Congenital CMV Infection

Epidemiology
Congenital CMV infection is the most common congenital infection with a birth
prevalence of 0.6– 0.7% in the developed countries, posing a major global burden which
exceeds most routinely screened diseases. CMV is a neurotropic virus, which establishes
lifelong latency in infected humans like other herpes viruses. The seroprevalence in women
of childbearing age is estimated to be 40 to 50%, and the rate of CMV acquisition is 1 to 7%
per year. The main risk factor contributing to CMV acquisition is prolonged contact with young
children. Maternal infection is mostly asymptomatic and fetal transmission can occur
transplacentally at any gestational age (Manicklal et al., 2013).

CMV virus
Cytomegalovirus (CMV) is a double-stranded DNA, β human herpesvirus. The viral
genome is divided into a unique long (UL) region, and a unique short (US) region,
which are necessary for the synthesis of the UL54 protein (DNA polymerase), the major
target of antiviral drugs used to treat CMV infections, and the UL97 protein (phos
photransferase protein), required for the phosphorylation of ganciclovir (GCV), a necessary
step to form its active metabolite in vivo. The outer envelope of the virus, which is derived
from the host cell nuclear membrane, contains multiple virally encoded glycoproteins.
Glycoprotein B (gB) and glycoproteinH (gH) seem to be the major determinants of
protective humoral immunity. Antibodies against these proteins are capable of neutralizing
the virus, and these glycoproteins are under study for the development of CMV subunit
vaccines (Buonsenso et al., 2012).

Pathophysiology
CMV is transmitted by close contact between individuals, through contamination
from urine, saliva, semen, cervical secretions and breast milk, while droplet contamination
is thought to be less important. Children in daycare facilities represent an im- portant
reservoir of CMV. Transmission of virus from a day care attendee to a seronegative
susceptible woman may, if she is pregnant, result in a primary maternal infection which
in turn leads to congenital CMV infection of the fetus. Therefore, CMV seronegative
women working in daycare centers are at increased risk of acquiring CMV infection,
while there is no evidence that healthcare providers have an increased risk of acquiring CMV
infection, compared with the general population (Stagno and Britt, 2010).
Primary CMV infection is reported in 1-4% of seronegative women during pregnancy
and the risk of transmission to the fetus is estimated to be about 30 to 40%. Reactivation of
CMV infection during pregnancy is reported in 10-30% of seropositive women and, in
this circumstance, the risk of transmission of the virus is about 1-3% (Ahlfors et al., 2009).
Congenital CMV infection most commonly occurs via intrauterine transmission, but
since the virus is shed in body fluids, transmission can also be acquired during delivery or
through breast milk. Only infants born to mother who had a primary infection during
pregnancy have symptomatic disease at birth when compared with those born to mother
who had a recurrent infection. Also, they are at substantially higher risk for the development
of long term and severe sequelae even though a few studies have identified severe
symptomatic disease in newborns born to women with preconceptional immunity. Moreover,
women who are seropositive for CMV may become re-infected with a new strain during
pregnancy, and this re-infection can lead to symptomatic disease in the neonate (Boppana
et al., 2011).
The risk of severe consequences is much greater when CMV infection is acquired
in the first half of pregnancy. In the first months of pregnancy, in fact, CMV has a
teratogenic potential in the fetus, as CMV infections may result in migrational disturbances
in the brain (Ornoy et al., 2006). Neocortical neurons migrate from their site of production in
the periventricular germinative zone towards the cortical plate between the 12th and
24th week of gestation. During this period, CMV may disturb the nor mal development of the
brain and produce malformations. Later in pregnancy, when the gross morphology of the
brain is completed and myelination is occurring, white matter lesions without cerebral
cortical malformations can develop (Jones, 2008).

Clinical Manifestation
The majority of infants born with congenital CMV infection are asymptomatic at
birth (asymptomatic congenital CMV infection is defined as the presence of CMV in any
secretions within the first 3 weeks of life, but with normal clinical, laboratory and imaging
evaluations), and only about 7 to 10% have clinically evident disease at birth. Jaundice
(62%), petechiae (58%), and hepatosplenomegaly (50%) are the most frequently noted
symptoms and constitute the classical triad on congeital CMV infection (Malm and Engman,
2007).
Other clinical manifestations include sensorineural hearing loss (SNHL, present
in about 30% of symptomatic infants at birth), oligohydramnios, polyhydramnios,
prematurity, intrauterine growth retardation, non-immune hydrops, fetal ascites, hypotonia,
poor feeding, lethargy, thermal instability, cerebral ventriculomegaly, microcephaly,
intracranial calcifications (central nervous system (CNS) involvement is present in
approximately two-thirds of infants with symptomatic CCMV infection), “blueberry muffin”
spots, and chorioretinitis and, less frequently, hepatitis, pneumonia, osteitis, and intracranial
hemorrhage (Schimmel et al., 2011). Moreover, infants with symptomatic CCMV infection may
be at increased risk for the presence of congenital malformations such as inguinal hernia in
males, high-arched palate, hydrocephalus, clasp thumb deformity, and clubfoot.Truemortality
rates are difficult to obtain and have been reported to be as high as 30% for symptomatic
infants but other Authors have suggested a more likely average of about 5-10%. Death is
usually due to non-CNS manifestations of the infection, such as hepatic dysfunction or
bleeding (Dollard et al., 2007).

