BACKGROUND AND OBJECTIVES

To describe differences in practice patterns and outcomes of young preterm versus age-matched term infants evaluated for sepsis, because evaluation and management of this group are not well defined.

METHODS

We conducted a retrospective single-center study at an academic, freestanding children’s hospital of previously healthy preterm and term infants aged 0 to 60 days, who presented for initial evaluation of fever and/or hypothermia from 2014 to 2019. We classified infants by gestational age as preterm (32–36 6/7 weeks) and term (37–42 weeks) and compared diagnostic evaluation, management, and clinical outcomes.

RESULTS

Out of 363 preterm infants evaluated for sepsis, 336 met inclusion criteria; within the same study period, 2331 term infants were evaluated for sepsis, of which 600 were randomly selected and 554 were included. Clinicians performed inflammatory marker testing and chest x-rays more frequently in preterm infants 31% vs 25% (P = .034) and 50% vs 32% (P < .001), respectively. Preterm infants had a higher rate of bacteremia 5.9% vs 2.5% (P = .035), were hospitalized more frequently 72% vs 63% (P = .006), and required ICU level of care more often 32% vs 5% (P < .001) than term infants. They had lower rates of viral infections 33% vs 42% (P = .015) and no significant increased return visits. Febrile preterm and term infants, and older hypothermic preterm infants had relatively higher rates of serious bacterial infections. Hypothermic preterm infants had the longest hospitalizations.

CONCLUSIONS

Preterm infants had increased rates of bacteremia and required higher level of care compared with age-matched term infants, likely reflecting their increased risk for sepsis and other concomitant morbidities associated with preterm birth.

Nearly half a million infants in the United States are evaluated annually for febrile illness, and ∼10% of those infants aged ≤60 days have serious bacterial infections (SBIs), including urinary tract infections, meningitis, and bacteremia.14  However, significant practice variation exists among physicians regarding sepsis evaluation and management in infants aged ≤60 days.57  Numerous models have been developed to risk-stratify and guide the diagnostic evaluation of this age group.4,811  Most recently, the American Academy of Pediatrics sought to standardize care with the release of a clinical practice guideline for the evaluation and management of well-appearing febrile infants aged 8 to 60 days.7  However, many of these algorithms and guidelines exclude preterm infants (<37 weeks’ gestation).

As the incidence of preterm births continues to rise,12  more febrile infants may be preterm, leaving clinicians to extrapolate guidelines to the preterm population without robust evidence of the clinical implications. Preterm infants have an increased risk of morbidity and mortality from early sepsis.13  They often lack the skin and mucosal barriers that prevent the entry of pathogens, and have altered innate and adaptive immunity compared with age-matched term infants.14  Additionally, preterm infants may present more often with hypothermia compared with term infants, making their evaluation more complex, because hypothermia is an independent risk factor for sepsis but also can be related to poor temperature regulation.15,16  Most data describing rates of sepsis and temperature dysregulation in preterm infants have been derived from studies of early onset neonatal sepsis in the NICU. To our knowledge, there are no large studies outlining the diagnostic workup and management of late preterm infants compared with term infants outside the NICU. This knowledge gap underscores the need for research in this area to optimize care and prevent harm.

Our objectives, therefore, were threefold. First, we aimed to understand current practice patterns in the evaluation and management of preterm infants aged 0 to 60 days with temperature dysregulation compared with age-matched term infants, including whether evaluation and management differed by chronological age (0–28 days versus 29–60 days). Second, we sought to identify potential differences in laboratory values and, more importantly, in rates of serious bacterial and viral infections and associated clinical outcomes between preterm and term infants. Lastly, we sought to understand the relationship between temperature at presentation, chronological age, and outcomes between preterm and term infants.

Our freestanding, academic, children’s hospital has 673 beds and is affiliated with the state university college of medicine. We have 2 associated emergency departments and 7 urgent care centers. There were >1.6 million combined inpatient and outpatient visits in 2019.

We conducted a single-center, retrospective analysis of the electronic medical records of infants aged 0 to 60 days presenting to our hospital from January 2014 to January 2019 for temperature dysregulation, as defined by International Classification of Diseases (ICD), Ninth and 10th Editions, group codes for fever and hypothermia (778.4, 780.6, 995.85, P81.9, R50.9, 778.3, 780.65, 991.6, P80.9, R68.0, T68XXXA). This list was then confirmed with our local data analytics team for completeness. We performed additional electronic medical record queries looking for urinary tract infection, bacteremia, meningitis, pneumonia, skin soft tissue infection, and viral infections. Subjects with reported fever (≥38°C) or hypothermia (≤36.5°C) at home and 1 of the above ICD codes were included. Subjects were included irrespective of temperature documented at the time of presentation to a health care setting given that term normothermic infants with history of fever at home have been shown to be at risk for invasive bacterial infection and SBI.17  Initial presenting temperature was also recorded for analysis, with fever defined as temperature ≥38.0°C and hypothermia defined as temperature ≤36.5°C. We elected to include both febrile and hypothermic infants, because hypothermia is an independent risk factor for sepsis in the preterm population in particular.15,16  The study was approved by the institutional review board.

