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GBS and Early Onset Bacterial Infection in the Late Preterm and Term Infant

Identification and Management of the At-Risk Infant

B.J. Wilson, Jr., MD

Medical Director

Pediatrix Medical Group of Nebraska

No Disclosures

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Overview General

– Definitions– Newborn Immune System– History/Epidemiology GBS EOS

Historical Risk Classification/Diagnosis– Risk Factors & Associations– Syndromes/Signs/Symptoms– Laboratory

Identifying the At-Risk Newborn 2019 Management

Definitions

Late Preterm – 34 0/7 – 36 6/7 weeks EGA at birth

Early Onset Sepsis (EOS) – positive blood or CSF culture in first 6d of life

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“Newborns should be regarded as immunodeficient hosts.”

Charles Prober

Newborn Defense

Neutrophils– Part of “innate” immune system

– chemotaxis, adhesion

– phagocytosis/microbicidal activity with stress

Decreased Antibody Response

Complement System– function of alternative pathway

– Classical pathway relies on antibody

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Why GBS?

1970s – GBS emergence

50% case fatality

20-30% pregnant women colonized by GBS in the genital/GI tracts.

Transmission– Amniotic fluid

– Passage through birth canal

– Colonization v. Infection

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Date of download: 5/31/2019 Copyright © 2019 American Academy of Pediatrics.All rights reserved.

From: Group B Streptococcal Infections

Red Book® 2018, 2018

Intrapartum Antibiotic Prophylaxis -Historical Perspective

Maternal GI/GU colonization primary RF

Mid-1980s– Trials – IV antibiotics given during labor to

at-risk women could prevent invasive disease in newborn

– IAP recommendations followed

– 86-89% reduction in EOS GBS disease

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Epidemiology EOS 2019

Overall rate ~0.5/1000 TERM births– 1/1000 in Late Preterm– Mortality Rate

• 2-3% at ≥35 weeks• Up to 10-20% in LPT only

– GBS 0.22/1000 live births

~900 infants/year in US with EOS GBS Sight/Hearing loss, CP, NDD in survivors Up to 85% of disease in GBS NEG mothers

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Historical Risk Classification and Diagnosis

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Predictive/Risk Factors Prematurity/GA Maternal Medical Conditions

– PTL,UTI, fever within 24 hours of delivery– Chorioamnionitis

Maternal GBS Colonization Premature and/or Prolonged (>18h) ROM Administration of appropriate IAP Newborn clinical condition

Risk Factors – Chorioamnionitis

Diagnosed clinically in 3-5%

MOST infants with EOS born to women with this diagnosis

CDC, AAP guidelines have recommended TREATMENT of well-appearing newborns born to women with suspected/confirmed chorio

However 450 term, chorio-exposed infants would need to be treated per case of confirmed EOS.

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ACOG COMMITTEE OPINION #712

INTRAPARTUM MANAGEMENT OF INTRAAMNIOTIC INFECTION

August 2017

IAI Diagnosis

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Syndromes – EOGBS

Type– Non-focal bacteremia – most common

– Pneumonia

– Meningitis – 9.5%

Timing– 60-70% present DOL 1

– 1/3 24-48 hours of life

– <10% at greater than 48 hours

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Signs of Sepsis

Clinical signs of infection usually SUBTLE!– Minimal deviation from usual activity

– Can mimic other disease processes

Respiratory distress may be the ONLYmanifestation of sepsis in a newborn

Risk of bacterial infection in asymptomatic newborn is low but not ZERO!

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Presentation – Effect of IAP

IAP does not delay presentation in infants who have EOGBS despite IAP!

IAP does not modify clinical spectrum of presentation!

Laboratory Screening Tests

CBC– WBC indices

C-Reactive Protein

Procalcitonin

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Screening Tests – CBC

CBC– WBC < 5000 or >30,000

• <50% with above have proven infections

– ANC – Neutropenia (Manroe)• <1800 at birth

• <7800 at 12-14 hours

• Early finding

CBC – I:T Ratio

I:T neutrophil ratio – Highest at birth (0.16)

– Elevated = ≥ 0.2

Good NPV (99%) – single determination

Poor PPV

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Jackson et al 2004

856 term/near term exposed to chorioamnionitis

2427 CBCs over first 48 hours– 99% of asymptomatic infants had ≥ 1

abnormal value (Manroe et al), 97% symptomatic

– One/Serial CBC post birth has poor Sens/Spec/PPV (42% at best)

– NPV 91-97%

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Hornik et al 2012

166k newborn with suspected EOS

Findings:– Low WBC count, Low ANC and High I:T

associated with increasing odds infection

– High Specificity and NPV

– Sensitivities LOW (0.3-54.5%)

Using CBC to diagnose, R/O EOS in newborn NOT indicated.

