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Abstract

Neonatal sepsis, a bloodstream infection in the first 28 days of life, is a leading cause of morbidity and mortality among infants in both developing and developed countries. Additionally, sepsis is distinguished in neonates by unique pathophysiological and presentational factors relating to its development in immature neonatal immune systems. This review focuses on the current understanding of the mechanics and implications of neonatal sepsis, providing a comprehensive overview of the epidemiology, aetiology, pathophysiology, major risk factors, signs and symptoms and recent consensus on the diagnosis and management of both early-onset and late-onset neonatal sepsis. It also includes a discussion on novel biomarkers and upcoming treatment strategies for the condition as well as the potential of COVID-19 infection to progress to sepsis in infants.

Keywords

Neonatal sepsis E Coli Group B Streptococci fungal sepsis meningitis procalcitonin antibiotic resistance intravenous immunoglobulin Covid-19

Introduction

Sepsis is a significant contributory factor of morbidity and mortality across all age groups; however, it is distinguished in neonates by unique pathophysiological and presentational factors attributable to the immaturity of their developing immune systems.¹

Neonatal sepsis can broadly be described as a life-threatening, dysregulated inflammatory response to bloodstream infection in infants less than 28 days old.^2,3

However, it is important to highlight the difference between early-onset neonatal sepsis (EOS), which occurs within 72 hours of life, and late-onset neonatal sepsis (LOS), which occurs after this 3-day period.^2,4 This classification helps explain some of the variation in aetiology, outcomes and treatments seen with neonatal sepsis.

This review will explore the epidemiology, aetiology, pathophysiology, risk factors, clinical features, diagnosis, management and complications of both LOS and EOS, taking into account historical and current/novel research findings.

Late diagnosis has always been a significant contributor to the challenges and complications associated with neonatal sepsis, and we will be exploring the large focus in current research on finding more sensitive biomarkers and faster diagnostic means to address this.^5,6 As the morbidity and mortality associated with this condition remain high and antibiotic resistance becomes a more pressing concern globally, efforts to standardise and improve prevention and management strategies are similarly a significant focus in this field and will also be discussed in this review.^6,7

In writing this narrative review, we conducted an extensive search on PubMed/MEDLINE, EMBASE and ClinicalKey. Articles on both established knowledge and novel findings were screened on their relevance and applicability to the key topics being explored.

Epidemiology

The incidence of neonatal sepsis in the UK and other developed countries is estimated to be between 6 to 8 per 1000 live births.^8,9 In the United States, EOS incidence is up to 1 per 1000 live births, and, in 2016, the mortality rate for neonatal bacterial sepsis was approximately 14 per 100 000 live births.^10,11 With the global incidence, when taking into account low and middle-income countries (LMIC), being much higher, neonatal sepsis and other neonatal infections (NSNIs) accounted for nearly a quarter of a million deaths globally in 2016.¹²

Divergence between developed and developing countries also emerges when considering the trends regarding incidence, as while the global incidence of NSNIs has increased by about 13% from 1990 to 2019, countries with middle, middle-high and high socio-demographic indexes saw a decrease in incidence over this time period.^12,13 In 2016, the incidence of (culture-positive) sepsis seen in South Asian hospitals was 15.8 per 1000 live births, around 2 to 3 times the incidence reported in western countries.¹⁴ This difference can partially be attributed to reduced EOS rates due to increased administration of intrapartum antibiotic prophylaxis against Group B Streptococcus (GBS) in richer countries.^15,16 Furthermore, the overwhelming majority of neonatal sepsis (99%) mortality occurs in LMICs,¹⁷ and in sub-Saharan Africa alone, an estimated 300,000 neonates die of sepsis annually.¹⁸

Positively, mortality rates associated with neonatal sepsis in both developed and developing countries have been decreasing, following from both generalised improvements in maternal and neonatal care as well as improved neonatal sepsis-specific knowledge and management strategies.^19,20 Nevertheless, sepsis still accounts for an estimated 15% of deaths in young infants.^13,21

Aetiology

EOS is commonly due to vertical transmission by way of infection spreading to the neonate as they move through the vaginal canal during delivery or in-utero transmission via retrograde movement of pathogens from the vagina/cervix to the uterus and into the amniotic fluid.²² As such, GBS, which is a common commensal coloniser of female genitourinary and gastrointestinal tracts, is often cited as the most common causative organism of EOS in developed countries.^23,24 E. Coli is another significant cause, implicated in between 10% and 35% percent of EOS cases and demonstrating a greater incidence in neonates with EOS than GBS in some studies.^23
-25 E. Coli isolation rates are also concerningly rising among very low birth weight (VLBW) infants.²⁵ Staphylococcus aureus, Listeria monocytogenes, Coagulase-negative staphylococci (CoNS) and Haemophilus influenzae are other important, although less common, causes of EOS.^2,22
-24,26 As a combination of an aminoglycoside (eg, gentamicin) and ampicillin or penicillin is used to treat EOS in most cases, information regarding sensitivity to these antibiotics among the most frequently isolated bacteria is important to monitor. Recent data from EOS cases in developed countries shows nearly all GBS isolates being sensitive to both ampicillin and penicillin.^25,27 While most E. Coli isolates are likely to be sensitive to gentamicin, there is a higher level of resistance seen in these isolates (10%) to standard cover.^25,27

Conversely, LOS results from environmental exposure to infection after birth. This can be through transmission via healthcare workers, healthcare environments and other caregivers. In this case, CoNS like Staphylococcus epidermidis are the most common infection sources. Enterobacteriaceae, Staphylococcus aureus and Candida species are also relevant causes.^{1,22,23,26,28} There is, however, contention regarding the proportion of cases where CoNs are contaminants rather than the sources of sepsis and how such instances may be assessed and differentiated.²⁴ CoNs are also often more resistant to standard antibiotic regimes than other isolated LOS pathogens and may require additional cover.^24,29

Viral infections are a relatively rare cause of sepsis. However, in many instances, especially with Herpes Simplex Virus (HSV) infections, they can mimic symptoms of bacterial sepsis and should be considered in antibiotic-resistant sepsis.^30
-32 In addition to vertically transmitted HSV, Cytomegalovirus (CMV) and other TORCH infections and enteroviruses are also among the viral agents implicated in sepsis or sepsis-like syndromes of the newborn.^33,34 CMV, for example, although itself a significant cause of congenital hearing loss and other neonatal morbidities, is also linked to and found in bacterial neonatal sepsis.^35,36 Both bacterial sepsis and CMV infection induce immune dysregulation that may lead to favourable conditions for the future or concurrent development of either infection.^34
-37

Fungal invasive candidiasis is a high-mortality, non-bacterial source of LOS with an increasing incidence in the 21st century. Candida is a coloniser present in around 30% of healthcare workers, and it’s the third most common cause of LOS in VLBW infants.^38
-40 The higher prevalence in this group may be linked to increased epithelial barrier translocation ability of pathogens in VLBW infants along with dexamethasone and antibiotic use promoting the growth of the virulent filamentous form of Candida albicans.^40,41

Table 1 summarises and contrasts the major causative agents of both EOS and LOS in developed countries. It is important to note that in developing countries, where nosocomial infection is more common and seen earlier, gram-negative bacteria like Klebsiella and E. Coli are responsible for a large proportion of neonatal sepsis cases while GBS is less commonly seen.^42,43 It is important to note that there are significant regional differences in the aetiological makeup of neonatal sepsis, with 1 analysis of patients in sub-Saharan Africa finding the most frequent cause of EOS to be Salmonella enterica and Acinetobacter species and no cases attributable to GBS.⁴⁴

Table 1.

Major causative pathogens of early-onset versus late-onset neonatal sepsis.^2,22
-25.

Early-onset sepsis major pathogens	Frequency (%)	Late-onset sepsis major pathogens	Frequency (%)
Group B Streptococcus	30-60	CoNS^a	39-85
E. Coli	10-35	Staphylococcus aureus	5-18
Gram -Ve Bacteria excluding E. Coli^a	7-30	E. Coli	5-13
Staphylococcus aureus	1-7	Klebsiella Species	4-9
CoNS	1-5	Candida Species	3-8
Listeria Monocytogenes	0-1	Enterococcus Species	6-15

Abbreviation: CoNS, coagulase negative staphylococci.

