Case Based Teaching – Sepsis
St. Joseph’s CTU
Objectives:
Medical Expert:
1. Review the different causes of sepsis in a newborn
2. Understand the indications and interpretation of investigations for sepsis
3. Review the initial investigations to come to a diagnosis
4. Understand the choice of antibiotics
Communicator:
1. Learn how to explain to parents why the team is concerned about infection
2. Learn the information needed to counsel around the impact of treatment for
sepsis in the case of culture negative and culture positive sepsis.
Resources:
1. Polin RA, MD and the committee on Fetus and Newborn. Management of
Neonates with suspected or Proven Early-Onset Bacterial Sepsis. American
Academy of Pediatrics. Pediatrics Vol. 129 No. 5 May 1, 2012 pp. 1006 -1015
2. Committee on Infectious Diseases and Committee on Fetus and Newborn. Policy
Statement-Recommendations for the Prevention of Perinatal Group B
Streptococcal (GBS) Disease. American Academy of Pediatrics. Pediatrics;
originally published online August 1, 2011
3. Baltimore R. Neonatal Sepsis: Epidemiology and Management. Paediatr Drugs.
2003;5(11):723-40.
4. Arnon S, Litmanovitz I. Diagnostic tests in neonatal sepsis. Current Opinion in
Infectious Diseases 2008 Jun;21(3):223-7
5. Management of the infant at increased risk for sepsis. Position Statement (FN
2007-03). Paediatr Child Health. 2007 December; 12(10): 893–898.
Case Review:
• 39 5/7 week gestational infant
• Born to 37 G3T1A1L1 mother
• VDRL, Hep B, HIV GBS neg
• O +ve Rubella immune
• Normal antenatal US, No blood sugar or blood pressure issues
• Induced for unstable lie
• ROM for 13 hrs
• SVD
• APGARS 9, 9
• BW 3400 grams
• Cord gas
•
•
•
•
•
- Art 7.16/66/19/24
- Ven 7.28/40/46/19
12 hrs later (midnight) call from NCR to peds.
Pt was born after they completed rounds and had not yet had newborn exam
Nurses called with tachypnea that developed at 10hrs of age
RR reported to be 80
Infant feeding well
On exam:
- RR 84 no indrawing, HR 140 SpO2 99%
- Occasional grunt
- Infant responsive good tone
- Good cap refill
- No murmur normal femoral pulses
- Good air entry no extra sounds
Discussion
Is this a normal respiratory rate?
What is your differential diagnosis at this time?
What tests if any would you order?
Case
CBC ordered at 0100, clotted times two
Now 3 a.m. infant still grunting HR 180’s BP 68/32 MAP 40 SPO2 95% caprefill 3-5
sec.
Discussion
What would you do now?
If you decided to start antibiotics which would you choose?
What are the most common organisms that cause sepsis in neonates?
Would your antibiotic choice be different if this infant was in the NICU for the past 7
days?
How do you calculate the IT ratio? What is the significance of the IT ratio?
Would you order a CRP?, How do you interpret the CRP?
What is your interpretation of the blood gas? What intervention if any would you
consider with the physical exam findings?
Results:
CORRECTED LKCS
|
3.7
|
| X10 9/L
| Corrected Leukocyte count appears when the Nucleated
| Erythrocyte count is greater than 5.
> LKCS
> ERCS
> **HB**
> **HCT**
> MCV
> MCH
> MCHC
> RDW
> **PLT**
|
4.2
| L | 5.0-21.0 X10 9/L
| 17/06/12 0633:
| LKCS previously reported as: X10 9/L
| TO FOLLOW
|
4.44
|
| 4.0-6.6 x10 12/L
|
169
|
| 145-225 g/L
|
0.479
|
| 0.450-0.670
|
107.9
|
| 95-121 fL
|
38.1
|
| 28-40 pg
|
353
|
| 290-360 g/L
|
16.3
| H | 11.5-15.0 %
|
| 150-400 x10 9/L
| Large platelet clumps present. Unable to estimate.
| Few very large platelet clumps and fibrin strands present.
| Query inadequate mixing of the sample at collection?
| PLT CT previously reported as: 126 L x10 9/L
| Preliminary count must be confirmed with morphology.
> MPV
|
> SMEAR EXAMINE
|
MANUAL DIFF.
|
> NERCS
|
> ABSOLUTE BANDS |
> ABSOLUTE NEUTS |
> ABSOLUTE LYMPHS |
> ABSOLUTE MONOS |
> ABSOLUTE MYELOS |
> ABSOLUTE METAS |
8.4
|
Blood film made
|
14
|
0.8
|
0.9
|
1.6
|
0.1
|
0.1
|
0.2
|
CRP 40.8
Blood gas 7.18/46/47/17/-11
• Blood GBS positive after 7 hrs
• CSF done June 18th
- BS 5.9 mmol/L
- Protein 2.28 g/L
- Leuks 3248
- RBC 4
• Gram Stain Pus cells Gram positive Cocci
• CSF culture neg
| 7.4-10.4 fL
|
|
|
| /100 LKC
| x10 9/L
L | 1.5-10.0 x10 9/L
L | 2.0-17.0 x10 9/L
L | 0.5-1.9 x10 9/L
| x10 9/L
| x10 9/L
Take Home Messages:
•
•
•
•
No Risk factors does not mean no chance of infection
Don’t rely on labs to make clinical decisions
Be wary of respiratory rates that are normal at birth and increase subsequently
Review the importance of doing a full septic workup in the case of suspected
sepsis.
Diagnostic tests in neonatal sepsis
Shmuel Arnona,b and Ita Litmanovitza,b
a
Neonatal Department, Meir Medical Center, Kfar Saba
and bSackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel
Correspondence to Dr Shmuel Arnon, Department of
Neonatology, Meir Medical Center Kfar Saba, 44281,
Israel
Tel: +972 9 747 2225; fax: +972 9 747 1189;
e-mail: [email protected]
Current Opinion in Infectious Diseases 2008,
21:223–227
Purpose of review
The present review examines the major developments in early detection of neonatal
sepsis, with an emphasis on the utility of diagnostic laboratory markers in clinical
practice.
Recent findings
Measures of acute phase proteins, cytokines, cell surface antigens, and bacterial
genomes have been used alone or in combination to improve diagnosis of neonatal
sepsis. Most studies evaluating laboratory diagnostic markers are retrospective cohorts
or single center experience with relatively small sample size. Interpretation of these
studies is confounded by inconsistent definitions of sepsis, heterogeneous sample
populations, and different thresholds for diagnostic markers. Furthermore, many
diagnostic markers are not available for routine care, they require specialized analytical
procedures, and are expensive to perform.
Summary
A better understanding of the neonatal inflammatory response to sepsis and
identification of sensitive and specific markers of inflammation or rapid microbe-specific
diagnostic tests would assist in the early detection of neonatal sepsis and in safely
withholding antibiotics for patients in whom sepsis is unlikely.
Keywords
acute phase reactant, cell surface antigens, cytokines, neonatal sepsis, polymerase
chain reaction
Curr Opin Infect Dis 21:223–227
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0951-7375
Introduction
The diagnosis of sepsis in infants is difficult because
clinical signs, particularly early in the course of disease,
are subtle and nonspecific, and laboratory tests including
blood culture, the ‘gold standard’, are not always reliable
[1]. Clinicians have long sought reliable markers to detect
sepsis early in its course and to exclude diseases of
noninfectious origin [2–4]. Recent studies propose new
diagnostic laboratory markers used alone or in combination to improve sensitivity and specificity for early
detection of sepsis.
Clinical and laboratory scores
The clinical signs of neonatal sepsis are nonspecific.
Fanaroff et al. [5] with the National Institute of Child
Health and Human Development (NICHD) Neonatal
Research Network found that increasing apnea, feeding
intolerance, abdominal distension or heme-positive
stools, increased respiratory support, lethargy, and hypotonia were the most common presenting signs of late
onset sepsis (LOS). None was found to have highpredictive accuracy [5]. However, many neonatologists,
particularly those practicing in clinical settings with limited resources, use clinical judgment or scores combined
with complete blood count (CBC) and blood cultures for
the detection of neonatal sepsis [6,7]. Components of the
CBC that may become abnormal in sepsis have a positive
predictive value (PPV) as low as 11% [1]. This may be
explained by inter-observer variability in immature and
mature neutrophil identification [8], factors other than
sepsis that cause abnormalities of the CBC, and timing
of the CBC that is often normal at the time of initial
evaluation but abnormal a few hours later. Okascharoen
et al. [6] devised and tested a scoring system for the
diagnosis of LOS in preterm infants composed of the
following five clinical indicators: hypotension, hypothermia, hyperthermia, respiratory insufficiency, and umbilical
venous catheters between 1 and 7 days or more than 7 days;
and the two following hematological parameters: immature neutrophil count more than 1% and platelet count less
than 150 000/ml3. The clinical score had an acceptable
predictive performance [PPV 43%, negative predictive
value (NPV) 96%] but was no better than the clinicians’
estimate of LOS risk. The addition of C-reactive protein
(CRP) and micro erythrocyte sedimentation rate (mESR)
to a clinical score in detecting LOS had a high sensitivity
(95%) but a low specificity (18%). The positive likelihood
ratio (a measure of predictive value that is independent of
prevalence) was 1.61 (Table 1) [7,9–19].
0951-7375 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
224 Paediatric and neonatal infections
Table 1 Accuracy of diagnostic tests at the time of sepsis evaluation
Diagnostic test [reference]
ClinicalþCBCþCRPþ mESR [7]
IL-6þCRP [9]
PCTþCRP [10]
PCT [11]
SAA [12]
CRP [13]
SAA [13]
CRP [14]
LPB [14]
LPB [14]
CD64 [15]
CD64 [16]
IL-8 [17]
IL-8þCRP [18]
PCR, 16S rRNA [19]
No. of
patients
No. of infected
patients
220
92
85
100
104
116
116
25
25
22
338
110
249
1291
172
60
37
28
61
23
42
42
8
8
8
115
32
61
13
8
EOS/LOS
Cutoff value
LOS
LOS
LOS
LOS
EOS
LOS
LOS
EOS
EOS
LOS
EOS
LOS
EOS
EOS
LOS
NA
60 pg/ml, 1.4 mg/dl
0.5 mg/l, 1 mg/dl
0.59 mg/l
0.8 mg/dl
1 mg/dl
1 mg/dl
2.1 mg/dl
21.5 mg/l
17.1 mg/l
6136 antibody PE molecules bound/cell
4000 antibody PE molecules bound/cell
18.000 pg/ml
70 pg/ml, 1mg/dl
NA
Sensitivity
(%)
Positive
LR
NPV
(%)
95
92
93
81
96
32
95
88
100
92
79
95
97
80
100
1.61
1.56
1.18
4.26
19
10.6
13.5
99.9
16.6
8.3
7.18
12
19.4
6.15
50
91
80
80
72
99
74
97
96
100
97
89
97
99
93
98
CBC, complete blood count; CRP, C-reactive protein; EOS, early onset sepsis; IL, interleukin; LPB, lipopolysaccharide-binding protein; LOS, late
onset sepsis; LR, likelihood ratio; mESR, micro erythrocyte sedimentation rate; NA, not available; NPV, negative predictive value; PCR, polymerase
chain reaction; PCT, procalcitonin; PE, phycoerythrin; rRNA, ribosomal ribonucleic acid; SAA, serum amyloid A.
A recent advance in the diagnosis of neonatal sepsis is heart
rate characteristic (HRC) that monitors the presence of
reduced variability and transient decelerations, which
occur with increased frequency in the preclinical phases
of septicemia [20,21,22,23]. The HRC index demonstrated a significant association with both blood culture
proven sepsis and clinical LOS in neonates. The odds ratio
for the prediction of neonatal sepsis with high HRC index
was more than two. Both the clinical score and the HRC
index rose before the clinical diagnosis of illness, with
HRC being first [21]. This noninvasive and inexpensive
index has the advantage of being available through continuous electrocardiogram monitoring and can add information to conventional measures in the early diagnosis of
neonatal sepsis [23]. There is currently a large, multicenter
randomized controlled trial underway to evaluate the
impact of HRC monitoring on initiation of timing of
treatment for sepsis and infection-related morbidities
[impact of heart rate characteristics monitoring in neonates
(HeRO)3. ClinicalTrials.gov Identifier: NCT00307333].
Acute phase reactants
Acute phase reactants are endogenous peptides produced
by the liver as part of an immediate response to infection
or tissue injury. The most widely used in neonates is CRP
[24–27]. Given that there is a time lag of 12–24 h in the
response of CRP to infection, some clinicians use it in
combination with another serum marker such as interleukins [26,27]. The specificity of CRP is low for early
onset sepsis (EOS), as a number of prenatal conditions
(maternal fever, fetal distress or stressful delivery, and
vacuum delivery) may lead to its elevation in the absence
of systemic infection. Recent studies, using CRP cutoff
values of 1.2–6 mg/dl to diagnose sepsis and guide
duration of therapy in EOS and LOS, showed specificity
between 84–96% and a NPV range of 93–99%. The
clinical practice of using higher CRP cutoff values led
to fewer days of antibiotics without an evidence of
infection relapse [24,25,27].
