CMV congenital infectionCMV congenital infection

Laurent J Salomon, Yves VilleMaternité Necker, AP-HP, Paris

Special Thanks to Guillaume BENOISTService de Gynécologie Obstétrique et Médecine de le reproduction

CHU de CAEN

Epidemiology of CMV

Infection

Seronegative pregnancies 43.5 [IC95%:42.1 – 44.9] to 51.5 [48 – 54.5] %

Seroconversion 1% [IC95%:0.6 – 1.4]

Vertical Transmission Rate 47.4 % [IC95%: 24.5 – 71.1]Vertical Transmission Rate 47.4 % [IC95%: 24.5 – 71.1]

Prevalence @ birth 0.5 % [IC95% :0.2 – 0.8]

Perinatal Mortality 0 [IC95%:0 – 8.2] to 4.7 [0.98 – 13.1] %

Symptomatic

Sequelae Symptomatic 25 [IC95%:3.2 – 65.1] to 43.7 [31.4 – 56.7] %

Asymptomatic 8.6 [IC95%:0 – 17.8] %

6.2-24.3% [IC95%:1.7 – 27.2]

1 000 000

women

500 000 CMV + 500 000 CMV -

5 000 primary

infectionBe aware of infection

2500 fetal

transmission

250

symptomatic.

2250

asymptomatic

.

~5 deaths

Sequellae++

.

~200 have

sequellae (HL)

Be aware of

secondary

infection...

Why should we care about

CMV ?CMV ?

Pediatrics 1980

• 34 symptomatic cases

+ 11 deaths

n=42

symptomatic

newborns

Outcome of

asymptomatic newborns

• �=35 asymptomatic newborns

• �=53 controls

• Similar neurological outcome at 21 months

and 7 years.

CMV & Hearing loss

• n=74 newborns CMV+

• 4 symptomatic (5,4%)

Pediatrics 2008

• SNHL:

– 21% of asymptomatic

– 33% of symptomatic

Viral load at birth and risk of SNHLViral load at birth and risk of SNHL

SNHL NO SNHL

10000

100000

Boppana et al, J Pediatr 2005

Vauloup-Fellous et al, JCM, 2007

1

10

100

1000

10000

Maternal infection

Diagnostic

Secondary infections are less symptomatic

Biological diagnosticBiological diagnostic

• Systematic screenning?

• Screening if maternal symptoms?

• Screening if foetal anomaly?

• Look for IgG and IgM for CMV• Look for IgG and IgM for CMV

• Positive IgM ≠ primary-infection

• May remain positive up to one year following PI

• Secondary infection CMV

• Non specifica reaction (PI EBV, Parvovirus…)

• Use IgG avidity.

1: Lazzarotto et al, 1997, Clin Diagn Lab Immunol 2: Busse et al, J Clin Virol, 2008

3: Revello et al, Congenital Cytomeglovirus Conference, nov 2008

IgG- and IgM- IgG+ and IgM- IgM+ IgG+

Dealing with Ig….Dealing with Ig….

No immunity

Past infection

Be careful at

2nd / 3rd

trimester

Infection may

have occurred

in the 1st

trimester1

Avidity is low

Recent infection

40% risk

Avidity is high

Past infection

Intermediate

Cannot conclude

Risk

≈ 2.5%

1:Munro et al, JCM, 2005. 2:Mace et al, Prenatal Diagn 2004

3:Guerra et al, AJOG, 2007

Prenatal diagnosisPrenatal diagnosis

Amniotic fluid analysisAmniotic fluid analysis

• Cellular culture:

• Se 50 - 82%

• Spe: 100%

• Cellular culture:

• Se 50 - 82%

• Spe: 100%

• Viral DNA PCR:

• Se: 72 - 100%

• Spe 83 - 100%

• Real time PCR+++ (Se & Spe ~100%)

• Viral DNA PCR:

• Se: 72 - 100%

• Spe 83 - 100%

• Real time PCR+++ (Se & Spe ~100%)

Revello et al,1995; Lazzarotto et al,1998; Nigro et al,1999; Antsaklis et al,2000;

Liesnard et al,2000; Gouarin et al,2001; Enders et al, 2001; Revello et al,2002, Ducroux JCM 2008

3 rules toobtain good results:

3 rules toobtain good results:

• 1) > 21 weeks’

• 2)>7 weeks following primary infection

• 1) > 21 weeks’

• 2)>7 weeks following primary infection• 2)>7 weeks following primary infection

• 3) PCR techniques in specialized lab

• Be aware that late transmissions do exist, but they are very rare.

• 2)>7 weeks following primary infection

• 3) PCR techniques in specialized lab

• Be aware that late transmissions do exist, but they are very rare.

