A 2-week-old Neonate with Fever
After reading this article and answering the review questions, the reader will be able to:
- List the causes of neonatal fever by time frame
- Describe the unique factors that place neonates at higher risk for serious bacterial infection
- Describe the workup and management of neonatal fever
You receive a call from an outpatient provider who has a 2-week-old male infant in his office. The baby, who had a normal birth history, newborn course and went home with mother at 48 hours, was brought in because he had a rectal temperature at home of 100.9°F. The baby is exclusively breastfed and has had no change in feeding, voiding, stooling or sleeping patterns. There was no cough, rhinorrhea, vomiting, diarrhea or rash. He seemed a little "irritable" when febrile but has otherwise been well. No acetaminophen was given. There are no ill contacts at home. In the office the baby is afebrile, has normal vital signs and a normal physical exam. The caller has several questions: 1) Does fever at home count as a fever if the baby is afebrile in the office, 2) Can the fever be attributed to over-bundling or a benign viral infection, and 3) Is the fever a sign of something more ominous like a severe bacterial or viral infection?
Fever is a common reason that neonates are brought to the attention of an ED or primary care physician. While in older children, we often counsel parents to pay less attention to the height of the fever and more attention to how a child looks, this same advice does not apply to neonates. Fever in the neonatal period, age 0-28 days, represents a true medical emergency because, in this age group, fever may be the only presenting sign or symptom of a more severe bacterial or viral infection. The differential diagnosis of fever in the neonate is broad but our foremost concern as providers is the potential of a life-threatening infection. The incidence of serious bacterial infection (SBI) is highest in neonates and has been reported to be between 7-13 percent.1-3 Other factors including an immature immune system, a relatively limited range of behaviors, and exposure to transplacentally, perinatally and postnatally acquired virulent bacteria and viruses place neonates at higher risk of severe infection than older children.4
The commonly accepted definition of fever, temperature ≥38°C or 100.4°F, has its roots in 19th century Germany. The largest study to date was done in the 1800s by Carl Wunderlich who took several million axillary temperature readings in 25,000 well subjects and arrived at 37°C as the average temperature and 38°C as the upper limit of normal temperature.5 Since then, two systematic reviews, in which rectal temperatures were compared with axillary and tympanic temperatures, concluded that temperatures measured at the axilla and tympanic membrane vary greatly from rectal temperatures.6-7 Subjective assessment of tactile fever by parental report is also variable and approaches roughly the same sensitivity as tympanic and axillary which is about 80%.8-9 Therefore, rectal temperature is the gold standard for fever detection and most closely represents core body temperature.6-9 Furthermore, objective assessment of fever at home of ≥38°C is considered a fever even in the absence of a fever in the office or emergency department. This is based on an outpatient study that found that 6/63 patients ≤3 months with a serious bacterial infection were febrile at home but afebrile in the office.10
Bundling and warm environments as a cause of fever appears to be more significant in the first hours and days of life than in older infants. One small study on term infants (average age 39 hours ± 20.3 hours) showed that in the first days of life, bundling and warm environments can indeed elevate core body temperature.12 However another study in older well term infants age 11 days to 95 days showed that bundling and warm environments raised skin temperature but not core body temperature.13 While environmentally induced fevers in the neonate are usually neither high nor sustained, other more serious causes of fever must be excluded. Obtaining an accurate and objective temperature is especially important in the neonate as it has implications for evaluation and management.
Causes of Neonatal Fever
The infectious causes of fever (see Table 1) are best understood with respect to risk of morbidity and mortality as well as age of onset, i.e., early-onset (0-6 days) and late-onset (7-28 days).