Procalcitonin (PCT) is an acute phase reactant produced
by monocytes and hepatocytes. PCT begins to rise 4 h
after exposure to bacterial endotoxin, peaks at six to
eight, and remains elevated for at least 24 h [28]. In
adults, it has been used for almost a decade to diagnose
the severity of systemic inflammatory response, to determine the progression of infection to sepsis and septic
shock, to assess responsiveness to treatment, and to
estimate prognosis [28]. A number of recent studies of
preterm infants confirmed that PCT compared with CRP
and proinflammatory cytokines had equivalent or better
sensitivity for diagnosis of LOS, but with lower values of
NPV and likelihood ratio [9–11,29] (Table 1). A recent
study showed that PCT had a lower diagnostic utility
(sensitivity 81.4%, specificity 80.6%) at the time of suspicion of sepsis. Therefore, PCT is not sufficiently reliable
to be the sole marker of LOS, but may be useful as part of
an evaluation for sepsis in a neonate [11]. The diagnostic
utility of PCT in EOS is limited by its rapid physiological
postnatal endogenous increase [30,31]. For this reason,
age-related nomograms of PCT values were proposed
during the first days of life [30]. In summary, PCT level is
elevated during EOS and LOS and its overall diagnostic
utility is comparable with CRP.
Serum amyloid A (SAA) is an acute phase protein induced
by the inflammatory cytokines IL-1 and IL-6, and tumor
necrosis factor (TNF)-a in response to lipopolysaccharide (LPS) gram-negative bacteria infection. There is a
robust increase in SAA levels from 8 to 24 h after the onset
of sepsis. Arnon et al. [12] showed that SAA had a better
diagnostic accuracy than CRP at septic evaluation in EOS
(5 h after birth) (Table 1). However, vaginal delivery
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Diagnostic tests in neonatal sepsis Arnon and Litmanovitz 225
that produces a transient elevation of SAA levels, even
higher than the cutoff point for the detection of sepsis
[32], might affect the diagnostic accuracy of SAA in EOS.
The same group of investigators showed that SAA levels
during LOS had a high sensitivity and NPV, suggesting it
may be a superior marker compared with CRP [13]
(Table 1). Recently, rapid SAA measurement has been
facilitated by the development of a fully automated kit
that required no specialized instrumentation and can be
done in any service laboratory [12].
shown to be sensitive and specific enough to allow
neonatologists to withhold antibiotic treatment in an
infant with clinical signs suggestive of infection. Furthermore, analysis of cell surface markers in the clinical
setting requires specialized equipment and qualified
personnel. Blood specimens, must be processed immediately to avoid neutrophil apoptosis and downregulation of
surface molecules [36]. This limits the practical application of this technology in the clinical setting.
Lipopolysaccharide-binding protein (LBP), a 50-kDa
acute-phase protein, is mainly synthesized in the liver.
It binds with high affinity to LPS in the plasma, transfers
LPS to membrane bound or soluble CD14, and modulates the microbial-induced activation of the inflammatory host response [33]. It was recently reported that LBP
has a better sensitivity and specificity for detecting sepsis
than LPS-soluble, CD14 complexes, and PCT in EOS,
but equally effective to CRP in detecting sepsis of infants
older than 48 h [14] (Table 1).
Chemokines and cytokines
A number of acute phase proteins including a1-antitrypsin, fibronectin, haptoglobin, lactoferrin, neopterin,
inter-a inhibitor proteins (IaIp), granulocyte colony
stimulating factor (G-CSF), orosomucoid, and antithrombin have been evaluated in relation to neonatal sepsis
[34]. Although these acute phase proteins may be candidate biomarkers for sepsis, none has been routinely used
clinically or studied on a large scale.
Cell surface antigens
In recent years, flow cytometric analysis of cell surface
antigens [CD11b, Fcg receptors I-III (CD64, CD32, and
CD16), CD69] has been performed to detect congenital
sepsis, EOS, and LOS [15,16,35]. For detection of EOS,
CD64 was shown to have a sensitivity of 81% and a NPV
of 89% [15] (Table 1). Twenty-four hours after onset of
sepsis, the sensitivity and NPV rose to 96 and 97%,
respectively. A large cohort study, assessing two neutrophil (CD11b and CD64) and two lymphocyte surface
markers (CD25 and CD45RO) for the diagnosis of LOS,
showed that CD64 had the highest sensitivity (95–97%)
and specificity (88–90%) for detecting sepsis at the onset
of infection and 24 h later [16] (Table 1). Combining
CD64 with IL-6 or CRP further enhanced the ability to
diagnose localized infections and improved the sensitivity and NPV to 100% [31]. In response to infection,
preterm infants increase cell numbers of lymphocyte
populations (CD3, CD19, CD25, CD26, and CD71)
and human leukocyte antigen (HLA)-DR expression
on monocytes, and upregulate neutrophil surface antigens (CD11b, CD11c, CD13, CD15, CD33, CD64, and
CD66b) [35,36]. However, to date, no cell surface
markers alone or in combination have been tested and
The regulation and trafficking of leukocytes into specific
body tissues are principally controlled by chemokines or
cytokines, which are mainly divided into two subsets.
Proinflammatory cytokines [IL-2, IL-6, interferon
(IFN)g, TNFa] that are primarily responsible for initiating an effective defense against exogenous pathogens
and anti-inflammatory cytokines (IL-4 and IL-10) that
are crucial for downregulating the exacerbated inflammatory process and maintaining homoeostasis for proper
functioning of vital organs. A study analyzing 127 episodes of suspected LOS in very low birth weight (VLBW)
infants found both proinflammatory and anti-inflammatory cytokines significantly increased in infected infants
compared with noninfected infants [37]. The very short
half-life of circulating cytokines increases the risk of false
negative results. For this reason, whole blood IL-8 (cellbound and extracellular IL-8) [17] (Table 1) or cytokines
combined with other more sustained markers of inflammation [9,38] have been suggested as a better diagnostic
tool. A multicenter, randomized, controlled trial of 1291
infants suspected of EOS by at least one clinical sign
showed that the use of IL-8 more than 70 pg/ml and/or
CRP more than 10 mg/l to diagnose sepsis significantly
reduced antibiotic therapy from 49.6 to 36.1% (P < 0.05)
and increased the diagnostic utility of these markers [18]
(Table 1). No infection was missed and no significant
difference in the diagnostic accuracy was observed
between the untreated group and the control group [18].
In VLBW infants with suspected sepsis, plasma IL-10
(>208 ng/l), IL-6 (>168 ng/l), and regulated upon activation normal T-cell expressed and secreted (RANTES)
(<3110 ng/l) had sensitivity, specificity, PPV, and NPV of
100, 97, 85, and 100%, respectively, for identifying
infected patients who subsequently developed disseminated intravascular coagulation [39]. Another recent study
by the same group of researchers revealed that four markers of a panel of key chemokines and cytokines (IP-10,
MIG, IL-6, IL-10) achieved a sensitivity of more than 80%
and a specificity of more than 75%, for detecting sepsis for
each tested marker. Among them, the IP-10 with a cutoff
value of at least 1250 pg/ml exhibited the best sensitivity
(93%) and specificity (89%) [40]. Owing to the rapid
decline of these inflammatory biomarkers after the onset of
sepsis, 24 h measurements had lower predictive values
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
226 Paediatric and neonatal infections
than those at 0 h. The use of multiple markers in combination only marginally improved the sensitivity of IP-10 by
0–7%, but adversely affected the specificity by 13–50%
[40]. Owing to the processing costs, most chemokines
and cytokines are not routinely used for identifying neonatal sepsis or for predicting the severity and outcome of
infection. The measurement of IL-8 in the urine has
recently proven to be a reliable and an effective alternative
for detecting neonatal sepsis [41].
defensin-2, calgranulin A and C) that provide qualitative
information (from a scale of 0–4 depending on the presence or absence of these 4 proteins) on the presence or
absence of intra-amniotic inflammation. Furthermore,
high mass restricted score (3–4) significantly correlated
with suspected or confirmed EOS. The strongest association was for calgranulin A with a sensitivity, specificity,
PPV, and NPV of 55, 80, 44, and 86%, respectively
[48,49]. Although intriguing, these findings need to be
validated in larger prospective studies of neonates suspected of having sepsis.
Molecular biomarkers
Nucleic acid amplification tests such as PCR have been
used successfully to diagnose a wide range of bacterial,
yeast, viral, and protozoal infectious diseases. In recent
years, PCR analysis has exploited the highly conserved
bacterial 16S ribosomal ribonucleic acid (rRNA) gene to
diagnose EOS and LOS. Shang et al. [19] used bacterial
16S rRNA gene PCR and DNA microarray analysis in 172
neonates with suspected sepsis and found a sensitivity of
100% and specificity of 97.8% (Table 1). Although the
16S rDNA PCR in near-term infants with EOS had high
specificity (97.5%) and NPV (99.2%) compared with
blood cultures, it failed to detect 59% of infants with
positive blood culture (sensitivity 41%, PPV 19%)
[42,43]. The use of staphylococcus-specific PCR to detect
bloodstream infection had comparable specificity (94.7–
100%) and NPV (95.4–98%) with inconsistent sensitivity
of 57.1–69.2% and PPV of 53.3–100% [44,45]. The main
advantage of PCR over blood cultures is that it is rapid
(4–6 h versus 18 h, respectively) and requires small
blood volume (0.2–0.3 ml versus 1 ml respectively).
PCR amplification does require specialized instrumentation and training perform and it is not routinely available
in many microbiology laboratories. A recent study [46]
showed that approximately eight antibiotic doses and 85
neonatal intensive care unit (NICU) hours per infant
could be saved using negative PCR results. Therefore,
due to the high NPV of PCR methods, it may influence
clinical practices and decision-making, leading to fewer
antibiotic doses per patient and shorter hospital stay.
Proteomic biomarker of intra-amniotic
inflammation
Recent advances in proteomics present a new opportunity to search for biomarkers and generation of protein
profiles that can rapidly (1–3 h) aid in the prediction of
amniotic fluid inflammation and early neonatal sepsis.
The use of specific biomarkers to identify neonates with
increased risk for sepsis in utero would aid in the initiation
of appropriate therapy. Buhimschi et al. [47] showed that
proteomic mapping of amniotic fluid, a profile designed
as the mass restricted score, is highly characteristic of
intra-amniotic inflammation. The profile comprised four
protein biomarkers (neutrophil defensin-1 and neutrophil
Conclusion
A better understanding of the neonatal inflammatory
response to infection has led to the identification of
multiple candidate biomarkers to improve diagnosis of
sepsis. At present, no single biomarker or panel of biomarkers is sufficiently reliable for early detection of
neonatal sepsis. Complicated analytical measurement
further limits the utility of many biomarkers in clinical
practice. The use of biomarkers as a diagnostic tool for
the early discontinuation of empirical antibiotic treatment for infants with suspected sepsis is promising, but
requires additional study.
Acknowledgements
The authors thank Robert L. Schelonka, MD, Department of Pediatrics,
University of Alabama, Birmingham, AL, for his critical review of the
manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 320).
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tests in neonatal sepsis. Pediatrics 2005; 115:937–941.
21 Griffin MP, Lake DE, O’Shea TM, Moorman JR. Heart rate characteristics and
clinical signs in neonatal sepsis. Pediatr Res 2007; 61:222–227.
The study examines the relationship between HRC index and a clinical score in
neonatal sepsis and points out that the former is adjunctive and not a substitute for
clinical information.
22 Moorman JR, Lake DE, Griffin MP. Heart rate characteristics monitoring for
neonatal sepsis. IEEE Trans Biomed Eng 2006; 53:126–132.
23 Goldstein B. Heart rate characteristics in neonatal sepsis: a promising test
that is still premature. Pediatrics 2005; 115:1070–1072; Comment on
Pediatrics. 2005; 115:937-941..
24 Bataineh HA, Alrashed KM. C-reactive protein in Neonates with suspected
septicemia. Rawal Med J 2007; 32:25–27.
25 Couto RC, Barbosa JA, Pedrosa TM, Biscione FM. C-reactive protein-guided
approach may shorten length of antimicrobial treatment of culture-proven
late-onset sepsis: an intervention study. Braz J Infect Dis 2007; 11:240–
245.
26 Franz AR, Kron M, Pohlandt F, Steinbach G. Comparison of procalcitonin with
interleukin 8, C-reactive protein and differential white blood cell count for the
early diagnosis of bacterial infections in newborn infants. Pediatr Infect Dis J
1999; 18:666–671.
27 Haque KN. Defining common infections in children and neonates. J Hosp
Infect 2007; 65 (Suppl 2):110–114.
31 Llorente E, Prieto B, Cardo L, et al. Umbilical cord blood serum procalcitonin
by time-resolved amplified cryptate emission (TRACE) technology: reference
values of a potential marker of vertically transmitted neonatal sepsis. Clin
Chem Lab Med 2007; 45:1531–1535.
32 Golden SM, Hague I, Elwood R, et al. Serum amyloid A concentrations in fullterm infant umbilical cord serum using a solid phase indirect ELISA. Lab Med
2005; 36:357–360.
33 Zweigner J, Schumann RR, Weber JR. The role of lipopolysaccharide-binding
protein in modulating the innate immune response. Microb Infect 2006;
8:946–952.
34 Ersoy B, Nehir H, Altinoz S, et al. Prognostic value of initial antithrombin levels
in neonatal sepsis. Indian Pediatr 2007; 44:581–584.
35 Hodge G, Hodge S, Han P, Haslam R. Multiple leucocyte activation markers
to detect neonatal infection. Clin Exp Immunol 2004; 135:125–129.
36 Gille C, Orlikowsky TW. Flow cytometric methods in the detection of neonatal
infection. Transfus Med Hemother 2007; 34:157–163.
Summarizing the different flow cytometric markers to detect neonatal sepsis and
their clinical and laboratory characteristics, the study stresses the role of cell
surface antigens to stop antibiotics when the child is healthy and the lack of
accuracy of these markers to withhold antibiotics when the child is sick and
suspected of having sepsis.
37 Ng PC, Li K, Wong RP, et al. Proinflammatory and anti-inflammatory cytokine
responses in preterm infants with systemic infections. Arch Dis Child Fetal
Neonatal Ed 2003; 88:F209–F213.