In addition to E. Coli, gram-negative causes of neonatal sepsis include Klebsiella, Pseudomonas, Serratia and Enterobacter Species.

Pathophysiology and Risk Factors

The way in which bacteria are able to breach immune defences and spread to the bloodstream is often linked to the unique characteristics and weaknesses of the developing immune system shortly after birth. The altered timeline of development for preterm babies also explains why they are at particular risk of initial infection and increased severity of infection.

The stratum corneum, which is the outer layer of the epidermis that forms the first barrier of innate immunity, does not gain full functionality until about 10 days after birth and this is extended several weeks in prematurity depending on the extent of early delivery.^45,46 Additionally, neonates born at less than 28 weeks of gestation lack adequate amounts of vernix, a biofilm produced in the third trimester that acts as an additional mechanical barrier until a few hours after birth. Vernix also provides antimicrobial peptides (AMPs) like lactoferrin and lysozyme.^47,48 The relative absence of vernix further serves to increase EOS risk in extremely preterm infants.

The largest amount of maternal igG antibody transference occurs in the third trimester, and premature delivery thus impacts the level of preformed antibodies available for neonates to access upon birth.^45,49 Furthermore, the relatively greater number of goblet cells in premature neonates increases the viscosity of respiratory secretions, which results in impaired mucociliary clearance, while surfactant proteins that play important roles in respiratory mucosal defence are also reduced in this group.^50,51 Ruptured membranes >18 hours, chorioamnionitis/intra-amniotic infection and maternal infection (Most commonly UTIs followed by vulvovaginitis) during pregnancy are other key risk factors to consider.^52
-54 Not only is there a risk of vertical transmission (eg, through foetal ingestion/inhalation of amniotic fluid) in these conditions, but there is also some evidence to suggest that maternal infection may cause hypermethylation (and, therefore, decreased expression) of genes involved in foetal immune development.^55
-57 Clinically important maternal, foetal and environmental factors linked with neonatal sepsis are highlighted in Table 2.^51
-53

Table 2.

Maternal, foetal and environmental risk factors predisposing the development of neonatal sepsis.^51
-53,58,59

Maternal factors	Foetal factors	Environmental factors
Previous baby infected with invasive GBS	Prematurity (<37 wk)	Intravenous line insertion, mechanical ventilation
Chorioamnionitis	low APGAR score	Antibiotic use in neonate
Current maternal GBS colonisation, bacteriuria or active infection (UTI)	Inability to breastfeed	Frequent blood sampling
Rupture of membranes >18 h (higher association if >24 h) before labour onset	Low birth weight	Unsanitary handling of baby and umbilical cord
Multiple vaginal examinations	Meconium-stained amniotic fluid

Risk for LOS is often similarly increased by the immaturity of the neonatal immune system; however, interventions like central venous catheter and intravenous line insertion present additional pathogen entry mechanisms.⁶⁰ Furthermore, antibiotic use and hypoxia potentiate intestinal mucosal injury and microflora disruption. This is particularly relevant in neonates, where specialised innate immune cells within the intestines produce interleukin-17 (IL-17), a cytokine that plays an important role in both infection prevention/removal and the exaggerated immune responses seen in the pathogenesis of sepsis.^61
-64

Sepsis, in both adults and neonates, can be characterised as an inadequate local immune containment response to infection that provokes dysregulated systemic immune activity, leading to systemic inflammatory response syndrome (SIRS).⁶⁵ Once physical barriers have been breached, the interaction of Bacterial Lipopolysaccharide (LPS – a Pathogen Associated Molecular Pattern (PAMP) molecule) with Toll-like receptor 4 (a Pattern Recognition Receptor on myeloid cells) is a significant instigator of a pro-inflammatory cascade that upregulates the production of cytokines like tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6).⁶⁶ While these inflammatory mediators are beneficial and indeed vital for pathogen removal in the presence of small amounts of LPS, larger amounts of this endotoxin can impair the coordination and regulation of the immune response and lead to out-of-proportion vasoactive changes.⁶⁷ A similar mechanism occurs with other causative pathogens that do not possess LPS, as various PAMPs can cause immune overstimulation while other virulence factors protect bacteria from host killing or facilitate easier access to the bloodstream (eg, GBS beta-hemolysin destroys alveolar linings, allowing bacteria to enter the blood).⁶⁸ The immune response in neonates also demonstrates subtle differences in character that may predispose it to dysregulation such as lower L-selectin adhesion molecule expression and impaired formation of neutrophil extracellular traps (NETs) that hinder neutrophil killing of pathogens at the local stage.^45,69,70

Changes in vascular permeability are a central driver of both the symptomatic presentation of sepsis and the end-organ damage it can cause. Overproduction of vasodilators like prostaglandins, leukotrienes and nitric oxide (via overexpression of inducible nitric oxide synthases) following pro-inflammatory stimulation increases fluid extraversion from the systemic circulation, leading to hypotension and eventually organ hypoperfusion and damage.^71,72

Current research suggests that the magnitude of anti-inflammatory compensation, which often occurs in conjunction with rather than following a proinflammatory response, is also a significant indicator of outcome.^45,73 Early production of interleukin-10 (IL-10), an anti-inflammatory cytokine which reduces neutrophil recruitment to sites of local inflammation, was found to be associated with lower survival rates in neonatal mice with GBS-induced sepsis, and when IL-10 effects were blocked, outcomes improved.⁷⁴ The interplay and role of pro-inflammatory and anti-inflammatory mediators in both the attenuation and stimulation of SIRS in the presence of infection are thus very complex and time sensitive.

A summary of the key contributors to the pathophysiology of neonatal sepsis is shown in Figure 1.

Figure 1.

Key risk factors and events in the pathophysiology of neonatal sepsis.

Presentation, Diagnosis and Biomarkers

While the SIRS criteria and Quick Sequential Organ Failure Assessment (qSOFA) score are clinically established methods to diagnose sepsis in adults, they rely on indicators of homeostatic instability that occur later in the disease course of neonatal sepsis (when the mortality rate has already reached unacceptable levels).⁷⁵ Additionally, babies with sepsis can present asymptomatically or with non-specific symptoms.^76,77

This being said, poor feeding, subcostal and intercostal contractions, bradycardia, tachycardia, vomiting, cyanosis, high-pitched crying, fever, hypotonicity, jaundice, petechiae, convulsion, lethargy, diminished sucking reflex and groaning are all commonly reported clinical findings.^78
-80 The presence of any of these features should prompt investigation for sepsis if there are no strong alternative explanations for them.

Blood culture is the first-line investigation with the greatest evidence-backing and should be done rapidly following initial suspicion of neonatal infection. The time to positivity (ie, time taken for pathogenic organisms to grow from the time of inoculation) of suspected EOS blood cultures is between 97% and 100% in 48 hours, suggesting that antibiotic use may be safely reduced after 2 days of admission if clinical assessment does not suggest further investigation.^81,82

According to British National Institute for Health and Care Excellence (NICE) guidelines, If blood culture is positive, a lumbar puncture should be performed.⁸³ Signs of CNS dysfunction, lack of response to antibiotic treatment and the presence of clinical features or laboratory results strongly suggestive of neonatal sepsis should also be followed up with a lumbar puncture, even if blood cultures are negative.^56,84 This is as slow-growing or culture-negative causative pathogens, inadequacies of specimens taken and antibiotic use can all produce false negatives despite improvements in blood culture detection technology.⁸⁵ Consequently, Polymerase chain reaction (PCR) can be performed on culture-negative blood samples, with 1 study showing PCR identifying organisms in 45% of culture-negative cases of suspected EOS.^86,87 PCR and culture can also be performed on the cerebrospinal fluid (CSF) obtained from lumbar puncture.⁸⁸ Reductions in CSF glucose concentration and elevations in protein and white blood cell (WBC) levels may point to an ongoing bacterial infectious process.^2,89