From the cohort that met inclusion criteria, we defined 2 groups for comparison: preterm infants (32–36 6/7 weeks) and term infants (37–42 weeks). Given that the initial group of term infants was significantly larger than the group of preterm infants, we then selected a sample of term infants approximately double the number of preterm infants using randomization software. Infants were excluded if:

  1. they had received antibiotics in the 48 hours before presentation;

  2. they had any preexisting medical conditions apart from prematurity; or

  3. they had indwelling devices.

Initial home births, admissions to the newborn nursery, or initial NICU admissions were excluded. The primary record of interest was limited to a readmission separate from these birthing events. Records of patients meeting inclusion criteria were manually reviewed by at least 2 investigators.

We collected information on the diagnostic evaluation for the index visit for each infant, including temperature at presentation, initial laboratory, and imaging ordered. If an infant presented for >1 visit during the study period, the subsequent visits were not included in evaluation. Testing for common respiratory pathogens was performed by multiplex polymerase chain reaction (PCR) (BioFire FilmArray) with nasopharyngeal swabs. Testing for enterovirus, parechovirus, and herpes simplex virus from blood and superficial sites was performed by laboratory-developed and validated PCR assays.18,19  Testing for common pathogens of meningitis was performed on cerebrospinal fluid (CSF) by multiplex PCR (BioFire FilmArray).18,20 

We recorded results of laboratory tests and rates of viral and bacterial infections. Elevated inflammatory markers were defined as follows: bands 10% of total white blood cells, C-reactive protein (CRP) ≥1.2 mg/dL, procalcitonin ≥0.5 ng/mL (CRP and procalcitonin based on local laboratory definitions of abnormal). Urine culture was considered positive if a catheterized urine specimen yielded a potential uropathogen in quantities of either:

  1. 10 000 to 49 000 colony-forming units/mL with pyuria or bacteriuria on urinalysis; or

  2. ≥50 000 colony-forming units/mL regardless of urinalysis results.2123 

Bacteremia was defined by isolation of a pathogenic organism from the blood, and bacterial meningitis was defined by CSF culture or identification of a bacterium in CSF by multiplex PCR. Cultures were considered to be contaminants if they contained an organism frequently known to cause contamination,24  and were treated as such and documented by the medical team.

We additionally collected information on the rates of hospitalization, location of admission (general floor versus ICU, including transfer to the PICU or NICU setting, Supplemental Table 4), and use and duration of IV antibiotics and antiviral therapy. We compared the use of vasopressors, radiant warmers, respiratory support, and mortality among those infants who were admitted to an ICU. We also evaluated the 7-day and 30-day unplanned sick visits to a primary care office or return visits to an acute health care facility (urgent care or the emergency department) and readmission to an inpatient unit.

Continuous variables are presented as median and interquartile range (IQR), and categorical variables are presented as frequencies and percentages. We compared the diagnostic evaluation, therapeutic management, and clinical outcomes between preterm and term infants. Additional analyses were performed between moderate (≥32, <34 weeks) and late (≥34, <36) preterm infants. Unadjusted associations between gestational age and categorical variables were assessed using Pearson’s χ2 test and Wilcoxon’s rank-sum test for continuous variables. Logistic regression models were used to estimate the relationship between selected outcomes (SBI, viral infection, admission to hospital, and ICU transfer) and predictor variables gestational age, chronological age, and presenting temperature. Similarly, a linear regression model was used to estimate the association between length of stay and the interaction of predictor variables gestational age, chronological age, and presenting temperature. Length of stay was log-transformed to improve model diagnostics, and estimates were back-transformed onto the original scale. For each regression model, estimated marginal effects were plotted and contrasts between preterm and term infants were summarized with corresponding 95% confidence intervals. Except where indicated, all P values presented are unadjusted for multiple comparisons, and complete case analysis was used for instances of missing data. Statistical significance was assessed at α = .05. Analyses were performed using the R system for statistical computing (R core team, 2022), version 4.2.1.

We identified 363 preterm infants who presented with temperature dysregulation; 336 infants met inclusion criteria. Of 2331 term infants who presented with temperature dysregulation, we randomly selected a sample of 600, of whom 554 met criteria for inclusion (Fig 1). Forty-nine percent of the preterm group were 0 to 28 days of age versus 46% of the term group. The median chronological age of preterm infants was similar to term infants (30 days versus 31 days). Of the 336 preterm infants, 31% presented with hypothermia, compared with 6.5% of the 554 term infants (P < .001) (Table 1). There were no statistically significant differences observed between the diagnostic approaches, rates of infection, and management between moderate (≥32, <34 weeks) and late (≥34, <36) preterm infants on the basis of results of Pearson’s χ2 test and Wilcoxon’s rank-sum test, and thus the groups were examined in aggregate.

FIGURE 1

Inclusion and exclusion of preterm and term infants who were evaluated for fever/hypothermia in the emergency department/urgent care settings or captured via direct admissions between January 2014 and January 2019.

FIGURE 1

Inclusion and exclusion of preterm and term infants who were evaluated for fever/hypothermia in the emergency department/urgent care settings or captured via direct admissions between January 2014 and January 2019.