Screening Tests – CRP Nonspecific acute phase reactant

– Synthesized in hepatocytes– Post surgery, viral infection

Important in first line of host defense– Activates complement– Functional effects on phagocytic cells

Newborn– Elevated in instrumented vaginal delivery (Mean

1.8 mg/dL) – Elevated in IVH, RDS, MAS, “asphyxia”, PTX– Peaks at 24 hours – values can exceed 1 mg/dL

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CRP – Benitz et al

CRP < 1.0 mg/dL– Best cut off value– Initial CRP normal in 30% of “sepsis episodes”– Good NPV (99.7%) of 2 normal CRPs – 8-48

hours after presentation– PPV (serial CRP) for culture proven, early onset

sepsis 5%

Conclusions: – 2 CRP values < 1.0 at ~24 and ~48 hours post

presentation make sepsis highly unlikely.– Don’t withhold antibiotics based on an early,

normal CRP because of low sensitivity.

Procalcitonin

Propeptide of calcitonin– Extrathyroid secretion in sepsis - ?endotoxins

Modestly higher sensitivity v. CRP Kinetics more rapid than CRP

– Physiologic post birth (24h)– 2-3h of beginning of infection– 12h to peak

Newborn– Elevated in RDS, IDM, PTX, asphyxia– Mild increase with viral infections

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Chiesa et al - 1998

83 healthy newborns– 0.08-0.7 ng/mL soon after birth

– Peak - 0.6-21 ng/mL at 21-24 hours

Screening Tests

Insufficient sensitivity to obviate evaluation/empiric treatment of infant with clinical signs of illness!!!!!!

Abnormal values ALONE should not be used to decide whether to administer antibiotics in absence of + culture

High NPV allows confidence to stop antibiotics in asymptomatic infant with normal laboratory values (CRP)

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Diagnosis

Blood Culture– Gold Standard in EOS

– 1 mL

– IAP Effect?

Urine Culture – NO

Surface Cultures/Gastric Aspirates – NO

Lumbar Puncture

Meningitis – 4% EOS (9.5% EOS GBS)

CSF cell counts obtained post initiation of antibiotics may be difficult to interpret

Balance– Diagnosis?

– Critically ill infant?

– Should NOT delay antibiotic administration

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Lumbar Puncture

Bacteremic infants – incidence of meningitis as high as 25%

BC sterile in up to 38% of newborns with meningitis

Indications for LP:– Positive Blood Culture

– Clinical course strongly suggest EOS

– “Critically Ill”

CSF Indices

Cell count– “Normal” <21 cells/mm3

– “You can’t polish a turd.” – Oski

Glucose– Low glucose has greatest specificity for

diagnosis of meningitis

– Using <20 – 98% specificity

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CSF Indices

Protein– Variable - >120 mg/dL with SENS 76%,

SPEC 63%

– Median• Meningitis – 273 mg/dL

• Without – 103 mg/dL

– Tends to be higher in term with meningitis v. preterm

CSF Indices

Impossible to construct an algorithm to predict meningitis based on abnormal CSF values.

DIAGNOSIS dependent on timely, adequate culture of CSF.

Real Time PCR

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How do we identify the infant who is at-risk of EOS in 2019?

Challenges 2019

Identifying the at-risk newborn– Rate of EOS – Chorio-Exposed rate

EOS 1.3-7.2/1000

Avoidance of overtreatment– 23-45% of all newborns

exposed to antibiotics antenatally

– 6-10% >=34 wk exposed

– Effect on breastfeeding

– Gut microbiome

– Current recommend-ations for treatment

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Risk Stratification Strategies

Categorical Risk Factor Assessment

Multivariate Risk Assessment

Newborn Clinical Condition

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Categorical Risk Factor Assessment

AAP Red Book/CDC

Risk Factor Threshold Values– Yes/No

– Chorio, “Signs of Neonatal Sepsis”, GBS Positivity, adequacy of IAP, ROM >18, GA <37

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Categorical Pros & Cons

Clinical Diagnosis of Chorio (IAI)

NNT for IAI Exposed Infants >450

Lack of clear definition for newborn clinical illness (“Signs of Sepsis”)

Define CBC abnormality & action?

Dichotomizing = loss of information

Does not account for interaction among variables

Multivariate Risk Assessment

Puopolo 2010 – Predictive Model

NSC (“KP” Tool)– Individualized

– Risk Factors (Objective)• GA

• Highest Maternal Temperature

• Duration of ROM

• Maternal GBS Status

• Intrapartum Antibiotics

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Escobar et al 2014

Likelihood Ratios of EOS for clinical condition of infant in first 12 hours– Well Appearing

– Equivocal

– Clinical Illness

Combined with sepsis risk at birth

Improved Risk Stratification– 3 Risk Groups

– Management Recommendations

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Infection Probability Calculator -Neonatal Sepsis Calculator

NSC Pros & Cons

Provides individual risk assessment

Objective data v. Clinical dx

Results in relatively few well appearing infants treated with empiric antibiotics

Ongoing clinical assessment over 6-12 hours (initial classification)

Need for clinical surveillance for some infants in well nursery

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Newborn Clinical Condition

Reliance on Clinical Signs of Illness– Most infants with EOS clinically

symptomatic at birth

– 60-70% reduction in risk for EOS IF appear well at birth

– Limited utility of CBC/CRP in well newborn

– Relies on close observation

– Ill at birth/Develop signs over the first 48 hours – Empiric antibiotics

Newborn Clinical Condition –Studies

Cantoni et al– Decreased lab ~ 90%

– Antibiotic usage ~ 60%

– No delay in signs of sepsis and Amp/Gent

– CBC as reason for starting antibiotics in <2% of total cohort

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Joshi et al 2013

34 weeks, well-appearing, chorio-exposed (n=277)

Admitted to level 2 for 24 hours, then room-in with mother if remained well

11.6% (32) became symptomatic

Among ALL ≥34 weeks antibiotic exposure 12.3% 5.5% (55%)

Newborn Clinical Condition –Pros & Cons

Significant reduction in antibiotic use

Which newborns to screen with exams?– Multivariate/Categorical classification?

