Back To Search Results

Fever in a Neonate

Editor: Matthew Mueller Updated: 8/14/2023 10:22:06 PM


The World Health Organization categorizes neonatal sepsis into early and late based on the age of onset. Early neonatal sepsis affects infants less than 72 hours of age ( some experts will advocate using 7 days as a limit for early-onset sepsis); whereas, we see late-onset infections in infants older than 72 hours to 28 days of age. Early recognition and treatment are necessary to decrease the significant morbidity and mortality in this age group.[1]


Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care


The etiology of early-onset neonatal sepsis is predominantly caused by Group Beta Streptococcal (GBS) infection followed by Escherichia coli.  Risk factors are maternal Group B streptococcal colonization, chorioamnionitis, premature or prolonged (greater than 18 hours) rupture of membranes, and preterm birth (less than 37 weeks).

The etiology of late-onset neonatal sepsis includes pathogens such as Group B strep, E. coli, Coagulase-negative Staphylococci, Staphylococcus aureus, Klebsiella pneumonia, Enterococci (more common in preterm infants), Pseudomonas, and Candida albicans. Risk factors for late-onset neonatal sepsis are prematurity, low birth weight, prolonged indwelling catheter use, invasive procedures, ventilator-associated pneumonia, and prolonged antibiotic usage.[1]


WHO statistics cite over one million neonatal deaths around the world each year result from neonatal sepsis/pneumonia making it the leading cause of infant mortality. According to the Centers for Disease Control and Prevention (CDC), the estimated incidence of early-onset neonatal sepsis in the United States is 0.77 to 1 per 1000 live births. With the establishment of guidelines for universal screening and treatment of maternal GBS colonization, the incidence of early-onset sepsis in full-term infants has decreased to 0.3 to 0.4/1000 live births. However, the incidence of late-onset sepsis remained the same (0.4/1000). [2]


The activation of the pattern recognition receptors (PRR) like extracellular, toll-like receptors (TLRs), and intracellular NOD-like receptors (NLR) and RIG-like receptors (RLR) helps in recognition of a pathogen by the local immunity.  Gram-positive, gram-negative sepsis activates TLR2 and TLR4, respectively; whereas, the double-stranded virus activates TLR3. They start an immune response by producing pro-inflammatory cytokines which cause endothelial activation and damage-causing SIRS, sepsis, and death. Premature neonates show dysregulation complement system making them susceptible to severe sepsis.[1]


Host defense proteins like opsonin (CRP), haptoglobin, lactoferrin, serum amyloid A and procalcitonin provide additional protection. Septic neonates have decreased the production of Interleukins (IL-1beta, TNF-alpha, IEN-gamma, and IL-12). The quantitative and qualitative deficits in neutrophils, neutrophil depletion of bone marrow, and decreased deformability and delayed apoptosis play a significant role in neonatal sepsis-causing endothelial damage, disseminated intravascular coagulation (DIC), and multi-organ failure.[3]

History and Physical

Neonatal sepsis has a varied presentation. The neonate could have hypo or hyperthermia, irritability or lethargy, apnea or tachypnea, bradycardia or tachycardia, poor feeding, excessive sleepiness, or being fussy. Necrotizing enterocolitis (NEC), ventilator-associated pneumonia, urinary tract infection are common in premature infants. The physical examination could be normal or may reveal signs that are suggestive of neonatal sepsis.

A careful history is very important. History should include both maternal and infant risk factors. Maternal risk factors are lack of or delayed prenatal care, maternal GBS colonization, intrapartum antibiotic use, maternal medical history including diabetes, hypertension, thyroid disease, and maternal drug abuse. Infant risk factors are prematurity, low birth weight, post-neonatal course, detailed history of NICU stay, prolonged rupture of membranes, and sick contacts.[4]


The initial workup of neonates with suspected sepsis should include complete blood count with differential (CBC-diff), chemistry panel, and cultures of the blood, urine, and cerebrospinal fluid (CSF). C- Reactive Protein (CRP) and procalcitonin can be used in conjugation with other factors as a risk stratification to identify infants at risk for serious bacterial infection. Based on the presentation, one could also include a Respiratory Pathogen panel or tests for RSV, influenza, gastrointestinal (GI) pathogens, and possibly a chest x-ray. Rochester criteria, Philadelphia criteria, and Boston criteria all recommend full septic workup in infants less than 28 days of age presenting with fever regardless of other risk factors.[5]

