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Diagcmv
Diagcmv
MP Landini (Italy)
1020% with subtle delayed sequelae (progressive hearing loss, mental deficiency, etc)
6.5 21
13 positives
1.1%
1.1%
5500 CMV-infected newborns/year
Endogenous infection
Preconceptional maternal immunity is protective against congenital CMV infection decreasing risk of infection by 91%
Stagno 1997
Seropositivity (%)
mononucleosis syndrome
Laboratory findings: atypical lymphocytosis
Bologna, Italy
No follow up
No follow up
Advanced diagnosis
IgM
Technogenetics 59 Sclavo 21
Bouty
Eurogenetics Sorin Behringwerke
21
53 52 30
19
37 39 27 41 38
39
37 39 40 31 40
2
16 13 3 24 10
41
11 10 31 5 13
31
77 80 46 89 74
95
70 75 93 56 80
57
73 77 66 71 77
Advanced diagnosis
Pregnant women at risk of transmitting CMV referred to our reference centre in Bologna for advanced diagnosis
CKS
50 40 30 20 10 0 0 5 10 15 20 25 30 35
Advanced diagnosis
4 Groups I Uninfected n=300 (49.1%) No congenital infections II Primary infections n=161 (26.3%) III Recurrent infections n=125 (20.5%) IV Undefined infections n=25 (4.1%) No congenital infections
YES No congenital congenital infections infections n=39 (24.4) With symptoms No symptoms n=18 (46.2%) n=21 (53.8%)
Why?
The newborn will be checked for CMV infection and, if necessary, treated with ganciclovir Prenatal therapy (?)
Transmission of CMV through the placenta barrier and infection of the fetus
Infected mother viraemia infection of placenta trophoblasts
Infection of the oropharynx Virus in amniotic fluid Infection of fetal endothelial cells
Fetal viraemia
When?
2123 weeks gestation
Prenatal diagnosis was offered to all women undergoing a primary CMV infection and to those with an undefined type of infection
20 requested amniocentesis
SV-positive=0 PCR-positive=0 Congenital infections=0
14 requested amniocentesis
SV-positive=0 PCR-positive=2 Congenital infections=0
16
16
6
22
57
57
63
79
22
20
42
0
22
37
37
37
79
103 <103
17 5 22
0 1 1
17 6 3
Prenatal diagnosis can identify congenital infections prenatally Can prenatal diagnosis identify fetuses at higher risk of CMV-related symptoms?
31 newborns
13 symptomatic (41.9%) 18 asymptomatic (58.0%)
8 fetuses
5 disseminated infections + macroscopic evidences of damage 3 disseminated infections
39 congenital infections
22 mothers had accepted amniocentesis
14 newborns 7 symptomatic 7 asymptomatic 8 fetuses 5 disseminated infections + macroscopic evidences of damage 3 disseminated infections
Results of prenatal diagnosis performed on primarily infected mothers in relationship with pregnancy outcomes
Case Ultrasonographic findings# 1 Normal 2 3 4 5 6 Normal Central ventriculomegaly Prenatal diagnosis on amniotic fluid Shell PCR qPCR6 + + >1.8x10 (GE/ml) + + >1.8x106 + + 1.1x106 + + + + + + 9.1x105 9x105 5.5x105 Outcome ToP/disseminated CMV infection (diffused microcalcified cerebral areas, hepatosplenomegaly, pneumonitis) CMV infected newborn with mild hepatitis, high CRP ToP/disseminated CMV infection, pneumonitis, agensis of corpus callosum, hepatomology ToP/disseminated CMV infection, hepatosplenomegaly, pneumonitis CMV-infected newborn with cerebral vasculitis ToP/disseminated CMV infection, Dandy Walker syndrome, borderline cerebral ventriculomegaly CMV-infected newborn, small for gestational age* Fetus with borderline cerebral ventriculomegaly resolved in utero. Newborn with mild hepatitis CMV-infected newborn with severe cerebral ventriculomegaly, diffused microcalcified cerebral areas, hepatosplenomegaly** CMV-infected newborn with depression of the platelets and cerebral microcalcification ToP/borderline cerebral ventriculomegaly and CMV-infections in liver and lung CMV-infected newborn with mild hepatitis ToP/disseminated CMV infection ToP/disseminated CMV infection ToP/disseminated CMV infection
Normal Normal Vermis defects, borderline cerebral ventriculomegaly hyperchogenic bowel 7 Normal 8 Borderline cerebral Ventriculomegaly 9 Cerebral ventriculomegaly hyperchogenic bowel 10 Normal 11 Borderline cerebral ventriculomegaly, hyperchogenic bowel 12 Normal 13 Normal 14 Normal 15 Normal
ToP: termination of pregnancy # detected at 2022 weeks gestation
+ + + + + + +
+ + + + +
*psychomotor reduction after first year **chrioretinitis and mental retardation (IQ<70) after first year
F
F F
CMV-GE/ml
NN N NN
Infected asymptomatic Infected symptomatic
Pregnancy outcomes
Main conclusions
The screening for CMV in pregnancy carried out by IgM and IgG avidity identifies all women who will deliver an infected infant The determination of the viral load in the amniotic fluid by qPCR can:
identify a congenital infection prenatally identify fetuses prenatally at higher risk of developing CMV-related symptoms (work still at the investigational stage)
Factors that may be involved in determining the severity of congenital CMV infection
Maternal viral load The strain of CMV The repertoire of CMV-specific maternal antibodies Factors linked to a good or weak placenta barrier
MP Landini T Lazzarotto S Varani P Spezzacatena L Gabrielli Department of Obstetrics and Gynecology B Guerra Department of Pediatrics Division of Neonatology M Lanari
IgM-positive
14.2
6.6
With low anti-CMV IgG avidity With PCR+ amniotic fluid With 103 GE/ml of amniotic fluid
26.2
12.1
50
29.3
100
85.7
100
100
First test
FIRST LEVEL
/+ +/ +/+
Avidity test -IgG Immunoblot-IgM latently recurrent
SECOND LEVEL
primary
OBSTETRIC COUNSELLING
PRENATAL DIAGNOSIS
+
qPCR
OBSTETRIC COUNSELLING
AUTOPTIC EXAMINATION FOR THE ABORTED FETUSES
+
NEO-NATAL FOLLOW UP
+
START FOLLOW-UP POST-NEONATAL
Sensitivity, specificity, positive predictive value and negative predictive value of virus isolation and PCR in the presence or absence of CMV in the fetus/newborn
CMV infection Yes No SNS* SPE* PPV* NPV* Virus isolation Positive Negative PCR Positive 16 6 22 0 72.7 57 20 100 64.9 52.4 100 100 100 90.5
Negative
37
*: SNS (number of true positives/total number of infection) x 100 SPE (number of true negatives/total number of np infection) x 100 PPV (number of true positives/number of true positives + number of false positives) x 100 NPV (number of true negatives/number of true negatives + number of false negatives) x 100
Antibody avidity: the strength with which a multivalent antibody binds a multivalent antigen