38 Horisberger T, Harbarth S, Nadal D, et al. G-CSF and IL-8 for early diagnosis
of sepsis in neonates and critically ill children – safety and cost effectiveness
of a new laboratory prediction model: study protocol of a randomized controlled trial. Crit Care 2004; 8:R443–R450.
39 Ng PC, Li K, Leung TF, et al. Early prediction of sepsis-induced disseminated
intravascular coagulation with interleukin-10, interleukin-6, and RANTES in
preterm infants. Clin Chem 2006; 52:1181–1189.
40 Ng PC, Li K, Chui KM, et al. IP-10 is an early diagnostic marker for
identification of late-onset bacterial infection in preterm infants. Pediatr
Res 2007; 61:93–98.
A well designed study showing that preterm infants have the ability to induce a
robust chemokine and cytokine response during sepsis, with IP-10 being a
sensitive early marker of infection.
41 Bentlin MR, de Souza Rugolo LM, Júnior AR, et al. Is urine interleukin-8 level a
reliable laboratory test for diagnosing late onset sepsis in premature infants?
J Trop Pediatr 2007; 53:403–408.
42 Jordan JA, Durso MB, Butchko AR, et al. Evaluating the near-term infant for
early onset sepsis. Progress and challenges to consider with 16S rDNA
polymerase chain reaction testing. J Mol Diagn 2006; 8:357–363.
43 Jordan JA, Durso MB. Real-time polymerase chain reaction for detecting
bacterial DNA directly from blood of neonates being evaluated for sepsis.
J Mol Diagn 2005; 7:575–581.
44 Makhoul IR, Yacoub A, Smolkin T, et al. Values of C-reactive protein,
procalcitonin, and Staphylococcus-specific PCR in neonatal late-onset sepsis. Acta Paediatr 2006; 95:1218–1223.
45 Makhoul IR, Smolkin T, Sujov P, et al. PCR-based detection of neonatal
Staphylococca bacteremias. J Clin Microbiol 2005; 43:4823–4825.
46 Brozanski BS, Jones JG, Krohn MJ, Jordan JA. Use of polymerase chain
reaction as a diagnostic tool for neonatal sepsis can result in a decrease in use
of antibiotics and total neonatal intensive care unit length of stay. J Perinatol
2006; 26:688–692.
47 Buhimschi CS, Bhandari V, Hamar BD, et al. Proteomic profiling of the
amniotic fluid to detect inflammation, infection, and neonatal sepsis. PLoS
Med 2007; 4:e18.
29 Kocabaş E, Sarkçoğlu A, Aksaray N, et al. Role of procalcitonin, C-reactive
protein, interleukin-6, interleukin-8 and tumor necrosis factor-a in the diagnosis of neonatal sepsis. Turk J Pediatr 2007; 49:7–20.
48 Buhimschi CS, Buhimschi IA, Abdel-Razeq S, et al. Proteomic biomarkers of
intra-amniotic inflammation: relationship with funisitis and early-onset sepsis in
the premature neonate. Pediatr Res 2007; 61:318–324.
The study presents the emerging field of proteomics in the evaluation of the
newborn at risk for EOS. Amniotic fluid proteomic analysis showed that high mass
restricted score was strongly associated with histological funisitis and with early
neonatal sepsis.
30 Turner D, Hammerman C, Rudensky B, et al. Procalcitonin in preterm infants
during the first few days of life: introducing an age related nomogram. Arch Dis
Child Fetal Neonatal Ed 2006; 91:F283–F286.
49 Buhimschi IA, Christner R, Buhimschi CS. Proteomic biomarker analysis of
amniotic fluid for identification of intra-amniotic inflammation. BJOG 2005;
112:173–181.
28 Tang BM, Eslick GD, Craig JC, McLean AS. Accuracy of procalcitonin for
sepsis diagnosis in critically ill patients: systematic review and meta-analysis.
Lancet Infect Dis 2007; 7:210–217.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Guidance for the Clinician in
Rendering Pediatric Care
CLINICAL REPORT
Management of Neonates With Suspected or Proven
Early-Onset Bacterial Sepsis
abstract
Richard A. Polin, MD and the COMMITTEE ON FETUS AND
NEWBORN
With improved obstetrical management and evidence-based use of
intrapartum antimicrobial therapy, early-onset neonatal sepsis is becoming less frequent. However, early-onset sepsis remains one of the
most common causes of neonatal morbidity and mortality in the preterm population. The identification of neonates at risk for early-onset
sepsis is frequently based on a constellation of perinatal risk factors
that are neither sensitive nor specific. Furthermore, diagnostic tests
for neonatal sepsis have a poor positive predictive accuracy. As a result,
clinicians often treat well-appearing infants for extended periods of time,
even when bacterial cultures are negative. The optimal treatment of
infants with suspected early-onset sepsis is broad-spectrum antimicrobial agents (ampicillin and an aminoglycoside). Once a pathogen is identified, antimicrobial therapy should be narrowed (unless synergism is
needed). Recent data suggest an association between prolonged empirical treatment of preterm infants (≥5 days) with broad-spectrum antibiotics and higher risks of late onset sepsis, necrotizing enterocolitis,
and mortality. To reduce these risks, antimicrobial therapy should be
discontinued at 48 hours in clinical situations in which the probability
of sepsis is low. The purpose of this clinical report is to provide a
practical and, when possible, evidence-based approach to the management of infants with suspected or proven early-onset sepsis. Pediatrics
2012;129:1006–1015
KEY WORDS
early-onset sepsis, antimicrobial therapy, group B streptococcus,
meningitis, gastric aspirate, tracheal aspirate, chorioamnionitis,
sepsis screen, blood culture, lumbar puncture, urine culture,
body surface cultures, white blood count, acute phase reactants,
prevention strategies
ABBREVIATIONS
CFU—colony-forming units
CRP—C-reactive protein
CSF—cerebrospinal fluid
GBS—group B streptococci
I/T—immature to total neutrophil (ratio)
PMN—polymorphonuclear leukocyte
PPROM—preterm premature rupture of membranes
This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors
have filed conflict of interest statements with the American
Academy of Pediatrics. Any conflicts have been resolved through
a process approved by the Board of Directors. The American
Academy of Pediatrics has neither solicited nor accepted any
commercial involvement in the development of the content of
this publication.
The guidance in this report does not indicate an exclusive
course of treatment or serve as a standard of medical care.
Variations, taking into account individual circumstances, may be
appropriate.
INTRODUCTION
“Suspected sepsis” is one of the most common diagnoses made in the
NICU.1 However, the signs of sepsis are nonspecific, and inflammatory
syndromes of noninfectious origin mimic those of neonatal sepsis. Most
infants with suspected sepsis recover with supportive care (with or
without initiation of antimicrobial therapy). The challenges for clinicians
are threefold: (1) identifying neonates with a high likelihood of sepsis
promptly and initiating antimicrobial therapy; (2) distinguishing “highrisk” healthy-appearing infants or infants with clinical signs who do not
require treatment; and (3) discontinuing antimicrobial therapy once
sepsis is deemed unlikely. The purpose of this clinical report is to
provide a practical and, when possible, evidence-based approach to the
diagnosis and management of early-onset sepsis, defined by the National Institute of Child Health and Human Development and Vermont
Oxford Networks as sepsis with onset at ≤3 days of age.
1006
FROM THE AMERICAN ACADEMY OF PEDIATRICS
www.pediatrics.org/cgi/doi/10.1542/peds.2012-0541
doi:10.1542/peds.2012-0541
All clinical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed,
revised, or retired at or before that time.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FROM THE AMERICAN ACADEMY OF PEDIATRICS
PATHOGENESIS AND
EPIDEMIOLOGY OF EARLY-ONSET
SEPSIS
Before birth, the fetus optimally is
maintained in a sterile environment.
Organisms causing early-onset sepsis
ascend from the birth canal either
when the amniotic membranes rupture
or leak before or during the course of
labor, resulting in intra-amniotic infection.2 Commonly referred to as “chorioamnionitis,” intra-amniotic infection
indicates infection of the amniotic fluid,
membranes, placenta, and/or decidua.
Group B streptococci (GBS) can also
enter the amniotic fluid through occult
tears. Chorioamnionitis is a major risk
factor for neonatal sepsis. Sepsis can
begin in utero when the fetus inhales
or swallows infected amniotic fluid.
The neonate can also develop sepsis in
the hours or days after birth when
colonized skin or mucosal surfaces are
compromised. The essential criterion
for the clinical diagnosis of chorioamnionitis is maternal fever. Other
criteria are relatively insensitive. When
defining intra-amniotic infection (chorioamnionitis) for clinical research
studies, the diagnosis is typically based
on the presence of maternal fever of
greater than 38°C (100.4°F) and at least
two of the following criteria: maternal
leukocytosis (greater than 15 000 cells/
mm3), maternal tachycardia (greater
than 100 beats/minute), fetal tachycardia (greater than 160 beats/minute),
uterine tenderness, and/or foul odor of
the amniotic fluid. These thresholds are
associated with higher rates of neonatal and maternal morbidity.
Nonetheless, the diagnosis of chorioamnionitis must be considered even
when maternal fever is the sole abnormal finding. Although fever is common
in women who receive epidural anesthesia (15%–20%), histologic evidence
of acute chorioamnionitis is very common in women who become febrile
after an epidural (70.6%).3 Furthermore,
PEDIATRICS Volume 129, Number 5, May 2012
most of these women with histologic
chorioamnionitis do not have a positive
placental culture.3 The incidence of clinical chorioamnionitis varies inversely
with gestational age. In the National
Institute of Child Health and Human
Development Neonatal Research Network, 14% to 28% of women delivering
preterm infants at 22 through 28 weeks’
gestation exhibited signs compatible
with chorioamnionitis.4 The major risk
factors for chorioamnionitis include
low parity, spontaneous labor, longer
length of labor and membrane rupture,
multiple digital vaginal examinations
(especially with ruptured membranes),
meconium-stained amniotic fluid, internal
fetal or uterine monitoring, and presence of genital tract microorganisms
(eg, Mycoplasma hominis).5
The major risk factors for early-onset
neonatal sepsis are preterm birth,
maternal colonization with GBS, rupture
of membranes >18 hours, and maternal signs or symptoms of intra-amniotic
infection.14–16 Other variables include
ethnicity (ie, black women are at higher
risk of being colonized with GBS), low
socioeconomic status, male sex, and
low Apgar scores. Preterm birth/low
birth weight is the risk factor most
closely associated with early-onset sepsis.17 Infant birth weight is inversely
related to risk of early-onset sepsis.
The increased risk of early-onset sepsis in preterm infants is also related to
complications of labor and delivery
and immaturity of innate and adaptive
immunity.18
At term gestation, less than 1% of
women with intact membranes will
have organisms cultured from amniotic fluid.6 The rate can be higher if
the integrity of the amniotic cavity is
compromised by procedures before
birth (eg, placement of a cerclage or
amniocentesis).6 In women with preterm labor and intact membranes, the
rate of microbial invasion of the amniotic cavity is 32%, and if there is preterm premature rupture of membranes
(PPROM), the rate may be as high as
75%.7 Many of the pathogens recovered
from amniotic fluid in women with preterm labor or PPROM (eg, Ureaplasma
species or Mycoplasma species) do
not cause early-onset sepsis.8–10 However, both Ureaplasma and Mycoplasma organisms can be recovered
from the bloodstream of infants whose
birth weight is less than 1500 g.11 When
a pathogen (eg, GBS) is recovered from
amniotic fluid, the attack rate of neonatal sepsis can be as high as 20%.12
Infants born to women with PPROM
who are colonized with GBS have an
estimated attack rate of 33% to 50%
when intrapartum prophylaxis is not
given.13
DIAGNOSTIC TESTING FOR SEPSIS
The clinical diagnosis of sepsis in the
neonate is difficult, because many of
the signs of sepsis are nonspecific and
are observed with other noninfectious
conditions. Although a normal physical
examination is evidence that sepsis is
not present,19,20 bacteremia can occur
in the absence of clinical signs.21 Available diagnostic testing is not helpful in
deciding which neonate requires empirical antimicrobial therapy but can
assist with the decision to discontinue
treatment.22
Blood Culture
A single blood culture in a sufficient
volume is required for all neonates
with suspected sepsis. Data suggest
that 1.0 mL of blood should be the
minimum volume drawn for culture
when a single pediatric blood culture
bottle is used. Dividing the specimen in
half and inoculating aerobic and anaerobic bottles is likely to decrease the
sensitivity. Although 0.5 mL of blood
has previously been considered acceptable, in vitro data from Schelonka
et al demonstrated that 0.5 mL would
not reliably detect low-level bacteremia
1007
(4 colony-forming units [CFU]/mL or
less). 23 Furthermore, up to 25% of
infants with sepsis have low colony
count bacteremia (≤4 CFU/mL), and
two-thirds of infants younger than 2
months of age have colony counts <10
CFU/mL.24,25 Neal et al demonstrated
that more than half of blood specimens
inoculated into the aerobic bottle were
less than 0.5 mL.26 A study by Connell
et al indicated that blood cultures with
an adequate volume were twice as
likely to yield a positive result.27 A blood
culture obtained through an umbilical
artery catheter shortly after placement
for other clinical indications is an acceptable alternative to a culture drawn
from a peripheral vein.28 The risk of
recovering a contaminant is greater
with a blood culture drawn from an
umbilical vein.29 There are, however,
data to suggest that a blood culture
drawn from the umbilical vein at the
time of delivery using a doubly clamped and adequately prepared segment
of the cord is a reliable alternative to
a culture obtained peripherally.30
Urine Culture
A urine culture should not be part of the
sepsis workup in an infant with suspected
early-onset sepsis.31 Unlike urinary tract
infections in older infants (which are
usually ascending infections), urinary
tract infections in newborn infants are
attributable to seeding of the kidney
during an episode of bacteremia.