While it is important not to prematurely rule out sepsis, the absence of an elevation in the proportion of immature neutrophils (immature neutrophils:total neutrophils <0.27) has been shown to have a high negative predictive value (NPV) for neonatal sepsis. However, elevations in this proportion are often physiological in many cases, limiting the usefulness of this measure as a diagnostic tool.^90,91 Still, this ratio shows higher sensitivity than absolute neutrophil or neutrophil band levels.⁶⁸ Leukocyte count and platelet count have also been shown to be significantly lower in neonatal sepsis cases compared to controls and may also be employed in the diagnostic workup.⁹²

Raised C-reactive protein (CRP) levels are characteristic of bacterial infection, as CRP is an acute phase protein produced by the liver that functions to promote opsonisation and phagocytosis of bacteria by binding to their polysaccharide capsules and facilitating complement blinding.^93,94 However, CRP, along with other acute phase proteins and white blood cells, can be raised in many acute inflammatory states as well as during normal foetal and neonatal development.^95,96 Similar to the immature:total neutrophil ratio, a lack of a rise in CRP is a feature that provides exclusionary utility, particularly if CRP levels remain normal 36 hours after the first administration of empirical antibiotics, as this period has been shown to be where CRP’s NPV plateaus.⁹⁷ Since CRP requires various upstream transcriptional signals to be produced, levels do not significantly rise until about 10 to 12 hours after infection, making it a relatively late marker of the infectious process.^98,99

IL-6, an inflammatory cytokine produced by lymphocytes, is an important stimulator of CRP transcription.¹⁰⁰ As such, its levels rise before CRP levels do in response to infection, and it can thus potentially suggest neonatal sepsis earlier in the disease course.⁹⁸ Unfortunately, IL-6 has a very short half-life, which limits the timeframe in which it can be used as a reliable biomarker.^98,100

Procalcitonin (PCT) is a calcitonin hormone precursor, which is produced physiologically at low concentrations by the thyroid gland in the process of calcium regulation but also by monocytes at an early stage in response to bacterial LPS.¹⁰¹ It has been shown to be a more sensitive acute phase reactant than CRP for the diagnosis of neonatal sepsis, with a 2019 meta-analysis finding PCT to have an 8% higher mean sensitivity for EOS and a 11.5% higher mean sensitivity for LOS compared to CRP.¹⁰² This being said, mean sensitivity of PCT was still only found to be 73.6% for EOS, and this entails that many neonatal infections will still go undetected, particularly at a more actionable stage.^102,103 Unfortunately, this issue reflects a wider problem with neonatal sepsis biomarkers currently in use in that their relatively suboptimal sensitivity remains a salient factor in the high morbidity and mortality of the condition.²⁴ More investigation on how to successfully implement early-phase and high sensitivity biomarkers as well as other diagnostic techniques with similar attributes into clinical practice is thus pertinent in advancing the overall outlook of neonatal sepsis management.¹⁰⁴

Prevention, Treatment and Management

Prevention strategies are a crucial factor behind EOS incidence reduction. Maternal intrapartum intravenous antibiotic administration with penicillin (or clindamycin for those with serious penicillin allergy) should ideally be given for at least 4 hours before delivery to target GBS in mothers with established GBS infection or those with relevant EOS risk factors.^56,105 These risk factors include having a previous infant with invasive GBS disease, current GBS bacteriuria, rupture of membranes >18 hours and fever in the mother.^56,105 Efforts to reduce prematurity rates, such as by improving maternal nutritional status and broader prenatal care, may also reduce neonatal sepsis incidence.^106,107

In those with suspected EOS, broad-spectrum antimicrobials should be used until the causative pathogen can be isolated and more guided therapy can be employed. A combination of intravenous aminoglycoside and either ampicillin (US guidelines) or benzylpenicillin (UK guidelines) is currently used in most settings, as this regime provides extended cover for both potential gram-positive and gram-negative sources (https://www.nice.org.uk/guidance/ng195).^{53,108,109,110} In low and middle-income countries, treatment often poses additional challenges, as there can be very high rates of resistance to this standard antibiotic therapy (particularly among gram-negative isolates) as well as technological and diagnostic limitations that hinder transitions to guided therapy.¹¹¹

Prevention of LOS can be best achieved by mitigating potential pathogen entry routes through reducing unnecessary intervention in neonatal intensive care units (eg, avoiding premature changing of central lines) and improving hygiene practices such as ensuring adequate hand washing.^28,112,113

LOS infections should normally be treated in line with guidance and incidence-data from local hospital boards. In addition to the antibiotic regime used for EOS, cephalosporins and vancomycin are also often employed due to their higher efficacy against the beta-lactamase-producing Staphylococcus bacteria more frequently encountered in LOS.^53,114

It’s important to note that there is variance between guidelines in different countries regarding when to investigate for neonatal sepsis or prescribe antibiotics. Table 3 compares the relevant criteria in the UK NICE guidelines and American Academy of Paediatrics (AAP) recommendations for EOS.^66,108,115 The inclusion of the Kaiser Permanente Sepsis Risk Calculator (SRC) as a tool in diagnosis and management is somewhat controversial, although its use is mentioned as a viable strategy in both sets of guidelines. This calculator takes into account regional EOS incidence, type of prophylaxis used, maternal GBS status and intrapartum temperature (highest value), time between membrane rupture and birth and gestational age to calculate whether there will be a clinical benefit with antibiotic prescription (depending on the baby’s clinical presentation). The score is, however, limited to evaluating babies with gestational age >34 weeks.^113,116,117

Table 3.

Key considerations from nice guidelines and aap guidelines for management of early-onset neonatal sepsis.^53,108,115

NICE guidelines	AAP guidelines
Presence of ‘red flag’ risk factor (ie, previous pregnancy with suspected/confirmed infection in baby) or a ‘red flag’ clinical Indicator (apnoea, seizures, mechanical ventilation requirement, signs of shock etc.) requires immediate antibiotics + investigation	Multivariable Analysis with the Kaiser-Permanente Sepsis Risk Calculator that yields a EOS risk estimated at ⩾3 per 1000 live births should be followed up with empirical antibiotics and relevant investigations while those with a risk of ⩾1 per 1000 live births should receive enhanced clinical observation and a blood culture; This is 1 of 3 outlined approaches that are equally recommended
Presence of 2 or more ‘non-red flag’ risk factors (invasive GBS infection in previous child of multiparous woman, rupture of membranes >18 h, chorioamnionitis diagnosis, preterm birth <37 mo gestation etc.) or 2 or more ‘non-red flag’ clinical indicators (feed intolerance, abnormalities in muscle tone, glucose level, heart rate, respiratory effort or acid-base status etc.) also requires immediate antibiotics + investigation	2nd approach (risk-factor based): suggests lab investigation and empirical antibiotics for any ill-appearing newborn or baby born to a mother with chorioamnionitis; For neonates born to a GBS-infected mother with inadequate prophylaxis, only laboratory investigation is recommended if rupture of membranes >18 h or preterm birth <37 mo gestation while observation for ⩾48 h is the sole recommendation if either of these 2 additional factors are not present
If only 1 ‘non-red flag’ risk factor or ‘non-red flag’ clinical indicator is present without any ‘red flag’ risk factors or clinical indicators, decision to prescribe antibiotics and perform investigations should be based on clinical judgement and can be adjusted based on continued monitoring	3rd approach: based on serial clinical observations and relies on the presence of clinical indicators to guide the prescribing of antibiotics or initiation of investigations
Kaiser Permanente NeonatalSepsis Calculator is mentioned as an alternative approach to these guidelines

Resistant organisms are a significant burden in both high and low-income countries, with multidrug-resistant (MDR) organisms estimated to be responsible for 30% of deaths linked to neonatal sepsis globally in 2016.¹¹⁸ In 1 Singapore healthcare setting, MDR isolates were found in 47% of neonatal sepsis infections.¹¹⁹ The incidence of Gram negative MDR isolates in particular has been increasing, and high levels of resistance to first and second-line antibiotics currently being used in neonatal sepsis guidelines is being seen on a global scale.^118,120
-122 As these revelations drive the usage of novel and less-commonly used and older antibiotics (eg, Fosfomycin) in neonatal populations, the data on safety profiles and appropriate dosing for these drugs may become worryingly scarce and in need of further investigation.^118,121