Table 1. Causes of Early- and Late-onset Septicemia in a Neonate
Group B Streptococcus
Group B Streptococcus
Early-onset bacterial septicemia is often non-focal, severe and rapidly progressive while late-onset disease often presents as a focal infection like urinary tract infection, meningitis or pneumonia. Ninety percent of early-onset neonatal sepsis occurs in the first 24 hours of life.11 Universal maternal screening for group B streptococcus (GBS) and prophylaxis has been a success story resulting in a dramatic reduction of early-onset GBS sepsis by 65%.14
Nonetheless, GBS is still the leading cause of early-onset neonatal sepsis and, in conjunction with Escherichia Coli, accounts for a majority of infections. While Streptococcus pneumoniae is relatively unusual in this age group, it is associated with extremely high morbidity and mortality approaching 50%.15 Certain maternal risk factors have been associated with early onset bacterial infections including preterm delivery, premature or prolonged rupture of membranes, chorioamnionitis, urinary tract infection, early post-partum fever, no prenatal care, and fetal hypoxia.11
Other causes of early onset fever include immature thermoregulation, maternal epidural fever, dehydration, and benign self-limiting viruses.16-19 Late onset causes of fever are also listed in Table 1. Most notably, the incidence of late-onset GBS sepsis has been unchanged by the 2002 GBS screening and prophylaxis guidelines.14 Because neonatal sepsis remains an important and sometimes difficult to detect cause of early and late-onset fever with significant morbidity and mortality, the more benign causes must remain diagnoses of exclusion.
Clinical Signs and Management of Neonatal Fever
The signs and symptoms of a SBI can range from subtle to more overt. Subtle signs include poor feeding, increased sleepiness, jaundice, abdominal distension, and alteration of voiding or stooling patterns. More dramatic signs include respiratory distress, apnea, seizures and poor perfusion progressing to shock. In neonates presenting with fever, obtaining a careful history and physical exam is paramount. Rash, bulging fontanel, and a paradoxical reaction to comfort measures can be important clues on physical exam. It is important to remember, however, that even in a neonate with a SBI, the physical exam can be completely normal. In a study done on infants <60 days with bacterial meningitis, neurologic signs like bulging fontanelle (30%) and nuchal rigidity (8%) were variably present.20
Ill-appearing neonates with fever and an obvious focal source of infection or abnormal laboratory evaluation have a higher likelihood of having a SBI.11 The dilemma lies with the well-appearing neonate with fever as is demonstrated in the case above. Roughly 20 percent of infants <60 days with fever look well and do not have an obvious focus of infection.3 Studies have shown that even very experienced clinicians are not good at determining which well-appearing neonates with fever have SBI and which do not.22,23 Objective behavioral scoring systems that predict serious bacterial infection in older children have not been validated in infants.23 Multiple screening criteria including the Rochester, Philadelphia, and Pittsburgh criteria (see Table 2) have been developed to try to identify those infants at low risk of SBI.
Table 2: Example of Screening Criteria - Rochester
Prior to the development of these guidelines, all well-appearing infants less than 90 days with fever were admitted to the hospital for empiric antibiotics after a complete laboratory evaluation. The use of these low-risk screening criteria has dramatically changed the way we treat older, well-appearing infants age 29 to 90 days with fever by reducing hospitalization and empiric antibiotic use. There is considerable debate in the literature as to whether these low-risk screening criteria may be safely applied to the neonatal population.1,2,24,25 The current standard of care for management of the well-appearing febrile neonate (less than 29 days old) is to do a complete laboratory evaluation of the blood, urine and CSF with admission to the hospital for empiric antibiotics until cultures show no growth for at least 48 hours. A recent meta-analysis that included infants from 0 to 60 days old suggested that careful and judicious use of the low-risk screening criteria in the neonatal period is safe and that certain very carefully selected neonates might be observed in the hospital without antibiotics after a complete and normal laboratory evaluation.25 While the jury is still out regarding withholding of antibiotics with close observation in the hospital in this population, there is absolutely no debate that even the well-appearing neonate with fever needs a complete laboratory evaluation including CBC with manual differential, blood culture, a catheterized urinalysis, urine culture, lumbar puncture with CSF cell count, glucose, protein, gram stain and culture and hospitalization.