Close modal
TABLE 1

Demographic Features, Clinical Presenting Temperature, and Diagnostic Evaluation of Preterm and Term Infants

Preterm, n = 336Term, n = 554PaOverall, n = 890
Demographics    
 Gestational age, wk, median (IQR) 35 (34–36) 39 (38–40) .013 38 (36–39) 
 Chronological age, d, median (IQR) 30 (12–44) 31 (18–46) .5 30 (16–45) 
 Age group, d, n (%)   .4  
  0–28 165 (49) 257 (46)  422 (47) 
  29–60 171 (51) 297 (54)  468 (53) 
 Sex, n (%)   .2  
  Male 195 (58) 296 (53)  491 (55) 
  Female 141 (42) 258 (47)  399 (45) 
 Race, n (%)   .8  
  White/Caucasian 174 (52) 280 (51)  454 (51) 
  Black/African American 97 (29) 176 (32)  273 (31) 
  Asian American 15 (4.5) 24 (4.3)  39 (4.4) 
  Other 50 (15) 74 (13)  124 (14) 
 Ethnicity, n (%)   .6  
  Hispanic or Latino 24 (7.3) 46 (8.4)  70 (8.0) 
  Other 304 (93) 502 (92)  806 (92) 
Clinical evaluation     
 Presenting temperature, n (%)   <.001  
  Hypothermia 105 (31) 36 (6.5)  141 (16) 
  History of fever 152 (45) 328 (59)  480 (54) 
  Febrile 79 (24) 190 (34)  269 (30) 
 Rates of diagnostic evaluation, n (%)    
  Serum testing    
  Complete blood count 262 (78) 409 (74) .2 671 (75) 
  CRP 105 (31) 137 (25) .034 242 (27) 
  Procalcitonin 88 (26) 126 (23) .2 214 (24) 
  Blood culture 226 (67) 397 (72) .2 623 (70) 
 Urinary testing    
  Urinalysis 245 (73) 400 (72) .8 645 (72) 
  Urine culture 252 (75) 413 (75) .9 665 (75) 
 Viral testing    
  Respiratory PCR 229 (68) 359 (65) .3 588 (66) 
  Surface PCR 143 (43) 287 (52) .007 430 (48) 
  Serum PCR 194 (58) 317 (57) .8 511 (57) 
 CSF testing   .2  
  Yes, obtained 185 (55) 276 (50)  461 (52) 
  Attempted, not obtained 20 (6.0) 27 (4.9)  47 (5.3) 
  No, not attempted 131 (39) 251 (45)  382 (43) 
 Radiographic studies    
  Chest x-ray 158 (50) 169 (32) <.001 327 (39) 
 Laboratory resultsb     
  WBC, serum, median (IQR) 9.0 (6.4–11.7) 9.9 (7.4–13.0) .002 9.3 (7.1–12.4) 
  ANC, serum, median (IQR) 2464 (1487–3846) 3038 (1935–5015) <.001 2880 (1701–4465) 
  Bandemia, serum, n (%) 30 (31) 52 (33) .8 82 (32) 
  Elevated CRP serum, n (%) 33 (32) 52 (40) .2 85 (36) 
  Elevated procalcitonin, serum, n (%) 13 (15) 26 (21) .3 39 (19) 
  Abnormal urinalysis, n (%) 25 (10) 52 (13) .3 77 (12) 
  WBC, CSF, median (IQR) 7 (3–19) 8 (3–23) .8 7 (3–22) 
 Bacterial infection by site, n (%)    
  Any bacterial infection 24 (7.1) 35 (6.3) .6 59 (6.6) 
  Urinary tract 12 (4.8) 27 (6.6) .3 39 (5.9) 
  Bloodstream 13 (5.9) 10 (2.5) .035 23 (3.7) 
  CSF 2 (1.1) 5 (1.8) 0.7 7 (1.5) 
 Viral infection by site, n (%)    
  Any viral infection 112 (33) 230 (42) .015 342 (38) 
  Nasopharyngeal 86 (26) 184 (33) .001 270 (30) 
  Surface (skin, eye, mucosa) 22 (6.5) 41 (7.4) >.9 94 (11) 
  Bloodstreamc 29 (8.6) 62 (11) .2 91 (10) 
  CSFd 22 (6.5) 41 (7.4) .4 63 (7/1) 
Preterm, n = 336Term, n = 554PaOverall, n = 890
Demographics    
 Gestational age, wk, median (IQR) 35 (34–36) 39 (38–40) .013 38 (36–39) 
 Chronological age, d, median (IQR) 30 (12–44) 31 (18–46) .5 30 (16–45) 
 Age group, d, n (%)   .4  
  0–28 165 (49) 257 (46)  422 (47) 
  29–60 171 (51) 297 (54)  468 (53) 
 Sex, n (%)   .2  
  Male 195 (58) 296 (53)  491 (55) 
  Female 141 (42) 258 (47)  399 (45) 
 Race, n (%)   .8  
  White/Caucasian 174 (52) 280 (51)  454 (51) 
  Black/African American 97 (29) 176 (32)  273 (31) 
  Asian American 15 (4.5) 24 (4.3)  39 (4.4) 
  Other 50 (15) 74 (13)  124 (14) 
 Ethnicity, n (%)   .6  
  Hispanic or Latino 24 (7.3) 46 (8.4)  70 (8.0) 
  Other 304 (93) 502 (92)  806 (92) 
Clinical evaluation     
 Presenting temperature, n (%)   <.001  
  Hypothermia 105 (31) 36 (6.5)  141 (16) 
  History of fever 152 (45) 328 (59)  480 (54) 
  Febrile 79 (24) 190 (34)  269 (30) 
 Rates of diagnostic evaluation, n (%)    
  Serum testing    
  Complete blood count 262 (78) 409 (74) .2 671 (75) 
  CRP 105 (31) 137 (25) .034 242 (27) 
  Procalcitonin 88 (26) 126 (23) .2 214 (24) 
  Blood culture 226 (67) 397 (72) .2 623 (70) 
 Urinary testing    
  Urinalysis 245 (73) 400 (72) .8 645 (72) 
  Urine culture 252 (75) 413 (75) .9 665 (75) 
 Viral testing    
  Respiratory PCR 229 (68) 359 (65) .3 588 (66) 
  Surface PCR 143 (43) 287 (52) .007 430 (48) 
  Serum PCR 194 (58) 317 (57) .8 511 (57) 
 CSF testing   .2  
  Yes, obtained 185 (55) 276 (50)  461 (52) 
  Attempted, not obtained 20 (6.0) 27 (4.9)  47 (5.3) 
  No, not attempted 131 (39) 251 (45)  382 (43) 
 Radiographic studies    
  Chest x-ray 158 (50) 169 (32) <.001 327 (39) 
 Laboratory resultsb     
  WBC, serum, median (IQR) 9.0 (6.4–11.7) 9.9 (7.4–13.0) .002 9.3 (7.1–12.4) 
  ANC, serum, median (IQR) 2464 (1487–3846) 3038 (1935–5015) <.001 2880 (1701–4465) 
  Bandemia, serum, n (%) 30 (31) 52 (33) .8 82 (32) 
  Elevated CRP serum, n (%) 33 (32) 52 (40) .2 85 (36) 
  Elevated procalcitonin, serum, n (%) 13 (15) 26 (21) .3 39 (19) 
  Abnormal urinalysis, n (%) 25 (10) 52 (13) .3 77 (12) 
  WBC, CSF, median (IQR) 7 (3–19) 8 (3–23) .8 7 (3–22) 
 Bacterial infection by site, n (%)    
  Any bacterial infection 24 (7.1) 35 (6.3) .6 59 (6.6) 
  Urinary tract 12 (4.8) 27 (6.6) .3 39 (5.9) 
  Bloodstream 13 (5.9) 10 (2.5) .035 23 (3.7) 
  CSF 2 (1.1) 5 (1.8) 0.7 7 (1.5) 
 Viral infection by site, n (%)    
  Any viral infection 112 (33) 230 (42) .015 342 (38) 
  Nasopharyngeal 86 (26) 184 (33) .001 270 (30) 
  Surface (skin, eye, mucosa) 22 (6.5) 41 (7.4) >.9 94 (11) 
  Bloodstreamc 29 (8.6) 62 (11) .2 91 (10) 
  CSFd 22 (6.5) 41 (7.4) .4 63 (7/1) 