Fetal infectionFetal infection

Infection Screen

Toxo IgM - IgG +

Rubella IgM - IgG +

CMV IgM - IgG +

HSV1/2 IgM - IgG +

Infection Screen

Toxo IgM - IgG +

Rubella IgM - IgG +

CMV IgM - IgG +

HSV1/2 IgM - IgG +

33 yr old G2 P2, 28 weeks, fundal

height of 22 cm2

++

HSV1/2 IgM - IgG +HSV1/2 IgM - IgG +

IgG Avidity

Toxo 70%

Rubella 80%

CMV 20 %

HSV1/2 NA

IgG Avidity

Toxo 70%

Rubella 80%

CMV 20 %

HSV1/2 NA

Booking Sample

CMV IgM +

IgG -

Amniocentesis

CMV PCR +500 000 cp/ml

+

+

EFW = 800 g

+

+

US Sensitivity for the

diagnosis of CMV:

Guerra 2000 30 20 %

Laurent J SALOMON

Liesnard 2000 55 25 %

Enders 2001 17 12 %

Hohlfeld 2001 26 19 %

US +

51 / 600 (8.5 %)

US + in fetus infected

23 / 154 (15 %)

Prenatal diagnosis and AF analysisimprove the predictive value of

Ultrasound

Prenatal diagnosis and AF analysisimprove the predictive value of

Ultrasound

• Low Se

• Low PPV without amniocentesis

• Many symptoms are unspecific: IUGR, ventriculomegaly,

hyperechogenic bowels, oligoanamnios...

• PPV ↑ if amniocentsis +

PrognosisPrognosis

CMV Congenital Infection

PRIMARY INFECTIONPRIMARY INFECTION

55--10% 10% SevereSevere 55--10% Moderate10% Moderate 90% 90% AsymptomaticAsymptomatic

••IUGRIUGR

••MicrocephalyMicrocephaly

••VentriculomegalyVentriculomegaly

•• MeconialMeconial peritonitisperitonitis

••HepatomegalyHepatomegaly

••SplenomegalySplenomegaly

••No No clinicalclinical signsign

••VentriculomegalyVentriculomegaly

••SeizuresSeizures

••SpasticitySpasticity

••SplenomegalySplenomegaly

••HepatitisHepatitis

••ThrombocytopeniaThrombocytopenia

NND NND

30%30%

SequelaeSequelae

60% 30%60% 30% 55--15%15%

Fowler et al 1992

AJOG 2008

US anomaly

Benoist, Salomon et al. BJOG 2008

Guerra et al. AJOG 2009

Sensitivity

(%)

Specificity

(%) PPV (%) NPV (%)

US+ 63.6 94.4 77.8 89.5

MRI+ 51 100 81 67

Targetted ultrasound v. MRI to depict brain lesions

in infected fetuses

Fetal Prognosis

Brain Imaging = Fetal US + Fetal MRI

US+ and MRI+ 54.5 100 100 87.8

US +and/or

MRI+72.7 88.9 66.7 91.4

Sensitivity

(%)

Specificity

(%)PPV (%) NPV (%)

MRI- US- 89.2 80 94.3 80

Prediction of a good outcome

Benoist , Salomon et al UOG 2008

• Univariate analysis

Fetal blood samplingFetal blood sampling

�US anomaly and Platelet counts

Multivariate analysisMultivariate analysis

Variable Adjusted OR 95% CI p

Anomaly at US

(if present)9.7 [2.7;34.6] <10-4

Multiple logistic regression to predict an abnormal perinatal outcome

(n=72 infected fetuses):

(if present)

Thrombocytopenia(per10000/mm3 decrease)

1.1 [1.01;1.20] 0.05

< 100,000 plt/dL

Viral load in AF and outcome

• A: US anomaly, TOPS • A: US anomaly, TOPS

n=13

• B: No anomaly

• n=13

• C: Minor anomaly n=4

GA at infection

• Vertical transmission may occur anytime • Vertical transmission may occur anytime

during pregnancy Monif J Ped 72

• The longer the fetal infection, the more

severe the symptoms Monif J Ped 72

• N=25 infections > 25w

BJOG 2008

• 20/25 (75%) transmission

• 1 TOP (US +++)

• 20 live births without sequellae

Primary/Recurrent

• Less

transmission if

recurrentAJOG 1999

recurrent

• Less severe

• But severe

infection may

also occur…

TreatementsTreatements

sept 2005

1/31 symtomatic 7/14 symptomatic

Fetal infection ???

6/37 infections 19/47 infections

Reduces viral load in fetus after 1-12weeks of treatment.

NEONATAL EVALUATION

• Main Objective: Composite:

Increased % Asymptomatic neonates Increased % Asymptomatic neonates

Decreased % TOPs for cerebral anomalies

with treatment.

• Secondary Objectives:

Viral load in cord blood at delivery

Viral load in urine of the neonates

lower with treatment5 year follow-up 22222..

2009

18/234

31/230p=0,02

Following the diagnosis of Maternal primary/recurrent

infection:

AMNIOCENTESIS

-+ OR UNPERFORMED

US -

DANGEROUS

REASSURANCE ?

US has poor performance,

especially if no amnio.

MRI?

FBS?

US follow-up

REASSURANCE

US+

BRAIN+

TOP ? / TTT

?

If amnio +

MRI, FBS?

TTT ?

If no amnio

Problem of

the poor PPV

BRAIN-