In addition to antibiotic resistance, antibiotic use in neonates is itself linked to necrotising enterocolitis development, autoimmunity later in life and other long-term effects.^123
-125 The gut microbiome plays a key role in the synthesis and availability of many inflammatory mediators and their precursors, and antibiotic use can disturb the composition of the microbiome at a critical stage in infancy, potentially giving rise to aberrant immune responses and promoting the growth of pathogenic bacteria.¹²⁶ Disruptions in gut flora may also cause changes within the gut-lung, gut-skin and gut-brain axis that have been implicated in the pathogenesis of various diseases.^127,128 As a result, although there have been limited trials to determine the reliability and accuracy of current neonatal sepsis scoring systems, the Kaiser Permanente SRC is seeing increased usage in hospitals seeking to reduce unnecessary antibiotic usage.¹⁰⁸ Serial observations may also help guide appropriate reductions in antibiotic administration.¹²⁹

Adequate management of the thermoregulatory and hemodynamic dysfunction that develops as part of a SIRS is a key factor in reducing mortality.¹³⁰ Intravenous fluids and nutrition are regularly indicated along with the transfusion of blood products. Incubator/radiant warmers can be employed to control neonatal temperature and humidity.^2,130

Intravenous immunoglobulin (IVIG) is sometimes considered in management strategies due to the theoretical enhancement it gives to the neonatal humoral immune response in addition to aiding in volume repletion. However, the transient nature of effects recorded, adverse effects and cost and sourcing considerations combined with most current data showing no clear reduction in mortality potentially suggest against its usage in this case.^131,132

Additional Recent Developments

Much of the current/recent research into sepsis affecting neonates has been focused on the discovery of novel biomarkers that will aid in the diagnosis of the condition, as late or missed diagnosis is a major factor in the high mortality of neonatal sepsis.¹³³ At the same time, the lack of definitive diagnostic methods reduces discrimination in antibiotic use and is likely linked to the growing number of antibiotic-resistant sepsis deaths (especially seen in developing countries).¹³⁴ Activin A, a member of the transforming growth factor-β (TGF-β) cytokine family, and serum amyloid A, an acute phase protein, are 2 molecular components of sepsis pathways that have shown higher sensitivity compared to more widely used markers like CRP, with their levels also rising at an earlier point in the disease course.^6,135 The value of such markers is further underscored by the low levels of bacteraemia needed to cause disease in infants (which can hinder culturing ability) and increasing focus/awareness regarding non-bacterial pathogens causing sepsis symptoms.^16,136

Metabolomics is an emerging field looking at the presence and concentration of certain metabolites/molecules produced in biological processes implicated in neonatal sepsis.¹³⁷ Technology employed in metabolomics, which has already been used to study infectious disease in adults and children, offers potential to both understand pathophysiological unknowns related to the development of neonatal sepsis and its differentiation from sepsis in other age demographics as well as to detect certain molecular patterns that are unique to the disease process and which, therefore, can be used to identify cases with more reliability.^138,139 The potential advantage of metabolomics in diagnostics over traditional biomarkers and PCR lies in its ability to discern complex and time-dependent changes in phenotypic expression that underlie the variability and nuances particularly present in the molecular development of neonatal infections.^138,140 Through metabolomic analysis, catabolites of glutathione and tryptophan pathways have been found to be raised in septic neonates. These pathways are thought to be involved in anti-inflammatory deficiencies/differences that increase sepsis susceptibility among infants. More research is ongoing to characterise these changes and additional metabolic alterations in view of improving conceptual understanding of neonatal sepsis and discovering valuable, new biomarkers.^138
-140

Given the limited options currently available to treat neonatal sepsis, there is great interest in the potential role of immunomodulation (eg, with granulocyte colony-stimulating factor or the aforementioned IVIG) in reducing sepsis rates and mortality.¹⁴¹ Success rates reported in recent trials is mixed, and more data needs to be collected clinically to realise and evaluate the translatability of strategies derived from knowledge of biochemical pathways and animal studies.^141,142 Administration of Pentoxifylline, a phosphodiesterase inhibitor, was found in 1 meta-analysis (comprising of 6 randomised control trials) to reduce all-cause mortality when used as an adjunct to antibiotics, while another meta-analysis looking at the effect of supplementation with the antimicrobial protein lactoferrin showed a reduction in incidence of the bacterial and fungal sepsis in neonates but no effect on mortality or hospital stay duration.^142
-144 Trained immunity, where an immune challenge is given in a non-lethal dose to improve innate immune mechanisms and protect against future sepsis, is also a key area of study, with 1 study showing improved survival in an experimental group of mice that were intraperitoneally given a non-lethal/low-dose septic challenge a few days before being receiving a lethal septic challenge dose.^141,145,146

In regards to COVID-19 and its ability to cause sepsis/sepsis-like presentations in neonates, as the expression of TMPRSS2 and ACE2 (transmembrane proteins that facilitate Sars-Cov-2 cellular entry) has been shown to be limited in the placenta, there is still ambiguity about the ability of the virus to be transmitted transplacentally and the mechanism for such transmission.¹⁴⁷ Furthermore, neonatal infection with COVID-19 is uncommon and largely asymptomatic, and a recent UK Obstetric Surveillance System study found only 5% of babies born to COVID positive mothers to be COVID positive themselves.^148,149 To date, there have been very few recorded cases of neonatal sepsis due to COVID-19, with 1 male premature infant with COVID-19 EOS showing a positive outcome after being treated with IVIG and corticosteroids in addition to receiving intubation and intratracheal surfactant.¹⁵⁰ The relatively lower incidence and milder presentation of neonatal COVID-19 infection compared to adult COVID-19 may be due to differences in ACE2 receptor distribution and density and less adaptive immune system-driven cytokine overactivity in neonates, but the specific pathophysiology and long-term sequelae of COVID-19 in infants are still largely unknown.^148,151,152

Complications

Complications of neonatal sepsis result from both hemodynamic stress/insufficiency as well as potential damage incurred from inflammatory mediators.

Sepsis may progress to septic shock, where persistent hypotension occurs along with largely hypoperfusion-driven end-organ damage in multiple sites. This results in acute multi-organ failure and increases the probability of death substantially.^153
-155 Other factors associated with higher mortality are low birthweight and the presence of sclerema neonatorum (hardening of subcutaneous tissue).^156,157,158

EOS is also associated with higher rates of respiratory distress and overall mortality than LOS, with global mortality estimates being 16.4% for EOS and 9.1% for LOS.^4,158

Bacterial antigens, together with inflammatory factors, stimulate tissue factor synthesis and downregulate anti-coagulative pathways, leading to a prothrombotic state and, in severe cases, disseminated intravascular coagulation (DIC).^159,160

Neonatal bacterial meningitis is another common complication of neonatal sepsis that occurs when septicaemia spreads to the meningeal linings. IL-6 and TNF-α are among the cytokines upregulated in sepsis that are brought into the brain via endothelial receptor-mediated endocytosis, where they can then activate microglial cells. Microglia stimulate apoptosis of neurons and neuronal damage through increased generation of reactive oxidative species and other inflammatory mechanisms. This may result in permanent brain damage that is reflected in the higher rates of neurological disorders like cerebral palsy seen in survivors of septic meningitis.^161,162

Conclusions

The incredible complexity of foetal and neonatal development would not be possible without nourishment from the mother and the outside world. However, these sources of life and growth also provide a portal of entry for microorganisms that can take advantage of differences between not only neonatal and adult immunity, but also between neonates at different developmental stages. Increased research needs to be undertaken to better understand these differences in order to further develop our knowledge of unique neonatal risk factors and what can be done to mitigate these.

