1 screening van zwangeren op groep b streptokokken. w.b.a. mei 2003 l. mahieu, dienst neonatologie,...
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1
Screening van Zwangeren op Groep B Streptokokken.
W.B.A. Mei 2003
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
2
Inhoud
• Epidemiologie
• Microbiologie
• Kliniek
• Pathogenese
• Preventie mogelijkheden
• Toestand in Vlaanderen
• Richtlijnen
3
The Disease - USA• GBS emerged as an important pathogen in the
1970s
• Leading cause of sepsis in neonates
• Incidence: 0.4-4/1000. (Belgium= 2/1000)
• Motality > 14%
• Belgium: – 240 cases/year– 48 deads/ year
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Comparison with other Killers in Childhood.
• Meningococcal Invasive Disease– Incidence 2.3/100.000 children– Dead 0.2/100.000 children
• Road Accidents– Incidence 2.5 deads/ 100.000 children
• GBS invasive disease– Incidence 220/ 100.000 newborns– Deads 33/100.000 newborns
Neonatal GBS is an underestimated Public Health Problem.
5
Invasive GBS Disease Incidence by Age Group and
Race
0.1
1
10
100
1000
Age group
Whites Blacks
MMWR Vol. 41 (No. SS-6) 1992
6
GBS Disease in Infants
0102030405060708090
< 1wk
1-3wk
1 2 3 4 5 6 7 8 9 10 11
Age (months)
Per
cen
t of
cas
es
A Schuchat. Clin Micro Rev 1998;11:497-513.
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Early-Onset Neonatal GBS Disease
0102030405060708090
0 1 2 3 4 5 6
Age (days)
Per
cen
t of
cas
es
A Schuchat. Clin Micro Rev 1998;11:497-513.
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Clinical Manifestations of Group B Streptococcus Infection
9
Early-Onset Infection• < 6 days of life
• 85% :within 24 hours of birth
• case:fatality ratio 5-10%
low 5 min Apgar, shock, neutropenia, pleural effusion, apnea, delay treatment, low birth weight, prematurity
10
• 25-40%
• respiratory signs = initial clinical findings
(apnea, grunting respirations, tachypnea, cyanosis)
• hypotension
• associated signs: – lethargy, poor feeding, hypothermia or fever,
abdominal distention, pallor, tachycardia, jaundice
Early-Onset Infectionbacteremia without focus
11
• 5-10%, especially serotype III strains
• clinical presentation ~ bacteremia
• most common sign = Convulsions
THUS: CSF !!
• persistent seizures, (semi)coma
= poor prognosis
Early-Onset Infectionmeningitis
12
• 35 - 55%• acute respiratory signs: grunting, tachypnea, apnea• often at birth, most < 24h• low Apgar (<5 at 1min)• X-ray abnormalities:
– > 50% HMD– 30% infiltrates– occasionally absent (~ persistent fetal circulation)
Early-Onset Infectionpneumonia
13
• Profound progressive hypoxemia that is usually out of proportion to the radiographic evidence of pulmonary disease
Early-Onset Infectionpersistent fetal circulation
14
Early-Onset Infectionpneumonia
15
17
18
• 7 days - 12 weeks postnatal age
• case:fatality ratio 2-6%
• serotype III strains
• “clusters” in NICU (~ early onset)
• manifestations:– meningitis– bacteremia without focus– focal: osteomyelitis, septic arthritis, cellulitis, adenitis
Late-Onset Infection
19
Late-Onset Infectionosteomyelitis / septic arthritis
20
• low incidence, high morbidity disease
• EOS = Pneumonia PFC hypoxia death
• LOS = Meningitis
GBS DiseaseBig Disease with a Little Name
21
Maternal to Infant TransmissionGBS colonized mother
Non-colonized newborn
Colonized newborn
Asymptomatic Early-onset sepsis, pneumonia, meningitis
50% 50%
98% 2%
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
Risk Factors
