Continuing Education Activity

Neonatal sepsis is a life-threatening bloodstream infection occurring in infants younger than 28 days and remains a major cause of neonatal morbidity and mortality worldwide. This course reviews the early-onset and late-onset classifications of neonatal sepsis based on timing after birth, and its pathophysiological mechanisms, which comprise a complex interplay of maternal, environmental, and neonatal risk factors. Because clinical signs are often subtle and nonspecific, delayed recognition and treatment can rapidly lead to organ failure, septic shock, or death. Therefore, this course also discusses the need for a high index of suspicion and timely diagnostic evaluation.

This activity explores neonatal sepsis, including its risk stratification, diagnostic strategies, and evidence-based management, which requires appropriate empiric antimicrobial therapy and vigilant supportive care, particularly in preterm and very low birth weight infants who are at greatest risk. Participants will gain an in-depth understanding of the early clinical and laboratory indicators, risk assessment tools, and antimicrobial therapy for neonatal sepsis, as well as balancing prompt treatment with antibiotic stewardship. This activity for healthcare professionals is designed to enhance the learner's competence in identifying neonatal sepsis, performing the recommended evaluation, and implementing an appropriate interprofessional approach to manage this condition, thereby improving clinical decision-making, patient safety, and neonatal outcomes.

Objectives:

• Identify risk factors associated with each type of neonatal sepsis.
• Evaluate various diagnostic findings associated with neonatal sepsis.
• Differentiate the various management options for each type of neonatal sepsis presentation.
• Collaborate management strategies with interprofessional team members to improve coordination of care and outcomes for neonates affected by sepsis.

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Introduction

Neonatal sepsis is an infection involving the bloodstream in infants younger than 28 days old and remains a leading cause of morbidity and mortality among neonates, especially in middle and lower-income countries.[1][2] Neonatal sepsis is divided into 2 groups based on the time of presentation after birth: early-onset sepsis (EOS) and late-onset sepsis (LOS). EOS refers to sepsis in neonates before 72 hours of life (some experts define it more broadly to include infections developing within the first week of life), and LOS is defined as sepsis occurring at or after 72 hours of life.[3][4][5] 

Prompt recognition and treatment of neonatal sepsis are crucial, as this infection can rapidly progress to severe complications, including organ failure, septic shock, and death. Management typically includes empiric antibiotic therapy, supportive care, and close monitoring in a neonatal intensive care unit. Delayed initiation of appropriate antibiotic therapy is associated with increased morbidity and mortality. Prevention strategies focus on improving maternal health, implementing infection control measures, and promoting early detection through screening protocols.[6]

Etiology

EOS is generally caused by the transmission of pathogens from the female genitourinary system or gastrointestinal flora to the newborn or the fetus.[7] These pathogens can ascend from the vagina, cervix, and uterus and infect the amniotic fluid. Maternal chorioamnionitis, also known as intra-amniotic infection, is a well-established risk factor for EOS.[8][9] Neonates can also become infected in utero or during delivery as they pass through the vaginal canal. Maternal colonization with group B Streptococcus (GBS) is also a major risk factor. The use of fetal scalp electrodes during deliveries has been associated with a small increased risk of the development of EOS.[10] Other maternal factors that increase the risk of neonatal sepsis include delivery before 37 weeks and prolonged rupture of membranes greater than 18 hours.[11]

LOS usually occurs when pathogens are transmitted from the surrounding environment after delivery, eg, through contact with healthcare workers or caregivers. A percentage of LOS may also be caused by a late manifestation of vertically transmitted infection. Infants requiring intravascular catheter insertion or other invasive procedures that disrupt the mucosa are at increased risk for developing LOS. Preterm neonates are at higher risk for sepsis or infection than term neonates.

GBS and Escherichia coli (E coli) are the most common pathogens causing both EOS and LOS, responsible for approximately two-thirds of early-onset infections.[12][13] Gram-negative bacteria, eg, Klebsiella, Enterobacter, Citrobacter spp., and Pseudomonas aeruginosa, are commonly associated with LOS, particularly among neonates admitted to neonatal intensive care units.[14] Coagulase-negative staphylococcal species, particularly Staphylococcus epidermidis, are often the cause of hospital-associated neonatal infections in preterm and term infants with intravenous catheters that remain in place for prolonged periods. Other bacterial pathogens that cause neonatal sepsis include Staphylococcus aureus, Listeria monocytogenes, and Enterococcus. A recent systematic review and meta-analysis examining the current bacterial pathogens responsible for EOS and LOS found that gram-negative bacteria are the leading cause of both conditions in low- and lower-middle-income countries.[15]

Pathogens associated with neonatal infections vary by the source of infection, including:

