Congenital CMV infection is a leading cause of sensorineural hearing loss and mental retardation. Approximately 0.15-2% of live births are affected. While most infections are asymptomatic, 10% of symptomatic newborns die and survivors often have lifelong disabilities. Congenital CMV is transmitted from mother to fetus via the placenta or during birth if the mother is infected. Young children are the primary transmitters of CMV through bodily fluids. Treatment with ganciclovir may help reduce hearing loss in symptomatic newborns but is associated with significant toxicity. Prevention through hygiene and education is important since there is no vaccine.

1. Congenital CMV
infection
Siriporn phongjitsiri,MD
Pediatric Infectious Division
Queen Sirikit National Institute of Child Health
July 27,2007

2. Congenital CMV infection
• Approximately 0.15–2% of live births
• Leading cause of sensorineural deafness
• Major cause of mental retardation, cerebral
palsy
• Approximately 10% death in symptomatic
newborns
• Lifelong habilitation for impaired survivors

3. How is CMV transmitted?
• Fetus: Via placenta from the mother
• Human milk
• Blood transfusion, organ
transplantation
• Children and adults: Mainly via bodily
fluids (esp. urine, saliva)

4. Who transmits CMV?
• Duration of viral shedding
following primary infection:
• 2-3 weeks for adults
• Months to years for
young children
• Therefore, CMV is most often
transmitted by young children

5. Transmission of CMV through the placenta
barrier and infection of the fetus
Infected mother viraemia infection of placenta trophoblasts
Infection of
the oropharynx
Infection of fetal
Virus in
endothelial cells
amniotic fluid
Fetal viraemia
Fetal viruria
Viral
replication in
target organs
(kidney)

6. PRIMARY MATERNAL CMV
INFECTION DURING PREGNANCY
• 95% clinically inapparent
• 35% transmitted to fetus
• No clear relationship between
gestational age and transmission
• Fetal damage more likely in first
26 weeks, (32%) than later (15%)

7. MATERNAL CMV INFECTION
DURING PREGNANCY
• Primary maternal infection leads to
fetal infection in 30-50% of
cases--10-15% of these have overt
clinical disease
• Secondary maternal infection less
likely to lead to fetal infection (1-2% )
but can do so and may lead to severe
disease (Boppana et al, NEJM 2001, 344:
1366)

8. Rates of primary CMV infection
during pregnancy
Study (Location) Rate as % of Rate as % of % cong CMV,
PregnanciesSeronegativesprimary mat
inf
Stern 1.1 4.1 45
(London)
Grant (Scotland) 0.29 0.71 38
Stagno (USA, 0.57 1.4 47
mid-income)
Ahlfors (Sweden) 0.32 1.4 43
Griffiths (London) 0.30 0.86 20

10. Symptomatic Congenital
CMV Infection
• Jaundice (67%)
• Petechiae (76%)
• Hepatosplenomegaly (60%)
• Microcephaly (53%)
• Chorioretinitis (20%)
• Seizure (7%)
• Fatal outcome (10%)
Boppana et al. (1999) Pediatrics 104:55

11. Sequelae of Congenital
CMV Infections
• Neurological sequelae are the most
common, and most severe:
• >90% of newborns with symptomatic
congenital CMV infection have visual,
audiologic and/or other neurological
sequelae
• - 5-17% of newborns with
asymptomatic congenital CMV
infection develop neurological
sequelae (esp. hearing loss)

12. Sequelae of Congenital
CMV Infections
• Cranial CT is a good predictor of
sequelae in neonates with congenital
CMV infection
• Most common abnormality is
intracerebral calcification (typically
periventricular)
• Boppana et al (Pediatrics 99:409,
1997) reported that 90% of neonates
with abnormal CT scan developed at
least 1 sequelae
• Only 1/17 neonates with normal CT
had IQ < 70

13. SEQUELAE OF SYMPTOMATIC
CONGENITAL CMV INFECTION
• Seizures
• Chorioretinitis
• Periventricular calcifications
• Sensorineural hearing loss
• motor deficits

14. CHORIORETINITIS

15. Congenital CMV

16. Congenital CMV

18. CHARACTERISTICS ASSOCIATED WITH
INCREASED RISK OF SEQUELAE
• Primary maternal infection
• Symptomatic congenital CMV
infection
• Presence of neonatal neurological
abnormalities
• Abnormal head CT scan
• Chorioretinitis in the newborn

19. CLINICAL IMPACT OF
CONGENITAL CMV INFECTION
Frequency of sequelae
Symptomatic (7%) Asymptomatic (93%)
Infant death 10% 0
Hearing loss 60% 7–15%
Mental retardation 45% 2–10%
Cerebral palsy 35% <1%
Chorioretinitis 15% 1–2%

20. Diagnosis of Congenital
CMV Infections
• Isolation of CMV from urine or other
body fluid (CSF, blood, saliva) in the
first 21 days of life is considered
proof of congenital infection
• Serologic tests are unreliable; IgM
tests currently available have both
false positive and false negative
results
• PCR may be useful in selected cases

22. Detection: screening for maternal
CMV infection
• CMV IgG antibody – sensitive and specific
screen for past infection
• CMV IgM antibody – variable sensitivity and
specificity
• Antibody avidity testing can increase accuracy
of detection of primary infection
• No test for immune mothers who will transmit

24. Advanced CMV diagnosis
 IgM confirmation by Western blot
 Determination of the IgG avidity
index
 Isolation of the virus from urine,
saliva and blood