Diagnosis
The diagnosis of CCMV infection in a neonate is based on demonstration of the virus
by isolation from urine, by identification of CMV-DNA by polymerase chain reaction (PCR) in
urine, blood, saliva and cerebrospinal fluid (CSF) sampled before 3 weeks of age or by
detection of antigen or CMV-IgM in blood. A rapid diagnosis may be obtained by detection of
CMV antigen in blood but the sensitivity is low. IgG antibodies in neonates are mostly
maternally transferred antibodies, while the demonstration of IgM antibodies in the newborn
is indicative of congenital infection, because maternal IgM antibodies can’t cross the placenta.
However, only 70% of neonates with CCMV infection have IgM antibodies at birth (Bounsenso
et al., 2012).
Concerning the mother, seroconversion of CMV-IgG between two serum samples
obtained in 2-3 weeks distance provides the most reliable diagnosis of primary infection. The
presence of CMV-IgM suggests a recent or ongoing infection, but they have a low specificity.
However, further confirmation of a diargnosis of primary CMV in pregnancy is always required.
The CMV-IgG avidity test, a measure of the binding capacity of CMV-IgG antibodies, is a
useful tool for confirmation and for dating the time of a primary CMV infection (Mace et al.,
2008).

Treatment
Antiviral treatment should be started within the first 30 days of life and is clearly
recommended in symptomatic newborn infants with CNS involvement; additionally, it
can be considered in symptomatic newborn infants with severe focal disease. In symptomatic
newborn infants with CNS involvement, ganciclovir therapy seems to reduce long-term
sequelae: SHNL progression and neurodevelopement delay were both reduced by 60% within
the first year of life. Up to 79% of treated patients were able to maintain normal hearing,
whereas only 31% of non-treated patients did. Only 10 versus 17 developmental milestones
were not met with therapy versus no therapy. However, there is no clear benefit with
regards to hepatitis, and ganciclovir cannot undo brain lesions, which exist at the start of
treatment (Gwee et al., 2014).
 Current guidelines suggest intravenous treatment with ganciclovir for two to three
weeks followed by oral therapy with valganciclovir to complete 6 weeks of therapy in total.
However, there is emerging evidence that prolonged antiviral treatment up to 6 months can
improve long-term outcomes. During treatment, weekly full blood count and renal function
tests should be followed to monitor for adverse effects (thrombocytopenia, neutropenia,
anemia) and because ganciclovir is excreted renally. Viral load usually drops one or two logs
during treatment, rises again drastically after treatment termination and children may excrete
CMV in urine for over a year. Long-term follow-up includes regular audiology, ophthalmologic
and neurodevelopment assessments since long-term sequelae can worsen or develop de
novo over time. Current guidelines are summarized in figure below (Kadambari et al., 2011):

Guidelines on management in congenital CMV infection

(adapted from Kadambari et al., 2011)
Refference

Stagno S, Britt B. Cytomegalovirus. In: Remington JS, Klein JO, Wilson CB, Baker CJ,
editors. Infectious diseases of the fetus and newborn infant. 6th ed. Philadelphia:
Elsevier Saunders, 2010; p. 740-781

Ahlfors K, I Varsson SA, Harris S. Report on a long-term study of maternal and congenital
cytomegalovirus infection in Sweden. Review of prospective studies available in the
literature. Scand J Infect Dis 2009; 31: 443-457.

Boppana SB, Rievera LB. Fowler KB, Machm, Britt WJ. Intrauterine transmission of
cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med
2011; 344: 1366-1371

Ornoy A, Davictrin. Fetal effect of primary and secondary cytomegalovirus infection in

pregnancy. Repro Toxic 2006; 21: 399-409.

Jones CA. Congenital cytomegalovirus infection. Curr Prob Pediatr Adolesc Health Care
2008; 33:65-100

Malm GE, Engman. Congenital cytomegalovirus infections. Semin Fetal Neonatal Med 2007;
12:154-159.

Schummel MS, Fisher D, Schlesiner Y. Congenital cytomegalovirus infection. J Perinatol

2011; 21:209-210

Macem et al. Serological testing algorithm for the diagnosis of primary CMV infection in
pregnant women. Pre nat Diagn 2008; 24: 861-863.

Manicklal S, Emery VC, Lazzarotto T, et al. The “silent” global burden of congenital
cytomegalovirus. Clin Microbiol Rev 2013;26:86-102

Kadambari S, Williams EJ, Luck S, et al. Evidence based management guidelines for the
detection and treatment of congenital CMV. Early Hum Develop 2011;87:723-728

Gwee A, Curtis N, Garland SM, et al. Question: which infants with congenital
cytomegalovirus infection benefit from antiviral therapy? Arch Dis Child 2014;99:597-
601