15-20% of CMV infected fetuses are symptomatic and up-to 60% of those symptomatic fetuses
have postnatal sequelae. Long-term sequelae are essentially neurological deficiencies and
hearing loss. Long-term sequelae are mainly seen in fetuses infected following a maternal
infection in the first trimester. The physiopathology of brain and inner ear lesions is
not completely elucidated but the viral lesions and viral replication play a major role
in this altered neurodevelopment. Fetuses with the most severe brain lesions are also
those presenting with high CMV replication in the brain and in all other organs.
Moreover, placenta infection affects fetal growth causing growth restriction and
therefore affects fetal development in that way. Finally, infected fetuses with high
blood viral load at diagnosis (around 22 weeks) are more likely to be symptomatic at
birth (OR=5.7 IC95% 2.02-16.53). This correlation between symptoms and high levels of
viral replication suggests that an antiviral treatment that could efficiently inhibit
viral replication could be beneficial.
Neonatal antiviral treatment with Ganciclovir or Valganciclovir has been used for more
than 20 years and is recommended for infected neonates that are symptomatic. Two
randomized studies demonstrated that this treatment improves hearing and intellectual
capacities of symptomatic neonates with central nervous system involvement. However, this
improvement is only modest. This modest benefit can probably be explained by the fact
that cerebral lesions developed in utero are already fixed in the neonatal period. The
investigators' hypothesis is that early prenatal antiviral therapy for infected fetuses
at high risk of cerebral lesions will be more efficient to alleviate long-term sequelae
than neonatal treatment. The prognosis of fetal infection can now be established upon
fetal imaging by ultrasound (US) and MRI, combined with fetal laboratory tests (fetal
platelets count and viral load). The prognosis is poor for severe brain lesions and good
when imaging and laboratory parameters are normal. In between these extremes, symptomatic
fetuses with extra-cerebral or mild cerebral features are an appropriate target for
antiviral therapy with the aim to prevent the development of irreversible cerebral
injury.
The 3 antiviral drugs (Ganciclovir, Foscarnet and Cidofovir) that are licensed to treat
CMV infection and disease in immunosuppressed patients are nucleotide inhibitors and
because of their potential carcinogenicity and teratogenicity, they should be avoided in
pregnancy. Valaciclovir is efficient to prevent CMV infection in transplanted patients,
is safe in pregnancy and crosses the placenta efficiently. The investigators carried a
phase II, not randomized, open label clinical trial to test the efficacy of Valaciclovir
in infected fetuses. Valaciclovir was given to women carrying a fetus with at least 1
non-severe ultrasound feature from prenatal diagnosis up until delivery. This led to 79%
asymptomatic neonates compared to 43% following natural history of the disease. However,
the efficacy of Valaciclovir seemed only partial. First, the antiviral effect was
partial: although fetal blood viral load decreased with treatment, 90% of treated fetuses
still had detectable CMV DNA in cord blood at birth and all had detectable CMV DNA in
neonatal saliva and urine. And second, the clinical efficacy was not optimal since only
57% of fetuses with more than 1 ultrasound feature were born asymptomatic, suggestive of
Valaciclovir lower efficacy in such cases.
The investigators therefore looked at new anti CMV drugs. Among them only Letermovir has
been licensed to prevent CMV disease in transplanted patients in 2018 and will be
available in 2019. Letermovir is not a nucleotide inhibitor and has specific anti-CMV
activity. In preclinical toxicity studies it was not genotoxic, not teratogenic and did
not impair fertility at the recommended human doses. Besides, no specific concern arises
from its safety profile in humans. It controls CMV infection and disease in bone marrow
transplant patients by achieving blood viral load clearance in 50-80% of cases.
The investigators' hypothesis is that maternal treatment with Letermovir will inhibit
fetal CMV replication better than Valaciclovir in symptomatic infected fetuses and lead
to a higher proportion of negative CMV PCR at birth in cord blood. Since severity is
largely related to viral replication, clearance of viral replication is a valid surrogate
endpoint for clinical outcome in such rare and phenotypically variable cases
The investigators' main objective is to demonstrate that Letermovir administered to women
carrying a CMV infected fetus following a maternal infection of the first trimester
increases the proportion of neonates with a negative CMV PCR in neonatal blood collected
in the first day of life or in cord blood in case of termination of pregnancy (TOP)
compared to Valaciclovir. The primary endpoint is the proportion of negative CMV PCR
(<500 IU/ml) in neonatal blood collected in the first day of life or in cord blood at
termination of pregnancy
The following will also to be compared between the 2 arms : the proportion of
asymptomatic neonates, the overall growth, the proportion of long-term sequelae at 2
years of age, the tolerance of treatment for mothers, fetuses and neonates, the maternal
adherence to treatment, the evolution of ultrasound features between Day0 and Week 2,
Week 4, and Week 6 of treatment, the changes in cerebral and placental features between
Day 1st magnetic resonance imaging (MRI) within the first month of inclusion and 2nd MRI
at 32 ± 2 WA, the post-mortem examination in cases with medical termination of pregnancy
(TOP).