ANC, absolute neutrophil count; WBC, white blood cell.

a

Wilcoxon rank-sum test; Pearson’s χ2 test.

b

White blood cell count represented as ×103/μL, absolute neutrophil count represented as mm3, bandemia defined as bands >10%, elevated CRP defined as value ≥1.2 mg/dL, elevated procalcitonin >0.5 ng/mL, abnormal urinalysis as defined by the presence of pyuria or bacturia, and CSF white blood cell count represented per mm3.

c

Includes enterovirus, parechovirus, and herpes simplex virus 1/2.

d

Includes enterovirus, parechovirus, herpes simplex virus 1/2, and human herpes virus-6.

Diagnostic evaluations differed between preterm and term infants in several tests performed (Table 1). Compared with term infants, preterm infants had a higher frequency of CRP testing (31% vs 25%, P = .034), but a similar frequency of procalcitonin testing (26% vs 23%, P = .2). Preterm infants had chest x-rays performed more frequently than term infants (50% vs 32%, P < .001). There were no differences between preterm and term infants in rates of lumbar punctures (55% vs 50%, P = .2) or blood cultures (67% vs 72%, P = .2).

We also examined rates of diagnostic testing of preterm infants compared with term infants when stratified by chronological age, 0 to 28 days and 29 to 60 days. Term infants in both the 0 to 28 days and 29 to 60 days groups were less likely to receive x-rays compared with the preterm counterparts. No further statistical differences in invasive testing, such as blood cultures and lumbar punctures, were detected between these 2 age groups (Supplemental Table 5).

When comparing/evaluating laboratory values and clinical outcomes between preterm and term infants, we found that overall preterm infants had lower white blood cell counts (9.0 X103/μL versus 9.9 X103/μL, P = .002) and absolute neutrophil counts (2464 mm3 vs 3038 mm3, P < .001) (Table 1).

Although preterm infants had similar rates of any bacterial infection compared with term infants (7.1% vs 6.3%, P = .6), they had more than double the rate of bacteremia (5.9% vs 2.5%, P = .035). Causative organisms were primarily group B Streptococcus (n = 4) and E. coli (n = 3). Preterm infants had lower rates of viral infections compared with term infants (33% vs 42%, P = .015), particularly respiratory viral infections (26% vs 33%, P = .001).