• Meningitis: This infection is most commonly caused by GBS and E coli, as well as other gram-negative enteric bacilli. Other less common pathogens include coagulase-negative staphylococci (CoNS), Enterococcus faecalis, Listeria monocytogenes, Neisseria meningitidis, nontypeable Haemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, and other streptococcal species, eg, groups A, C, or G and viridans streptococci.
• Pneumonia: This condition is most commonly caused by GBS. Other pathogens include Chlamydia trachomatis, Citrobacter, Enterobacter, group A streptococci, Klebsiella, Pseudomonas, S aureus, S pneumoniae, and Serratia.
• Urinary tract infections: Infections involving the urinary tract are most frequently due to E coli, but may also involve Citrobacter, Enterobacter, Enterococcus, Klebsiella, and Proteus.
• Skin and soft tissue infections: These infections commonly arise from S aureus, GBS, and group A streptococci.
• Intestinal infections: Infections from an intestinal source, including necrotizing enterocolitis (NEC), often involve E coli, Klebsiella, other enteric gram-negative bacilli, Clostridium species, and anaerobes, eg, Bacteroides.

Viruses and fungi can also cause neonatal sepsis. Viral etiologies are less common but can lead to severe infections, with herpes simplex virus (HSV) being a significant concern.[16] HSV transmission often occurs during delivery from mothers with active genital lesions. Other viral pathogens include cytomegalovirus (CMV), enteroviruses, adenoviruses, influenza viruses, parainfluenza viruses, and respiratory syncytial virus (RSV).

Fungal infections, primarily caused by Candida species, are more prevalent in preterm infants and those with prolonged hospital stays. Risk factors for fungal sepsis include the use of broad-spectrum antibiotics, the presence of central venous catheters, and the administration of parenteral nutrition. Candida albicans and Candida parapsilosis are the most common fungal pathogens in neonatal sepsis.[17][7]

Epidemiology

The epidemiology of neonatal sepsis has been changing with time.[18] The incidence of EOS has decreased since the 1990s, primarily due to the introduction of universal screening for GBS in pregnant women and intrapartum antibiotic prophylaxis.[19] However, rates of LOS have remained relatively the same. E coli now accounts for more cases of EOS.[20] Current evidence suggests that approximately 2,200 per 100,000 live births develop neonatal sepsis, with a mortality rate of 11% to 19%, translating to about 3 million cases each year.[21] The incidence of neonatal sepsis rises as gestational age decreases.

The incidence of EOS with positive blood cultures in the United States is estimated to be 0.77 to 1 per 1,000 live births.[22][23] Due to the nonspecific neonatal presentation for sepsis and the high risk of mortality and morbidity without treatment, many asymptomatic neonates undergo a sepsis workup if risk factors are present or clinically indicated. Although approximately 7% to 13% of all neonates are treated for sepsis, only 3% to 8% have positive cultures.[11] Maternal administration of antibiotics and the low blood volume obtained for blood culture could explain the low rate of positive blood cultures.

The incidence of sepsis is significantly higher in premature infants, as well as those with very low birth weight (<1500 g). African American infants have an increased risk of GBS and LOS, likely secondary to the higher rate of GBS carrier rates in African American females. Males have a higher risk of sepsis and meningitis, especially with gram-negative enteric bacilli.[11][24] 

Pathophysiology

The immature immune system of infants is the primary factor contributing to increased neonatal susceptibility to sepsis. The immature function of polymorphonuclear neutrophils, macrophages, and T lymphocytes renders these cells unable to mount a complete inflammatory response in neonates. Furthermore, neonates have limited immunoglobulins at birth and cannot mount an adequate, quantitative, or qualitative immune response against infectious agents. 

The limited duration that premature infants spend in the uterus results in a reduced transfer of immunoglobulins to the fetus. This deficiency in immunoglobulins significantly increases the susceptibility of premature infants to sepsis compared to term infants.[25] Additionally, the innate immune system of preterm neonates is compromised by an immature epithelial barrier, which provides inadequate defense against microbial invasion[26].

Beyond these intrinsic vulnerabilities, premature infants often require multiple invasive devices, including vascular access lines, endotracheal tubes, and feeding tubes to support their survival and manage comorbidities associated with prematurity. While lifesaving, these devices serve as potential entry points for pathogens, further amplifying the risk of severe infections. Collectively, these factors create a confluence of immunologic and iatrogenic challenges, rendering preterm neonates particularly susceptible to sepsis and related complications.

History and Physical

Neonatal Sepsis Clinical Features

Clinical features of neonatal sepsis can range from nonspecific symptoms to hemodynamic instability. Early symptoms may include irritability, lethargy, or poor feeding. Signs of neonatal sepsis may develop rapidly, including respiratory distress, apnea, hypotonia, fever, hypothermia, tachycardia or bradycardia, and hypotension with poor perfusion. Furthermore, seizures can occur as the presenting manifestation in approximately 20% to 50% of cases of bacterial meningitis.[27] Therefore, the presence of seizures or a bulging fontanelle in a neonate should raise concern for meningitis.[28] Other less common findings include diarrhea, vomiting, abdominal distension, and hepatomegaly. Occasionally, the diagnosis of neonatal sepsis may only be suspected based on laboratory findings, which may reveal hyperglycemia or hypoglycemia, acidosis, or hyperbilirubinemia. 