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• GBS strain virulence• Genital inoculum• GBS bacteriuria• Delivery <37 weeks’ gestation• Premature rupture of membranes• Rupture of membranes >18 hours• Low levels of CPS-specific IgG• Complement component deficiency• Immature WBC function
Early-Onset Infectionrisk factors
23
GBS Maternal Colonization
• GBS Carriers– 10% - 30% of women (Belgium= 13-25%)– higher in African Americans and nonsmokers– clinical signs not predictive (Asymptomatic)– dynamic condition
• When to culture?– culture at delivery -- too late– prenatal cultures predict delivery status
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Prevention with Antibiotics
• WHEN are antibiotics most effective?– Antenatal– Postnatal– Intrapartum
• WHO should receive antibiotics ?– GBS carriers– OB risk factors– GBS carriers with OB risk factors
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Consensus Guidelines
• Key Issues– predictive value of prenatal cultures– culture methods– disease in the asymptomatic carrier– risk stratification of women– cost-effectiveness
31
GBS Screening
WHEN ?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Predictive Value of Antenatal Cultures by Interval to
Delivery
0
20
40
60
80
100
120
6 5 4 3 2 1
Weeks before delivery
Per
cent
PPV NPV
N=826; 26.5% GBS carriersYancey et al., OB GYN 1996;88:811-5.
>
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Sensitivity and Specificity of Late Antenatal Cultures
43
898597
0
20
40
60
80
100
120
6 1-5
Weeks before delivery
Per
cent
sensitivity specificity
>
N=826Yancey et al., OB GYN 1996;88:811-5.
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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GBS screening
WHERE ?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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GBS Carriage by Culture Site
Women instudy (#)
Vagina (%) Anorectum (%) Both (%)
789 10 18 21*
94 18 28 31*
301 11 14 18*
* P <0.05 both vs. vaginal only
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Specimen technique
• Lower vagina + Rectum (through anal sphincter)– One swab
– Without speculum
– Out patient setting or patient herself
• Transport– non-nutritive medium (Amies, Stuart’s without
charcoal)
– Store at room t° or in fridge (max. 48h)
37
GBS culture
HOW ?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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GBS Carriage by Culture Method
Women instudy (#)
Selectivebroth (%)
Blood agarplate (%)
166 34 14*
952 17 9*
383 20 13*
* P <0.05 selective broth vs. blood agar
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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What is ‘Selective Broth Medium’?
• 1. Incubatie overnight on 35-37°C:– Todd-Hewitt broth supplemented with:
• nalidixic acid (15 mg/L) and colistin (10 mg/L)
– Appropriate media are commercially available (e.g. LIM broth [BD])
• 2. Subculture 18-24h:– Granada medium agar (Biomedics, Spain or
distr. by International Medical)• (anaerobically or glass coverslip)
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Granada mediumOrange colonies
41
Is Intrapartum Screening an Alternative?
42
Intrapartum screening
• Sensitivity should be > 85% (= culture)
• Rapid
• Covenient for laboratory– 24h a day– 7 days a week
• Alternatives
43
Intrapartum GBS Screening- Intrapartum GBS Screening- AlternativesAlternatives
• GBS antigen test.– Sensitivity to low
(65%)
– Positive= heavy colonization.
– Negative = Unknown colonization.
• Real time PCR.– Sensitivity 97%,
– Specificity 96.9%
– 45 min. Maximum
– Not available on 24h basis
– Not available in every Lab.