Additionally, while progress has been made regarding mortality rates, the incidence of neonatal sepsis, especially in preterm infants and in low-income countries, remains worryingly high. It is vital that thorough screening for maternal infection and other risk factors is more widely implemented, with preventive prophylaxis employed in all relevant circumstances. Progression of infection to the inflammatory challenges that sepsis entails can be especially rapid in the neonatal demographic and is more often accompanied by dramatic hemodynamic changes that may emerge unexpectedly from an asymptomatic picture. As such, improving detection and understanding of markers with high specificity and sensitivity should be another priority among neonatologists.

Lastly, although current antibiotic guidelines are effective in treating many of those affected, growing antibiotic resistance, late diagnosis and cases that have a non-bacterial aetiology or are otherwise nonresponsive necessitate more investigation into alternative treatment strategies and their effectiveness. The impact of intervention, including antibiotic use, on future development and infection risk should also be considered.

Footnotes

Acknowledgements

We would like to thank Dr Carolyn Abernathy, consultant neonatologist at the Princess Royal Maternity Hospital in Glasgow, for her feedback and guidance.

Declarations

ORCID iD

Adi Raturi

References

Marcdante

Kliegman

Schuh

. Nelson Essentials of Pediatrics. 9th ed. Elsevier; 2023.

Singh

Alsaleem

Gray

Neonatal sepsis. StatPearls Publishing; 2022. Accessed April 19, 2023. https://www.ncbi.nlm.nih.gov/books/NBK531478/

Singer

Deutschman

Seymour

, et al. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 2016;315:801.

Ogundare

Akintayo

Aladekomo

Adeyemi

Ogunlesi

Oyelami

Presentation and outcomes of early and late onset neonatal sepsis in a nigerian hospital. Afr Health Sci. 2019;19:2390-2399.

Celik

Hanna

Canpolat

Pammi

Diagnosis of neonatal sepsis: the past, present and future. Pediatr Res. 2021;91(2):337-350.

Gilfillan

Bhandari

Neonatal sepsis biomarkers: where are we now?

Res Rep Neonatol. 2019; 9:9-20.

Yadav

Kumar Yadav

Progress in diagnosis and treatment of neonatal sepsis: a review article. J Nepal Med Assoc. 2022;60:318-324.

Staphylococcal sepsis in UK neonatal units. Arch Dis Childhood. 2012;97:210.

Cailes

Kortsalioudaki

Buttery

, et al. Epidemiology of UK neonatal infections: the neonin infection surveillance network. Arch Dis Childhood Fetal Neonatal Ed. 2017;103:F547-F553.

10.

Kumar

Shah

Fayyad

, et al. Association between hypoglycemia and the occurrence of early onset sepsis in premature infants. J Pediatr Infect Dis Soc. 2023;12:S28-S36.

11.

Ely

Driscoll

Mathews

. Infant mortality by age at death in the United States, 2016 key findings data from the national vital statistics system. 2018. Accessed April 30, 2023. https://www.cdc.gov/nchs/data/databriefs/db326-h.pdf

12.

Shen

Qian

Global, regional, and national incidence and mortality of neonatal sepsis and other neonatal infections, 1990-2019. Front Public Health. 2023;11:1139832.

13.

Gan

Lee

Yap

, et al. Contemporary trends in global mortality of sepsis among young infants less than 90 Days: a systematic review and meta-analysis. Front Pediatr. 2022;10:890767.

14.

Chaurasia

Sivanandan

Agarwal

Ellis

Sharland

Sankar

MJ.

Neonatal sepsis in South Asia: huge burden and spiralling antimicrobial resistance. BMJ. 2019; 364:k5314.

15.

American College of Obstetricians and Gynecologists. Prevention of group B streptococcal early-onset disease in newborns. American College of Obstetricians and Gynecologists. 2020. Accessed May 1, 2023. https://www.acog.org/clinical/clinical-guidance/committee-opinion/articles/2020/02/prevention-of-group-b-streptococcal-early-onset-disease-in-newborns

16.

Heath

Jardine

. Neonatal infections: group B streptococcus. U.S. National Library of Medicine. 2014. Accessed May 2, 2023. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938141/

17.

Milton

Gillespie

Dyer

, et al. Neonatal sepsis and mortality in low-income and middle-income countries from a facility-based birth cohort: an international multisite prospective observational study. Lancet Glob Health. 2022;10:e661-e672.

18.

Traoré

Sidibé

Diallo

EHM

, et al. Prevalence and factors associated with maternal and neonatal sepsis in sub-Saharan Africa: a systematic review and meta-analysis. Front Public Health. 2024;12:1272193.

19.

Xiang

Chen

, et al. Global, regional, and national burden of neonatal sepsis and other neonatal infections, 1990-2019: findings from the global burden of disease study 2019. Eur J Pediatr. 2023;182(5):2335-2343.

20.

Shane

Stoll

BJ.

Neonatal sepsis: progress towards improved outcomes. J Infect. 2014;68:S24-S32.

21.

Sinnar

Schiff

SJ.

The problem of microbial dark matter in neonatal sepsis. Emerg Infect Dis. 2020;26:2543-2548.

22.

Cortese

Scicchitano

Gesualdo

, et al. Early and late infections in newborns: where do we stand? A review. Pediatr Neonatol. 2016;57:265-273.

23.

Cailes

Vergnano

Kortsalioudaki

Heath

Sharland

The current and future roles of neonatal infection surveillance programmes in combating antimicrobial resistance. Early Hum Dev. 2015;91:613-618.

24.

Zea-Vera

Ochoa

TJ.

Challenges in the diagnosis and management of neonatal sepsis. J Trop Pediatr. 2015;61:1-13.

25.

Stoll

Puopolo

Hansen

, et al. Early-onset neonatal sepsis 2015 to 2017, the rise of escherichia coli, and the need for novel prevention strategies. JAMA Pediatr. 2020;174:e200593.

26.

Roy Chowdhury

Bharadwaj

Chandran

. Fatal, fulminant and invasive non-typeable haemophilus influenzae infection in a preterm infant: a re-emerging cause of neonatal sepsis. Trop Med Infect Dis. 2020;5:30.

27.

Flannery

Puopolo

Hansen

Gerber

Sánchez

Stoll

BJ.

Antimicrobial susceptibility profiles among neonatal early-onset sepsis pathogens. Pediatr Infect Dis J. 2021;41:263-271.

28.

Dong

Speer

CP.

Late-onset neonatal sepsis: recent developments. Arch Dis Child Fetal Neonatal Ed. 2014;100:F257-F263.

29.

Vergnano

Menson

Kennea

, et al. Neonatal infections in England: the neonin surveillance network. Arch Dis Child Fetal Neonatal Ed. 2010;96:F9-F14.

30.

Tan

LE.

Gram negative organisms and viral infections in neonatal sepsis. BMJ. 2020;371:m4248.

31.

Amel Jamehdar

Mammouri

Sharifi Hoseini

, et al. Herpes simplex virus infection in neonates and young infants with sepsis. Iran Red Crescent Med J. 2014;16:e14310.

32.

Riediger

Sauer

Matevossian

Müller

Büchler

Friess

Herpes simplex virus sepsis and acute liver failure. Clin Transplant. 2009;23:37-41.

33.

Simonsen

Anderson-Berry

Delair

Davies

HD.

Early-onset neonatal sepsis. Clin Microbiol Rev. 2014;27:21-47.

34.

Gupta

Richter

Robert

Kong

Viral sepsis in children. Front Pediatr. 2018;6:252.

35.

Ssentongo

Hehnly

Birungi

, et al. Congenital cytomegalovirus infection burden and epidemiologic risk factors in countries with Universal Screening. JAMA Network Open. 2021;4:e2120736.

36.

Mansfield

Grießl

Gutknecht

Cook

CH.

Sepsis and cytomegalovirus: foes or conspirators?

Med Microbiol Immunol. 2015;204:431-437.

37.

Silva

Concato

Tomiotto-Pellissier

, et al. Reactivation of cytomegalovirus increases nitric oxide and IL-10 levels in sepsis and is associated with changes in renal parameters and worse clinical outcome. Sci Rep. 2019;9:9016.