Preterm infants were hospitalized more frequently than term infants (72% vs 63%, P = .006) (Table 2). Preterm infants had a longer duration of treatment with intravenous antibiotics compared with term infants (38 hours versus 33 hours, P < .001). Preterm infants also received acyclovir more frequently (51% vs 43%, P = .006.)

TABLE 2

Management and Outcomes of Preterm and Term Infants With Fever or Hypothermia

Preterm, n = 336Term, n = 554PaOverall, n = 890
Hospital admission, n (%) 243 (72) 351 (63) .006 594 (67) 
Rate of ICU, n (%) 107 (32) 26 (4.7) <.001 133 (15) 
 NICU 43 (12) 0 (0)  43 (4.8) 
 PICU 64 (19) 26 (4.7)  90 (10) 
Treatment     
 IV antimicrobial agents, n (%) 217 (65) 324 (58) .071 541 (61) 
 IV antimicrobial duration, h, median (IQR) 38 (31–50) 33 (25–43) <.001 36 (26–46) 
 IV acyclovir, n (%) 173 (51) 239 (43) .015 412 (46) 
 IV acyclovir duration, h, median (IQR) 16 (8–24) 16 (8–23) .5 16 (8–23) 
Discharge    
 Length of stay, h, median (IQR) 49 (6–111) 39 (4–51) <.001 42 (4–63) 
Return to acute care, d, n (%)   .1  
  <7 28 (8) 59 (11)  87 (10) 
  7–30 42 (13) 54 (10)  96 (11) 
Hospital readmission, n (%) 35 (10) 46 (8) .2 81 (9) 
Preterm, n = 336Term, n = 554PaOverall, n = 890
Hospital admission, n (%) 243 (72) 351 (63) .006 594 (67) 
Rate of ICU, n (%) 107 (32) 26 (4.7) <.001 133 (15) 
 NICU 43 (12) 0 (0)  43 (4.8) 
 PICU 64 (19) 26 (4.7)  90 (10) 
Treatment     
 IV antimicrobial agents, n (%) 217 (65) 324 (58) .071 541 (61) 
 IV antimicrobial duration, h, median (IQR) 38 (31–50) 33 (25–43) <.001 36 (26–46) 
 IV acyclovir, n (%) 173 (51) 239 (43) .015 412 (46) 
 IV acyclovir duration, h, median (IQR) 16 (8–24) 16 (8–23) .5 16 (8–23) 
Discharge    
 Length of stay, h, median (IQR) 49 (6–111) 39 (4–51) <.001 42 (4–63) 
Return to acute care, d, n (%)   .1  
  <7 28 (8) 59 (11)  87 (10) 
  7–30 42 (13) 54 (10)  96 (11) 
Hospital readmission, n (%) 35 (10) 46 (8) .2 81 (9) 

IV, intravenous.

a

Pearson’s χ2 test; Wilcoxon rank-sum test.

Preterm infants required ICU level of care more frequently than term infants (32% vs 5%, P <.001). For preterm infants, 40% of ICU stays were in the NICU, whereas no term infants were admitted to a NICU. Preterm infants in the ICU needed radiant warmers more often than term infants (33% vs 12%, P = .032) (Table 3). Despite the need for a higher level of care, preterm infants did not have increased rates of intubation (P = .6), vasopressor support (P = .5), or mortality (P > .9). Preterm infants admitted to the ICU required noninvasive positive pressure about half as often as term infants (21% vs 44%, P = .015).

TABLE 3

Characteristics, Therapeutic Interventions, and Outcomes of Preterm and Term Infants Admitted to the ICU

Preterm, n = 109Term, n = 26PaOverall, n = 135
Demographics, n (%)     
Age group, d   .074  
 0–28 82 (75) 15 (58)  97 (72) 
 29–60 27 (25) 11 (42)  38 (28) 
Sex   .062  
 Male 68 (62) 11 (42)  79 (59) 
 Female 41 (38) 15 (58)  56 (41) 
Race   .8  
 White 59 (54) 17 (65)  76 (56) 
 Black 30 (28) 6 (23)  36 (27) 
 Asian American 5 (4.6) 0 (0)  5 (3.7) 
 Other 15 (14) 3 (12)  18 (13) 
Clinical presentation     
Temperature, n (%)   <.001  
 Hypothermia 78 (72) 10 (38)  88 (65) 
 History of fever 23 (21) 7 (27)  30 (22) 
 Fever 8 (7.3) 9 (35)  17 (13) 
Location, n (%)   <.001  
 NICU 43 (40) 0 (0)  43 (32) 
 PICU 64 (60) 26 (100)  90 (68) 
Therapeutic interventions, n (%)    
 NIPPV 22 (21) 11 (44) .015 33 (25) 
 Intubation 42 (40) 9 (35) .6 51 (39) 
 Vasopressors 12 (11) 4 (15) .5 16 (12) 
 Radiant warmer 35 (33) 3 (12) .032 38 (29) 
Mortality, n (%) 2 (1.9) 0 (0) >.9 2 (1.5) 
Preterm, n = 109Term, n = 26PaOverall, n = 135
Demographics, n (%)     
Age group, d   .074  
 0–28 82 (75) 15 (58)  97 (72) 
 29–60 27 (25) 11 (42)  38 (28) 
Sex   .062  
 Male 68 (62) 11 (42)  79 (59) 
 Female 41 (38) 15 (58)  56 (41) 
Race   .8  
 White 59 (54) 17 (65)  76 (56) 
 Black 30 (28) 6 (23)  36 (27) 
 Asian American 5 (4.6) 0 (0)  5 (3.7) 
 Other 15 (14) 3 (12)  18 (13) 
Clinical presentation     
Temperature, n (%)   <.001  
 Hypothermia 78 (72) 10 (38)  88 (65) 
 History of fever 23 (21) 7 (27)  30 (22) 
 Fever 8 (7.3) 9 (35)  17 (13) 
Location, n (%)   <.001  
 NICU 43 (40) 0 (0)  43 (32) 
 PICU 64 (60) 26 (100)  90 (68) 
Therapeutic interventions, n (%)    
 NIPPV 22 (21) 11 (44) .015 33 (25) 
 Intubation 42 (40) 9 (35) .6 51 (39) 
 Vasopressors 12 (11) 4 (15) .5 16 (12) 
 Radiant warmer 35 (33) 3 (12) .032 38 (29) 
Mortality, n (%) 2 (1.9) 0 (0) >.9 2 (1.5) 