At Present No Good Alternative
44
Communication
• To laboratory;– Clearly request “GBS screening”– Expected site of delivery– Expected time of delivery
• To Clinician; – address of expected delivery (Fax?) – Physician’s office.– Report only QUALITATIVE (Positive or Negative)
45
GBS screeningGBS screening
WHO ?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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CDC’s Prevention Recommendations 1996
PICK EITHER APPROACH:
Screening-based approach
• 35-37 wk culture, offer IAP to preterm and to GBS carriers
Risk-based approach
• IAP to preterm, ROM > 18 h, or intrapartum fever (T > 38 C)
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
47
Prevention Strategy Using Risk-Based Approach
Any of the following:• Delivery < 37 wks gestation*• ROM > 18 hrs• Intrapartum temp > 38C (100.4 F)• Previous infant w/GBS disease• GBS bacteriuria this pregnancy
Give intrapartum penicillin
No intrapartum antibiotics
YES
NO
* For ROM w/out labor at <37 wks, collect GBS culture and EITHER:• treat until cultures complete and negative• or begin treatment once positive culture results available
49
Obstetric Risk Factors Among Women with GBS Infants
54%
46%
* obstetric risk factors
* no obstetric risk factors
n = 245
* premature < 37 wk, ROM > 18 hr, temp > 100.4 F (38 C)
Rosenstein N. OB GYN 1997;90:901-6.
50
Rates of Early-Onset GBS Disease by Rates of Early-Onset GBS Disease by Prenatal Colonization & Risk FactorsPrenatal Colonization & Risk Factors
40.8
5.10.9 0.3
0
5
10
15
20
25
30
35
40
45
Col+,RF+ Col+,RF- Col-,RF+ Col-,RF-
Cas
es p
er 1
000
live
bir
ths
Col: prenatal vag/rect cultureRF: risk factors (gest. <37 wks, ROM >12 hr, fever > 37.5 C)
Boyer & Gotoff, Antibiot Chemother 1985.
51
Advantages of the Risk-Based Strategy
• Logistically easier
• Potentially less expensive
• Particularly applicable to settings with low prenatal care
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
53
Prevention Strategy Using Screening-Based Approach
Risk factors:• Previous infant w/GBS disease• GBS bacteriuria this pregnancy• Delivery < 37 wks gestation
Collect rectal & vaginal swab at 35-37 wks
No intrapartum prophylaxis needed
Risk factors:• Intrapartum fever > 38C• ROM > 18 hrs
Give intrapartum penicillin
Offer intrapartum penicillin
Give intrapartum penicillin
YES
NO
NO
GBS-
GBS+
YES
Not done, incomplete, or results unknown
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
54
Advantages of the Screening-Based Strategy
• Optimizes prenatal screening– fewer false negatives– less pressure on physicians to treat
• Antibiotics to all GBS carriers– antibiotics start earlier before development of
risk factors– adequate time for antibiotic effectiveness
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
55
Comparison of Prevention Strategies
Prevention Strategy EO GBS casesprevented (%)
Deliveries receivingIAP (%)
Cost compared to nostrategy (%)
Screening-based:35-37 wk screen/IAPfor preterm and GBScarriers
86.0 26.7 43.7
Risk-based:no screen/IAP for allwith risk factors*
68.8 18.3 35.6
* fever, ROM > 12 hr, gestation < 37 wks
Rouse et al., OB GYN 1994;83:483-94.
56
Potential Impact of Each Strategy
0
0.5
1
1.5
2
2.5
1989 1990 1991 1992 1993 1994 1995 1996
Year
Cas
es p
er 1
000
live
birt
hs
Early-onset GBS disease by Year, Area A
Screening-BasedApproach
Risk-BasedApproach
Rosenstein N, et al., OB GYN 1997;90:901-6.
57
GBS chemoprophylaxis
WHEN to Start ?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
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Timing of Intrapartum Ampicillin and Transmission of
GBSInterval between
ampicillin and birthNo. of GBS carrier
mothersNo. (%) GBS
colonized babiesControls
(no ampicillin)209 98 (47)
< 1 hour 30 13 (43)
1-2 hours 36 7 (19)
2-4 hours 80 2 (2.4)
>4 hours 105 1 (0.9)
De Cueto et al., OB GYN 1998;91:112-4.
59
GBS chemoprophylaxis
What to Start ?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
60
Antimicrobial Resistance in Antimicrobial Resistance in Belgium.Belgium.
-lactams (Pen, Amp, Cephalo-I) : – Today 100 % Sensitive!