Gastric Aspirates
The fetus swallows 500 to 1000 mL of
amniotic fluid each day. Therefore, if
there are white blood cells present in
amniotic fluid, they will be present in
gastric aspirate specimens at birth.
However, these cells represent the maternal response to inflammation and
have a poor correlation with neonatal
sepsis.32 Gram stains of gastric aspirates
to identify bacteria are of limited value
and are not routinely recommended.33
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
Body Surface Cultures
Bacterial cultures of the axilla, groin,
and the external ear canal have a poor
positive predictive accuracy. They are
expensive and add little to the evaluation of an infant with possible bacterial sepsis.34,35
Tracheal Aspirates
Cultures and Gram stains of tracheal
aspirate specimens may be of value if
obtained immediately after endotracheal tube placement.36 Once an infant
has been intubated for several days,
tracheal aspirates are of no value in
the evaluation of sepsis.37
Lumbar Puncture
The decision to perform a lumbar puncture in a neonate with suspected earlyonset sepsis remains controversial. In
the high-risk, healthy-appearing infant, data suggest that the likelihood
of meningitis is extremely low.38 In the
infant with clinical signs that are thought
to be attributable to a noninfectious
condition, such as respiratory distress
syndrome, the likelihood of meningitis
is also low.39 However, in bacteremic
infants, the incidence of meningitis may
be as high as 23%.40,41 Blood culture
alone cannot be used to decide who
needs a lumbar puncture, because
blood cultures can be negative in up
to 38% of infants with meningitis.42,43
The lumbar puncture should be performed in any infant with a positive
blood culture, infants whose clinical
course or laboratory data strongly
suggest bacterial sepsis, and infants
who initially worsen with antimicrobial therapy. For any infant who is
critically ill and likely to have cardiovascular or respiratory compromise
from the procedure, the lumbar puncture can be deferred until the infant is
more stable.
Cerebrospinal fluid (CSF) values indicative of neonatal meningitis are controversial. In studies that have excluded
infants with “traumatic taps” (or
nonbacterial illnesses), the mean
number of white blood cells in uninfected preterm or term infants was
consistently <10 cells/mm3.44–50 Cell
counts 2 standard deviations from the
mean were generally less than 20
cells/mm3.46 In a study by Garges et al,
the median number of white blood cells
in infants who were born at greater
than 34 weeks’ gestation and had
bacterial meningitis was 477/mm3.43
In contrast, the median number of white
blood cells in infants who were born at
less than 34 weeks’ gestation and had
meningitis was 110/mm3.51 Infants with
meningitis attributable to Gram-negative
pathogens typically have higher CSF
white blood cell counts than do infants
with meningitis attributable to Grampositive pathogens.52 Adjusting the
CSF white blood cell count for the
number of red blood cells does not
improve the diagnostic utility (loss of
sensitivity with marginal gain in specificity).53 In addition, the number of bands
in a CSF specimen does not predict
meningitis.54 With a delay in analysis
(>2 hours), white blood cell counts
and glucose concentrations decrease
significantly.55
Protein concentrations in uninfected,
term newborn infants are <100 mg/
dL.44–50 Preterm infants have CSF protein concentrations that vary inversely
with gestational age. In the normoglycemic newborn infant, glucose concentrations in CSF are similar to those
in older infants and children (70%–80%
of a simultaneously obtained blood
specimen). A low glucose concentration
is the CSF variable with the greatest
specificity for the diagnosis of meningitis.43,51 Protein concentrations are
higher and glucose concentrations are
lower in term than in preterm infants
with meningitis. However, meningitis
occurs in infants with normal CSF
values, and some of these infants have
high bacterial inocula.43,51
FROM THE AMERICAN ACADEMY OF PEDIATRICS
Peripheral White Blood Cell Count
and Differential Count
Total white blood cell counts have little
value in the diagnosis of early-onset
sepsis and have a poor positive predictive accuracy. 56,57 Many investigators have analyzed subcomponents
of the white blood cell count (neutrophil
indices)—absolute neutrophil count,
absolute band count, and immature to
total neutrophil (I/T)ratio—to identify
infected infants. Like most diagnostic
tests for neonatal sepsis, neutrophil indices have proven most useful for excluding infants without infection rather
than identifying infected neonates. Neutropenia may be a better marker for
neonatal sepsis and has better specificity than an elevated neutrophil count,
because few conditions besides sepsis
(maternal pregnancy-induced hypertension, asphyxia, and hemolytic disease) depress the neutrophil count of
neonates.58 The definitions for neutropenia vary with gestational age,58–61
type of delivery (infants born by cesarean delivery without labor have lower
counts than infants delivered vaginally),61 site of sampling (neutrophil
counts are lower in samples from
arterial blood),62 and altitude (infants
born at elevated altitudes have higher
total neutrophil counts).63 In late preterm and term infants, the definition
for neutropenia most commonly used
is that suggested by Manroe et al
(<1800/mm3 at birth and <7800/mm3
at 12–14 hours of age).58 Schmutz et al
reinvestigated these reference ranges
using modern cell-counting instrumentation in 30 254 infants born at 23 to 42
weeks’ gestation.61 Infants with diagnoses
known to affect neutrophil counts (eg,
those born to women with pregnancyinduced hypertension or those with
early-onset sepsis) were excluded. In
this study, the lower limits of normal
for neutrophil values at birth were
3500/mm3 in infants born at >36 weeks’
gestation, 1000/mm3 in infants born at
PEDIATRICS Volume 129, Number 5, May 2012
28 through 36 weeks’ gestation, and
500/mm3 in infants born at <28 weeks’
gestation. Peak values occurred at 6 to
8 hours after birth; the lower limits of
normal at that time were 7500/mm3,
3500/mm3, and 1500/mm3 for infants
born at >36 weeks’ gestation, 28 to
36 weeks’ gestation, and <28 weeks’
gestation, respectively.61 It is noteworthy that the study by Schmutz et al was
performed at 4800 feet above sea level,
whereas that of Manroe et al was performed at 500 feet above sea level.
Counts obtained 6 to 12 hours after
birth are more likely to be abnormal
than are counts obtained at birth, because alterations in the numbers (and
ratios) of mature and immature neutrophils require an established inflammatory
response. Therefore, once the decision is
made to start antimicrobial therapy
soon after birth, it is worth waiting 6 to
12 hours before ordering a white blood
cell count and differential count.68,69
The absolute immature neutrophil count
follows a similar pattern to the absolute
neutrophil count and peaks at approximately 12 hours of life. The number of
immature neutrophils increases from a
maximal value of 1100 cells/mm3 at
birth to 1500 cells/mm3 at 12 hours of
age.58 Absolute immature counts have
a poor sensitivity and positive predictive accuracy for early-onset sepsis.22
Furthermore, if exhaustion of bone marrow reserves occurs, the number of immature forms will remain depressed.64
Despite the frequency of low platelet
counts in infected infants, they are a
nonspecific, insensitive, and late indicator of sepsis.70,71 Moreover, platelet
counts are not useful to follow clinical
response to antimicrobial agents, because they often remain depressed for
days to weeks after a sepsis episode.
The I/T ratio has the best sensitivity of
any of the neutrophil indices. However,
with manual counts, there are wide
interreader differences in band neutrophil identification.65 The I/T ratio is
<0.22 in 96% of healthy preterm infants
born at <32 weeks’ gestational age.66
Unlike the absolute neutrophil count
and the absolute band count, maximum
normal values for the I/T ratio occur at
birth (0.16) and decline with increasing
postnatal age to a minimum value of
0.12.58 In healthy term infants, the 90th
percentile for the I/T ratio is 0.27.59
A single determination of the I/T ratio
has a poor positive predictive accuracy
(approximately 25%) but a very high
negative predictive accuracy (99%).66
The I/T ratio may be elevated in 25% to
50% of uninfected infants.67
Exhaustion of bone marrow reserves
will result in low band counts and lead
to falsely low ratios. The timing of the
white blood cell count is critical. 68
Platelet Counts
Acute-Phase Reactants
A wide variety of acute-phase reactants
have been evaluated in neonates with
suspected bacterial sepsis. However, only
C-reactive protein (CRP) and procalcitonin concentrations have been investigated in sufficiently large studies.72,73 CRP
concentration increases within 6 to 8
hours of an infectious episode in neonates and peaks at 24 hours.74,75 The
sensitivity of a CRP determination is
low at birth, because it requires an
inflammatory response (with release
of interleukin-6) to increase CRP concentrations.76 The sensitivity improves
dramatically if the first determination
is made 6 to 12 hours after birth. Benitz
et al have demonstrated that excluding
a value at birth, 2 normal CRP determinations (8–24 hours after birth and
24 hours later) have a negative predictive accuracy of 99.7% and a negative likelihood ratio of 0.15 for proven
neonatal sepsis.76 If CRP determinations remain persistently normal, it is
strong evidence that bacterial sepsis is
unlikely, and antimicrobial agents can be
safely discontinued. Data are insufficient
to recommend following sequential CRP
1009
concentrations to determine the duration of antimicrobial therapy in an infant
with an elevated value (≥1.0 mg/dL).
Procalcitonin concentrations increase
within 2 hours of an infectious episode,
peak at 12 hours, and normalize within
2 to 3 days in healthy adult volunteers.77
A physiologic increase in procalcitonin
concentration occurs within the first
24 hours of birth, and an increase in
serum concentrations can occur with
noninfectious conditions (eg, respiratory distress syndrome).78 Procalcitonin
concentration has a modestly better
sensitivity than does CRP concentration
but is less specific.73 Chiesa and colleagues have published normal values
for procalcitonin concentrations in term
and preterm infants.79 There is evidence
from studies conducted in adult populations, the majority of which focused
on patients with sepsis in the ICU, that
significant reductions in use of antimicrobial agents can be achieved in
patients whose treatment is guided by
procalcitonin concentration.80
Sepsis Screening Panels
Hematologic scoring systems using
multiple laboratory values (eg, white
blood cell count, differential count, and
platelet count) have been recommended as useful diagnostic aids. No matter
what combination of tests is used, the
positive predictive accuracy of scoring
systems is poor unless the score is
very high. Rodwell et al described a
scoring system in which a score of 1 was
assigned to 1 of 7 findings, including
abnormalities of leukocyte count, total
neutrophil count, increased immature
polymorphonuclear leukocyte (PMN)
count, increased I/T ratio, immature to
mature PMN ratio >0.3, platelet count
≤150 000/mm3, and pronounced degenerative changes (ie, toxic granulations)
in PMNs. 81 In this study, two-thirds
of preterm infants and 90% of term
infants with a hematologic score
≥3 did not have proven sepsis. 81
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
Furthermore, scores obtained in the
first several hours after birth have been
shown to have poorer sensitivity and
negative predictive value than scores
obtained at 24 hours of age.67 Sepsis
screening panels commonly include
neutrophil indices and acute-phase reactants (usually CRP concentration). The
positive predictive value of the sepsis
screen in neonates is poor (<30%);
however, the negative predictive accuracy
has been high (>99%) in small clinical
studies.22 Sepsis screening tests might be
of value in deciding which “high-risk”
healthy-appearing neonates do not need
antimicrobial agents or whether therapy
can be safely discontinued.
TREATMENT OF INFANTS WITH
SUSPECTED EARLY-ONSET SEPSIS
In the United States, the most common
pathogens responsible for early-onset
neonatal sepsis are GBS and Escherichia
coli.17 A combination of ampicillin and
an aminoglycoside (usually gentamicin)
is generally used as initial therapy, and
this combination of antimicrobial agents
also has synergistic activity against
GBS and Listeria monocytogenes.82,83
Third-generation cephalosporins (eg,
cefotaxime) represent a reasonable alternative to an aminoglycoside. However,
several studies have reported rapid
development of resistance when cefotaxime has been used routinely for the
treatment of early-onset neonatal sepsis,84 and extensive/prolonged use of
third-generation cephalosporins is a risk
factor for invasive candidiasis.85 Because of its excellent CSF penetration,
empirical or therapeutic use of cefotaxime should be restricted for use in
infants with meningitis attributable to
Gram-negative organisms.86 Ceftriaxone is contraindicated in neonates
because it is highly protein bound
and may displace bilirubin, leading to a
risk of kernicterus. Bacteremia without an
identifiable focus of infection is generally
treated for 10 days.87 Uncomplicated
meningitis attributable to GBS is treated for a minimum of 14 days.88 Other
focal infections secondary to GBS (eg,
cerebritis, osteomyelitis, endocarditis)
are treated for longer durations.88 Gramnegative meningitis is treated for
minimum of 21 days or 14 days after
obtaining a negative culture, whichever
is longer.88 Treatment of Gram-negative
meningitis should include cefotaxime
and an aminoglycoside until the results
of susceptibility testing are known.87,88
The duration of antimicrobial therapy
in infants with negative blood cultures
is controversial. Many women receive
antimicrobial agents during labor as
prophylaxis to prevent early-onset GBS
infections or for management of suspected intra-amniontic infection or
PPROM. In those instances, postnatal
blood cultures may be sterile (false
negative). When considering the duration of therapy in infants with negative
blood cultures, the decision should
include consideration of the clinical
course as well as the risks associated
with longer courses of antimicrobial
agents. In a retrospective study by Cordero and Ayers, the average duration of
treatment in 695 infants (<1000 g)
with negative blood cultures was 5 ±
3 days.89 Cotten et al have suggested
an association with prolonged administration of antimicrobial agents (>5 days)
in infants with suspected early-onset
sepsis (and negative blood cultures)
with death and necrotizing enterocolitis.90 Two recent papers also support
this association.91,92
PREVENTION STRATEGIES FOR
EARLY-ONSET SEPSIS
The only intervention proven to decrease
the incidence of early-onset neonatal
sepsis is maternal treatment with
intrapartum intravenous antimicrobial agents for the prevention of GBS
infections.93 Adequate prophylaxis is
defined as penicillin (the preferred
agent), ampicillin, or cefazolin given for
FROM THE AMERICAN ACADEMY OF PEDIATRICS
≥4 hours before delivery. Erythromycin
is no longer recommended for prophylaxis because of high resistance rates.