38.

Hsieh

Smith

Jacqz-Aigrain

, et al. Neonatal fungal infections: when to treat? Early Hum Dev. 2012;88:S6-S10.

39.

James

Ninan

. Clinical profile of neonatal candidiasis in newborn nursery. Int J Contemp Pediatr. 2018;5:334. doi:10.18203/2349-3291.ijcp20180034

40.

Leibovitz

Strategies for the prevention of neonatal candidiasis. Pediatr Neonatol. 2012;53:83-89.

41.

Arkowitz

Bassilana

Recent advances in understanding candida albicans hyphal growth. F1000Res. 2019;8:700. doi:10.12688/f1000research.18546.1

42.

Sands

Spiller

Thomson

Portal

Iregbu

Walsh

TR.

Early-onset neonatal sepsis in low- and middle-income countries: current challenges and future opportunities. Infect Drug Resist. 2022;15:933-946. doi:10.2147/idr.s294156

43.

Zelellw

Dessie

Worku Mengesha

Balew Shiferaw

Mela Merhaba

Emishaw

A systemic review and meta-analysis of the leading pathogens causing neonatal sepsis in developing countries. BioMed Res Int. 2021;2021:1-20.

44.

Blumenröder

Wilson

Ndaboine

, et al. Neonatal infection in Sub-Saharan africa: a cross-sectional pilot study on bacterial pathogens and maternal risk factors. Front Microbiol. 202325;14.

45.

Wynn

Wong

HR.

Pathophysiology of neonatal sepsis. Fetal Neonatal Physiol. 2017;2017:1536-1552.e10.

46.

Oranges

Dini

Romanelli

Skin physiology of the neonate and infant: clinical implications. Adv Wound Care. 2015;4:587-595.

47.

Singh

Archana

Unraveling the mystery of Vernix Caseosa. Indian J Dermatol. 2008;53:54.

48.

Akinbi

Narendran

Pass

Markart

Hoath

SB.

Host defense proteins in vernix caseosa and amniotic fluid. Am J Obstet Gynecol. 2004;191:2090-2096.

49.

Palmeira

Quinello

Silveira-Lessa

Zago

Carneiro-Sampaio

IGG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012;2012:1-13.

50.

Looi

Evans

Garratt

, et al. Preterm birth: born too soon for the developing airway epithelium? Paediatr Respir Rev. 2019;31:82-88.

51.

Chakraborty

Kotecha

Pulmonary surfactant in newborn infants and children. Breathe. 2013;9:476-488.

52.

Araújo

Guimarães

Risk factors for neonatal sepsis: an overview. J Pediatr Neonat Individual Med. 2020;9:e090206.

53.

Paul

Khattak

Kini

Heaton

Goel

NICE guideline review: neonatal infection: antibiotics for prevention and treatment (NG195). Arch Dis Child Educ Pract Ed. 2022;107:292-297.

54.

Centers for Disease Control and Prevention. Prevention of Perinatal Group B Streptococcal Disease: A Public Health Perspective. Centers for Disease Control and Prevention. 1996. Accessed July 13, 2024. https://www.cdc.gov/mmwr/preview/mmwrhtml/00043277.htm#:~:text=For%20women%20at%20greater%20thanhttps://www.cdc.gov/mmwr/preview/mmwrhtml/00043277.htm#:~:text=For%20women%20at%20greater%20than,been%20greater%20than%2018%20hours

55.

Ballambattu

Gurugubelli

. Neonatal sepsis: recent advances in pathophysiology and management. In: Bagchi

Das

Downs

, eds. Viral, Parasitic, Bacterial, and Fungal Infections. Academic Press; 2023:503-513.

56.

Polin

Papile

L-A

Baley

, et al. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012;129:1006-1015.

57.

Al-lawama

AlZaatreh

Elrajabi

Abdelhamid

Badran

Prolonged rupture of membranes, neonatal outcomes and management guidelines. J Clin Med Res. 2019;11:360-366.

58.

Christopher

Oral

Rose

C. A

. Multiple vaginal examinations and early neonatal sepsis. Int J Reprod Contracept Obstet Gynecol. 2019;8:876.

59.

Gallo

Romero

Bosco

, et al. Meconium-stained amniotic fluid. Am J Obstetr Gynecol. 2023;228:S1158-S1178.

60.

Kochanowicz

Nowicka

Al-Saad

Karbowski

Gadzinowski

Szpecht

Catheter-related bloodstream infections in infants hospitalized in Neonatal Intensive Care Units: a single center study. Sci Rep. 2022;12:13679.

61.

Sun

Song

Mao

Xiao

Jiang

Intrauterine hypoxia changed the colonization of the gut microbiota in newborn rats. Front Pediatr. 2021;9:675022.

62.

Chaaban

Patel

Burge

, et al. Early antibiotic exposure alters intestinal development and increases susceptibility to necrotizing enterocolitis: a mechanistic study. Microorganisms. 2022;10:519.

63.

Lawrence

Ruoss

Wynn

JL.

Il-17 in neonatal health and disease. Am J Reprod Immunol. 2017;79:e12800.

64.

Wynn

Wilson

Hawiger

, et al. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18. Proc Natl Acad Sci USA. 2016;113:E2627-E2635.

65.

Chakraborty

. Systemic Inflammatory Response Syndrome. StatPearls Publishing; 2023. Accessed April 21, 2023. https://www.ncbi.nlm.nih.gov/books/NBK547669/

66.

Swanson

Katkar

Tam

, et al. TLR4 signaling and macrophage inflammatory responses are dampened by Giv/Girdin. Proc Natl Acad Sci USA. 2020;117:26895-26906.

67.

Opal

SM.

Endotoxins and other sepsis triggers. Contrib Nephrol. 2010;167:14-24.

68.

Hanna

Streptococcus Group B. StatPearls Publishing; 2023. Accessed May 2, 2023. https://www.ncbi.nlm.nih.gov/books/NBK553143/

69.

Kim

Keeney

Alpard

Schmalstieg

FC.

Comparison of L-selectin and CD11B on neutrophils of adults and neonates during the first month of life. Pediatr Res. 2003;53:132-136.

70.

Hensler

Petros

Gray

Chung

C-S

Ayala

Fallon

EA.

The neonatal innate immune response to sepsis: checkpoint proteins as novel mediators of this response and as possible therapeutic/diagnostic levers. Front Immunol. 2022;13:940930.

71.

Hofer

Muller

Resch

. The role of C-reactive protein in the diagnosis of neonatal sepsis. In: Resch B ed. Neonatal Bacterial Infection. IntechOpen; 2013:45-58. doi:10.5772/54255

72.

Wong

Billiar

TR.

Regulation and function of inducible nitric oxide synthase during sepsis and acute inflammation. Adv Pharmacol. 1995;34:155-170.

73.

Nedeva

Menassa

Puthalakath

Sepsis: inflammation is a necessary evil. Front Cell Dev Biol. 2019;7:108.

74.

Andrade

Alves

Madureira

, et al. TLR2-induced IL-10 production impairs neutrophil recruitment to infected tissues during neonatal bacterial sepsis. J Immunol. 2013;191:4759-4768.

75.

Singh

Katheria

Vora

Advances in diagnosis and management of hemodynamic instability in neonatal shock. Front Pediatr. 2018;6:2.

76.

UTMB. Neonatal Sepsis and Other Infections. UTMB; 2014. Accessed April 24, 2023. https://www.utmb.edu/pedi_ed/NeonatologyManual/InfectiousDiseases/InfectiousDiseases2.html

77.

Tesini

. Overview of neonatal infections - pediatrics. MSD Manuals; 2023. Accessed May 1, 2023. https://www.msdmanuals.com/en-sg/professional/pediatrics/infections-in-neonates/overview-of-neonatal-infections

78.

Jatsho

Nishizawa

Pelzom

Sharma

Clinical and bacteriological profile of neonatal sepsis: a prospective hospital-based study. Int J Pediatr. 2020;2020:1-9.

79.