Erythromycine & Clindamycine– Belgium : 10 à 20 % in 2001– 88 % type MLS (20 % inducable)
P. Melin (ULG)
61
Intrapartum Prophylaxis
• Penicillin G– 5 million units IV load, then 2.5 million units
IV every 4h until delivery
• Ampicillin– 2 g IV load, then 1g IV every 4h until delivery – acceptable alternative, but broader spectrum
may select for resistant organisms
62
• Penicillin “allergic”– History = 12%
– Proven peni-allergy is only 1-2%
• Alternative drugs:– No anaphylaxic history: cephalosporins 1st. Gen.
(cephazolin)• Loading: 2g, then 1g IV Q8h
– Clindamycin (Dalacin)• 900 mg Q8h
– Vancomycin (Vancocin) in Clinda-R organisms?
Intrapartum Prophylaxis
Efficacy of these drugs NOT proven !
64
Impact of
Prevention?
65
Incidence of GBS Disease and Hospital Prevention Policy
1.8
1.5
0.7
0.90.8
0.70.6
0
0.20.4
0.6
0.81
1.2
1.4
1.61.8
2
TN GA MN OR MD CA CT
Cas
es p
er 1
000
live
bir
ths
30
48 50
6256
71
83
0
10
20
30
40
50
60
70
80
90
TN GA MN OR MD CA CT
Cas
es p
er 1
000
live
bir
ths
Rate of Early-OnsetGroup B Streptococcal Disease
By Surveillance Site in 1996
Percent of Hospitals with aGroup B Streptococcal
Prevention Policy in 1996
66
Early-Onset GBS Disease by Year and Location
Active Surveillance (190,000 births/year)
0
0.5
1
1.5
2
2.5
SF MD Atlanta TN Total
Cas
es p
er 1
000
live
bir
ths
1993 1994 1995 1996 1997
MMWR 1997;46 (No. 21):473-77.
67
What we Think
is NOT
What we Do !
68
Flemish Obstetricians’ profile Flemish Obstetricians’ profile in 1999in 1999
- A Survey.- A Survey.
L.MahieuL.Mahieu et al, 2000, J Obst Gyn;5:460-4 et al, 2000, J Obst Gyn;5:460-4
69
Survey - ObjectiveSurvey - Objective
– Flemish obstetricians’ attitude regarding the prevention of perinatal GBS.
– To determine the physician characteristics that predict divergent opinions from the screening based approach
70
• Mailing list (VVOG)• Anonymous survey:
– 4 pages– 5 min.– Dichotomized questions (yes/no)– Items: screening, prophylaxis, demografic
• Send ones• Pre-stamped envelope
Survey - MethodsSurvey - Methods
71
ResultsResultsDemografic CharacteristicsDemografic Characteristics
• Surveys returned by 310 (53%) of 582
• Age: 40 (25-79) years
• Gender: 62% male
• No. of deliveries: 153 (10-500) / year
• Hospital: 18% university, 64% non-academic, 18% rural
• Obstetrical interests: 61%
• Group practice: 56%
73
• Never (4.2%):– No consensus– Does not influence AB prophylaxis
• Always (44%):– Indication for AB therapy– Negative experience– Routine
• If “risk factor” (52%):– PPROM– previous child GBS+
ResultsResultsScreening - Screening - Who?Who?
75
ResultsResultsScreening - Screening - Where?Where?
0
5
10
15
20
25
30
35
40%
Cervix Vagina Vagina +Rectum
Cervix +Introitusvaginae
76
ResultsResultsScreening - Screening - When?When?
0
10
20
30
40
50
60
70
80%
26-28w 28-34w 35-37w intralabour
77
ResultsResultsProphylaxis - Prophylaxis - When?When?
0
10
20
30
40
50
60
70
80%
OnsetLabour
BeforeLabour
BeforePartus
OnsetPartus
AfterPartus
78
ResultsResultsProphylaxis - Prophylaxis - What?What?