In parturients who have a nonserious
penicillin allergy, cefazolin is the drug
of choice. For parturients with a history
of serious penicillin allergy (anaphylaxis, angioedema, respiratory compromise, or urticaria), clindamycin is
an acceptable alternative agent, but
only if the woman’s rectovaginal GBS
screening isolate has been tested and
documented to be susceptible. If the
clindamycin susceptibility is unknown
or the GBS isolate is resistant to clindamycin, vancomycin is an alternative
agent for prophylaxis. However, neither clindamycin nor vancomycin has
been evaluated for efficacy in preventing early-onset GBS sepsis in
neonates. Intrapartum antimicrobial
agents are indicated for the following
situations93:
1. Positive antenatal cultures or molecular test at admission for GBS (except for women who have a cesarean
delivery without labor or membrane
rupture)
hours of life. Approximately 1% of infants
will appear healthy at birth and then
develop signs of infection after a variable time period.21 Every critically ill
infant should be evaluated and receive
empirical broad-spectrum antimicrobial
therapy after cultures, even when there
are no obvious risk factors for sepsis.
The greatest difficulty faced by clinicians is distinguishing neonates with
early signs of sepsis from neonates
with noninfectious conditions with relatively mild findings (eg, tachypnea with
or without an oxygen requirement). In
this situation, data are insufficient to
guide management. In more mature
neonates without risk factors for infection who clinically improve over the
first 6 hours of life (eg, need for oxygen
is decreasing and respiratory distress
is resolving), it is reasonable to withhold antimicrobial therapy and monitor
the neonates closely. The 6-hour window should not be considered absolute;
however, most infants without infection demonstrate some improvement
over that time period. Any worsening of
the infant’s condition should prompt
starting antimicrobial agents after cultures have been obtained.
Challenge 2: Identifying
Healthy-Appearing Neonates With
a “High Likelihood” of Early-Onset
Sepsis Who Require Antimicrobial
Agents Soon After Birth
This category includes infants with 1 of
the risk factors for sepsis noted previously (colonization with GBS, prolonged
rupture of membranes >18 hours, or
maternal chorioamnionitis). GBS is not
a risk factor if the mother has received
adequate intrapartum therapy (penicillin, ampicillin, or cefazolin for at least
4 hours before delivery) or has a cesarean delivery with intact membranes
in the absence of labor.93 The risk of
infection in the newborn infant varies
considerably with the risk factor present. The greatest risk of early-onset
sepsis occurs in infants born to women
with chorioamnionitis who are also
colonized with GBS and did not receive
intrapartum antimicrobial agents. Earlyonset sepsis does occur in infants who
appear healthy at birth.21 Therefore,
2. Unknown maternal colonization status with gestation <37 weeks, rupture of membranes >18 hours, or
temperature >100.4°F (>38°C)
3. GBS bacteriuria during the current
pregnancy
4. Previous infant with invasive GBS
disease
Management guidelines for the newborn infant have been published93 and
are available online (http://www.cdc.
gov/groupbstrep/guidelines/index.html).
CLINICAL CHALLENGES
Challenge 1: Identifying Neonates
With Clinical Signs of Sepsis With
a “High Likelihood” of Early-Onset
Sepsis Who Require Antimicrobial
Agents Soon After Birth
Most infants with early-onset sepsis
exhibit abnormal signs in the first 24
PEDIATRICS Volume 129, Number 5, May 2012
FIGURE 1
Evaluation of asymptomatic infants <37 weeks’ gestation with risk factors for sepsis. aThe diagnosis
of chorioamnionitis is problematic and has important implications for the management of the
newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical
colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with
a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, response to treatment, and laboratory results. IAP, intrapartum antimicrobial prophylaxis; WBC, white
blood cell; Diff, differential white blood cell count.
1011
some clinicians use diagnostic tests
with a high negative predictive accuracy
as reassurance that infection is not
present (allowing them to withhold
antimicrobial agents). The decision of
whether to treat a high-risk infant
depends on the risk factors present,
the frequency of observations, and
gestational age. The threshold for
initiating antimicrobial treatment generally decreases with increasing numbers of risk factors for infection and
greater degrees of prematurity. Suggested algorithms for management of
healthy-appearing, high-risk infants are
shown in Figs 1, 2, and 3. Screening
blood cultures have not been shown to
be of value.21
CONCLUSIONS
The diagnosis and management of neonates with suspected early-onset sepsis
are based on scientific principles modified by the “art and experience” of the
practitioner. The following are wellestablished concepts related to neonatal sepsis:
1. Neonatal sepsis is a major cause of
morbidity and mortality.
2. Diagnostic tests for early-onset
sepsis (other than blood or CSF cultures) are useful for identifying infants with a low probability of sepsis
but not at identifying infants likely to
be infected.
3. One milliliter of blood drawn before
initiating antimicrobial therapy is
needed to adequately detect bacteremia if a pediatric blood culture bottle is used.
FIGURE 2
Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis. The diagnosis
of chorioamnionitis is problematic and has important implications for the management of the
newborn infant. Therefore, pediatric providers are encouraged to speak with their obstetrical
colleagues whenever the diagnosis is made. bLumbar puncture is indicated in any infant with
a positive blood culture or in whom sepsis is highly suspected on the basis of clinical signs, response to treatment, and laboratory results. WBC, white blood cell; Diff, differential white blood cell
count.
a
FIGURE 3
Evaluation of asymptomatic infants ≥37 weeks’ gestation with risk factors for sepsis (no
chorioamnionitis). aInadequate treatment: Defined as the use of an antibiotic other than penicillin,
ampicillin, or cefazolin or if the duration of antibiotics before delivery was <4 h. bDischarge at 24 h
is acceptable if other discharge criteria have been met, access to medical care is readily accessible,
and a person who is able to comply fully with instructions for home observation will be present. If
any of these conditions is not met, the infant should be observed in the hospital for at least 48 h and
until discharge criteria are achieved. IAP, intrapartum antimicrobial prophylaxis; WBC, white blood
cell; Diff, differential white blood cell count.
1012
FROM THE AMERICAN ACADEMY OF PEDIATRICS
4. Cultures of superficial body sites,
gastric aspirates, and urine are of
no value in the diagnosis of earlyonset sepsis.
5. Lumbar puncture is not needed in
all infants with suspected sepsis (especially those who appear healthy)
but should be performed for infants
with signs of sepsis who can safely
undergo the procedure, for infants
with a positive blood culture, for infants likely to be bacteremic (on the
basis of laboratory data), and infants
who do not respond to antimicrobial
therapy in the expected manner.
6. The optimal treatment of infants with
suspected early-onset sepsis is
broad-spectrum antimicrobial agents
(ampicillin and an aminoglycoside).
Once the pathogen is identified,
antimicrobial therapy should be
narrowed (unless synergism is
needed).
7. Antimicrobial therapy should be
discontinued at 48 hours in clinical
situations in which the probability
of sepsis is low.
FROM THE AMERICAN ACADEMY OF PEDIATRICS
Richard A. Polin, MD
Rosemarie C. Tan, MD, PhD
Kasper S. Wang, MD
Kristi L. Watterberg, MD
COMMITTEE ON FETUS AND
NEWBORN, 2011–2012
FORMER COMMITTEE MEMBER
LEAD AUTHOR
Lu-Ann Papile, MD, Chairperson
Jill E. Baley, MD
William Benitz, MD
Waldemar A. Carlo, MD
James Cummings, MD
Praveen Kumar, MD
Richard A. Polin, MD
Ann L. Jefferies, MD – Canadian Paediatric Society
Rosalie O. Mainous, PhD, RNC, NNP – National
Association of Neonatal Nurses
Tonse N. K. Raju, MD, DCH – National Institutes
of Health
Vinod K. Bhutani, MD
FORMER LIAISON
LIAISONS
CAPT Wanda Denise Barfield, MD, MPH – Centers
for Disease Control and Prevention
George Macones, MD – American College of
Obstetricians and Gynecologists
William Barth, Jr, MD – American College of
Obstetricians and Gynecologists
STAFF
Jim Couto, MA
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14(suppl B):161–165
87. Nizet V, Klein JO. Bacterial sepsis and meningitis. In: Remington JS, Klein JO, Wilson
Christopher B, Nizet V, eds. Infectious Diseases of the Fetus and Newborn Infant. 7th
ed. Philadelphia, PA: Saunders; 2010:222–275
88. Pickering LK, Baker CJ, Kimberlin DW, Long
SS, eds. Red Book: 2009 Report of the
Committee on Infectious Diseases. 28th ed.
Elk Grove Village, IL: American Academy of
Pediatrics; 2009
89. Cordero L, Ayers LW. Duration of empiric
antibiotics for suspected early-onset sepsis in extremely low birth weight infants.
Infect Control Hosp Epidemiol. 2003;24(9):
662–666
90. Cotten CM, Taylor S, Stoll B, et al; NICHD
Neonatal Research Network. Prolonged duration of initial empirical antibiotic treatment is associated with increased rates of
necrotizing enterocolitis and death for
extremely low birth weight infants. Pediatrics. 2009;123(1):58–66
91. Kuppala VS, Meinzen-Derr J, Morrow AL,
Schibler KR. Prolonged initial empirical
antibiotic treatment is associated with adverse outcomes in premature infants.
J Pediatr. 2011;159(5):720–725
92. Alexander VN, Northrup V, Bizzarro MJ.
Antibiotic exposure in the newborn intensive care unit and the risk of necrotizing enterocolitis. J Pediatr. 2011;159(3):
392–397
93. Centers for Disease Control and Prevention.
Prevention of perinatal group B streptococcal disease—revised guidelines from
CDC, 2010. MMWR Recomm Rep. 2010;59
(RR-10):1–36
1015
Recommendations for the Prevention of Perinatal Group B Streptococcal (GBS)
Disease
COMMITTEE ON INFECTIOUS DISEASES AND COMMITTEE ON FETUS AND
NEWBORN
Pediatrics; originally published online August 1, 2011;
DOI: 10.1542/peds.2011-1466
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2011/07/28/peds.2011-1466
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2011 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from pediatrics.aappublications.org at Mc Master University on November 26, 2012
FROM THE AMERICAN ACADEMY OF PEDIATRICS
Organizational Principles to Guide and Define the Child
Health Care System and/or Improve the Health of all Children
POLICY STATEMENT
Recommendations for the Prevention of Perinatal Group
B Streptococcal (GBS) Disease
COMMITTEE ON INFECTIOUS DISEASES AND COMMITTEE ON
FETUS AND NEWBORN
abstract
KEY WORDS
group B Streptococcus, early onset, diagnosis, prophylaxis,
penicillin allergy, treatment
The Centers for Disease Control and Prevention (CDC) guidelines for
the prevention of perinatal group B streptococcal (GBS) disease were
initially published in 1996. The American Academy of Pediatrics (AAP)
also published a policy statement on this topic in 1997. In 2002, the CDC
published revised guidelines that recommended universal antenatal
GBS screening; the AAP endorsed these guidelines and published recommendations based on them in the 2003 Red Book. Since then, the
incidence of early-onset GBS disease in neonates has decreased by an
estimated 80%. However, in 2010, GBS disease remained the leading
cause of early-onset neonatal sepsis. The CDC issued revised guidelines in 2010 based on evaluation of data generated after 2002. These
revised and comprehensive guidelines, which have been endorsed by
the AAP, reaffirm the major prevention strategy— universal antenatal
GBS screening and intrapartum antibiotic prophylaxis for culturepositive and high-risk women—and include new recommendations for
laboratory methods for identification of GBS colonization during pregnancy, algorithms for screening and intrapartum prophylaxis for
women with preterm labor and premature rupture of membranes,
updated prophylaxis recommendations for women with a penicillin
allergy, and a revised algorithm for the care of newborn infants. The
purpose of this policy statement is to review and discuss the differences between the 2002 and 2010 CDC guidelines that are most relevant for the practice of pediatrics. Pediatrics 2011;128:000
ABBREVIATIONS
GBS—group B streptococcal/Streptococcus
IAP—intrapartum antibiotic prophylaxis
CDC—Centers for Disease Control and Prevention
CBC—complete blood cell
This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors
have filed conflict of interest statements with the American
Academy of Pediatrics. Any conflicts have been resolved through
a process approved by the Board of Directors. The American
Academy of Pediatrics has neither solicited nor accepted any
commercial involvement in the development of the content of
this publication.
www.pediatrics.org/cgi/doi/10.1542/peds.2011-1466
doi:10.1542/peds.2011-1466
All policy statements from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed,
revised, or retired at or before that time.