Neonatal Sepsis Risk Factors

A high index of suspicion is therefore necessary for a timely diagnosis. Physicians must be aware of any factors that may increase an infant’s risk of developing sepsis. Prematurity and very low birth weights are also significant risk factors to consider. Maternal risk factors for EOS include GBS colonization, chorioamnionitis, preterm labor, or prolonged rupture of membranes.[11] For LOS evaluation, consideration should be given to the presence of indwelling devices, eg, central venous catheters or endotracheal tubes, as well as dependence on parenteral nutrition.

Evaluation

Laboratory Studies

Neonates with bacteremia can be asymptomatic and have a normal physical examination. Thus, laboratory testing plays a crucial role in diagnosis, and the threshold for performing lab tests should be low. 

Blood and urine culture

Bacteremia represents the predominant presentation, accounting for 82.9% of documented infections, whereas pneumonia and meningitis occur less frequently at 5% and 4.2%, respectively.[13] Therefore, collecting at least 1 mL of blood is recommended, as low-level bacteremia may not be detected with smaller aliquots.[29] Urine studies are generally not obtained during EOS evaluations, as urinary tract infections in this age group are usually secondary to hematogenous dissemination to the kidneys; however, they should be performed to evaluate LOS.[30][11]

Lumbar puncture

Notably, approximately 23% of neonates with bacteremia have concurrent meningitis, and up to 38% of those with meningitis may have negative blood cultures.[31][11] Lumbar puncture with cerebrospinal fluid (CSF) analysis and culture should be performed in any neonate with a positive blood culture, a clinical presentation that suggests central nervous system involvement (eg, bulging fontanelles, seizures), an ill-appearing neonate, or infants who deteriorate or fail to improve while on antibiotic therapy.[32][11][4] In term infants who appear clinically well and are being assessed for EOS solely on the basis of maternal risk factors, lumbar puncture is not routinely indicated.[31] Lumbar puncture is usually performed in neonates being evaluated for LOS. CSF should be analyzed for cell count and differential, protein, and glucose levels. Gram stain, culture, and molecular assays should be performed. CSF findings suggestive of meningitis include pleocytosis (CSF white blood cell [WBC] count ≥16 WBCs/mm³) with neutrophilic predominance, elevated protein levels, and reduced glucose levels.[33]

Complete blood count

A complete blood count with differential and C-reactive protein (CRP) are important lab tests, often collected serially. These indices are poor at identifying neonatal sepsis but are more effective at ruling it out.[29] Neutropenia has better specificity than neutrophilia as a marker of neonatal sepsis.[34] An elevated immature-to-total neutrophil ratio of more than 0.2 has high sensitivity and negative predictive value for predicting neonatal sepsis.[35][11] WBC and absolute neutrophil count are usually high in the first 6 hours of birth. Therefore, performing a complete blood count 12 to 24 hours after birth improves its sensitivity and negative predictive value for detecting sepsis compared with testing performed within the first 7 hours of life.[36][31] 

Additional Diagnostic Studies

An elevated neutrophil-to-lymphocyte ratio has been shown to aid in the diagnosis of neonatal sepsis.[37] CRP levels begin to rise within 6 to 8 hours of infection and peak at approximately 24 hours.[38] Persistently normal CRP levels have a 99.7% negative predictive value for neonatal sepsis.[11] Other inflammatory markers, including procalcitonin, haptoglobin, and cytokines, can also be obtained to support the diagnosis or evaluate treatment efficacy. A chest radiograph should be performed in a neonate with respiratory symptoms or signs. 

Sepsis Calculator

The EOS Kaiser sepsis calculator is a key resource for diagnosing and managing neonatal sepsis, particularly EOS in newborns.[39] The American Academy of Pediatrics (AAP) endorses this calculator for risk stratification in neonates ≥35 weeks' gestational age with suspected bacterial sepsis.[4] This risk assessment tool incorporates maternal risk factors, clinical presentation, and laboratory data to estimate the probability of EOS in infants at 35 weeks' gestation or later.

By considering factors, eg, maternal GBS status, intrapartum antibiotic prophylaxis, and infant clinical parameters, the calculator provides a more nuanced approach to sepsis evaluation than traditional methods. This approach has been shown to reduce unnecessary antibiotic use and sepsis workups in newborns, potentially decreasing healthcare costs and minimizing the risks associated with antibiotic overuse. However, clinicians should use the calculator in conjunction with clinical judgment, rather than as a standalone diagnostic tool.

