CMV and pregnancy

An update for healthcare providers

Natural history

Cytomegalovirus (CMV) is a double-stranded DNA virus belonging to the herpes viridae. Transmission mainly occurs through contact with bodily fluids (mainly saliva but also urine, blood, breast milk, stool). After a primary infection, the virus remains latent at the level of epithelial cells and macrophages. A reactivation with production of virus particles can occur at any time. It is still unknown which factors trigger reactivation. A secondary infection with another subtype is also possible.

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Via hematogenous vertical transmission, CMV colonizes the placenta and causes placentitis; this causes placental insufficiency, relative hypoxemia and ultimately fetal growth restriction. The virus behaves neurotropically with a natural attraction to and replication in the cells of the central nervous system. The germinal matrix in particular is susceptible to viral infestation due to the rapidly dividing and highly metabolic character of the tissue. Neurological damage can be directly due to the viral infection or indirectly to the inflammatory response and relative hypoxia in severe placentitis.

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In adults, CMV infection is usually asymptomatic and self-limiting; symptoms are mild and resemble an Epstein-Barr virus infection (sore throat, fever, swollen lymph nodes, abnormal liver function tests).

In immunocompromised people and during pregnancy, CMV can lead to serious consequences.

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Epidemiology

The seroprevalence of CMV is highly dependent on age, region and socio-economic status. In industrialized countries, the seroprevalence in women of childbearing age is between 40 and 50%. The prevalence of congenital CMV is estimated at 0.7-1.5% per year. 

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The risk of fetomaternal infection depends on the nature and time of infection. A primary infection leads to fetal infection in 20-40%, in contrast to a reactivation or secondary infection where the risk is only 0.2-2%. 

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A primary infection during the periconceptual period or the first trimester has a transmission risk of 15-30%. The risk of serious fetal consequences is 20-30%.

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Later in pregnancy, after a primary infection during the second and third trimesters, the risk of fetal transmission is 50 and 70%, respectively. However, infections in the second and third trimesters rarely (0.5%) cause serious fetal consequences.

This illustrates the importance of screening for CMV in the first trimester of pregnancy (<14w).

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Recommendations for follow-up during pregnancy

Maternal screening
Screening for CMV serology is only useful up to 14 weeks of pregnancy and is based on the detection of IgM and IgG antibodies and the avidity of the IgG antibodies in the maternal serum.
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Recommended screening moments: 

- Preconception if possible. This is the only time the test is reimbursed. 

- Screening during intake at 6-8w and repetition simultaneously with the NIPT test at 12-14w.

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The patient has had a recent infection with CMV when

1) IgM + with clear seroconversion from IgG negative to IgG positive

2) IgM + with increase in the IgG titer and low IgG avidity (<35% depending on your lab cut-off).

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Interpretation of the results:

1) IgM+ and IgG-

A recent infection is possible; repeat the blood collection within 1-2w.

In the event of a seroconversion of IgG, a primo infection is confirmed and the patient is eligible for the TreatCMV study. 

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2) IgM and IgG

There is no recent infection. The patient is susceptible to a primary infection, which makes insisting on hygienic preventive measures important. If <14w pregnancy, test again before 14 weeks.

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3) IgM+ and IgG+

- Low avidity (<35%): recent infection (< 3 months ago). The patient is eligible for the TreatCMV study.

- High avidity (>50%): infection > 3 months ago with persistent IgM antibodies. A secondary infection or reactivation cannot be excluded. Hygienic preventive measures remain important.

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4) IgM- and IgG+

The patient has previously had a CMV infection. A secondary infection or reactivation cannot be excluded. Hygienic preventive measures remain important.

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​Preventive hygienic measures

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There is a significant reduction in primary infections by a factor of 2.5 to 6 in pregnant women who are aware of their negative CMV serology and adhere to the prevention measures. 

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Much research is being done on vaccination against CMV, but to date no clinically useful vaccines are available.

 

Follow-up if serology indicates a recent primary infection

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​Secundary prevention
 

1) Hyperimmunoglobulins

Observational studies (with clear, limited inclusion criteria) have shown that in the case of a primo infection during the first trimester of pregnancy, maternal administration of CMV hyperimmune globulins leads to a significant reduction in maternal transmission (from an average of 30% to 10%).

In particular, the cost (the dose depends on the maternal body weight, not reimbursed for this indication) and the intravenous administration method are factors that hinder the standard recommendation of immunoglobulins.

 

2) Antivirals

A recent randomized controlled trial shows that maternal intake of Valaciclovir reduces vertical transmission by 66%. Valaciclovir has a high bioavailability and sufficient presence in amniotic fluid after oral ingestion. In this double-blind study, 90 patients were randomized to take Valaciclovir 8g/d or placebo. At amniocentesis, significantly fewer fetal CMV infections were detected in the Valaciclovir group compared to the placebo group (11% vs. 30%; p=0.027).

 

In addition to the reduction in fetal infections, this study also demonstrates high compliance and good tolerability of Valaciclovir. These results were recently confirmed in a systematic review.

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Currently, Valaciclovir has not yet been registered for the prevention of congenital CMV and can only be offered in a research setting (see further "TreatCMV trial"). ​

Research is ongoing into new antiviral drugs such as Letermovir and Maribavir.

