Consequences and Risk factors Of congenital CytomegalovirUS infection

Cytomegalovirus (CMV) is a member of the herpes virus family with the capacity
of lifelong latency and intermittent reactivation. CMV infection is common
among the general population. In the USA, between 1988 and 1994, 58% of the
women of childbearing age was IgG-seropositive, indicating previous
CMV-infection. The overall seroprevalence for CMV infection in the Netherlands
in 2006-2007 was 49%. In healthy individuals it rarely causes symptoms. In
contrast, fetal infection with CMV can cause significant morbidity.
Congenital CMV infection can occur with a primary maternal CMV-infection or
with a recurrent maternal CMV-infection (re-infection or reactivation).
In the Netherlands the birth prevalence of congenital CMV infection in 2007 was
estimated at 0.5%, which is in accordance with the reported world-wide
prevalence of 0.6-0.7%.
International studies have shown that congenital CMV infection can cause severe
disability in young children. About 10 to 15% of children with congenital CMV
infection show symptoms at birth. The typical symptoms at birth include
blue-berry muffin rash, petechiae, microcephaly, low birth weight,
hepatosplenomegaly and jaundice. Of these children approximately half will
develop long term sequelae such as sensorineural hearing loss, visual
impairment and mental retardation. Notably of the almost 90% of children with
initial asymptomatic congenital CMV infection, 10-15% may develop long term
sequelae, predominantly hearing loss.
Insight into the disease burden due to congenital CMV infections including long
term sequelae in the Netherlands is lacking. With the aim to prevent serious
consequences of congenital CMV infection in the future, this insight is needed
to be able to estimate the population impact of primary and secondary
prevention measures.

- To assess the burden of disease of congenital CMV infection in the
Netherlands at the age of 5 to 6 years through the assessment of the occurrence
of sensorineural hearing loss due to congenital CMV infection.
- To establish the burden of disease of congenital CMV infection in the
Netherlands during early childhood (0-6 year) through retrospective evaluation
of the reported long-term sequelae of congenital CMV infection, including
neonatal hearing loss and visual, cognitive and motor impairment and through
the evaluation of the quality of life of both children and their parents.
- To determine the association between CMV viral load in dried blood spots and
long-term sequelae of congenital CMV infection.

This study enables the assessment of the disease burden of congenital CMV
infection in the Netherlands at the age of 5 to 6 years. Many international
studies describing the burden of disease had a short follow-up term (up to 3
years). The added value of the proposed study is that insight will be given in
the long term consequences of congenital CMV infection and the specific
situation in the Netherlands. This information is essential to assess both the
need and the potential benefits of primary and secondary preventive measures
that are expected in the future.

For this study we will test, with consent of the parents, around 25.000 dried
blood spots (DBS) for congenital CMV infection. We expect to find about 135
children with congenital CMV infection. We intend to include at least 100
children with congenital CMV infection and at least 200 children without
congenital CMV infection. Of these children we will request information that is
routinely collected during regular examinations by the youth health care
organization. We will request data from the preventive health check at the age
of 5 or 6 years and the schoolresults of the first two years in primary school.
In addition we will ask parents to fill out for questionnaires. One concerning
the health of their child and demographic features of their family, one on the
development of their child and two short questionnaires to assess the quality
of life of both the children and their parents. Finally we will request data
from the child health centre visits and the neonatal hearing screening.

The burden of this observational study is minimal for the children and their
parents. There are no apparent risks involved in this study.
Congenital CMV infection will be assessed retrospectively in dried blood spots
which have been collected almost 5 years previously. Therefore no blood sample
has to be taken from the child for the diagnosis of congenital CMV infection.
The clinical outcome measures will be predominantly assessed during the child
health centre visits and the voluntary standard preventive health check by the
youth health care organization. These assessments routinely take place and are
independent of participation in the study.
In addition to the standard youth health care examinations the parents will be
asked to fill out for questionnaires.A general questionnaire, concerning
demographic features of the child and parents, a questionnaire concerning the
development of their child (Child Development Inventory, CDI) and two
questionnaires concerning the quality of life of both the children and their
parents. This will take approximately two to two and a half hours of their time
in total.
However the knowledge that the child has congenital CMV infection, even if the
child will never develop sequelae, can have impact on parents since they might
be anxious about the possible consequences of this congenital infection.

For the children in the study the assessment of CMV in DBS will allow the
retrospective diagnosis of congenital CMV infection. This will lead to a
possible explanation for potential disabilities of the child that are detected
during or before this study.
The knowledge of the underlying reason of the disabilities of their child can
be a relief for parents. Disabilities can affect parents and families on
emotional, practical and psychological level and a clarification of the
possible cause of disabilities can sometimes enhance the coping with these
difficulties.
On a broader level this study will provide knowledge on the burden of disease
in congenital CMV infection at the age of 5 to 6 years and its risk factors. It
will contribute to the considerations with regard to primary and secondary
preventive measures. For example with the introduction of neonatal screening
for congenital CMV infection an additional hearing screening between the age of
1 to 5 years could be establish for children who are at risk for hearing loss.
This would enable early recognition and intervention which could improve the
development of the child.