In general, antibiotic choice includes ampicillin for listeria and GBS coverage and a third generation cephalosporin for coverage of E. coli and other enteric gram-negative organisms. Ceftriaxone is avoided in the first 28 days of life due to the risk of hyperbilirubinemia and biliary sludging. In the ill-appearing neonate birth to six days of age, ampcillin and gentamicin are used. Vancomycin is added in the ill-appearing neonate over seven days of age for coverage of resistant S. pneumoniae. Testing for HSV and empiric acyclovir are not indicated in the well-appearing infant and are reserved for the neonate with seizures, septic appearance or mononuclear CSF pleocytosis.21,26
Despite clear guidelines for the workup of fever in the well-appearing neonate, adherence to these guidelines in the ED and ambulatory setting is quite variable. One study showed that even in tertiary pediatric emergency departments there are wide differences in the approach to fever in infants.27 Another study done in the outpatient setting showed that Pediatric providers only followed current guidelines 42% of the time.10
What's New in Neonatal Fever
In the never ending search for predictors of SBI in neonates with fever, two laboratory markers, C-reactive protein (CRP) and Procalcitonin (PCT) have been evaluated. CRP is an acute phase protein released by the liver about 12 hours after onset of tissue damage or inflammation, reaching a plateau between 20-72 hours.28 A recent study in well-appearing febrile neonates who presented to the ED showed that CRP and ANC obtained >12 hours after onset of fever were accurate and much better than a CBC at predicting SBI.29 However, other studies have shown that CRP is not sensitive or specific enough as it can remain low in bacterial infections and can be high in viral infections.30,31 Its kinetics may also limit its use as an early marker of SBI in neonates. PCT, a peptide having characteristics of a cytokine, hormone and an acute phase reactant, is detected in the plasma two hours after injection of endotoxins and reaches a plateau at 12 hours.28 While PCT is an excellent marker of SBI in children, it has some limitations in predicting SBIs in neonates for the following reasons: 1) in the immediate newborn period there is a physiologic rise in PCT, 2) it is not specific for severe bacterial infection as it rises in disease processes other than SBI (such as respiratory distress syndrome, asphyxia, intracranial hemorrhage, and pneumothorax, and 3). it can be blunted by prepartum and intrapartum antibiotics.28 Although most studies show that PCT is superior to CRP in sensitivity and specificity, the limitations above and its cost make it less clinically useful at the present time.
Fever in the neonate remains a common and challenging problem. Because of the high risk and difficulty of identifying those with SBI, it is a problem that demands a cautious approach. Ongoing investigation into improving the care and management of fever in the neonate is needed. The role of newer laboratory screening tests in ruling out SBI is still unclear. Until further evidence and reliable guidelines are available in this age group, comprehensive and meticulous evaluation is essential; hospitalization (with or without antibiotics) is recommended until the results of cultures are available to guide treatment.
- Kadish HA, Loveridge B, Tobey J, Bolte RG, Corneli HM. Applying outpatient protocols in febrile infants 1-28 days of age: can the threshold be lowered? Clin Pediatr (Phila). Feb 2000;39(2):81-88.
- Baker MD, Bell LM. Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. Arch Pediatr Adolesc Med. May 1999;153(5):508-511.
- Baraff LJ. Management of infants and young children with fever without source. Pediatr Ann. Oct 2008;37(10):673-679.
- Smith PBB, D.K. Clinical Approach to the Infected Neonate. In: Long SP, L.K.; Prober, C.G., ed. Principles and Practice of Pediatric Infectious Diseases. Third ed. Philadelphia: Elsevier Inc.; 2008:530.
- Mackowiak PAW, G. Carl Reinhold August Wunderlich and the Evolution of Clinical Thermometry. Clinical Infectious Diseases. 1994;18:458-467.
- Craig JV, Lancaster GA, Taylor S, Williamson PR, Smyth RL. Infrared ear thermometry compared with rectal thermometry in children: a systematic review. Lancet. Aug 24 2002;360(9333):603-609.
- Craig JV, Lancaster GA, Williamson PR, Smyth RL. Temperature measured at the axilla compared with rectum in children and young people: systematic review. BMJ 2000; 320: 1174-78.
- Akinbami FO, Orimadegun AE, Tongo OO, Okafor OO, Akinyinka OO. Detection of fever in children emergency care: comparisons of tactile and rectal temperatures in Nigerian children. BMC Res Notes. 2010;3:108.
- Asekun-Olarinmoye EO, Egbewale BE, Olajide FO. Subjective assessment of childhood fever by mothers utilizing primary health care facilities in Osogbo, Osun State, Nigeria. Niger J Clin Pract. Dec 2009;12(4):434-438.