NIPPV, non-invasive positive pressure ventilation.

a

Pearson’s χ2 test; Fisher’s exact test.

Preterm infants were also hospitalized longer than their term counterparts (49 hours versus 39 hours, P < .001), though there was increased variability in length of stay (IQR 6–111 hours versus IQR 4–51 hours) (Table 2). Preterm infants did not have statistically significant increased return visits >or readmission rates.

We repeated the analyses for the subgroup of 231 preterm and 518 term infants with fever, excluding those with hypothermia. The results of this analysis were similar to the full cohort analysis with a few exceptions. Febrile preterm infants were nearly twice as likely to have bacteremia as term infants, though this difference was not statistically significant (2.7% vs 5%, P = .2) as compared with when both febrile and hypothermic infants were examined in aggregate. (Supplemental Table 6). Preterm infants continued to require ICU admissions more frequently than term infants (13% vs 3%, P < .001), although overall hospital admission rates for both groups decreased (Supplemental Table 7).

Next, we examined the subgroup-specific effects for gestational age, chronological age, and presenting temperature with selected outcomes. Point estimates and 95% confidence intervals are provided in Fig 2. Infants presenting with fever had the highest probability of serious bacterial infection and viral infection; however, preterm infants aged 29 to 60 days presenting with hypothermia (n = 23) had similar probabilities of bacterial and viral infections as the fever group. Furthermore, preterm infants with hypothermia were more likely than term infants to require ICU level care and had longer lengths of stay. Expected length of stay was 2.3 times greater for 0 to 28-day-old preterm infants presenting with hypothermia compared with the corresponding term infants (P = .069).

FIGURE 2

Marginal effect plots showing subgroup specific outcomes for SBI, viral infections (virus), ICU admissions, admission to hospital, and length of stay. Point estimates and corresponding 95% confidence intervals are shown. Analysis of admittance to ICU outcomes was based on the group of patients who were admitted to the hospital (N = 594).

FIGURE 2

Marginal effect plots showing subgroup specific outcomes for SBI, viral infections (virus), ICU admissions, admission to hospital, and length of stay. Point estimates and corresponding 95% confidence intervals are shown. Analysis of admittance to ICU outcomes was based on the group of patients who were admitted to the hospital (N = 594).

Close modal

In the current study, we found that preterm infants aged 0 to 60 days presenting with temperature dysregulation underwent more extensive diagnostic workup than term infants of the same age. Preterm infants had higher rates of bacteremia and more often presented with hypothermic illness. In concordance with these findings, preterm infants were hospitalized and required ICU level of care more frequently and had longer hospitalizations, even when adjusting for chronological age and presenting temperature. Importantly, these infants did not have increased rates of mortality or readmission. We found that hypothermia was an important risk factor for severity of illness in both preterm and term infants.

The recent American Academy of Pediatrics febrile infant guidelines discuss the value and use of inflammatory markers in guiding evaluation of infants at risk for sepsis.7  In our study, we found that preterm infants underwent inflammatory marker testing more frequently than term infants. Given the lack of guidance and uncertainty with managing preterm infants at risk for sepsis, clinicians may use these tests to risk stratify. Similarly, despite evidence showing minimal diagnostic utility of chest x-rays for the evaluation of infants at risk for sepsis,2527  we found that preterm infants were more likely to receive imaging studies. It is possible that preterm infants were more likely to undergo radiographic testing given increased severity of illness at time of presentation, with more NICU stays/ICU level of care required despite lower rates of viral infections and less frequent need for noninvasive positive pressure ventilation.

Importantly, we found that rates of blood culture testing were similar between preterm and term infants. It may be prudent to evaluate preterm infants with blood cultures more frequently given that preterm infants had higher rates of serious bacterial infections than term infants, and with more than twice the rate of bacteremia. Almost half of preterm infants with bacteremia were hypothermic at time of presentation, reflecting that preterm infants with serious bacterial infection may present differently than term infants, and caution should be taken when approaching this population. Additionally, we found that preterm infants had lower absolute neutrophil counts, making it harder to extrapolate these results to the newest febrile infant guidelines that use absolute neutrophil count cutoffs of >4000 mm3.