Akyüz

Gökce

Neopterin, procalcitonin, clinical biochemistry, and hematology in calves with neonatal sepsis. Trop Anim Health Prod. 2021;53:354.

80.

Chen

Shi

. Progress of research in neonatal sepsis. n: Fu

Liu

eds. Severe Trauma and Sepsis. Springer: 2019:277-303.

81.

De Rose

Perri

Auriti

, et al. Time to positivity of blood cultures could inform decisions on antibiotics administration in neonatal early-onset sepsis. Antibiotics. 2021;10:123.

82.

Kuzniewicz

Mukhopadhyay

Walsh

Puopolo

KM.

Time to positivity of neonatal blood cultures for early-onset sepsis. Pediatr Infect Dis J. 2020;39:634-640.

83.

Hajjar

Ting

Khurshid

28 blood culture collection practices in NICU; A national survey. Paediatr Child Health. 2022;27:e14.

84.

Raina

Kaul

Harish

Ganjoo

Mahajan

Koul

Importance of obtaining lumbar puncture in neonates with late onset septicemia a hospital based observational study from north-west india. J Clin Neonatol. 2013;2:83.

85.

Mudey

Challenges in the diagnosis of neonatal septicemia. J Datta Meghe Inst Med Sci Univ. 2021;16:579.

86.

Oeser

Pond

Butcher

, et al. PCR for the detection of pathogens in neonatal early onset sepsis. PLoS One. 2020;15:e0226817.

87.

van den Brand

van den Dungen

Bos

, et al. Evaluation of a real-time PCR assay for detection and quantification of bacterial DNA directly in blood of preterm neonates with suspected late-onset sepsis. Crit Care. 2018;22:105.

88.

Oeser

Pond

Butcher

, et al. PCR for the detection of pathogens in neonatal early onset sepsis. PLoS One. 2020;15:e0226817.

89.

Tamune

Takeya

Suzuki

, et al. Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis. Am J Emerg Med. 2014;32:263-266.

90.

Hornik

Benjamin

Becker

, et al. Use of the complete blood cell count in late-onset neonatal sepsis. Pediatr Infect Dis J. 2012;31:803-807.

91.

Saied

DA.

Can we rely on the neutrophil left shift for the diagnosis of neonatal sepsis? Need for re-evaluation. Egypt Pediat Asso Gaz. 2018;66:22-27.

92.

Worku

Aynalem

Biset

Woldu

Adane

Tigabu

Role of complete blood cell count parameters in the diagnosis of neonatal sepsis. BMC Pediatr. 2022;22:411.

93.

Du Clos

. Function of C-reactive protein. Ann Med. 2000;32:274-278.

94.

Hisamuddin

Hisam

Wahid

Raza

Validity of C-reactive protein (CRP) for diagnosis of neonatal sepsis. Pak J Med Sci. 1969;31:527-531.

95.

Priyadarsini

Behera

Mohapatra

Study of C-reactive protein in healthy neonates. Pediatr Rev: Int J Pediatr Res. 2016;3:380-384.

96.

Kaur

Singh

Early-onset neonatal sepsis: role of C-reactive protein, Micro-ESR, and gastric aspirate for polymorphs as screening markers. Int J Pediatr. 2021;2021:1-6.

97.

Stocker

van Herk

el Helou

, et al. C-reactive protein, procalcitonin, and white blood count to rule out neonatal early-onset sepsis within 36 hours: a secondary analysis of the Neonatal Procalcitonin Intervention Study. Clin Infect Dis. 2020;73:e383-e390.

98.

Eichberger

Resch

Diagnosis of neonatal sepsis: the role of inflammatory markers. Front Pediatr. 2022;10:840288.

99.

Blake

Ridker

PM.

C-reactive protein and other inflammatory risk markers in acute coronary syndromes. J Am Coll Cardiol. 2003;41:37S-42S.

100.

Liu

Fang

Xie

The value of interleukin-6 (IL-6) within 6 hours after birth in the prompt diagnosis of early-onset neonatal sepsis. Transl Pediatr. 2020;9:629-635.

101.

Morad

Rabie

Almalky

Gebriel

MG.

Evaluation of procalcitonin, C-reactive protein, and interleukin-6 as early markers for diagnosis of neonatal sepsis. Int J Microbiol. 2020;2020:1-9.

102.

Eschborn

Weitkamp

J-H.

Procalcitonin versus C-reactive protein: review of kinetics and performance for diagnosis of neonatal sepsis. J Perinatol. 2019;39:893-903.

103.

Heo

JS.

Neutrophil CD11B as a promising marker for early detection of neonatal sepsis. Clin Exp Pediatr. 2021;64:28-30.

104.

Boscarino

Migliorino

Carbone

, et al. Biomarkers of neonatal sepsis: where we are and where we are going. Antibiotics. 2023;12:1233.

105.

Committee opinion no. 797: prevention of group B streptococcal early-onset disease in newborns: correction. Obstetr Gynecol. 2020;135:978-979.

106.

Edmond

Zaidi

New approaches to preventing, diagnosing, and treating neonatal sepsis. PLoS Med. 2010;7:e1000213.

107.

Mousa

Naqash

Lim

Macronutrient and micronutrient intake during pregnancy: an overview of recent evidence. Nutrients. 2019;11:443.

108.

Fleiss

Schwabenbauer

Randis

Polin

RA.

What’s new in the management of neonatal early-onset sepsis?

Arch Dis Child Fetal Neonatal Ed. 2022;108:10-14.

109.

Du Pont-Thibodeau

Joyal

J-S

Lacroix

. Management of neonatal sepsis in term newborns. F1000Prime Rep. 2014;6:67.

110.

Fernandes

Winckworth

Lee

Akram

Struthers

Screening for early-onset fneonatal sepsis on the Kaiser Permanente sepsis risk calculator could reduce neonatal antibiotic usage by two-thirds. Pediatr Investig. 2022;6:171-178.

111.

University of Oxford. New research on preventing infant deaths due to neonatal sepsis. University of Oxford. 2021. Accessed July 13, 2023 https://www.ox.ac.uk/news/2021-08-10-new-research-preventing-infant-deaths-due-neonatal-sepsis

112.

Downey

Smith

Benjamin

DK.

Risk factors and prevention of late-onset sepsis in premature infants. Early Hum Dev. 2010;86:7-12.

113.

Vaccina

Luglio

Ceccoli

, et al. Brief comments on three existing approaches for managing neonates at risk of early-onset sepsis. Ital J Pediatr. 2021;47:159.

114.

Korang

Safi

Gluud

Lausten-Thomsen

Jakobsen

JC.

Antibiotic regimens for neonatal sepsis: a protocol for a systematic review with meta-analysis. Syst Rev. 2019;8:306.

115.

Puopolo

Benitz

Zaoutis

, et al. Management of neonates born at ⩾35 0/7 weeks’ gestation with suspected or proven early-onset bacterial sepsis. Pediatrics. 2018;142:e20182894.

116.

Pettinger

Mayers

McKechnie

Phillips

Sensitivity of the Kaiser Permanente early-onset sepsis calculator: a systematic review and meta-analysis. EClinicalMedicine. 2020;19:100227.

117.

Kimpton

Verma

Thakkar

, et al. Comparison of NICE guideline CG149 and the sepsis risk calculator for the management of early-onset sepsis on the Postnatal Ward. Neonatology. 2021;118:562-568.

118.

Folgori

Ellis

Bielicki

Heath

Sharland

Balasegaram

Tackling antimicrobial resistance in neonatal sepsis. Lancet Glob Health. 2017;5:e1066-e1068.

119.

Baharin

Duan

Loe

, et al. Burden of antibiotic resistance in infections among very-low-birthweight infants in Singapore. Ann Acad Med. 2023;52:561-569.

120.

Rallis

Giapros

Serbis

Kosmeri

Baltogianni

Fighting antimicrobial resistance in neonatal intensive care units: rational use of antibiotics in neonatal sepsis. Antibiotics. 2023;12:508.

121.

Shah

Mulla

Revdiwala

Neonatal sepsis: high antibiotic resistance of the bacterial pathogens in a neonatal intensive care unit of a tertiary care hospital. J Clin Neonatol. 2012;1:72.

