Infect Dis Trop Med 2021; 7: e689

Congenital cytomegalovirus
infection in the absence
of maternal CMV-IgM antibodies:
a case report
S. Fanaro1, C. Valastro2, A. Tarocco1

1
Medical Science Department, Section of Pediatrics, Neonatal Intensive Care Unit,
University Hospital of Ferrara, Ferrara, Italy
2
Neonatal Intensive Care Unit, University Hospital of Ferrara, Ferrara, Italy

— Keywords: Citomegalovirus, Newborn, Prenatal infection, Serologic tests.

INTRODUCTION ter. Up to 10% of newborn with congenital CMV in-

fection are symptomatic at birth. Symptoms range from
Congenital CMV infection is the most frequently re- systemic disease to exclusive central nervous system
ported viral infection in newborn infants. The preva- (CNS) involvement. Forty to sixty percent of symptom-
lence of this infection is estimated between 0.3% and atic newborns may develop long-term sequelae, includ-
2.2% of live births1. Congenital CMV infection contrib- ing sensorineural hearing loss, chorioretinitis and cog-
utes to thousands of children each year being born with nitive impairment5-7.
or developing permanent disability such as hearing loss,
blindness, cerebral palsy and cognitive impairment.
In Italy the incidence is between 0.57% and 1% of live CASE REPORT
births2. Maternal infections during pregnancy rarely, if
ever, result in a clinically identifiable infection, and ex- A full term male newborn was admitted to a tertiary
posure to CMV occurs repeatedly in pregnant women. care NICU because of prenatal ultrasound finding (24
There are well-described exposure risks to CMV that weeks GA) of hyperechogenic spots in basal ganglia and
include exposure to young children, sexual activity white matter. Maternal anamnestic data reported flu-like
and living in crowded environments. CMV infection symptoms during 1st trimester. Maternal serological
in pregnant women can occur by primary or non-pri- tests performed during her previous pregnancy showed
mary infection3. Non-primary infection can occur after seropositivity for CMV. Serological screening for CMV
reactivation of the latent endogenous CMV strain or by performed during the first trimester showed negative
reinfection with a different exogenous viral strain. The IgM- and positive IgG-CMV antibodies, confirming a
risk of transmission to the fetus and the severity of the past infection. In order to exclude vertical infections,
disease depend on two conditions: the maternal serolog- other maternal serological tests were performed, show-
ical status and the trimester in which CMV infection ing seronegativity for Toxoplasmosis, Rubella, Zyka vi-
occurs4. The risk of transmission to the fetus during a rus, Chikungunya virus, Dengue virus and absence of
primary infection is approximately between 14.2% and IgM antibodies for Parvovirus B19, Herpes virus and
52.4%; for non-primary infection the risk is between 1% Cytomegalovirus. In particular, CMV antibodies profile
and 2.2%1. Transmission rate is higher in the third tri- characterized by IgM negativity and IgG positivity re-
mester; however, the most significant neonatal sequelae mained unchanged at 22, 26 and 30 weeks of gestation.
occur when transmission takes place in the first trimes- The fetal MRI performed at 32 weeks of GA showed