After the wide use of the streptococcal vaccination, the prevalence of bacteremia in febrile infants has decreased. Gomez et al. validated the “Step by Step” approach,[6] which showed that risk stratification is a workable strategy to identify low-risk infants with fever. Infants with fever at high risk for serious bacterial infection may demonstrate evidence of leukocytes in the urine, and elevated procalcitonin (greater than 0.5 Ng/ml), CRP (greater than 20 mg/L) and ANC (greater than 10,000/mm3). Wallace and Brown et al.  showed that the frequency of bacterial meningitis with urinary tract infection (UTI) is minimal.[7] Greenhow et al. concluded that 24% of well-appearing neonates with fever despite having no laboratory studies done and none of them had delayed bacteremia or meningitis.[8] Recently some centers are using the CSF molecular testing which has a turn around time of two hours to aid in the evaluation and management of febrile neonates, especially during the enteroviral season. This test is also useful if the CSF is contaminated with blood, to differentiate between bacterial and viral pathogens.

Treatment / Management

The ill-appearing neonate requires a full septic work and broad-spectrum antibiotic coverage with ampicillin and cefotaxime, the combination of which covers 100% of early neonatal infections and 93% of late-onset bacteremia. Gentamicin and penicillin can cover 94% of early infections.[9] Cefotaxime does not treat some Escherichia coli, Pseudomonas, Enterococci, Acinetobacter, and Listeria monocytogenes. Use of Cefotaxime in the NICU can cause outbreaks of drug-resistant nosocomial infections, which is a serious concern in many centers. Pediatric Infectious diseases specialists consider empiric treatment of neonatal herpes with Intravenous Acyclovir if the CSF has an elevated red cell count or in any ill-looking neonate with suspected herpes.[10] We admit and empirically treat ill-looking infants and infants with risk factors while waiting for the cultures.(B2)

Fluid resuscitation is different to treat septic shock. In term neonate, the fluid bolus is 20 ml/kg as rapidly as possible up to 60 ml/kg, whereas in the preterm neonate the fluid bolus comprises 10 ml/kg in 30-60 minutes and repeat if needed and then vasopressor support for the fluid refractory shock with dopamine and dobutamine. For catecholamine-resistant shock consider milrinone for a shock with poor LV function and normal blood pressure, nitrous oxide for low blood pressure and poor RV function,  vasopressin, or terlipressin and Inotropes for warm shock and low blood pressure and consider ECMO if the child develops persistent fetal circulation.

Based on the laboratory data, you can risk stratifying the well-looking febrile infants greater than 21 days of age with no risk factors and with no source of invasive infection into high risk, medium risk, and low risk.  You can safely observe low-risk infants at home or in the hospital without empiric treatment, meanwhile, high-risk infants are observed and treated in the hospital. You also can observe medium-risk infants in the hospital or at home before treating them empirically.[11] If in doubt admit them to the pediatric unit for observation while waiting for the culture results.[12](B2)

Differential Diagnosis

One can consider the following differential diagnoses:

  • Hypoglycemia
  • Congenital heart disease
  • Inborn errors of metabolism.
  • Congenital adrenal insufficiency
  • Congenital hypothyroidism
  • Neglect/abuse


Prognosis is excellent if treated early in full-term neonates. The prognosis is different in premature and very premature infants.


  • Neonatology
  • Infectious disease
  • Pulmonary

Enhancing Healthcare Team Outcomes

The outcome of well looking febrile infants is excellent with care coordination between the emergency medicine providers and hospitalist service. Early recognition is the most important factor in decreasing the morbidity and mortality in neonatal sepsis. The premature septic infants require a dedicated team and cooperation among various specialists like the neonatologist, pediatric infectious disease specialists, intensivist, and specialized centers to provide ECMO for the optimum outcome. Take the help of the pharmacists and infectious disease specialists in choosing and in calculating the doses for the of empiric antibiotics in premature and full-term infants both in early-onset and late-onset neonatal sepsis.

The management of well looking previously healthy febrile infants from age 7-90 days is changing from traditional teaching.  Infants from 7 to 28 days of age received full septic workup in 58% of the cases. That number dropped to 25% in infants aged 29 days-60 days, further dropped to 5% in infants aged 61 days to 90 days.[8] Evidence Level 2.