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2011 by the American Academy of Pediatrics
PEDIATRICS Volume 128, Number 3, September 2011
INTRODUCTION
Group B streptococcal (GBS) disease has been a leading cause of neonatal morbidity and mortality since the 1970s.1,2 Maternal colonization
with GBS in the genitourinary or gastrointestinal tract and transmission to the infant during the labor-and-delivery process is the principal
risk factor for early-onset invasive GBS disease.3 Women who are identified as being GBS-colonized through culture-based screening are
more than 25 times more likely to deliver an infant with early-onset
infection than are women with negative prenatal cultures.4 Identification of maternal colonization through universal, culture-based screening with intrapartum antibiotic prophylaxis (IAP) for women with positive screening results has been recommended since 2002.5 This
strategy, endorsed by the American Academy of Pediatrics, has been
widely adopted in the United States and has resulted in an estimated
80% decrease in early-onset GBS infection.6
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1
TABLE 1 Evidence-Based Rating System Used to Determine Strength of Recommendations
Category
Strength of recommendation
A
B
C
D
E
Quality of evidence supporting
recommendation
I
II
III
Definition
Recommendation
Strong evidence for efficacy and substantial clinical benefit
Strong or moderate evidence for efficacy, but only limited clinical benefit
Insufficient evidence for efficacy, or efficacy does not outweigh possible adverse consequences
Moderate evidence against efficacy or for adverse outcome
Strong evidence against efficacy or for adverse outcome
Strongly recommended
Generally recommended
Optional
Generally not recommended
Never recommended
Evidence from at least 1 well-executed randomized, controlled trial or 1 rigorously designed
laboratory-based experimental study that has been replicated by an independent
investigator
Evidence from at least 1 well-designed clinical trial without randomization; cohort or casecontrolled analytic studies (preferably from more than 1 center); multiple time-series
studies; dramatic results from uncontrolled studies; or some evidence from laboratory
experiments
Evidence from opinions of respected authorities based on clinical or laboratory experience,
descriptive studies, or reports of expert committees
Adapted with permission from Centers for Disease Control and Prevention. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected
children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society,
and the American Academy of Pediatrics. MMWR Recomm Rep. 2009;58(RR-11):1–166.
However, even in the era of universal
screening, cases of GBS disease continue to occur.7–11 To evaluate data
published after the Centers for Disease Control and Prevention (CDC) issued guidelines for the prevention of
GBS perinatal disease in 2002, the CDC
called a meeting of clinical and public
health representatives in June 2009.
The goal of the meeting was to identify
potentially modifiable reasons for continued GBS disease and to address
these issues. The American Academy
of Pediatrics was represented by
members of its Committee on Infectious Diseases and Committee on Fetus and Newborn. The purpose of this
policy statement is to review and discuss the differences between the 2002
and 2010 CDC guidelines that are most
relevant for the practice of pediatrics.
Table 1 outlines the evidence-based
rating system that supports each recommendation; strength (indicated by
a letter) and quality (indicated by a
roman numeral) of evidence are
shown in parentheses. The 2010 CDC
guidelines can be accessed online
(www.cdc.gov/groupbstrep/guidelines/
guidelines.html).
2
FROM THE AMERICAN ACADEMY OF PEDIATRICS
LABORATORY DIAGNOSIS OF GBS
COLONIZATION
The 2002 guidelines from the CDC recommended universal culture-based screening for GBS at 35 to 37 weeks of gestation.
In the intervening years, new diagnostic
technologies have been developed, including pigmented enrichment broths,
chromogenic agars, DNA probes, and
nucleic acid amplification tests (NAATs).
These methods have been validated for
antenatal testing for GBS colonization
and are used in many clinical laboratories, which enables more rapid identification of GBS. A positive test result for
GBS by culture, DNA probe, or NAAT performed during antenatal screening indicates colonization, and the woman
should receive IAP. However, infants with
early-onset GBS can be born to women
with negative antenatal screening results, because all laboratory-screening
methods are imperfect. Culture-based
screening, especially if processing in the
laboratory does not always follow the
CDC guidelines, may not identify all colonized women.7,11 Infants with signs and
symptoms of sepsis should be managed
according to the neonatal algorithm (Fig
1) and receive an initial antibiotic reg-
imen that includes ampicillin regardless of maternal screening results.
Recommendations
● Options for GBS identification from
culture of maternal vaginal/rectal
swabs have been expanded to include a positive identification from
chromogenic agar media. Identification of GBS directly by nucleic acid
amplification tests (NAATs), such as
commercially available polymerase
chain reaction assays, can also be
used after broth enrichment if laboratories have validated their NAAT
performance and instituted appropriate quality controls (CII).
INTRAPARTUM ANTIBIOTIC
PROPHYLAXIS
Penicillin and ampicillin have each
been demonstrated in controlled clinical trials to be effective in preventing
early-onset GBS disease when administered during labor.12,13 Penicillin and
ampicillin at the recommended dosages for IAP rapidly achieve therapeutic concentrations in the fetal circulation and then amniotic fluid. Cefazolin
has similar pharmacokinetics when
compared with penicillin, and IAP dos-
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
Signs of neonatal sepsis?
Yes
Full diagnostic evaluationa
Antibiotic therapyb
Yes
Limited evaluationd
Antibiotic therapyb
No
Maternal chorioamnionitis?c
No
GBS prophylaxis indicated for
mother?e
No
Routine clinical caref
Yes
Mother received ≥4 h of
penicillin, ampicillin, or cefazolin IV?
Yes
Observation for ≥48 hf,g
No
≥37 wk and duration of
membrane rupture < 18 h?
Yes
Observation for ≥48 hf,h
Recommendations
No
Either <37 wk or duration of
membrane rupture ≥ 18 h?
women at low risk of anaphylaxis, current data indicate that approximately
20% of GBS isolates are resistant
to clindamycin. Clindamycin should
never be used for IAP if susceptibility
testing of the mother’s GBS isolate has
not been performed. Several recent
studies have revealed that susceptibility testing is rarely performed on GBS
isolates,5,6,17 and early-onset GBS disease has been reported in infants born
to mothers who have received clindamycin IAP.11,17
Yes
Limited evaluationd
Observation for ≥48 hf
FIGURE 1
Algorithm for the prevention of early-onset GBS infection in the newborn. (Adapted with permission
from Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal
disease: prevention of perinatal group B streptococcal disease from CDC, 2010. MMWR Recomm Rep.
2010;59[RR-10]:1–32.) a Full diagnostic evaluation includes a blood culture; CBC count, including white
blood cell differential and platelet counts; chest radiograph (if respiratory abnormalities are present); and lumbar puncture (if the patient is stable enough to tolerate procedure and sepsis is
suspected). b Antibiotic therapy should be directed toward the most common causes of neonatal
sepsis, including intravenous ampicillin for GBS and coverage for other organisms (including Escherichia coli and other Gram-negative pathogens) and should take into account local antibioticresistance patterns. c Consultation with obstetric providers is important in determining the level of
clinical suspicion for chorioamnionitis. Chorioamnionitis is diagnosed clinically, and some of the
signs are nonspecific. d Limited evaluation includes blood culture (at birth) and CBC count with
differential and platelets (at birth and/or at 6 –12 hours of life). e GBS prophylaxis is indicated if 1 or
more of the following is true: (1) mother is GBS-positive within the preceding 5 weeks; (2) GBS status
is unknown and there are 1 or more intrapartum risk factors, including ⬍37 weeks’ gestation,
rupture of membranes for ⱖ18 hours, or temperature of ⱖ100.4°F (38.0°C); (3) GBS bacteriuria
during current pregnancy; or (4) history of a previous infant with GBS disease. f If signs of sepsis
develop, a full diagnostic evaluation should be performed, and antibiotic therapy should be initiated.
g If at ⱖ37 weeks’ gestation, observation may occur at home after 24 hours if other discharge criteria
have been met, there is ready access to medical care, and a person who is able to comply fully with
instructions for home observation will be present. If any of these conditions is not met, the infant
should be observed in the hospital for at least 48 hours and until discharge criteria have been
achieved. h Some experts recommend a CBC count with differential and platelets at 6 to 12 hours of
age.24 IV indicates intravenously.
ing achieves high intra-amniotic concentrations.14–16 Cefazolin has been the
preferred alternative for IAP for
penicillin-allergic women at low risk of
anaphylaxis since 2002, although it has
been used uncommonly for this indication. At least 4 hours of IAP with one of
these ␤-lactam antibiotics is effective
in preventing early-onset GBS disease
in neonates. The definition of adequate
IAP has been clarified to include penicillin, ampicillin, or cefazolin for at
least 4 hours before delivery. Duration
PEDIATRICS Volume 128, Number 3, September 2011
of IAP shorter than 4 hours and all
other regimens, including clindamycin
and vancomycin, are considered to be
inadequate prophylaxis for infants because of lack of data regarding efficacy and limited data regarding favorable pharmacokinetics. No clinical
trials have evaluated the efficacy of
non–␤-lactam regimens for IAP in
women with serious penicillin allergy.
Although clindamycin is the most commonly chosen IAP regimen in the
United States for penicillin-allergic
● Penicillin remains the agent of
choice for IAP, and ampicillin is an
acceptable alternative (AI).
● Penicillin-allergic women who do
not have a history of anaphylaxis,
angioedema, respiratory distress,
or urticaria after administration of
penicillin or a cephalosporin should
receive cefazolin (BII).
● Penicillin-allergic women at high
risk of anaphylaxis should receive
clindamycin if their GBS isolate is
susceptible or vancomycin if their
GBS isolate is intrinsically resistant
to clindamycin (CIII).
● The definition of adequate IAP has
been clarified to be at least 4 hours
of penicillin, ampicillin, or cefazolin.
The initial intravenous dose of penicillin is 5 million units; for ampicillin
and cefazolin, the initial dose is 2 g
(AIII).
● All other antibiotics, doses, or dura-
tions are considered inadequate for
the purposes of neonatal management (AIII).
PREVENTION OF EARLY-ONSET GBS
DISEASE
The revised 2010 GBS American Academy of Pediatrics guidelines for neonatal management were designed to
broaden the scope to include all neonates, to increase the clarity of the recommendations, and to decrease un-
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3
necessary laboratory evaluations and
empirical antibiotics for infants at low
risk. Although this strategy will never
prevent all infections, the revised
guidelines should result in a further
decrease in cases of perinatal GBS disease. The management of neonates
continues to be based on clinical signs,
the presence of maternal risk factors
for GBS neonatal disease, and the
likely efficacy of IAP (or maternal antimicrobial treatment in the case of clinical or occult chorioamnionitis) in
preventing early-onset disease. The revised infant management algorithm
(Fig 1) is derived from recent data
summarized in the published CDC document regarding the epidemiology of
GBS disease and the usefulness of a
“limited evaluation” of well-appearing
neonates.
All newborn infants with signs suggestive of sepsis should have a full diagnostic evaluation, including a lumbar
puncture if the infant is stable enough
to undergo the procedure; 15% to 38%
of infants with early-onset meningitis
have sterile blood cultures, so evaluating the cerebrospinal fluid is required
for optimal diagnostic sensitivity.18–21 If
the care provider believes that a noninfectious condition is responsible for
the infant’s signs (eg, transient tachypnea of the newborn) and there are no
maternal risk factors for sepsis in an
otherwise well-appearing infant, the
lumbar puncture can be deferred or
eliminated. Empirical antimicrobial
therapy, typically intravenous ampicillin and gentamicin (unless local
antibiotic-resistance patterns suggest
the need for another combination),
then should be initiated promptly. Chorioamnionitis continues to be a significant risk factor for early-onset GBS
sepsis in infants born to GBS-colonized
women. All well-appearing newborn infants born to women who have a clinical diagnosis of chorioamnionitis from
their obstetric provider should un4
FROM THE AMERICAN ACADEMY OF PEDIATRICS
dergo a “limited evaluation,” which includes a complete blood cell (CBC)
count and differential and a blood culture before initiation of empirical antimicrobial therapy. The sensitivity of
the CBC count is improved if delayed
for 6 to 12 hours after birth. Empirical
therapy should be discontinued as
soon as the clinical course and laboratory evaluation exclude sepsis.
The indications for maternal IAP
remain unchanged and include 1 of
more of the following: (1) GBS
culture–positive within preceding 5
weeks; (2) GBS status unknown with
1 or more intrapartum risk factors including less than 37 weeks’ gestation,
prolonged rupture of membranes
for ⱖ18 hours, or temperature of
ⱖ100.4°F (38.0°C); (3) GBS bacteriuria
during current pregnancy; and (4) history of a previous infant with GBS disease. When a cesarean delivery is
performed before onset of labor with
intact amniotic membranes, the risk of
early-onset GBS disease among infants
is extremely low22,23; therefore, IAP is
not recommended as a routine practice for cesarean deliveries performed
under these circumstances, regardless of the GBS colonization status of
the woman or the gestational age of
the infant.
In well-appearing newborn infants
born to women without an indication
for IAP, routine clinical care is indicated unless signs of sepsis develop.
For well-appearing term newborn infants born to mothers with an indication for IAP to prevent GBS disease
and receipt of 4 or more hours of
penicillin, ampicillin or cefazolin at
the appropriate doses before delivery, routine care, and 48 hours of observation continue to be recommended. However, if these infants
meet other discharge criteria, including term birth and ready access
to medical care, discharge can occur
as early as 24 hours after birth. In
this latter circumstance, follow-up
care by a care provider within 48 to
72 hours is recommended.
In well-appearing term newborn infants whose mothers had an indication
for GBS prophylaxis and rupture of
membranes for ⬍18 hours but who received inadequate IAP— either by duration before delivery or by inappropriate agent or dose— observation in
the hospital for at least 48 hours is recommended. These infants would include infants born to women with a serious penicillin allergy who received
either clindamycin or vancomycin. This
revised recommendation is based on
the poor sensitivity of the “limitedevaluation” assessments in this circumstance and also data indicating
that signs of early-onset GBS sepsis appear in more than 98% of neonates
within this interval of hospitalization.