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License

Corresponding Author : Silvia Fanaro, MD; e-mail: fnrslv @ unife.it 1

 Infect Dis Trop Med

microcephaly, cerebral atrophy, cortical and subcortical may show flu-like symptoms. Historically, pre-existing
calcifications and cerebellar hypoplasia. The baby was maternal immunity was known to reduce the probability
born by elective C-section at 38 weeks of gestation, with of symptomatic congenital CMV infection and the number
a birthweight of 3265 g (55°P), a length of 49 cm (49°P) and severity of sequelae. In recent years, however, increas-
and a head circumference of 32.5 cm (8°P)8. The Apgar ing evidence suggests that non-primary infection may be
scores were 8 and 9 at 1 and 5 minutes, respectively. a significant cause of severe congenital CMV disease11-14.
Prenatal findings were confirmed by cranial ultrasound, The gold standard of serological diagnosis of maternal
CT scan and MRI performed in the first week of life CMV infection during pregnancy is maternal serocon-
(Figure 1). Auditory brainstem response (ABR) resulted version or the presence of serum anti-CMV specific IgM
abnormal in the left ear. Second level metabolic screen- combined with low avidity anti-CMV IgG avidity10. How-
ing tests resulted negative, as well as serological tests ever, both American College of Obstetricians and Gyne-
for EBV, Parvovirus B19, HHV6, and HSV1 and 2. De- cologist (ACOG) and Center for Disease Control and Pre-
spite maternal serological pattern, the newborn under- vention (CDC) do not recommend routine screening for
went a full examination for congenital CMV infection. CMV during pregnancy because there is neither vaccine
CMV virus was detected by polymerase chain reaction nor effective treatment available15,16. Furthermore, it is
(PCR) test in urine and blood samples (11.5 x 105 cop- difficult to discriminate primary from recurrent infection
ies/ml and 35.5 x 103 copies/ml, respectively). Orally on the basis of maternal IgM antibody screening: specific
Valganciclovir was started on DOL 35, at 6 mg/kg/dose IgM anti-CMV antibodies may be produced during both
every 12 hours but was withdrawn after 12 days because primary and secondary infections, an elevated IgM titer
of leucopenia. Therapy was resumed 2 weeks later and may persist for months after acute infection and could be
continued for 5 months. At 2 years of age the neurolog- frequently falsely positive because of cross-reaction with
ical follow up showed microcephaly, monolateral hear- other viral infections or in autoimmune disease9. The
ing loss, cognitive impairment and epilepsy treated with anti-CMV IgG avidity test is currently the most reliable
clonazepam and levetiracetam. commercial procedure to identify primary infection in
pregnant women. Antibody avidity indicates the strength
of a multivalent antibody to bind a multivalent antigen.
DISCUSSION During the first weeks following primary infection, IgG
antibodies show a low avidity for the antigen, but they
Primary CMV infection during pregnancy occurs in 1 progressively and slowly mature, acquiring a moderate
to 4% of previously seronegative women9. The trans- and then a high avidity. IgG avidity test may be very
mission rate of CMV to the fetus following maternal useful in the diagnostic process: combination of elevated
primary infection during pregnancy has been reported specific IgM-CMV and elevated specific IgG-CMV anti-
to range between 14.2 and 52.4%, with the most studies bodies with low avidity suggest a recent CMV infection.
reporting rates of around 30%10. In contrast, the risk and Low avidity CMV-IgG usually last for approximately
the rate of intrauterine transmission following non-pri- 16-18 weeks after the onset of CMV infection. Negative
mary maternal infection range between 0.15% to 2%. Im- IgM-CMV antibodies combined with positive IgG-CMV
portantly, maternal primary and non-primary infections antibodies with high avidity index during the first 12-16
are rarely associated with any clinical symptoms. Acute weeks of gestation could be considered a good indication
infection is usually asymptomatic, sometimes women of past infection10.

Figure 1. Cranial MRI scan showing cortical and subcortical calcification, venriculomegaly, increased cisterna magna, reduced cerebral
2 convolution and diffuse hyperechoic spots.
 Congenital cytomegalovirus infection in the absence of maternal CMV-IgM antibodies : a case report

In our case, despite fetal US and MRI findings, sug- 3. Britt WJ. Maternal Immunity and the Natural History of
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in literature. Gunkel et al17 described the case of a fe- 5. Fowler KB, Boppana SB. Congenital cytomegalovirus infec-
male infant, diagnosed with congenital CMV infection tion. Semin Perinatol 2018; 42: 149-154.
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N, Garofoli F, Heath P, Iosifidis E, Klein N, Lombardi G,
at 22+2 weeks of gestation. It is known that presence
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Conflict of Interest: CA, Palasanthiran P, Schleiss MR, Shand AW, van Zuylen
The Authors declare that they have no conflict of inte- WJ. Congenital cytomegalovirus infection in pregnancy and
rests. the neonate: consensus recommendations for prevention, di-
agnosis, and therapy. Lancet Infect Dis 2017; 17: e177-e188.
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