inflation and ventilation breaths for 2 minutes and was admitted to the special care baby unit (SCBU) on continuous positive airway pressure (CPAP).
Examination
An initial assessment was performed by an ANNP, who completed a NEWS scoring. This showed that the baby had a pulse of 153 beats/minute, a blood pressure of 54/36 mmHg, a respiratory rate of 64 breaths/minute and oxygen saturations of 91* on room air. The senior paediatrician was contacted for urgent assessment and advice.
What is the immediate priority intervention?
Stabilisation of the baby using the ABCDE approach. Increasing the concentration of oxygen was done by starting CPAP and oxygen in SCBU, and siting an intravenous (IV) cannula. First dose of IV antibiotics (benzylpenicillin and gentamicin) was administered at 45 minutes of age.
What are the urgent investigations?
Essential blood tests, such as full blood count, CRP, blood gas, blood glucose, blood culture, were carried out. In addition, a chest X-ray completed at 4 hours of age showed right-sided consolidation. The baby's initial CRP was 63 mg/L and the white cell count was 26.5x109/L.
What other steps would need to be initiated?
Close monitoring of the baby with NEWS scoring was continued and a lumbar puncture considered. A cranial ultrasound scan may be considered, if there is evidence for meningitis because it will be useful to rule out major intracranial abnormalities or bleeds.
Comment
The blood culture results, available at 18 hours, showed Gram-negative rods that were later confirmed to be E. coli. The CPAP was weaned off on day 2 and the baby needed low flow oxygen for 2 further days. At 36 hours, CRP had increased to 107 mg/L and a lumbar puncture was done showing no pleocytosis. On advice from the microbiologist, the antibiotics were changed to IV cefotaxime for 14 days, with the mother also receiving 10 days of antibiotics as she gradually improved. A cranial ultrasound was performed on day 7 and was reported to be normal. The neonate was established on bottle-feeding and showed continued improvement. The baby was discharged on day 15 with the mother. At follow-up 2 months later, the baby was reported to be doing well.
Case 2. Late onset sepsis
History
A 2½ month-old female infant, born prematurely at 33 weeks' gestation and weighing 1.53 kg, was discharged home after an uneventful stay in the SCBU. The infant presented 2 days later with 24-hour history of poor feeding, drowsiness and low temperature.
Examination
The infant was assessed by the paediatric advanced nurse practitioner. On assessment the baby was drowsy, appeared mottled and was having intermittent short apnoeas. Observations showed a temperature of 35.2°C, heart rate of 170 beats/minute, respiratory rate of 62 cycles/minute, blood pressure of 48/28 mmHg, oxygen saturation 89* on room air, and central capillary refill time of 3-4 seconds. The infant was difficult to rouse and responding to voice on the AVPU scale, and appeared very pale. The rest of the clinical examination was normal.
What is the immediate priority intervention?
Stabilisation using the ABCDE approach, ensure patency of airway, and intubate and ventilate, if necessary. Give an IV fluid bolus and start on IV cefotaxime, preferably after taking a blood culture.
What investigations might be helpful?
Blood investigations (full blood count, urea and electrolytes, CRP, coagulation screen, blood gas and glucose) and a blood culture. A CT scan should be considered and a lumbar puncture, when the infant is stable. Initial CRP was 32 mg/L and white cell count 17.3x109/L. Blood gas showed a mixed acidosis with raised lactate of 6.5mmol/L. A CT scan done 1 hour later was normal. CRP peaked on day 3 at 69 mg/L and settled to normal levels by day 14.
What other steps would need to be initiated?
The infant was intubated and ventilated and was transferred to the paediatric intensive care unit. At 48 hours, there was no growth from blood cultures. A lumbar puncture on day 3 showed a white cell count of 90x106/L, glucose 1.2 mmol/L (concurrent blood glucose 4.6 mmol/L) and a Gram stain showed a Gram-positive coccus, confirmed to be GBS 24 hours later.
Comment
The diagnosis made was late onset GBS meningitis. The baby made a gradual recovery and was transferred back to the local unit on day 7. The baby received 21 days of IV antibiotics in total (changed from IV cefotaxime to IV benzylpenicillin on day 5). Although neonatal sepsis theoretically is considered to be in the first 28 days of life, GBS is known to cause LOS in babies up to 3 months of age, more so in premature babies. (Stoll et al, 1996).
At discharge, the mother was informed that in future pregnancies the newborn baby would require GBS prophylactic treatment soon after birth. Clinical follow-up over the next 2 years found the infant to have normal neurodevelopment and she was discharged from paediatric care.
Conclusion
Neonatal sepsis can be difficult to diagnose due to its non-specific and varying presenting features. Early suspicion and appropriate management, along with administration of antibiotics within the golden hour is likely to be associated with a better outcome. It is important that health professionals remain aware of the risk factors and various red flag features in a neonate presenting with non-specific features.
KEY POINTS
- Neonatal sepsis can be associated with serious morbidity and mortality
- Two most common bacterial pathogens causing neonatal sepsis are Group B Streptococcus and Escherichia coli
- Early recognition and a structured approach are necessary for assessing neonates with suspected neonatal sepsis
- Input from senior clinicians should be sought early to expedite the decision-making process
- Administration of antibiotics within the golden ‘first’ hour is likely to be associated with a better outcome
CPD reflective questions
- Why is it important to identify neonatal sepsis early and refer for urgent assessment by the paediatric team?
- Nurses are suitably placed to identify and manage neonatal sepsis. Based on your experience, consider a few challenging scenarios you may have come across of neonatal sepsis and how these were managed
- Reflecting on the case studies in the article, can you identify three or four scenarios where nurses in different clinical settings have made a difference, either by recognising neonatal sepsis early or by identifying deterioration in clinical status through regular observations, or clinical assessment, and escalating concerns to senior health professionals?