- Pantell RH, Newman TB, Bernzweig J, et al. Management and outcomes of care of fever in early infancy. Jama. Mar 10 2004;291(10):1203-1212.
- Edwards MS; Baker, CJ; Bacterial Infections in the Neonate. In: Long SP, L.K.; Prober, C.G., ed. Principles and Practice of Pediatric Infectious Diseases. Philadelphia: Elsevier Inc.; 2008:532-539.
- Cheng TL, Partridge JC. Effect of bundling and high environmental temperature on neonatal body temperature. Pediatrics. Aug 1993;92(2):238-240.
- Grover G, Berkowitz CD, Lewis RJ, Thompson M, Berry L, Seidel J. The effects of bundling on infant temperature. Pediatrics. Nov 1994;94(5):669-673.
- Verani JR, McGee L, Schrag SJ. Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. MMWR Recomm Rep. Nov 19 2010;59(RR-10):1-36.
- Hoffman JA, Mason EO, Shultze Ge, et al. Streptococcus pneumoniae infections in the neonate. Pediatrics, Nov 2003;112(5):1095-1102.16.
- Maayan-Metzger A, Mazkereth R, Kuint J. Fever in healthy asymptomatic newborns during the first days of life. Arch Dis Child Fetal Neonatal Ed. Jul 2003;88(4):F312-314.
- Boskabadi H, Maamouri G, Ebrahimi M, et al. Neonatal hypernatremia and dehydration in infants receiving inadequate breastfeeding. Asia Pac J Clin Nutr. 2010;19(3):301-307.
- Ng PC, Chan HB, Fok TF, et al. Early onset of hypernatraemic dehydration and fever in exclusively breast-fed infants. J Paediatr Child Health. Dec 1999;35(6):585-587.
- Sharma SK. Epidural analgesia during labor and maternal fever. Curr Opin Anaesthesiol. Jun 2000;13(3):257-260.
- Zanelli S, Gillet Y, Stamm D, Lina G, Floret D. [Bacterial meningitis in infants 1 to 8 weeks old]. Arch Pediatr. Jun 2000;7 Suppl 3:565s-571s.
- Colletti JE, Homme JL, Woodridge DP. Unsuspected neonatal killers in emergency medicine. Emerg Med Clin North Am. Nov 2004;22(4):929-960.
- Baker D, Bell, L, Avner, J. Outpatient management without antibiotics of fever in selected infants. New England Journal of Medicine. 1993 1990;329:1427-1441.
- Baker MD, Avner JR, Bell LM. Failure of infant observation scales in detecting serious illness in febrile, 4- to 8-week-old infants. Pediatrics. Jun 1990;85(6):1040-1043
- Jaskiewicz JA, McCarthy,CA et al. Febrile Infants at Low Risk for Serious Bacterial Infection--An appraisal for the Rochester Criteria and Implications for Management. Pediatrics. 1994;94:390-396.
- Huppler AR, Eickhoff JC, Wald ER. Performance of low-risk criteria in the evaluation of young infants with fever: review of the literature. Pediatrics. Feb 2010;125(2):228-233.
- Caviness AC, Demmler GJ, Almendarez Y, Selwyn BJ. The prevalence of neonatal herpes simplex virus infection compared with serious bacterial illness in hospitalized neonates. J Pediatr. Aug 2008;153(2):164-169.
- Goldman R, et al. Practice Variations in the Treatment of Febrile Infants Among Pediatric Emergency Physicians. Pediatrics. 2009;124:439.
- Van Rossum Aea. Procalcitonin as an early marker of infection in neonates and children. The Lancet. 2004;4(Infectious Diseases).
- Bressan S, et al. Predicting Severe Bacterial Infections in the Well-Appearing Febrile Neonate. Pediatr Infect Dis J. March 2010 2010;29(3).
- Jaye DL, Waites KB. Clinical applications of C-reactive protein in pediatrics. Pediatr Infect Dis J. Aug 1997;16(8):735-746; quiz 746-737.
- Peltola H, Jaakkola M. C-reactive protein in early detection of bacteremic versus viral infections in immunocompetent and compromised children. J Pediatr. Oct 1988;113(4):641-646.