Perinatal CMV Perinatal CMV InfectionInfectionKadri MattKadri Matt

Karin AsserKarin Asser

Tartu University Women`s ClinicTartu University Women`s Clinic

Tallinn 2006Tallinn 2006

Non - Human CMVNon - Human CMV

What about CMV Infection in What about CMV Infection in Humans?Humans?

The knowledge about the The knowledge about the virus and its pathogenity virus and its pathogenity has increasedhas increased

A majority of CMV infections A majority of CMV infections are asymptomaticare asymptomatic

Some symptomatic cases Some symptomatic cases have tremendous clinical have tremendous clinical importanceimportance

Combination of lesions: HSV and CMV

Descriription of a CaseDescriription of a Case

The patient was 20 years The patient was 20 years of age, unmarriedof age, unmarried

During the first trimester of During the first trimester of pregnancy she was pregnancy she was treated fortreated for

- - Chlamydiosis Chlamydiosis

urogenitalis urogenitalis

- Anaemia gravidarum- Anaemia gravidarum

Description of a CaseDescription of a Case The patient was referred to Tartu University The patient was referred to Tartu University

WomenWomen`s Hospital for a second opinion `s Hospital for a second opinion ultrasound because of suspected fetal ultrasound because of suspected fetal hydrocephalyhydrocephaly

At the gestational age of 18 weeks and 6 days At the gestational age of 18 weeks and 6 days the fetal cerebral lateral ventricles were within the fetal cerebral lateral ventricles were within a normal range, 9 mma normal range, 9 mm

The patient was asked to come back in 2 The patient was asked to come back in 2 weeksweeks

The next ultrasound at our hospital was The next ultrasound at our hospital was performed at 24 weeks and 2 days: it showed performed at 24 weeks and 2 days: it showed bilateral fetal cerebral ventriculomegaly bilateral fetal cerebral ventriculomegaly (posterior horns 1.2 cm)(posterior horns 1.2 cm)

Cordocentesis revealed normal fetal karyotype Cordocentesis revealed normal fetal karyotype 46xy46xy

Maternal blood analysis showed fresh CMV Maternal blood analysis showed fresh CMV infection (positive IgG and IgM antibodies)infection (positive IgG and IgM antibodies)

Ultrasound at 30 weeks and 2 Ultrasound at 30 weeks and 2 daysdays

Estimated fetal weight (EFW) 1150 g Estimated fetal weight (EFW) 1150 g ((corresponding corresponding to 28 weeks)to 28 weeks)

Ventriculomegaly: posterior horns of fetal Ventriculomegaly: posterior horns of fetal cerebral ventricles 1.4 cm, cerebral ventricles 1.4 cm,

and periventricular hyperechogenic fociand periventricular hyperechogenic foci

Polyhydramnios: amniotic fluid index (AFI) 27Polyhydramnios: amniotic fluid index (AFI) 27

Normal blood flow in Normal blood flow in arteria umbilicalisarteria umbilicalis

Fetal cerebral ventriculomegaly at 30 weeks 2 days

Ex consilio: Ex consilio: Graviditas in hebdomines 30+5Graviditas in hebdomines 30+5 Infectio cytomegaloviralis congenita Infectio cytomegaloviralis congenita Hydrocephalus Hydrocephalus Polyhydramnion Polyhydramnion Retardatio incrementi foetalis intrauterina Retardatio incrementi foetalis intrauterina

Decision:Decision: to terminate the pregnancy by induction in to terminate the pregnancy by induction in the 36th week of gestation or earlier in the the 36th week of gestation or earlier in the case of maternal/fetal indications.case of maternal/fetal indications.

Ultrasound at 36 weeks and 3 Ultrasound at 36 weeks and 3 daysdays

Intrauterine growth retardationIntrauterine growth retardation:: EFW 1830 g (corresponding to 32 weeks), EFW 1830 g (corresponding to 32 weeks), BPD 7.3 cm (29 weeks)BPD 7.3 cm (29 weeks)

Fetal cerebral lateral ventricles 1.7 cmFetal cerebral lateral ventricles 1.7 cm

AFI 28AFI 28

Reduced diastolic blood flow in Reduced diastolic blood flow in arteria arteria umbilicalisumbilicalis: PI 1.78 : PI 1.78

Delivery at 36 weeks andDelivery at 36 weeks and 5 days 5 days

•• Stimulatio partus cum OxytociniStimulatio partus cum Oxytocini - male neonate 2000g/42cm- male neonate 2000g/42cm - Apgar score: 3 - 5 - 6- Apgar score: 3 - 5 - 6 - cord blood: - cord blood: pH 7.13pH 7.13

pCOpCO2 2 58.3 58.3

pOpO22 16.2 16.2

BE – 9.0BE – 9.0 •• The neonate was intubated 5 minutes The neonate was intubated 5 minutes after birth and was taken into the neonatal after birth and was taken into the neonatal intensive care unit.intensive care unit.