Treatment / Management

Empiric Antibiotic Therapy

Empiric antibiotic treatment should be initiated when sepsis is clinically suspected, even in the absence of confirmatory laboratory data. In general, antimicrobial resistance patterns of common bacteria in the neonatal intensive care unit should guide the initial choice of antibiotics. Typical treatment regimens include intravenous (IV) ampicillin and aminoglycosides (gentamicin or amikacin) to cover the most common pathogens in EOS (GBS, E coli, Enterococcus, and Listeria monocytogenes).[29] Neonates who are critically ill and are at risk of resistant pathogens, ampicillin combined with a third- or fourth-generation cephalosporin (eg, cefotaxime, ceftazidime, or cefepime), is recommended. Cephalosporins lack antimicrobial activity against Listeria monocytogenes.

Empiric therapy in neonates with suspected LOS includes intravenous (IV) ampicillin and aminoglycosides (gentamicin or amikacin) or ampicillin combined with a third- or fourth-generation cephalosporin (eg, cefotaxime, ceftazidime, or cefepime). A combination of nafcillin (or, in severe cases, vancomycin) and an aminoglycoside can be used in neonates with LOS who have been hospitalized since birth.[40] Neonates with severe infection or hemodynamic instability should receive vancomycin and third- or fourth-generation cephalosporin (eg, ceftazidime or cefepime) to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA) and gram-negative bacteria. Aminoglycosides have poor central nervous system (CNS) penetration; for that reason, a third-generation cephalosporin should be considered if CNS infection is suspected.[41] However, ceftriaxone should be avoided, as it can lead to hyperbilirubinemia and the serious precipitation of calcium-ceftriaxone crystals.

Additionally, increasing antibiotic resistance is a concern for neonatal sepsis. Antibiotic stewardship teams play a crucial role in preventing the unjustified and prolonged use of antibiotics.[42] In neonates with culture-proven sepsis, empiric antibiotic therapy should be adjusted according to the identified pathogen and its antimicrobial susceptibility profile.

Neonatal Viral Sepsis Treatment

Neonatal sepsis caused by viral pathogens presents a significant challenge in neonatal care. Treatment typically involves targeted antiviral agents, eg, acyclovir for HSV infections or ganciclovir for CMV infections. However, the efficacy of antiviral therapy in neonatal viral sepsis can vary depending on the specific pathogen, timing of intervention, and the overall health status of the neonate. Early diagnosis and prompt initiation of antiviral treatment are crucial for improving outcomes, as delayed therapy can lead to increased morbidity and mortality.

Antifungal Therapy

Antifungal therapy plays a vital role in the management of neonatal fungal infections, significantly improving survival rates and clinical outcomes. The choice of antifungal agent depends on factors, eg, the severity of infection, gestational age, and potential adverse effects. Amphotericin B deoxycholate remains a first-line treatment option due to its broad spectrum of activity and extensive clinical experience. However, lipid formulations of amphotericin B are increasingly preferred due to their reduced nephrotoxicity. Fluconazole is another commonly used antifungal, especially for prophylaxis in high-risk preterm infants. Prompt initiation of antifungal therapy, along with supportive care and removal of central venous catheters when possible, is essential for improving survival rates and reducing complications associated with neonatal fungal sepsis.

Differential Diagnosis

Given the nonspecific signs of neonatal sepsis, several differentials must be considered, including:

• Infection due to other agents (virus, fungal, or parasite)
• Congenital heart disease
• Metabolic disease
• Neonatal vascular encephalopathy
• Prematurity and associated complications (respiratory distress syndrome, intraventricular hemorrhage, apnea of prematurity, and others)
• Hypo or hyperthyroidism
• Transient tachypnea of the newborn
• Meconium aspiration

Treatment Planning

The treatment regimen for neonatal sepsis varies based on various risk factors and conditions. The duration of therapy can vary based on the isolated organisms, the type of infection, and the presence of any neonatal complications. Most symptomatic neonates with culture-confirmed sepsis improve clinically within 24 to 48 hours. For neonates with uncomplicated bacteremia and no evidence of meningitis, antibiotic therapy is typically administered for 7 to 10 days.[43][44] 

In neonates with bacteremia, a follow-up blood culture should be performed 24 to 48 hours after starting treatment to assess treatment response. Continued signs of bloodstream infection suggest either inadequate antimicrobial activity against the pathogen or the presence of an undetected infectious focus, eg, infected central venous access devices, cardiac vegetations, abscesses, or osteomyelitis, which requires targeted management. The recommended duration of antibiotic therapy for neonates with an uncomplicated bacterial urinary tract infection is 10 to 14 days. The treatment for suspected EOS with negative cultures is variable. According to the AAP's recommendation, if blood cultures show no bacterial growth, antibiotics should be stopped within 36 to 48 hours of incubation unless definitive evidence of an infection at a specific site is obtained.[4][45]

A 14-day antibiotic course is sufficient for neonates with meningitis caused by GBS or other gram-positive organisms; however, a 3-week course is necessary for neonates with meningitis caused by E coli or other gram-negative organisms. Prolonged therapy—sometimes extending up to 8 weeks—may be necessary for neonates with ventriculitis, abscesses, or subdural empyema. The duration of therapy in pretreated neonates is guided by the following CSF findings and culture results:

• Therapy for 10 days for gram-positive and 14 days for gram-negative infection when CSF pleocytosis and a positive blood culture are present
• Therapy may be discontinued after 48 hours if the CSF results are normal and all cultures remain negative.
• Individualized meningitic-dose therapy when CSF pleocytosis is present, but cultures are negative, based on clinical assessment and alternative infectious or noninfectious causes. 

