1 Screening van Zwangeren op Groep B Streptokokken. W.B.A. Mei 2003 L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen

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


4

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.


7

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.


8

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%


Risk Factors

22

• 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


25

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


30

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 ?


32

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.

>


33

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.


34

GBS screening

WHERE ?


35

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


36

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 ?


38

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


39

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)


40

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 ?


46

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)


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


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


Offer intrapartum penicillin


YES

NO

NO

GBS-

GBS+

YES

Not done, incomplete, or results unknown


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


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 ?


58

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 ?


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?


93

Perinatale GBS.

Beter voorkomen.

Dan genezen !


Documents

1 Screening van Zwangeren op Groep B Streptokokken. W.B.A. Mei 2003 L. Mahieu, Dienst Neonatologie, U. Z. Antwerpen