In the NICUIn the NICU The newborn is pallid, with The newborn is pallid, with

petechial rash and with petechial rash and with multiple deformities, multiple deformities, abnormal build, and abnormal build, and arthrogryposis. Movements arthrogryposis. Movements absent, consciousness absent, consciousness disorder, insufficient disorder, insufficient hemodynamics.hemodynamics.

Ultrasound: developed Ultrasound: developed hydrocephalyhydrocephaly

Blood at PCR: CMV Blood at PCR: CMV positivepositive

In the NICUIn the NICU X-ray: arthro-sceletal X-ray: arthro-sceletal athrogryposisathrogryposis

Ex consilio in the NICUEx consilio in the NICU

Prognosis for neonate`s life is absent due Prognosis for neonate`s life is absent due to congenital multiorgan insufficiency.to congenital multiorgan insufficiency.

The parents share the same opinion.The parents share the same opinion.

After 6 hours artificial ventilation is After 6 hours artificial ventilation is stopped – stopped – exitus letalisexitus letalis

Pathoanatomical diagnosisPathoanatomical diagnosis Primary diseases:Primary diseases: Infectio cytomegaloviralis congenita: Infectio cytomegaloviralis congenita:

meningoencephalitis, hepatitis, pancreatitis, meningoencephalitis, hepatitis, pancreatitis, nephritis et pneumonitis cytomegaloviralis et ex nephritis et pneumonitis cytomegaloviralis et ex descriptionibus clinicis.descriptionibus clinicis.

Complications:Complications: Hydrocephalus et arthrogryposis totalis ex Hydrocephalus et arthrogryposis totalis ex

infectionis cytomegaloviralis. Retardatio infectionis cytomegaloviralis. Retardatio incrementi foetalis intrauterina. Asphyxia incrementi foetalis intrauterina. Asphyxia perinatalis:hyperaemia venosa acuta organorum perinatalis:hyperaemia venosa acuta organorum parenhymatosum et ex descriptionibus clinicic.parenhymatosum et ex descriptionibus clinicic.

CMV infectionCMV infection

Is rarely of Is rarely of consequence to the consequence to the pregnant woman pregnant woman herselfherself

Intrauterine infection Intrauterine infection may result in may result in devastating congenital devastating congenital disease disease

Congenital CMV infectionCongenital CMV infection

•• The incidence of congenital CMV The incidence of congenital CMV infection among live birthsinfection among live births

0.2 – 2.0%0.2 – 2.0%

•• 6-20% of neonates with congenital 6-20% of neonates with congenital CMV infection are symptomaticCMV infection are symptomatic

at birth – at birth – cytomegalic inclusioncytomegalic inclusion disease disease develops develops

•• In asymptomatic newborns In asymptomatic newborns it is the common cause of it is the common cause of

sensorineural hearing loss and sensorineural hearing loss and mental retardationmental retardation

Congenital CMV – Cytomegalic Congenital CMV – Cytomegalic Inclusion DiseaseInclusion Disease

•• Clinical findings are Clinical findings are variable:variable:

hepatosplenomegalyhepatosplenomegaly jaundicejaundice thrombocytopenia with thrombocytopenia with purpurapurpura chorioretinitischorioretinitis cerebral calcificationscerebral calcifications microcephalymicrocephaly hydrocephalyhydrocephaly

Cytomegaloviruses areCytomegaloviruses are

•• Among the oldest known Among the oldest known viruses viruses

•• Belong to the group of Belong to the group of herpes virusesherpes viruses

•• Incl. DNA virusesIncl. DNA viruses

The virus isThe virus is

•• Intranuclear and is assembled Intranuclear and is assembled

in the nucleus of the hostin the nucleus of the host

•• Individuals can be infected by Individuals can be infected by

more than one strain – recurrent more than one strain – recurrent infections may developinfections may develop

•• This makes diagnosis and This makes diagnosis and management difficultmanagement difficult