Prognosis

Mortality rates are inversely proportional to gestational age, such that preterm or younger neonates have higher mortality rates than term neonates.[46] E coli has also been found to be associated with a higher mortality rate than GBS. The introduction of GBS intrapartum antibiotic prophylaxis has led to a decrease in mortality rates caused by GBS. The treatment of clinically suspected neonates with negative cultures has also significantly decreased mortality rates. Preterm infants with sepsis are at risk for impaired neurodevelopment as well as vision impairment. Those infants pretreated with aminoglycosides may also develop ototoxicity and nephrotoxicity.

Complications

Neonatal sepsis remains a significant contributor to morbidity and mortality in neonates. Prematurity and delayed treatment are commonly associated with adverse outcomes. Very low birth weight infants have been found to have a higher risk of chronic lung disease, and extremely low birth weight infants are at a greater risk of neurodevelopmental risks, eg, hearing and visual deficits, cerebral palsy, and impaired psychomotor and mental development.[47] On the other hand, the unnecessary overuse of antibiotics can increase the chances of severe candidiasis and multidrug-resistant organisms.

Consultations

Pediatricians or neonatologists can adequately manage neonatal sepsis. However, the following subspecialties and ancillary services can provide essential support in complicated cases:

• Pediatric surgery to manage associated surgical complications (gastrointestinal perforation, abscess, necrotizing fasciitis, omphalitis, and others)
• Pediatric infectious disease specialist for infants not responding to antibiotics, or if concern regarding adequate antimicrobial coverage is present
• Pediatric pharmacists can provide meaningful input and recommendations about monitoring medication levels in the blood to avoid toxicity

Deterrence and Patient Education

Deterrence of neonatal sepsis centers on prevention, early recognition, and consistent implementation of infection-control and screening practices. Strategies include optimizing maternal health, screening and treating GBS during pregnancy, minimizing prolonged rupture of membranes, and adhering to strict hand hygiene and aseptic techniques in neonatal care settings. In hospitalized neonates, especially preterm infants, limiting unnecessary invasive procedures and promptly removing indwelling devices reduce the risk of late-onset sepsis. Judicious antibiotic use guided by evidence-based protocols and stewardship programs further deters the emergence of resistant organisms and secondary infections.

Patient and caregiver education is a critical component of neonatal sepsis management. Clinicians should clearly explain the disease process, required diagnostic tests, and treatment rationale, while providing regular updates and communicating any changes in therapy. Because neonatal sepsis is often unexpected and distressing, empathetic communication helps reduce caregiver anxiety and promotes trust. At discharge, caregivers should be educated to recognize warning signs, eg, fever, jaundice, lethargy, feeding difficulties, respiratory distress, or cyanosis, and instructed to seek immediate medical care if these occur, supporting early detection and improved outcomes.

Pearls and Other Issues

Preventing neonatal sepsis is crucial for reducing infant mortality and morbidity. Key strategies include proper hand hygiene for healthcare workers and family members, aseptic techniques during invasive procedures, and early initiation and continuation of breastfeeding. Maternal screening and treatment for GBS during pregnancy can significantly reduce the risk of early-onset sepsis, mainly caused by GBS.

Timely administration of intrapartum antibiotics to at-risk mothers and prompt recognition of sepsis symptoms in newborns are essential. Maintaining a clean birthing environment, ensuring sterile umbilical cord care, and minimizing unnecessary interventions, eg, prolonged use of central lines or mechanical ventilation, also contribute to prevention. Additionally, educating clinicians and parents about the signs of neonatal sepsis and the importance of seeking immediate medical attention can lead to earlier diagnosis and treatment, improving outcomes for affected infants.

Enhancing Healthcare Team Outcomes

Neonatal sepsis is a life-threatening bloodstream infection that remains a leading cause of morbidity and mortality among newborns. Early recognition, prompt diagnostic evaluation, and timely initiation of empiric antimicrobial therapy are critical to improving outcomes. Prevention strategies, including maternal infection screening, strict infection control practices, and judicious use of invasive devices, are essential in reducing the incidence of both early- and late-onset sepsis. Despite advances in care, recovery can be prolonged, and affected infants remain at risk for complications, including neurodevelopmental impairments, highlighting the need for vigilant, coordinated care and ongoing monitoring.