The modified Philadelphia criteria have high sensitivity and low specificity when applied to the febrile infants in this age of the improved vaccination as opposed to the age before Hemophilus influenza and streptococcal vaccination than the Rochester criteria. Evidence Level 2[13]



Shah BA, Padbury JF. Neonatal sepsis: an old problem with new insights. Virulence. 2014 Jan 1:5(1):170-8. doi: 10.4161/viru.26906. Epub 2013 Nov 1     [PubMed PMID: 24185532]


Qazi SA, Stoll BJ. Neonatal sepsis: a major global public health challenge. The Pediatric infectious disease journal. 2009 Jan:28(1 Suppl):S1-2. doi: 10.1097/INF.0b013e31819587a9. Epub     [PubMed PMID: 19106756]


Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clinical microbiology reviews. 2014 Jan:27(1):21-47. doi: 10.1128/CMR.00031-13. Epub     [PubMed PMID: 24396135]


Laptook AR, Bell EF, Shankaran S, Boghossian NS, Wyckoff MH, Kandefer S, Walsh M, Saha S, Higgins R, Generic and Moderate Preterm Subcommittees of the NICHD Neonatal Research Network. Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants. The Journal of pediatrics. 2018 Jan:192():53-59.e2. doi: 10.1016/j.jpeds.2017.09.021. Epub     [PubMed PMID: 29246358]


Aronson PL, McCulloh RJ, Tieder JS, Nigrovic LE, Leazer RC, Alpern ER, Feldman EA, Balamuth F, Browning WL, Neuman MI, Febrile Young Infant Research Collaborative. Application of the Rochester Criteria to Identify Febrile Infants With Bacteremia and Meningitis. Pediatric emergency care. 2019 Jan:35(1):22-27. doi: 10.1097/PEC.0000000000001421. Epub     [PubMed PMID: 29406479]


Gomez B, Mintegi S, Bressan S, Da Dalt L, Gervaix A, Lacroix L, European Group for Validation of the Step-by-Step Approach. Validation of the "Step-by-Step" Approach in the Management of Young Febrile Infants. Pediatrics. 2016 Aug:138(2):. pii: e20154381. doi: 10.1542/peds.2015-4381. Epub 2016 Jul 5     [PubMed PMID: 27382134]

Level 1 (high-level) evidence


Wallace SS, Brown DN, Cruz AT. Prevalence of Concomitant Acute Bacterial Meningitis in Neonates with Febrile Urinary Tract Infection: A Retrospective Cross-Sectional Study. The Journal of pediatrics. 2017 May:184():199-203. doi: 10.1016/j.jpeds.2017.01.022. Epub 2017 Feb 6     [PubMed PMID: 28185626]

Level 2 (mid-level) evidence


Greenhow TL, Hung YY, Pantell RH. Management and Outcomes of Previously Healthy, Full-Term, Febrile Infants Ages 7 to 90 Days. Pediatrics. 2016 Dec:138(6):. pii: e20160270. Epub 2016 Nov 1     [PubMed PMID: 27940667]


Puopolo KM, Eichenwald EC. No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years. Pediatrics. 2010 May:125(5):e1031-8. doi: 10.1542/peds.2009-1573. Epub 2010 Apr 12     [PubMed PMID: 20385650]

Level 2 (mid-level) evidence


Muller-Pebody B, Johnson AP, Heath PT, Gilbert RE, Henderson KL, Sharland M, iCAP Group (Improving Antibiotic Prescribing in Primary Care). Empirical treatment of neonatal sepsis: are the current guidelines adequate? Archives of disease in childhood. Fetal and neonatal edition. 2011 Jan:96(1):F4-8. doi: 10.1136/adc.2009.178483. Epub 2010 Jun 28     [PubMed PMID: 20584804]


Hyde TB, Hilger TM, Reingold A, Farley MM, O'Brien KL, Schuchat A, Active Bacterial Core surveillance (ABCs) of the Emerging Infections Program Network. Trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in San Francisco and Atlanta. Pediatrics. 2002 Oct:110(4):690-5     [PubMed PMID: 12359781]


Madhi F, Jung C, Timsit S, Levy C, Biscardi S, Lorrot M, Grimprel E, Hees L, Craiu I, Galerne A, Dubos F, Cixous E, Hentgen V, Béchet S, Urinary-tract Infection due to Extended-Spectrum Beta-lactamase–producing Enterobacteriaceae in Children Group, Bonacorsi S, Cohen R. Febrile urinary-tract infection due to extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: A French prospective multicenter study. PloS one. 2018:13(1):e0190910. doi: 10.1371/journal.pone.0190910. Epub 2018 Jan 25     [PubMed PMID: 29370234]

Level 2 (mid-level) evidence


Aronson PL, Wang ME, Shapiro ED, Shah SS, DePorre AG, McCulloh RJ, Pruitt CM, Desai S, Nigrovic LE, Marble RD, Leazer RC, Rooholamini SN, Sartori LF, Balamuth F, Woll C, Neuman MI, Febrile Young Infant Research Collaborative. Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture. Pediatrics. 2018 Dec:142(6):. doi: 10.1542/peds.2018-1879. Epub 2018 Nov 13     [PubMed PMID: 30425130]