The authors of several studies have reported the sensitivity of an abnormal
CBC count in predicting GBS sepsis to
range from 41% to 68%, whereas the
presence of clinical signs has a sensitivity of 92%.24–27 The yield of blood
culture can be low among newborn
infants exposed to intrapartum antibiotics.28 Finally, for all preterm neonates (⬍37 weeks of gestation) or for
term newborn infants born in the setting of rupture of membranes 18 hours
or more before delivery without adequate maternal IAP, a limited evaluation and observation for at least 48
hours is recommended.
Recommendations for
Management of Newborn Infants
● All newborn infants with signs of
sepsis should undergo a full diagnostic evaluation (including a lumbar puncture) and receive empirical antimicrobial therapy (AII).
● All well-appearing newborn infants
born to women given a diagnosis
of chorioamnionitis by their obstetrical provider should undergo a
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FROM THE AMERICAN ACADEMY OF PEDIATRICS
limited diagnostic evaluation (no
lumbar puncture) and receive empirical antimicrobial therapy (AII).
● For all women who received ade-
quate IAP defined as penicillin (preferred), ampicillin, or cefazolin
(penicillin-allergic women at low
risk of anaphylaxis) for 4 or more
hours before delivery, their newborn infants require only routine
care and observation in the hospital
for 48 hours (BIII). If these infants
meet other discharge criteria, including term birth and ready access
to medical care, discharge can occur as early as 24 hours after birth
with follow-up care by a care provider within 48 to 72 hours (CII).
● Well-appearing term newborn in-
fants whose mothers received no or
inadequate IAP (including clindamycin or vancomycin) and had rupture
of membranes for less than 18
hours require only observation for
48 hours (BIII).
● Well-appearing term infants born to
women with no or inadequate IAP
and rupture of membranes for 18 or
more hours before delivery should
undergo a “limited evaluation” (ie,
blood culture and CBC count with
differential and platelets at birth)
and observation for at least 48
hours (BIII).
● All preterm infants born to women
with no or inadequate IAP should undergo a limited evaluation and observation for at least 48 hours (BIII).
Jack Swanson, MD – Committee on Practice
Ambulatory Medicine
Tina Q. Tan, MD – Pediatric Infectious Diseases
Society
EX OFFICIO
Carol J. Baker, MD
Carrie L. Byington, MD
Richard A. Polin, MD
Carol J. Baker, MD – Red Book Associate Editor
Sarah S. Long, MD – Red Book Associate Editor
H. Cody Meissner, MD – Red Book Associate
Editor
Larry K. Pickering, MD – Red Book Editor
COMMITTEE ON INFECTIOUS DISEASES,
2010 –2011
CONSULTANT
LEAD AUTHORS
Michael T. Brady, MD, Chairperson
Henry H. Bernstein, DO
Carrie L. Byington, MD
Kathryn M. Edwards, MD
Margaret C. Fisher, MD
Mary P. Glode, MD
Mary Anne Jackson, MD
Harry L. Keyserling, MD
David W. Kimberlin, MD
Yvonne A. Maldonado, MD
Walter A. Orenstein, MD
Gordon E. Schutze, MD
Rodney E. Willoughby, MD
LIAISONS
Beth Bell, MD, MPH – Centers for Disease
Control and Prevention
Robert Bortolussi, MD – Canadian Paediatric
Society
Marc A. Fischer, MD – Centers for Disease
Control and Prevention
Bruce Gellin, MD – National Vaccine Program
Office
Richard L. Gorman, MD – National Institutes of
Health
Lucia Lee, MD – Food and Drug Administration
R. Douglas Pratt, MD – Food and Drug
Administration
Jennifer S. Read, MD – National Institutes of
Health
Jeffrey R. Starke, MD – American Thoracic
Society
Lorry G. Rubin, MD
STAFF
Jennifer Frantz, MPH
COMMITTEE ON FETUS AND NEWBORN,
2010 –2011
Lu-Ann Papile, MD, Chairperson
James Cummings, MD
Jill E. Baley, MD
Vinod K. Bhutani, MD
Waldemar A. Carlo, MD
Praveen Kumar, MD
Richard A. Polin, MD
Rosemarie C. Tan, MD, PhD
Kasper S. Wang, MD
Kristi L. Watterberg, MD
LIAISONS
Capt Wanda D. Barfield, MD, MPH – Centers for
Disease Control and Prevention
William H. Barth Jr, MD – American College of
Obstetricians and Gynecologists
Ann L. Jefferies, MD – Canadian Paediatric
Society
Rosalie O. Mainous, PhD, RNC, NNP – National
Association of Neonatal Nurses
Tonse N. K. Raju, MD, DCH – National Institutes
of Health
STAFF
Jim Couto, MA
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term [abstract]. Am J Obstet Gynecol. 1999;
180(suppl):S85
Håkansson S, Axemo P, Bremme K, et al;
Swedish Working Group for the Prevention
of Perinatal Group B Streptococcal Infections. Group B streptococcal carriage in
Sweden: a national study on risk factors for
mother and infant colonisation. Acta Obstet
Gynecol Scand. 2008;87(1):50 –58
24. Greenberg DN, Yoder BA. Changes in the differential white blood cell count in screening
for group B streptococcal sepsis. Pediatr
Infect Dis J. 1990;9(12):886 – 889
25. Hsu KK, Pelton SI, Shapiro DS. Detection of
group B streptococcal bacteremia in simulated intrapartum antimicrobial prophylaxis. Diagn Microbiol Infect Dis. 2003;45(1):
23–27
26. Gerdes JS, Polin RA. Sepsis screen in neonates with evaluation of plasma fibronectin.
Pediatr Infect Dis J. 1987;6(5):443– 446
27. Ottolini MC, Lundgren K, Mirkinson LJ, Cason S, Ottolini MG. Utility of complete blood
count and blood culture screening to diagnose neonatal sepsis in the asymptomatic
at risk newborn. Pediatr Infect Dis J. 2003;
22(5):430 – 434
28. Escobar GJ, Li DK, Armstrong MA, et al. Neonatal sepsis workups in infants ⱖ2000
grams at birth: a population-based study.
Pediatrics. 2000;106(2 pt 1):256 –263
Downloaded from pediatrics.aappublications.org at Mc Master University on November 26, 2012
Recommendations for the Prevention of Perinatal Group B Streptococcal (GBS)
Disease
COMMITTEE ON INFECTIOUS DISEASES AND COMMITTEE ON FETUS AND
NEWBORN
Pediatrics; originally published online August 1, 2011;
DOI: 10.1542/peds.2011-1466
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
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POSITION STATEMENT (FN 2007-03)
Management of the infant at increased risk
for sepsis
Français en page 899
eonatal sepsis continues to cause a significant proportion of perinatal mortality and long-term morbidity in
the term and preterm infant population. The most common
single organism that causes early-onset neonatal sepsis is the
group B streptococcus (GBS or Streptococcus agalactiae) (1).
Invasive early-onset GBS disease has an incidence of
approximately two per 1000 live-born infants in the
absence of intrapartum antibiotic prophylaxis (IAP) (2,3),
with a case-fatality rate of between 2% and 13% in recent
studies (4-6). Therefore, preventive strategies have been
promoted and recently endorsed by the Society of
Obstetricians and Gynaecologists of Canada (7). It has
been demonstrated that the administration of intravenous
penicillin at least 4 h before delivery to mothers colonized
with GBS is highly effective in preventing perinatal transmission and early-onset invasive infection in the newborn
(8). The recommendations are to screen all mothers with
rectovaginal cultures at 35 to 37 weeks, and treat those with
positive cultures for GBS at the time they present in labour.
This strategy leads to as many as 22% of all mothers in
labour at term being treated with IAP to prevent disease in
0.2% of infants and prevent mortality in 0.01% of infants
(9). In the United Kingdom, it was calculated that it would
require 24,000 antepartum cultures and 7000 women in
labour treated with antibiotics to prevent one neonatal
death (10). As a consequence, other authorities have developed different recommendations, questioning whether
routine IAP is an appropriate use of resources (10,11), and
whether the pressure exerted for the development of bacterial resistance is justified. In Canada, the current incidence
of invasive neonatal GBS disease is uncertain because there
is no centralized or mandatory reporting system.
N
PURPOSE OF THE STATEMENT
The aim of the present statement is to develop evidencebased practice guidelines answering the following question:
How should an infant be monitored, investigated and
treated given the presence of clinical signs of sepsis, the
GBS culture status of the mother (positive, negative or
unknown), the treatment status of the mother (completed,
incomplete or no IAP), and the presence or absence of
maternal risk factors for neonatal sepsis?
METHODS OF STATEMENT DEVELOPMENT
A search was carried out in MEDLINE and the Cochrane
library, and last updated in January 2006. The MEDLINE
search terms were ‘Streptococcus agalactiae’ and ‘newborn’.
The hierarchy of evidence from the Centre for EvidenceBased Medicine (United Kingdom) was applied and, for this
statement, the levels of evidence for treatment, prognosis
and diagnosis were used (www.cebm.net, click on the EBM
Tools tab or www.cebm.net/levels_of_evidence.asp#levels).
DEFINITIONS
Limited diagnostic evaluation
Limited diagnostic evaluation consists of a complete blood
count (CBC), and observation of vital signs every 4 h for a
period of 24 h. The newborn can be cared for and observed
in the mother’s postpartum room. If the CBC shows a low
total white blood cell (WBC) count of less than 5.0×109/L,
then the risk of sepsis is substantially increased and a full
diagnostic evaluation and initiation of therapy would
usually be indicated.
Full diagnostic evaluation
Full diagnostic evaluation consists of a CBC, blood culture
and lumbar puncture (LP); a chest x-ray should be obtained
if respiratory difficulties are present. LP can be deferred in
unstable infants, and performed later to ascertain the
presence of hypoglycorrhachia or pleocytosis. Infants whose
only sign of sepsis is respiratory distress may also be
considered for deferment of LP if close follow-up can be
ensured.
THE UNWELL INFANT
The initial signs of sepsis may be subtle, and may include
temperature instability, tachycardia, poor peripheral
perfusion and respiratory distress. Because the progression of
invasive disease is very rapid, any infant with clinical signs
suggestive of infection should be treated immediately
following a prompt full diagnostic evaluation; delay
between presentation and therapy increases the risk of a
poor outcome (12) (evidence level 2b). There is no clear
distinction in the clinical signs present when the infant has
GBS sepsis compared with any other invasive organism.
Correspondence: Canadian Paediatric Society, 2305 St Laurent Boulevard, Ottawa, Ontario K1G 4J8. Telephone 613-526-9397,
fax 613-526-3332, Web sites www.cps.ca, www.caringforkids.cps.ca
Paediatr Child Health Vol 12 No 10 December 2007
©2007 Canadian Paediatric Society. All rights reserved
893
CPS Statement: FN 2007-03
Table 1
Empirical therapy for infants with positive cerebrospinal fluid (CSF) evaluation
Suggested expectant antimicrobials
for early-onset meningitis
CSF findings
Most common organisms
Gram-positive cocci
Group B streptococci, less commonly:
Staphylococcus species or enterococci
Ampicillin or penicillin plus gentamicin
Gram-positive rods
Listeria monocytogenes
Ampicillin plus gentamicin
Gram-negative rods
Escherichia coli, less commonly: Klebsiella,
Pseudomonas and Citrobacter
Cefotaxime plus gentamicin
Gram-negative cocci
Uncommon
Cefotaxime
Pleocytosis, or other findings strongly
suggestive of meningitis, but Gram stainnegative, or too unstable to have an LP
Any of the above are possible
Ampicillin plus gentamicin
LP Lumbar puncture. Source: Canadian Paediatric Society, 2007
Although IAP with a penicillin dramatically reduces the
frequency of early-onset invasive GBS disease, it does not
affect the frequency of sepsis caused by other organisms
(1,13) (evidence level 2b). Of note, invasive GBS can still
occur in infants of mothers who have had a negative
screening culture at 35 to 37 weeks; now that IAP is
widespread and effective, the majority of the remaining
infants with invasive GBS are those whose maternal
cultures were negative (14), but who became colonized
between screening and delivery (evidence level 2b). Also,
invasive GBS disease is still possible, even if very rare, in
mothers who received adequate IAP (15) (evidence level 4).
Thus, neither the maternal screening history nor
intrapartum exposure to antibiotics should affect the
approach to the management of the infant with clinical
signs of sepsis (recommendation category B). Therefore,
prospective therapy, while awaiting culture results, should
cover the most common bacteria: GBS, other streptococci,
Escherichia coli, other Gram-negative organisms and Listeria
monocytogenes.
An infant with signs of sepsis does not require confirmatory tests other than obtaining cultures before commencing
therapy, because no other tests have an adequately high negative predictive value to avoid therapy (evidence level 2a).
In particular, a normal WBC count or differential should not
prevent treatment in such an infant because the negative
likelihood ratio of a normal CBC is approximately 0.7
(recommendation grade B) (16).
Empirical therapy
There are no good prospective studies to indicate optimal
choice of therapy in the newborn infant with possible sepsis
(17), but ampicillin and gentamicin are usually appropriate
based on the usual susceptibilities of the predominant
organisms causing early-onset sepsis (evidence level 4).
Infants with a positive cerebrospinal fluid (CSF) evaluation
or with clinical signs of meningitis if the LP has been
deferred, should be treated with antibiotics which both
penetrate the CSF and are active against the likely organisms (Table 1). If there is information from the maternal
894
history suggesting an organism that is unlikely to respond to
these antibiotics, empirical therapy should be adjusted
appropriately. Blood cultures using modern automated systems are almost always positive by 48 h (18). Therefore, if
the laboratory results and clinical course do not indicate
bacterial infection, therapy may be discontinued after 48 h.