Effective management of neonatal sepsis requires an interprofessional approach that integrates clinical expertise, communication, and coordinated care. Physicians and advanced pediatric practitioners oversee diagnostic and therapeutic decisions, adjusting antimicrobials based on culture results and clinical progression. Nurses play a key role in early detection, monitoring, and patient-family education, while pharmacists guide antimicrobial selection and dosing, supporting stewardship. Obstetric clinicians ensure maternal risk factors are identified and treated, and social workers and lactation consultants support family-centered care and discharge planning. Clear communication among all team members ensures patient-centered care, promotes safety, enhances clinical decision-making, and improves overall neonatal outcomes.

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References

1.

Seale AC, Blencowe H, Manu AA, Nair H, Bahl R, Qazi SA, Zaidi AK, Berkley JA, Cousens SN, Lawn JE., pSBI Investigator Group. Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect Dis. 2014 Aug;14(8):731-741. [PMC free article: PMC4123782] [PubMed: 24974250]

2.

Milton R, Gillespie D, Dyer C, Taiyari K, Carvalho MJ, Thomson K, Sands K, Portal EAR, Hood K, Ferreira A, Hender T, Kirby N, Mathias J, Nieto M, Watkins WJ, Bekele D, Abayneh M, Solomon S, Basu S, Nandy RK, Saha B, Iregbu K, Modibbo FZ, Uwaezuoke S, Zahra R, Shirazi H, Najeeb SU, Mazarati JB, Rucogoza A, Gaju L, Mehtar S, Bulabula ANH, Whitelaw AC, Walsh TR, BARNARDS Group. Chan GJ. 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 May;10(5):e661-e672. [PMC free article: PMC9023753] [PubMed: 35427523]

3.

Wynn JL. Defining neonatal sepsis. Curr Opin Pediatr. 2016 Apr;28(2):135-40. [PMC free article: PMC4786443] [PubMed: 26766602]

4.

Puopolo KM, Benitz WE, Zaoutis TE., COMMITTEE ON FETUS AND NEWBORN. COMMITTEE ON INFECTIOUS DISEASES. Management of Neonates Born at ≥35 0/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018 Dec;142(6) [PubMed: 30455342]

5.

Jefferies AL. Management of term infants at increased risk for early-onset bacterial sepsis. Paediatr Child Health. 2017 Jul;22(4):223-228. [PMC free article: PMC5804707] [PubMed: 29480905]

6.

Kariniotaki C, Thomou C, Gkentzi D, Panteris E, Dimitriou G, Hatzidaki E. Neonatal Sepsis: A Comprehensive Review. Antibiotics (Basel). 2024 Dec 25;14(1) [PMC free article: PMC11761862] [PubMed: 39858292]

7.

Yu YQ, He XR, Wan LJ, Yang YH, Chen PY. Etiology, antimicrobial resistance, and risk factors of neonatal sepsis in China: a systematic review and meta-analysis from data of 30 years. J Matern Fetal Neonatal Med. 2022 Dec;35(25):7541-7550. [PubMed: 34470123]

8.

Escobar GJ, Li DK, Armstrong MA, Gardner MN, Folck BF, Verdi JE, Xiong B, Bergen R. Neonatal sepsis workups in infants >/=2000 grams at birth: A population-based study. Pediatrics. 2000 Aug;106(2 Pt 1):256-63. [PubMed: 10920148]

9.

Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol. 1999 Aug;94(2):274-8. [PubMed: 10432142]

10.

Kawakita T, Reddy UM, Landy HJ, Iqbal SN, Huang CC, Grantz KL. Neonatal complications associated with use of fetal scalp electrode: a retrospective study. BJOG. 2016 Oct;123(11):1797-803. [PMC free article: PMC4899296] [PubMed: 26643181]

11.

Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014 Jan;27(1):21-47. [PMC free article: PMC3910904] [PubMed: 24396135]

12.

Stoll BJ, Puopolo KM, Hansen NI, Sánchez PJ, Bell EF, Carlo WA, Cotten CM, D'Angio CT, Kazzi SNJ, Poindexter BB, Van Meurs KP, Hale EC, Collins MV, Das A, Baker CJ, Wyckoff MH, Yoder BA, Watterberg KL, Walsh MC, Devaskar U, Laptook AR, Sokol GM, Schrag SJ, Higgins RD., Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Early-Onset Neonatal Sepsis 2015 to 2017, the Rise of Escherichia coli, and the Need for Novel Prevention Strategies. JAMA Pediatr. 2020 Jul 01;174(7):e200593. [PMC free article: PMC7199167] [PubMed: 32364598]

13.

Schrag SJ, Farley MM, Petit S, Reingold A, Weston EJ, Pondo T, Hudson Jain J, Lynfield R. Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014. Pediatrics. 2016 Dec;138(6) [PubMed: 27940705]

14.

Gordon A, Isaacs D. Late onset neonatal Gram-negative bacillary infection in Australia and New Zealand: 1992-2002. Pediatr Infect Dis J. 2006 Jan;25(1):25-9. [PubMed: 16395098]

15.

