Transcript
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-
top related