The majority of antibiotic courses are given to infants who
eventually prove not to have had sepsis; strategies for
further reduction of the duration of antibiotic therapy in
such infants should be considered. For example, because
gentamicin is usually now given once per day in the fullterm infant, and ampicillin is given every 12 h, the initial
antibiotic order could be to give ampicillin for four doses
every 12 h and gentamicin for two doses every 24 h,
followed by reassessment after verification of culture results
at 48 h, and reordering the antibiotics in case of positive
cultures (or ongoing signs of sepsis).
WELL-APPEARING INFANT OF A GBS-POSITIVE
MOTHER, WHO RECEIVED IAP MORE THAN
4 H BEFORE DELIVERY
IAP with a penicillin for least 4 h is highly effective at
eradicating GBS transmission (19), and thus preventing
the majority of invasive neonatal GBS disease (evidence
level 1b) (20). Therefore, if a GBS-positive woman receives
intrapartum antibiotics for at least 4 h before delivery and if
the newborn appears healthy and is more than 35 weeks
gestational age, the newborn requires no therapy for
prevention of early-onset GBS (recommendation grade A).
If the baby remains well at 24 h of age and is otherwise
eligible for discharge at this time, early discharge can be
contemplated provided the caregiver knows the appropriate
resources in the community for accessing health care and is
able to transport the baby immediately to a health care
facility if clinical signs of sepsis develop.
There is insufficient information regarding the efficacy
of alternative antibiotics (used when the mother is at risk of
anaphylaxis from penicillin). Such infants should be
managed as if the mother received incomplete IAP (next
heading) until further data are available.
Paediatr Child Health Vol 12 No 10 December 2007
CPS Statement: FN 2007-03
WELL-APPEARING INFANT OF A GBS-POSITIVE
MOTHER WHO RECEIVED IAP LESS THAN 4 H
BEFORE DELIVERY OR NOT AT ALL
The risk of invasive early-onset GBS disease in an infant
whose mother is GBS-positive and does not receive IAP is
approximately 1% (21). Only one-quarter of these babies
are asymptomatic at birth. This risk of significant disease
probably does not justify routine empirical treatment in
these circumstances, and careful observation with treatment at the first clinical sign of infection appears to be reasonable. Ninety-five per cent of infants with early-onset
GBS infection present with clinical signs within 24 h (22)
(either temperature instability, tachycardia, poor peripheral
perfusion, respiratory distress or abnormal CBC). Four per
cent of infected infants present between 24 h and 48 h of
age, with only 1% developing signs after 48 h of age. Thus,
prolonging hospitalization from 24 h to 48 h would require
the observation of more than 2000 infants to detect each
case of invasive infection. Therefore, if careful assessment
of the infant at 24 h confirms that they remain well, discharge at that time may well be appropriate as long as adequate patient education and follow-up are ensured.
The use of the CBC is sometimes promoted for determining risk, both for GBS and for other organisms, among
infants who are at elevated risk but appear well. However,
the positive predictive value of an abnormal CBC is low in
the newborn and it is, therefore, uncertain how to proceed
when an infant is clinically well but has an abnormal CBC;
unfortunately, most studies investigating the usefulness of the
CBC have not been confined to well-appearing infants and,
therefore, their usefulness in this specific situation is somewhat conjectural. One study (23) confined to well-appearing
term infants showed a positive predictive value of 1.5% of an
‘abnormal’ CBC (total WBC of 5.0×109/L or lower, or
30×109/L or greater, or an absolute polymorphonuclear cell
count of less than 1.5×109/L or an immature to mature polymorphonuclear cell ratio greater than 0.2) in identifying the
development of ‘clinical sepsis’ in 1665 healthy term infants
who were at risk; of note, none of these infants developed a
positive blood culture (evidence level 2b).
Several scoring systems have been developed for
analyzing CBC results (24), and all involve analysis of the
count of immature neutrophils, but there is very wide interobserver variability in the identification of immature or
‘band’ neutrophils (25). Even the best scoring system only
achieves a likelihood ratio of between four and eight (24)
(evidence level 2a). Finding a ‘left-shift’ or an elevated
total WBC count is not sufficiently predictive to alter management. The individual finding on a CBC with the highest
positive predictive value is a low total WBC count of less
than 5.0×109/L; if this finding is present, the likelihood
ratio is between 10 and 20 (16), leading to a post-test probability of sepsis of approximately 10% to 20% (evidence
level 2b) and, therefore, probably justifying treatment even
in a well-appearing infant after a full diagnostic workup.
However, only between 22% and 44% of infants with sepsis
will have such a low total WBC count (16).
Paediatr Child Health Vol 12 No 10 December 2007
WELL-APPEARING INFANT OF A
GBS-NEGATIVE MOTHER WHO HAD RISK
FACTORS AT DELIVERY
Before the recommendation for universal culture-based
screening, IAP was recommended for mothers with any one
of the following five risk factors: over 18 h rupture of
membranes, pyrexia higher than 38°C, premature labour at
less than 36 weeks, GBS bacteriuria at anytime during
pregnancy or previous child with invasive GBS disease.
These risk factors were present in as many as 22% of
mothers, and only identified approximately 50% of infants
who eventually developed invasive GBS disease (26,27)
(evidence level 2b).
Although invasive GBS disease does occur in infants
whose mothers have negative screening cultures at 35 to
37 weeks, the risk is very low even in those with prolonged
rupture of membranes or intrapartum pyrexia (28)
(evidence level 2b). It is suggested that a limited diagnostic evaluation be performed in this newborn population
(recommendation grade B).
WELL-APPEARING INFANT OF A MOTHER WITH
UNKNOWN GBS STATUS AND NO RISK FACTORS
A mother who has not had an antenatal GBS culture or
whose results are not readily available, and her newborn
baby, should be managed according to the risk factors listed
in the previous section. In the absence of these risk factors,
and if the baby remains well, no specific intervention is
required (recommendation grade B).
WELL-APPEARING INFANT OF A MOTHER
WITH UNKNOWN GBS STATUS
WITH RISK FACTORS
The five risk factors mentioned above occur in approximately 20% of deliveries at term, and are present in approximately 50% of infants with invasive GBS disease (26,27).
This fourfold increase in risk to the infant in a mother with
unknown GBS status has led to the recommendation that
she should receive IAP (7). In this circumstance, the infant
should be treated in the same way as he or she would be
treated if the mother were GBS-positive (ie, IAP more than
4 h before delivery and routine neonatal care; IAP less than
4 h or no IAP, limited diagnostic evaluation and minimum
24 h observation) (recommendation grade B).
THE LATE PRETERM INFANT
The mother who delivers at less than 37 weeks will often
not have results of antenatal GBS screening available. In
such a case, the infant has a ‘risk factor’ (prematurity) for
invasive GBS disease and, if he or she appear well, should
have a limited diagnostic evaluation. Infants of this
gestational age should not be discharged before 48 h at the
earliest (Figure 1).
CHORIOAMNIONITIS
Chorioamnionitis is a difficult condition to diagnose
because the prevalence of pyrexia during labour is high
895
CPS Statement: FN 2007-03
Is the baby
unwell
Yes
GBS Group B streptococcus
IAP Intrapartum prophylaxis with
penicillin or ampicillin
No
Close observation = 4 h check
of pulse rate, respiratory rate and
temperature at mother’s bedside
Is the mother
colonized
with GBS?
Known to be positive
Known to be negative
Full diagnostic evaluation = blood
culture, spinal tap ± chest x-ray
(urine culture not indicated)
GBS status not known
No
Risk factors for sepsis = maternal
fever or signs of chorioamnionitis,
ruptured membranes >18 h,
previous child with GBS sepsis or
preterm labour (<36 weeks)
Are there perinatal
risk factors for
sepsis?
Yes
Yes
Immediate full
diagnostic
evaluation
Did the mother
receive more than
4 h of IAP?
No
Yes
Check
CBC
Check CBC: Is
the total WBC count
<5.0×109/L?
No
Findings or
progress
consistent with
sepsis?
Yes
No
Routine
neonatal care
and discharge
with relevant
parental
counselling
Yes
Close
observation
Empirical
antibiotic
therapy for up
to and
including
36 h.
Consider
consultation
Baby remains
well?
No
Antibiotic
therapy to
cover
underlying
illness for at
least 5 days.
Consider
consultation
Figure 1) Algorithm for the management of newborn babies who may be at risk for neonatal sepsis. Source: Canadian Paediatric Society, 2007
896
Paediatr Child Health Vol 12 No 10 December 2007
CPS Statement: FN 2007-03
(29), especially if the mother has had epidural analgesia (30).
Other signs of chorioamnionitis are less frequent; there is
poor correlation between clinical signs of chorioamnionitis
and histology (29). Therefore, chorioamnionitis is frequently
classified as ‘possible’, when the main sign is fever, and
‘definite’, when the classical triad of fever, left-shift in the
WBC and lower uterine tenderness is present.
The risk of sepsis (which may be due to a variety of
different organisms, including GBS, E coli and other Gramnegative organisms) in an infant whose mother had definite
chorioamnionitis is approximately 8%, and is approximately
3% to 4% if ‘possible’ and ‘definite’ chorioamnionitis are
considered together (31,32) (evidence level 2b); among all
mothers with fever, the incidence is 2% to 6% depending
on the height of the fever (31) (evidence level 2b). Infants
who do not have signs at birth are unlikely to develop
sepsis, the odds ratio for sepsis among infants who are well
at birth is 0.26 (95% CI 0.11 to 0.63) (31). The incidence
of invasive infection in the present study in an initially
well-appearing infant with a maternal history of fever or
chorioamnionitis was less than 2%, and this is confirmed by
other data (33) (evidence level 2b). Therefore, it seems
reasonable to perform a CBC and closely observe such an
infant, and to only perform a full diagnostic evaluation and
treat with antibiotics if the CBC is strongly suggestive of
infection (low total WBC count) or if clinical signs
develop. A requirement for extensive resuscitation at birth
should be considered a sign of possible infection in such
infants (32,33).
RECOMMENDATIONS
• Any newborn infant with clinical signs suggestive of
sepsis should have an immediate full diagnostic
evaluation followed by the institution of empirical
antibiotic therapy without delay (recommendation
category B).
• If a mother who is GBS-positive receives IAP with a
penicillin more than 4 h before delivery, no further
evaluation or observation for invasive GBS disease in a
well-appearing infant is required (recommendation
category A).
• If a GBS-positive woman receives IAP less than 4 h
before delivery (or receives no antibiotics or a
nonpenicillin regimen), then a limited diagnostic
evaluation is required, and the infant should not be
discharged before 24 h of age. At the time of discharge,
the infant should be evaluated and the parents should
be educated regarding signs of sepsis in the newborn.
Discharge at 24 h to 48 h is conditional on the
parents’ ability to immediately transport the baby to a
health care facility if clinical signs of sepsis develop
(recommendation grade B).
• If the CBC reveals a total WBC count less than
5.0×109/L, full diagnostic evaluation and empirical
antibiotic therapy should be considered
(recommendation grade B).
• If a GBS-negative woman with risk factors delivers a
baby who remains well, the infant does not require
evaluation for GBS (recommendation grade B).
• If a woman with unknown GBS status and with risk
factors at the time of delivery receives IAP more than
4 h before delivery, the infant requires no specific
intervention (recommendation grade B).
• If a woman with unknown GBS status and with risk
factors at the time of delivery receives IAP less than
4 h before delivery, limited diagnostic evaluation is
required and the infant is not discharged before 24 h of
life (recommendation grade B).
• The well-appearing infant born at less than 36 weeks
gestation with an unknown maternal GBS status
should have a limited diagnostic evaluation and is not
a candidate for early discharge.
• The well-appearing infant of a mother with possible
chorioamnionitis requires a limited diagnostic
evaluation for sepsis (recommendation grade B).
ACKNOWLEDGEMENTS: The present position statement was
reviewed by the Canadian Paediatric Society Community
Paediatrics Committee and the Infectious Diseases and
Immunization Committee.
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FETUS AND NEWBORN COMMITTEE
Members: Drs Khalid Aziz, Royal Alexandra Hospital, Edmonton, Alberta (board representative 2000-2006); Keith James Barrington, Royal Victoria
Hospital, Montreal, Quebec (chair); Joanne E Embree, University of Manitoba, Winnipeg, Manitoba (board representative); Haresh M Kirpalani,
McMaster Children’s Hospital, Hamilton, Ontario; Shoo Lee, Capital Health, Edmonton, Alberta (2000-2006); Koravangattu Sankaran, Royal
University Hospital, Saskatoon, Saskatchewan; Hilary EA Whyte, The Hospital for Sick Children, Toronto, Ontario; Robin K Whyte, IWK Health
Centre, Halifax, Nova Scotia
Liaisons: Drs Dan Farine, Mount Sinai Hospital, Toronto, Ontario (Society of Obstetricians and Gynaecologists of Canada); David Keegan, London,
Ontario (College of Family Physicians of Canada); Catherine McCourt, Public Agency of Canada, Ottawa, Ontario (Health Canada); Alfonso J
Solimano, BC’s Children’s Hospital, Vancouver, British Columbia (Canadian Paediatric Society, Neonatal-Perinatal Medicine Section); Ann Stark,
Texas Children’s Hospital, Houston, Texas, USA (American Academy of Pediatrics, Committee on Fetus and Newborn); Ms Shahirose Premji,
University of Calgary, Calgary, Alberta (Canadian Association of Neonatal Nurses); Ms Amanda Symington, McMaster Children’s Hospital,
Hamilton, Ontario (Canadian Association of Neonatal Nurses, 1999-2006)
Principal Author: Dr Keith James Barrington, Royal Victoria Hospital, Montreal, Quebec
The recommendations in this statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking
into account individual circumstances, may be appropriate. Internet addresses are current at time of publication
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Paediatr Child Health Vol 12 No 10 December 2007