Preterm infants were not only admitted/hospitalized more frequently, but also required ICU level of care more frequently than their term counterparts, particularly those with hypothermia. This finding may have several potential explanations. First, given increased concerns for sepsis in prematurity,28  it is possible that providers were more likely to admit for concerns of potential deterioration. Second, given the frequency of hypothermia in this population, it may be that premature infants required ICU level of care for rewarming alone, which may or may not have been related to an infectious etiology.16  Finally, we found that a greater number of these premature infants were admitted to a NICU rather than a PICU, which may be related to the medical equipment available in the NICU, such as an incubator, or potentially related institutional staffing and admitting policies in times of high patient census.

These findings are consistent with previous studies that have established that preterm infants have significantly more medical comorbidities and costly hospitalizations than term infants in the immediate postnatal period outside of the NICU.28,29  Our study suggests that these health outcome discrepancies may continue outside the initial birthing hospitalization and well into the second month of life, because preterm infants continue to be hospitalized more frequently and have longer lengths of stay. However, despite these differences, discharge outcomes for these infants did not seem to be affected, because the rates of return visits and readmissions for preterm infants were similar to those of term infants in our study.

Our study had several limitations. First, it is a single-center review and it may lack generalizability. Although our findings may not capture the potential variability at other institutions, to our knowledge, our study is 1 of the largest manual reviews comparing the evaluation and management of preterm and term infants aged <60 days with temperature dysregulation who are evaluated for sepsis. Second, some of the microbiology assays available at our institution may not be universally available, such as blood and mucosal viral PCR testing (including herpes simplex virus, enterovirus, and parechovirus) allowing clinicians to readily incorporate results into risk-stratifying models. Additionally, other facilities may not have the ability to care for infants in a level IV NICU, and therefore disposition and management of this population may be different. Furthermore, although we did additional queries of the chart for meningitis, bacteremia, urinary tract infection, skin soft tissue infections, and pneumonia, and these were verified by our local data analytics team, we may have potentially missed some infants with SBI and invasive bacterial infection by using ICD codes for patient identification.

However, despite these limitations, our study cohort was large and may help inform the design of future prospective studies, because national guidelines for the evaluation and management of sepsis in preterm infants outside the NICU do not exist.

The results of our study suggest that previously healthy preterm infants are a population clinically distinct from term infants. At our institution, preterm infants underwent more extensive diagnostic evaluations, and showed higher rates of bacteremia and longer hospitalizations compared with term infants. Further, those presenting with hypothermia, which is likely multifactorial and associated with concomitant issues of prematurity, required higher acuity care more often. Larger prospective studies are urgently needed to determine the best strategies to evaluate and manage young, healthy preterm infants at risk for sepsis.

We thank The Ohio State University Center for Clinical and Translational Science for their collaboration and Beth Burkhart from Nationwide Children’s Research Institute for her contributions.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: Dr Ramilo has received research grants from the National Institutes of Health, Bill & Melinda Gates Foundation, and Janssen; fees for participation in advisory boards from Merck, MedImmune/Sanofi-Pasteur, and Pfizer; and fees for lectures from Pfizer. All those relations are unrelated to the present work, and all authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

Drs Marsh, Lin, Black, Allen, Ramilo, and Kasick conceptualized and designed the study, and drafted the initial manuscript; Dr Weiner assisted with the data collection and critically reviewed the manuscript; Dr Watson assisted with study design and subsequent analyses, and reviewed and revised the manuscript; Mr Klamer conducted the initial and subsequent analyses, and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Deidentified individual participant data will not be made available.