Risk factors, transmissionRisk factors, transmission

•• The highest prevalence of antibodies The highest prevalence of antibodies is found among lower socioeconomic is found among lower socioeconomic groupsgroups

•• Most frequently transmission occursMost frequently transmission occurs

by the ororespiratory route…by the ororespiratory route…

•• Seroconversion in Estonia is 90% Seroconversion in Estonia is 90%

CMV in pregnancyCMV in pregnancy

•• Pregnancy Pregnancy per seper se does does not alter the incidence of not alter the incidence of primary diseaseprimary disease

•• The virus is transmitted in The virus is transmitted in the absence of specific the absence of specific T-immunity T-immunity

•• CMV transmission is possible CMV transmission is possible during pregnancy, delivery and during pregnancy, delivery and lactationlactation

possibly by placental routepossibly by placental route

TransmissionTransmission

Maternal CMV-specific IgG have a Maternal CMV-specific IgG have a protective effect against fetal infectionprotective effect against fetal infection

Transmission depends on the pre-Transmission depends on the pre-conceptional serological status of the conceptional serological status of the mothermother

•• Transmission rate is 1.2 % for seropositive Transmission rate is 1.2 % for seropositive

and 12.9 % for seronegative womenand 12.9 % for seronegative women

Prenatal counselling of the Prenatal counselling of the gravida with evidence of gravida with evidence of primary infectionprimary infection

Counselling of a gravida with primary CMV Counselling of a gravida with primary CMV infection is difficultinfection is difficult

Negative amniocentesis fluid analyses by viral Negative amniocentesis fluid analyses by viral culture and PCR confirm a reasonably high culture and PCR confirm a reasonably high probability that the fetus is not infectedprobability that the fetus is not infected

Vertical transmission is possible in later Vertical transmission is possible in later gestation gestation

Diagnosis of Infection in Diagnosis of Infection in Pregnant WomenPregnant Women

•• Serologic tests for CMV specific Serologic tests for CMV specific IgG and IgM antibody from IgG and IgM antibody from

maternal or fetal sera usingmaternal or fetal sera using ELISA, ABBOT IM or IMMULITEELISA, ABBOT IM or IMMULITE

•• CMV – DNA tests by PCR (B-CMV – DNA tests by PCR (B-CMV-DNA) from , maternal/fetal CMV-DNA) from , maternal/fetal blood, sera, amniotic fluid, blood, sera, amniotic fluid,

neonate`s urine neonate`s urine

Prenatal Diagnosis of Congenital Prenatal Diagnosis of Congenital CMV InfectionCMV Infection

A reliable prenatal diagnosis of congenital CMV A reliable prenatal diagnosis of congenital CMV infection is based on PCR from amniocentesis samplesinfection is based on PCR from amniocentesis samples

Best sensitivity and 100% specificity by PCR from Best sensitivity and 100% specificity by PCR from amniotic fluid is after 21 gestational weeksamniotic fluid is after 21 gestational weeks

Mean interval between the diagnosis of maternal Mean interval between the diagnosis of maternal infection and antenatal procedure is 7 weeksinfection and antenatal procedure is 7 weeks

CMV- specific IgM antibody detection from cord blood CMV- specific IgM antibody detection from cord blood samples has a sensitivity of 60%samples has a sensitivity of 60%

Prenatal Diagnosis of Prenatal Diagnosis of Congenital CMV InfectionCongenital CMV Infection

Ultrasound has limited Ultrasound has limited sensitivity in detection of sensitivity in detection of fetal infectionfetal infection

Pregnancies with evidence Pregnancies with evidence of vertical transmission and of vertical transmission and definite ultrasound findings definite ultrasound findings indicating suspected fetal indicating suspected fetal damage are at significant damage are at significant risk of abnormal sequelaerisk of abnormal sequelae

SummarySummary

•• Primary maternal infection is difficult to diagnose unless Primary maternal infection is difficult to diagnose unless identified by seroconversion.identified by seroconversion.

•• Routine serologic screening for CMV infection during Routine serologic screening for CMV infection during pregnancy cannot be recommended.pregnancy cannot be recommended.

•• The documentation of maternal disease during The documentation of maternal disease during pregnancy or confirmed congenital fetal CMV infection pregnancy or confirmed congenital fetal CMV infection may be an indication for therapeutic abortion/ may be an indication for therapeutic abortion/ termination of pregnancy. termination of pregnancy.

Thank YouThank You