Harrison ML, Dickson BFR, Sharland M, Williams PCM. Beyond Early- and Late-onset Neonatal Sepsis Definitions: What are the Current Causes of Neonatal Sepsis Globally? A Systematic Review and Meta-analysis of the Evidence. Pediatr Infect Dis J. 2024 Dec 01;43(12):1182-1190. [PMC free article: PMC11542974] [PubMed: 39264197]

16.

Fernandes ND, Arya K, Syed HA, Ward R. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 21, 2024. Congenital Herpes Simplex. [PubMed: 29939674]

17.

Molla A, Albadrani M. Prevalence and Species Distribution of Neonatal Candidiasis: A Systematic Review and Meta-Analysis. Diseases. 2024 Jul 12;12(7) [PMC free article: PMC11276108] [PubMed: 39057125]

18.

Bizzarro MJ, Raskind C, Baltimore RS, Gallagher PG. Seventy-five years of neonatal sepsis at Yale: 1928-2003. Pediatrics. 2005 Sep;116(3):595-602. [PubMed: 16140698]

19.

Van Dyke MK, Phares CR, Lynfield R, Thomas AR, Arnold KE, Craig AS, Mohle-Boetani J, Gershman K, Schaffner W, Petit S, Zansky SM, Morin CA, Spina NL, Wymore K, Harrison LH, Shutt KA, Bareta J, Bulens SN, Zell ER, Schuchat A, Schrag SJ. Evaluation of universal antenatal screening for group B streptococcus. N Engl J Med. 2009 Jun 18;360(25):2626-36. [PubMed: 19535801]

20.

Shane AL, Stoll BJ. Recent developments and current issues in the epidemiology, diagnosis, and management of bacterial and fungal neonatal sepsis. Am J Perinatol. 2013 Feb;30(2):131-41. [PubMed: 23297182]

21.

Fleischmann-Struzek C, Goldfarb DM, Schlattmann P, Schlapbach LJ, Reinhart K, Kissoon N. The global burden of paediatric and neonatal sepsis: a systematic review. Lancet Respir Med. 2018 Mar;6(3):223-230. [PubMed: 29508706]

22.

Weston EJ, Pondo T, Lewis MM, Martell-Cleary P, Morin C, Jewell B, Daily P, Apostol M, Petit S, Farley M, Lynfield R, Reingold A, Hansen NI, Stoll BJ, Shane AL, Zell E, Schrag SJ. The burden of invasive early-onset neonatal sepsis in the United States, 2005-2008. Pediatr Infect Dis J. 2011 Nov;30(11):937-41. [PMC free article: PMC3193564] [PubMed: 21654548]

23.

Stoll BJ, Hansen NI, Sánchez PJ, Faix RG, Poindexter BB, Van Meurs KP, Bizzarro MJ, Goldberg RN, Frantz ID, Hale EC, Shankaran S, Kennedy K, Carlo WA, Watterberg KL, Bell EF, Walsh MC, Schibler K, Laptook AR, Shane AL, Schrag SJ, Das A, Higgins RD., Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011 May;127(5):817-26. [PMC free article: PMC3081183] [PubMed: 21518717]

24.

Nordberg V, Iversen A, Tidell A, Ininbergs K, Giske CG, Navér L. A decade of neonatal sepsis caused by gram-negative bacilli-a retrospective matched cohort study. Eur J Clin Microbiol Infect Dis. 2021 Sep;40(9):1803-1813. [PMC free article: PMC8346411] [PubMed: 33761020]

25.

Beudeker CR, Vijlbrief DC, van Montfrans JM, Rooijakkers SHM, van der Flier M. Neonatal sepsis and transient immunodeficiency: Potential for novel immunoglobulin therapies? Front Immunol. 2022;13:1016877. [PMC free article: PMC9623314] [PubMed: 36330515]

26.

True H, Blanton M, Sureshchandra S, Messaoudi I. Monocytes and macrophages in pregnancy: The good, the bad, and the ugly. Immunol Rev. 2022 Jul;308(1):77-92. [PMC free article: PMC10317112] [PubMed: 35451089]

27.

Pong A, Bradley JS. Bacterial meningitis and the newborn infant. Infect Dis Clin North Am. 1999 Sep;13(3):711-33, viii. [PubMed: 10470563]

28.

Puopolo KM, Lynfield R, Cummings JJ., COMMITTEE ON FETUS AND NEWBORN. COMMITTEE ON INFECTIOUS DISEASES. Management of Infants at Risk for Group B Streptococcal Disease. Pediatrics. 2019 Aug;144(2) [PubMed: 31285392]

29.

Polin RA., Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012 May;129(5):1006-15. [PubMed: 22547779]

30.

Visser VE, Hall RT. Urine culture in the evaluation of suspected neonatal sepsis. J Pediatr. 1979 Apr;94(4):635-8. [PubMed: 430312]

31.

Benitz WE. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin Perinatol. 2010 Jun;37(2):421-38. [PubMed: 20569816]

32.