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Amniocentesis
 

After a maternal seroconversion, a fetal infection can be detected in the amniotic fluid. Through excretion of the virus in the fetal urine, CMV becomes detectable by PCR 6 to 8 weeks after maternal seroconversion. The negative predictive value of the PCR test in amniotic fluid is significantly higher after an interval of 8 weeks between seroconversion and amniocentesis. The infection status of the fetus can be demonstrated or ruled out with great accuracy. In experienced hands, an amniocentesis around 20 weeks has only a 0.1% risk of complications such as miscarriage and/or bleeding.

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Interpretation of the results: 

1) Amniocentesis CMV PCR positive: The risk of serious fetal consequences increases up to 25%. Biweekly follow-up with expertise ultrasound and MRI around 28-30 weeks is recommended.

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2) Amniocentesis CMV PCR negative: The risk of serious fetal consequences reduces to 0.5%. Expertise ultrasound is recommended at 28-30w.

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The risk of a false negative result is 8% if no transmission occurred at the time of amniocentesis. In these fetuses the chance of a symptomatic fetal infection has been proven to be <1%.

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Imaging

Fetal infection shows great phenotypic variation. Serial prenatal ultrasound and neurosonography are used to detect associated lesions and estimate the potential fetal/neonatal outcome.

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The combination of a positive PCR for CMV in the amniotic fluid, fetal neurosonographic follow-up (transabdominal and transvaginal) and a fetal MRI increases the sensitivity to detect fetal brain abnormalities to 95%.

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Treatment

To date, there is no treatment available for fetal CMV infection during pregnancy. Research is ongoing into the effectiveness of antiviral drugs such as Valaciclovir for tertiary prevention.

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TreatCMV trial

A multicenter prospective cohort study into secondary prevention of CMV with Valaciclovir started in 2024. This is a collaboration between UZ Leuven, UZA Antwerp, UZ Brussels, UZ Ghent, ZAS Antwerp, AZ Sint-Jan Brugge and Ziekenhuis Oost-Limburg, financed by the FWO.

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Study aim

- To assess the effectiveness of Valaciclovir as secondary prevention for maternal CMV in the Flemish population. 

- To evaluate the long-term safety of Valaciclovir for mother and child

- Increasing awareness about CMV

- Establishing a standardized screening protocol in Flanders

- A cost-effectiveness analysis of screening and treatment

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Outcomes

1) Primary outcome:

Rate of congenital CMV infection on amniocentesis (and confirmed on postnatal urine sample) after treatment with Valaciclovir. 

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2) Secondary outcomes:

- Nature and evolution of CMV-related abnormalities on imaging.

- Long-term effects on neurological development, balance and hearing. 

- Maternal and fetal safety of Valaciclovir

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Patient trajectory

- A pregnant woman can be included in the study with a confirmed primary CMV infection up to and including 13w6d pregnancy. Patient must be of legal age. 

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- The patient is referred to one of the 7 participating centers as quickly as possible.

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- After informed consent, the patient can opt to start Valaciclovir PO 4x2g/d for 8 weeks.

If the patient does not want this treatment, she can still be included in the same follow-up process.

During the treatment, the patient visits every two weeks.

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- An amniocentesis is scheduled after 8 weeks of treatment. For the patient who does not wish treatment, amniocentesis can be performed at the earliest 6-8 weeks after seroconversion.

If PCR CMV in amniotic fluid is positive: biweekly ultrasound/neurosonography and MRI at 28-30w

If PCR CMV in amniotic fluid is negative: ultrasound and MRI (only in study context) at 28-30w

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- After birth:

Blood tests and urine tests (with PCR CMV determination) within 72 hours after birth 

An eye test, hearing screening, transfontanellar ultrasound and neonatal MRI before the age of 21 days.

Patients who did not take Valaciclovir and tested negative for CMV in urine will not be followed up in the study.

To ensure that all these studies run smoothly, the delivery takes place in one of the seven participating hospitals. ​

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- Pediatric follow-up:

Hearing and balance tests at 6m - 1y - 2y - 3y - 4y

Neurological development is tested via online questionnaires at 1y - 2y - 5y

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Cost

The patient only bears the costs of the screening (approx. 17 euros per blood test); all other costs are within the study context.​

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Start/Duration

July 1, 2024 

Expected duration: 5-8 years

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Progress

Inclusion started since 01/07/2024​

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Contact

treatcmv@uzleuven.be

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Postnatal

To assess the severity of infection postnatally, a series of examinations are preferably performed within the first months of life: transfontanellar ultrasound, MRI, eye fundus examination, blood sampling and audiology. Treatment with Valganciclovir can be initiated in severe symptomatic disease and may be considered in moderate symptoms. Valganciclovir can only slow down the further deterioration of the disease, most symptoms are irreversible. The toxicity of this medication must always be taken into account. This treatment has no place in the prevention of hearing damage or neurodevelopmental disorders in asymptomatic CMV neonates.

For more information please visit https://cmvreg.be/news-publications/.

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There is currently no standard neonatal screening for CMV in Flanders.

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Recent updates

TBA