122.

Downie

Armiento

Subhi

Kelly

Clifford

Duke

Community-acquired neonatal and infant sepsis in developing countries: efficacy of WHO’s currently recommended antibiotics: systematic review and meta-analysis. Arch Dis Child. 2012;98:146-154.

123.

Cotten

CM.

Adverse consequences of neonatal antibiotic exposure. Curr Opin Pediatr. 2016;28:141-149.

124.

Tripathi

Cotten

Smith

PB.

Antibiotic use and misuse in the neonatal intensive care unit. Clin Perinatol. 2012;39:61-68.

125.

Neuman

Forsythe

Uzan

Avni

Koren

Antibiotics in early life: dysbiosis and the damage done. FEMS Microbiol Rev. 2018;42:489-499.

126.

Shekhar

Petersen

FC.

The Dark Side of antibiotics: adverse effects on the infant immune defense against infection. Front Pediatr. 2020;8:544460.

127.

Stocker

Klingenberg

Navér

, et al. Less is more: antibiotics at the beginning of life. Nat Commun. 2023;14:2423.

128.

O’ Mahony

Stilling

Dinan

Cryan

JF.

The microbiome and childhood diseases: focus on brain-gut axis. Birth Defects Res C: Embryo Today: Rev. 2015;105:296-313.

129.

Frymoyer

Joshi

Allan

, et al. Sustainability of a clinical examination-based approach for ascertainment of early-onset sepsis in late preterm and term neonates. J Pediatr. 2020;225:263-268.

130.

Kurimoto

Ibara

Ishihara

Naito

Hirakawa

Yamamoto

Incubator humidity and temperature control in infants born at 22-23 weeks’ gestation. Early Hum Dev. 2022;166:105550.

131.

Ohlsson

Lacy

JB.

Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. 2020;1:CD001239.

132.

Weiss

Burchfield

DJ.

Adjunct therapies to bacterial sepsis in the neonate. Newborn Infant Nurs Rev. 2004;4:46-50. doi:10.1053/j.nainr.2003.09.003

133.

Bai

Zhao

Zhang

Jia

Zhang

Dong

Identification and validation of a novel four-gene diagnostic model for neonatal early-onset sepsis with bacterial infection. Eur J Pediatr. 2022;182:977-985. doi:10.1007/s00431-022-04753-9

134.

GARDP. Gardp study reveals that babies are increasingly dying of neonatal sepsis caused by drug-resistant bacterial infections. GARDP; 2023. Accessed May 8, 2023. https://gardp.org/gardp-study-reveals-that-babies-are-increasingly-dying-of-neonatal-sepsis-caused-by-drug-resistant-bacterial-infections/

135.

Khashana

Saleeh

Fouad

Mosbah

B-E.

Activin A is a novel biomarker in early screening of neonatal sepsis. J Clin Neonatol. 2020;9:32.

136.

H-J

Zhang

G-Q

Zhang

Shakya

Z-Y.

Probiotics prevent candida colonization and invasive fungal sepsis in preterm neonates: a systematic review and meta-analysis of randomized controlled trials. Pediatr Neonatol. 2017;58:103-110.

137.

Clish

CB.

Metabolomics: an emerging but powerful tool for precision medicine. Mol Case Stud. 2015;1:a000588.

138.

Mardegan

Giordano

Stocchero

, et al. Untargeted and targeted metabolomic profiling of preterm newborns with EarlyOnset sepsis: a case-control study. Metabolites. 2021;11:115.

139.

Wang

Cha

Zhang

Qian

Discrimination of serum metabolomics profiles in infants with sepsis, based on Liquid Chromatography-mass spectrometer. BMC Infect Dis. 2023;23:46.

140.

Bjerkhaug

Granslo

Klingenberg

Metabolic responses in neonatal sepsis: a systematic review of human metabolomic studies. Acta Paediatr. 2021;110:2316-2325.

141.

Sarafidis

Special issue “recent advances in neonatal sepsis.”

J Clin Med. 2023;12:1385.

142.

Schüller

Kramer

Villamor

Spittler

Berger

Levy

Immunomodulation to prevent or treat neonatal sepsis: past, present, and future. Front Pediatr. 2018;6:199.

143.

Pammi

Haque

KN.

Pentoxifylline for treatment of sepsis and necrotizing enterocolitis in neonates. Cochrane Database Syst Rev. 2015;3:CD004205.

144.

Pammi

Suresh

Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2017;6:CD007137.

145.

Netea

Domínguez-Andrés

Barreiro

, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20:375-388.

146.

Nakasone

Ashina

Kido

, et al. Protective role of an initial low-dose septic challenge against lethal sepsis in neonatal mice: a pilot study. J Clin Med. 2021;10:5823.

147.

Peng

Zhang

Shi

Research progress in vertical transmission of SARS-COV-2 among infants born to mothers with covid-19. Fut Virol. 2022;17:211-214.

148.

Molloy

Bearer

CF.

Covid-19 in children and altered inflammatory responses. Pediatr Res. 2020;88:340-341.

149.

Knight

Bunch

Vousden

, et al. Characteristics and outcomes of pregnant women admitted to hospital with confirmed SARS-COV-2 infection in UK: national population based cohort study. BMJ. 2020;369:m2107.

150.

Kaveh

Sadatinejad

SM.

Management of neonatal sepsis with COVID-19 infection in a premature newborn: a case report. J Neonatal Nurs. 2023;29:409-412.

151.

Ryan

Plötz

van den Hoogen

, et al. Neonates and covid-19: state of the art. Pediatr Res. 2021;91:432-439.

152.

Zimmermann

Curtis

Why is COVID-19 less severe in children? A review of the proposed mechanisms underlying the age-related difference in severity of SARS-COV-2 infections. Arch Dis Child. 2020;106:429-439.

153.

Wynn

Wong

HR.

Pathophysiology and treatment of septic shock in neonates. Clin Perinatol. 2010;37:439-479.

154.

Schoenberg

Weiss

Radermacher

Outcome of patients with sepsis and septic shock after ICU treatment. Langenbecks Arch Surg. 1998;383:44-48.

155.

Gyawali

Ramakrishna

Dhamoon

AS.

Sepsis: the evolution in definition, pathophysiology, and management. SAGE Open Med. 2019;7:205031211983504.

156.

Wilar

Lestari

Risk factors and clinical outcomes of neonatal sepsis in Manado Tertiary Referral Hospital: a single-center study. Open Access Maced J Med Sci. 2022;10:93-98.

157.

Turhan

Gürsoy

Ovali

Factors which affect mortality in neonatal sepsis. Türk Pediatri Arşivi. 2015;50:170-175.

158.

Fleischmann

Reichert

Cassini

, et al. Global incidence and mortality of Neonatal Sepsis: a systematic review and meta-analysis. Arch Dis Child. 2021;106:745-752.

159.

Semeraro

Ammollo

Semeraro

Colucci

Sepsis-associated disseminated intravascular coagulation and thromboembolic disease. Mediterr J Hematol Infect Dis. 2010;2:e2010024.

160.

Ohto

Nollet

, et al. Risk factors and treatments for disseminated intravascular coagulation in neonates. Ital J Pediatr. 2020;46:54.

161.

Sekino

Selim

Shehadah

Sepsis-associated brain injury: underlying mechanisms and potential therapeutic strategies for acute and long-term cognitive impairments. J Neuroinflammation. 2022;19:101.

162.

Mwaniki

Atieno

Lawn

Newton

CR.

Long-term neurodevelopmental outcomes after intrauterine and neonatal insults: a systematic review. Lancet. 2012;379:445-452.

Neonatal Sepsis: Aetiology,Pathophysiology,Diagnostic Advances and Management Strategies

Abstract

Keywords

Introduction

Epidemiology

Aetiology

Pathophysiology and Risk Factors

Presentation, Diagnosis and Biomarkers

Prevention, Treatment and Management

Additional Recent Developments

Complications

Conclusions

Footnotes

Acknowledgements

Declarations

ORCID iD

References