25. A confirmatory test for CMV-IgM
New immunoblot µ
1) Contains both structural Vp150 Purified
Vp82
and nonstructural proteins native
Vp65 viral
2) Reactivity to vp 150 can Vp28 proteins
be confirmed with
rp150
recpUL32
rp52 Recombinant
3) Agrees with consensus of rp130 proteins
different ELISAs
rp38
4) Is easy to standardize
5) Is easy to interpret CKS

26. Congenital CMV infections
Low IgG avidity is linked to primary
infection
70
60
Avidity index (%)
50
40
30
20
10
0
0 5 10 15 20 25 30 35
Weeks after beginning of symptoms

27. Evaluation of mothers at risk of
transmitting CMV to the fetus
T e s t fo r I g G a n t ib o d y
a t fir s t p r e n a t a l v is it
P o s it iv e N e g a t iv e
T e s t fo r I g M A n t ib o d y R e t e s t la t e r
N e g a t iv e , P o s it iv e = I g G P o s it iv e = N e g a t iv e ,
n o fu r t h e r t e s t in g p r im a r y in fe c t io n S e r o c o n v e r s io n n o fu r th e r te s ts
Refer for prenatal diagnosis

28. Intervention: using results of maternal
screening to prevent congenital CMV
disease
Possible intervention Problems
• Counsel regarding • No proven means to
prevention (seroneg prevent maternal
mother) infection
• Use prenatal diagnosis,
• ~75% infected fetuses
abort infected fetus
will be normal
• Use antivirals to prevent
or treat fetal infection • No available antiviral
treatment for prenatal
use

29. Case Report: “Oral ganciclovirfor the
treatment of intrauterine cytomegalovirus
infection
• Nulligravid cmv seronegative pt. received
renal allograft from seropositive donor
• Pt. became pregnant 3 months following
acute CMV infection
• AF CMV DNA+(80 copies) at 21 wks.
• Oral CGV administered at 22 wks.
• AF CMV DNA-at 26 weeks (8 copies)
• Vigorous female delivered at birth
• Newborn urine and blood CMV DNA-
• Normal development @ 3 years of age
Puliyandaet al. (2005)Transplant Infectious Disease 7:71-7

30. Antiviral Therapy
for
Congenital CMV
Infection?

31. Phase lll randomized trial of ganciclovir for
symptomatic congenital CMV infections
involving the CNS
• 100 Neonates enrolled to receive 6 weeks of IV
ganciclovir (6 mg/kg/dose q 12 hours)
• No significant difference in mortality (6% GCV, 12%
untreated)
• Hearing Improvement was more likely in the GCV
treated group at 6 and 12 mos (OR 4.31, 4.03)
• 29/46 (63%) GCV recipients experienced
neutropenia, compared with 9/43 (21%) untreated
control patients
Kimberlin et al, J. Pediatrics,143:17,2003

32. USE OF GANCICLOVIR IN SYMPTOMATIC
CONGENITAL CMV INFECTION
• 12 newborns treated for 2 weeks with 5
mg/kg/day or 7.5 mg/kg/day + 3 months of 10
mg/day 3x/week
• Higher, but not lower dose, cleared viruria
• Abnormal liver and haematologic function
appeared to clear faster with higher dose
• Although outcome appeared better with
higher dose, CNS sequelae appeared in both
groups
from Nigro etal J Pediat 1 994; 1 24: 31 8
, r

33. A PHASE II STUDY OF GANCICLOVIR IN 47
NEWBORNS WITH SYMPTOMATIC CONGENITAL
CMV INFECTION
• Patients with CNS disease treated with
8mg/kg/d or 12mg/kg/d iv for 6 weeks
• 19 % of participants had neutropenia
requiring dose modification
• 12 mg/kg reduced viral shedding; shedding
returned when drug was discontinued
• 3 patients had improved hearing at 6
months; 25 had abnormal hearing
from Whitley etal J InfectDis, 1 997; 1 75: 1 080
,

34. Antiviral Therapy for
Congenital CMV Infection?
• Ganciclovir has been shown to be effective
therapy for certain CMV infections in
immunocompromised hosts (e.g., retinitis
or enterocolitis in HIV-infected patients)
• Neonatal experience with ganciclovir is
limited, the toxicity of the drug is
considerable (e.g., platelets, neutrophils),
and oral bioavailability unreliable

35. Ganciclovir Therapy for
Congenital CMV? 2006
• A six week course of IV ganciclovir may
reduce the rate of long-term hearing loss in
neonates with symptomatic CMV infection
• However, this regimen is associated with
significant toxicity, long-term followup
data are lacking, and the optimal duration
of therapy (if any) is unknown
• Potential benefits of antiviral therapy for
asymptomatically infected neonates may
be greater

36. Antiviral Therapy for
Congenital CMV? 2006
• Current role for IV ganciclovir uncertain:
therapy “may be considered for patients
with symptomatic congenital CMV disease
involving the CNS” (Kimberlin et al, 2003)
• 2006 Red Book says that it “is not
recommended routinely because of
insufficient efficacy data”
• ?? Treatment of neonates with worsening
retinitis or hepatitis, severe pneumonia, or
persistent severe thrombocytopenia ??
Duration of therapy ??

37. Prevention of CMV
Infections?
• A vaccine to prevent CMV infections
is desperately needed
• Trials of candidate vaccines are
underway
• CMV Vaccine development a “Level
One” priority !!

38. How is congenital CMV
prevented?
• Many different ways to
prevent CMV
• Our approach:
• Hygiene, especially
handwashing
• Education about CMV
and how to prevent it
through hygiene

39. How do we communicate
this message?

40. The End