– All?

Imposes significant changes to NB care

ID of initially well-appearing infants who develop clinical illness is an EXPECTED RESULT, not failure!

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Other Summary Points in AAP Clinical Report:

Birth centers should develop locally tailored, documented guidelines for EOS risk assessment and management.

EOS cannot be DX by CBC, CRP, urine cx, surface cultures or gastric aspirate.

Amp/Gent are appropriate EMPIRIC TX.

When BC are sterile – D/C antibiotics by 36-48 hours.

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AAP Clinical Report: Management of Infants at Risk for Group B Streptococcal Disease

Following are highlights of the AAP recommendations:

Risk assessment for early-onset GBS disease should follow the general principles established in the AAP clinical reports on management of neonates with suspected or proven early-onset bacterial sepsis. These include separate consideration of infants born at ≥35 and <35weeks’ gestation

For the purpose of neonatal management, the administration of intrapartum PCN G, ampicillin or cefazolin can provide adequate IAP against EO GBS disease.

Clindamycin and vancomycin should be administered to women at high risk of anaphylaxis to beta-lactam antibiotics as recommended by the ACOG. There is insufficient evidence to consider these antibiotics to provide fully adequate IAP for the purpose of neonatal risk assessment.

Early-onset GBS infection is diagnosed by blood or cerebrospinal fluid culture. Laboratory tests such as the complete blood cell count and C-reactive protein do not perform well in predicting early-onset infection, particularly among those with low baseline risk of infection.

Empirical antibiotic therapy for early- and late-onset GBS disease differs by postnatal age at the time of evaluation. PCN G is the preferred antibiotic for definitive treatment of GBS in infants; ampicillin is an acceptable alternative.

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ACOG Committee Opinion 782

Obstet Gynecol. 2019;134:e19-e40 (AAP endorsed)

Prevention of Group B Streptococcal Early-Onset Disease in Newborns. ACOG Committee Opinion No. 782

Notable aspects of the guidance include the following:

The optimal window for antenatal GBS screening has been changed to 36 0/7 to 37 6/7 weeks’ gestation instead of beginning at 35 0/7 weeks’ gestation. The correlation between antenatal GBS colonization results and colonization status at the time of delivery decreases significantly when the culture-to-birth interval is longer than five weeks; therefore, moving antenatal culture timing to 36-37 weeks optimizes the value of the screening result up to 41 weeks’ gestation.

It is recommended that GBS IAP be administered to the following: all laboring women with GBS colonization detected by antenatal culture; those with GBS bacteriuria detected during the pregnancy; those who previously delivered a newborn with GBS disease; and women with unknown GBS status who present with preterm labor or preterm, prelabor rupture of membranes (ROM) prior to 37 weeks’ gestation.

Women who present at >37 weeks’ gestation with unknown status should be administered GBS IAP if risk factors develop (duration of ROM ≥18 hours or intrapartum temperature of ≥100.4°F [38°C]. Additionally, women with known GBS colonization in a prior pregnancy may be offered IAP if status is unknown at >37 weeks’ gestation given that such women have increased risk of colonization in the current pregnancy.

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EOS – Empiric Therapy

Ampicillin and Gentamicin– Unchanged after 3+ decades!

– Bactericidal for GBS, E. coli, Enterococcus, L. monocytogenes, other Streptococci and enteric bacilli

– Synergy for GBS, L. monocytogenes

Supportive Care

Duration of Therapy

Bacteremia w/o Focus – 10 days

GBS Meningitis – 14 days

Gram Negative Meningitis– 21 days, OR

– 14 days after negative culture

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Selected References AAP Committee on Infectious Diseases. Group B Streptococcal

Infection, in Red Book 2018-2021 Report of the Committee on Infectious Diseases, 31st Ed.

ACOG Committee on Obstetric Practice. ACOG Committee Opinion 712: Intrapartum Management of Intraamniotic Infection, August 2017.

KM Puopolo et al, AAP Committee on Fetus and Newborn, Committee on Infectious Disease. Management of Neonates Born at >=35 0/7 Weeks’ Gestation with Suspected or Proven Early-Onset Bacterial Sepsis. Pediatrics 2018;142(6):2894.

KM Puopolo et al, AAP Committee on Fetus and Newborn, Committee on Infectious Disease. Management of Infants at Risk for group B Streptococcal Disease. Pediatrics 2019; 144(2):1881.