1.
McCaig
LF
,
Nawar
EW
.
National hospital ambulatory medical care survey: 2004 emergency department summary
.
Adv Data
.
2006
;(
372
):
1
29
2.
Woll
C
,
Neuman
MI
,
Aronson
PL
.
Management of the febrile young infant: update for the 21st century
.
Pediatr Emerg Care
.
2017
;
33
(
11
):
748
753
3.
Huppler
AR
,
Eickhoff
JC
,
Wald
ER
.
Performance of low-risk criteria in the evaluation of young infants with fever: review of the literature
.
Pediatrics
.
2010
;
125
(
2
):
228
233
4.
Kuppermann
N
,
Dayan
PS
,
Levine
DA
, et al
.
Febrile Infant Working Group of the Pediatric Emergency Care Applied Research Network
.
A clinical prediction rule to identify febrile infants 60 days and younger at low risk for serious bacterial infections
.
JAMA Pediatr
.
2019
;
173
(
4
):
342
351
5.
Aronson
PL
,
Thurm
C
,
Alpern
ER
, et al
.
Febrile Young Infant Research Collaborative
.
Variation in care of the febrile young infant <90 days in US pediatric emergency departments
.
Pediatrics
.
2014
;
134
(
4
):
667
677
6.
Jain
S
,
Cheng
J
,
Alpern
ER
, et al
.
Management of febrile neonates in US pediatric emergency departments
.
Pediatrics
.
2014
;
133
(
2
):
187
195
7.
Pantell
RH
,
Roberts
KB
,
Adams
WG
, et al
.
Subcommittee on Febrile Infants
.
Evaluation and management of well-appearing febrile infants 8 to 60 days old
.
Pediatrics
.
2021
;
148
(
2
):
e2021052228
8.
Baraff
LJ
.
Management of infants and young children with fever without source
.
Pediatr Ann
.
2008
;
37
(
10
):
673
679
9.
Esposito
S
,
Rinaldi
VE
,
Argentiero
A
, et al
.
Approach to neonates and young infants with fever without a source who are at risk for severe bacterial infection
.
Mediators Inflamm
.
2018
;
2018
:
4869329
10.
Jaskiewicz
JA
,
McCarthy
CA
,
Richardson
AC
, et al
.
Febrile Infant Collaborative Study Group
.
Febrile infants at low risk for serious bacterial infection–an appraisal of the Rochester criteria and implications for management
.
Pediatrics
.
1994
;
94
(
3
):
390
396
11.
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
;
138
(
2
):
e20154381
12.
Martin
JA
,
Hamilton
BE
,
Sutton
PD
, et al
.
Centers for Disease Control and Prevention National Center for Health Statistics National Vital Statistics System
.
Births: final data for 2005
.
Natl Vital Stat Rep
.
2007
;
56
(
6
):
1
103
13.
Kramer
MS
,
Demissie
K
,
Yang
H
,
Platt
RW
,
Sauvé
R
,
Liston
R
.
Fetal and Infant Health Study Group of the Canadian Perinatal Surveillance System
.
The contribution of mild and moderate preterm birth to infant mortality
.
JAMA
.
2000
;
284
(
7
):
843
849
14.
Collins
A
,
Weitkamp
JH
,
Wynn
JL
.
Why are preterm newborns at increased risk of infection?
Arch Dis Child Fetal Neonatal Ed
.
2018
;
103
(
4
):
F391
F394
15.
Perry
MC
,
Yaeger
SK
,
Noorbakhsh
K
,
Cruz
AT
,
Hickey
RW
.
Hypothermia in young infants: frequency and yield of sepsis workup
.
Pediatr Emerg Care
.
2021
;
37
(
8
):
e449
e455
16.
Wood
JK
,
Halvorson
EE
,
Auriemma
JR
, et al
.
Clinical characteristics and health outcomes of neonates reporting to the emergency department with hypothermia
.
Hosp Pediatr
.
2018
;
8
(
8
):
458
464
17.
Mintegi
S
,
Gomez
B
,
Carro
A
,
Diaz
H
,
Benito
J
.
Invasive bacterial infections in young afebrile infants with a history of fever
.
Arch Dis Child
.
2018
;
103
(
7
):
665
669
18.
Tomatis Souverbielle
C
,
Feister
J
,
Leber
A
, et al
.
Multiple sites PCR testing for enteroviruses in young febrile infants
.
Lancet Infect Dis
.
2019
;
19
(
3
):
239
240
19.
Leber
AL
,
Everhart
K
,
Daly
JA
, et al
.
Multicenter evaluation of BioFire FilmArray respiratory panel 2 for detection of viruses and bacteria in nasopharyngeal swab samples
.
J Clin Microbiol
.
2018
;
56
(
6
):
e01945-17
20.
Leber
AL
,
Everhart
K
,
Balada-Llasat
JM
, et al
.
Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens
.
J Clin Microbiol
.
2016
;
54
(
9
):
2251
2261
21.
Bonadio
W
,
Maida
G
.
Urinary tract infection in outpatient febrile infants younger than 30 days of age: a 10-year evaluation
.
Pediatr Infect Dis J
.
2014
;
33
(
4
):
342
344
22.
Arshad
M
,
Seed
PC
.
Urinary tract infections in the infant
.
Clin Perinatol
.
2015
;
42
(
1
):
17
28
,
vii
23.
Roberts
KB
.
Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management
.
Urinary tract infection: clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months
.
Pediatrics
.
2011
;
128
(
3
):
595
610
24.
Hall
KK
,
Lyman
JA
.
Updated review of blood culture contamination
.
Clin Microbiol Rev
.
2006
;
19
(
4
):
788
802
25.
Crain
EF
,
Bulas
D
,
Bijur
PE
,
Goldman
HS
.
Is a chest radiograph necessary in the evaluation of every febrile infant less than 8 weeks of age?
Pediatrics
.
1991
;
88
(
4
):
821
824
26.
Heulitt
MJ
,
Ablow
RC
,
Santos
CC
,
O’Shea
TM
,
Hilfer
CL
.
Febrile infants less than 3 months old: value of chest radiography
.
Radiology
.
1988
;
167
(
1
):
135
137
27.
Bramson
RT
,
Meyer
TL
,
Silbiger
ML
,
Blickman
JG
,
Halpern
E
.
The futility of the chest radiograph in the febrile infant without respiratory symptoms
.
Pediatrics
.
1993
;
92
(
4
):
524
526
28.
Cohen-Wolkowiez
M
,
Moran
C
,
Benjamin
DK
, et al
.
Early and late-onset sepsis in late preterm infants
.
Pediatr Infect Dis J
.
2009
;
28
(
12
):
1052
1056
29.
Wang
ML
,
Dorer
DJ
,
Fleming
MP
,
Catlin
EA
.
Clinical outcomes of near-term infants
.
Pediatrics
.
2004
;
114
(
2
):
372
376

Supplementary data