52
24 22
0,3 1,3
0
10
20
30
40
50
60
%
Ampicillin Amoxi-Clav Penicillin Clindamycin Other AB
80
9.86
9.648.227.63 9.09
Independent Demographic Predictors of Independent Demographic Predictors of Compliance to CDC Guidelines (*)Compliance to CDC Guidelines (*)
81
0
2
4
6
8
10
12
2 3 4 5 6 7
Leeftijd van de verloskundige (decaden)
Gem
idd
eld
e S
co
reIndependent Demographic Predictors of Independent Demographic Predictors of
Compliance to CDC Guidelines (*)Compliance to CDC Guidelines (*)
83
• Minority (44%) believe in routine prenatal GBS screening.
• 1/3 screen at cervix.
• 3/4 use broadspectrum AB (ampi, +/- clavulanic acid).
• Compliance to guidelines is influenced by:– province (E- & W-Flanders)– High age of Obstetrician
ConclusionsConclusionsPriorities for Improvement?Priorities for Improvement?
84
Managment of the Neonate at Risk for GBS.
85
The Symptomatic Neonate• Full diagnostic evaluation
– FBC + differential– CRP– Culture blood– Culture CSF (if indicated)– Endotracheal cultures (ventilated infant)– Surface cultures (nose and/or ear)
• Start antibiotics: Ampicillin + AG.– 10 days for sepsis, 14 days for meningitis, 28 days for ventriculitis,
osteomyletis– AG stop after 3-5 days.
86
Asymptomatic Newborn at Risk.
• Limited evaluation if– Duration of IAP < 4h (< 2 doses)– Optimal IAP but Gestation < 35 weeks
• Serial measurement at birth, 12h and/or 24h – FBC– CRP– No cultures unless AB treatment is started.
87
Laboratory Indices for EOS.
LimitsNeutrophil
0H 6H 12H 18H 24H
LOW 1800 5400 8000 8000 7200
HIGH 7000 13000 14400 13000 12500
CRP > 1.4 mg/dL or Increase (X 2-4).
Leucopenia < 5000/mm³
88
Sample Algorithm for Management of Newborn if Maternal IAP
Maternal IAP for GBS?
• Full diagnostics evaluation• Empiric therapy
yesSigns/sx of sepsis in newborn?
Gestational age
Duration of maternal IAP before delivery
• No evaluation• No therapy• Observe at least 48 hrs
no
35 wks+
>4 hrs or >2 doses
< 4 hrs or< 2 doses
• Limited evaluation• Observe at least 48 hrs• If sepsis suspected, full diagnostic evaluation and empiric therapy
< 35 wks
89
Adjuvant Treatment
• IV Immunoglobulines?– opsonisation
• Cytokines?– GM-CSF– G-CSF
• Surfactant?– SP-A
• NO
90
Hoge Gezondheidsraad-2003Ministerie van Volksgezondheid en
Leefmilieu
Microbilogist:• Mellin P.• Claeys G.• Naessens A.•Hubinon C.
Gynecologists:• De Mol P.• Donders G.• Temmerman M.• Beckstedde I.• Foulon W.•Van Eldere J.
Pediatricians:• Mahieu L.• Tuerlinckx D• Levy J• Lepage P.
Ministery: DeVleeschouwer G./ Dubois J.
91
Need for Continuous Medical
Education
and
development ofWritten Guidelines
L. Mahieu et al. Obstet. Gynecol. 2000; 20: 460-464
92
Evaluating Prevention Programs
• Consider developing surveillance for:– Neonatal GBS disease?– Adverse reactions to prophylaxis?– Emergence of resistant perinatal infections?
• Economic evaluation?
• Compliance to guidelines?
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen
93
Perinatale GBS.
Beter voorkomen.
Dan genezen !
L. Mahieu, Dienst Neonatologie, U. Z. AntwerpenL. Mahieu, Dienst Neonatologie, U. Z. Antwerpen