Aleem S, Greenberg RG. When to Include a Lumbar Puncture in the Evaluation for Neonatal Sepsis. Neoreviews. 2019 Mar;20(3):e124-e134. [PubMed: 31261050]

33.

Fleischer E, Neuman MI, Wang ME, Nigrovic LE, Desai S, DePorre AG, Leazer RC, Marble RD, Sartori LF, Aronson PL., FEBRILE YOUNG INFANT RESEARCH COLLABORATIVE. Cerebrospinal Fluid Profiles of Infants ≤60 Days of Age With Bacterial Meningitis. Hosp Pediatr. 2019 Dec;9(12):979-982. [PMC free article: PMC6877427] [PubMed: 31690569]

34.

Manroe BL, Weinberg AG, Rosenfeld CR, Browne R. The neonatal blood count in health and disease. I. Reference values for neutrophilic cells. J Pediatr. 1979 Jul;95(1):89-98. [PubMed: 480023]

35.

Jethani S, Bhutani N, Yadav A. Diagnostic utility of combined immature and total neutrophil counts along with C-reactive protein in early detection of neonatal sepsis: A cross-sectional study. Ann Med Surg (Lond). 2022 May;77:103589. [PMC free article: PMC9142396] [PubMed: 35637988]

36.

Rozycki HJ, Stahl GE, Baumgart S. Impaired sensitivity of a single early leukocyte count in screening for neonatal sepsis. Pediatr Infect Dis J. 1987 May;6(5):440-2. [PubMed: 3601489]

37.

Chen J, Yasrebinia S, Ghaedi A, Khanzadeh M, Quintin S, Dagra A, Peart R, Lucke-Wold B, Khanzadeh S. Meta-analysis of the role of neutrophil to lymphocyte ratio in neonatal sepsis. BMC Infect Dis. 2023 Nov 28;23(1):837. [PMC free article: PMC10683320] [PubMed: 38012554]

38.

Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med. 1999 Feb 11;340(6):448-54. [PubMed: 9971870]

39.

Kuzniewicz MW, Puopolo KM, Fischer A, Walsh EM, Li S, Newman TB, Kipnis P, Escobar GJ. A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis. JAMA Pediatr. 2017 Apr 01;171(4):365-371. [PubMed: 28241253]

40.

Cortese F, Scicchitano P, Gesualdo M, Filaninno A, De Giorgi E, Schettini F, Laforgia N, Ciccone MM. Early and Late Infections in Newborns: Where Do We Stand? A Review. Pediatr Neonatol. 2016 Aug;57(4):265-73. [PubMed: 26750406]

41.

Sullins AK, Abdel-Rahman SM. Pharmacokinetics of antibacterial agents in the CSF of children and adolescents. Paediatr Drugs. 2013 Apr;15(2):93-117. [PubMed: 23529866]

42.

Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017 Oct 14;390(10104):1770-1780. [PubMed: 28434651]

43.

Rohatgi S, Dewan P, Faridi MMA, Kumar A, Malhotra RK, Batra P. Seven versus 10 days antibiotic therapy for culture-proven neonatal sepsis: A randomised controlled trial. J Paediatr Child Health. 2017 Jun;53(6):556-562. [PubMed: 28398692]

44.

Islam K, Khatun N, Das K, Paul S, Ghosh T, Nayek K. Ten- vs. 14-day antibiotic therapy for culture-positive neonatal sepsis. J Trop Pediatr. 2023 Oct 05;69(6) [PubMed: 37986651]

45.

Puopolo KM, Benitz WE, Zaoutis TE., COMMITTEE ON FETUS AND NEWBORN. COMMITTEE ON INFECTIOUS DISEASES. Management of Neonates Born at ≤34 6/7 Weeks' Gestation With Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics. 2018 Dec;142(6) [PubMed: 30455344]

46.

Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, Hale EC, Newman NS, Schibler K, Carlo WA, Kennedy KA, Poindexter BB, Finer NN, Ehrenkranz RA, Duara S, Sánchez PJ, O'Shea TM, Goldberg RN, Van Meurs KP, Faix RG, Phelps DL, Frantz ID, Watterberg KL, Saha S, Das A, Higgins RD., Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics. 2010 Sep;126(3):443-56. [PMC free article: PMC2982806] [PubMed: 20732945]

47.

Wynn JL, Wong HR. Pathophysiology and treatment of septic shock in neonates. Clin Perinatol. 2010 Jun;37(2):439-79. [PMC free article: PMC2891980] [PubMed: 20569817]

Disclosure: Meenakshi Singh declares no relevant financial relationships with ineligible companies.

Disclosure: Ankit Agarwal declares no relevant financial relationships with ineligible companies.

Disclosure: Priyam Pattnaik declares no relevant financial relationships with ineligible companies.

Disclosure: Mahdi Alsaleem declares no relevant financial relationships with ineligible companies.