Bibliographic and Educational Resources in Fetal Medecine

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Each topic is grounded in a curated selection of recent publications, accompanied by in-depth summaries that go far beyond traditional abstracts—offering clear, clinically relevant insights without the time burden of reading full articles. These summaries act as gateways to the original literature, helping users identify which articles warrant deeper exploration.

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CMV During Pregnancy: Risks and Prenatal Diagnosis

Dr Marianne Leruez-Ville

Hm-envelop

Pr Yves Ville

Hm-envelop

Overview

Cytomegalovirus (CMV), a common herpes virus, is a significant public health concern, especially during pregnancy. It is the most common congenital viral infection worldwide, affecting approximately 0.5–2% of all live births. CMV infection in immunocompetent individuals is often asymptomatic or causes mild symptoms, rarely requiring treatment. However, early diagnosis and proper management are crucial in pregnant women due to the potential for severe consequences for the fetus.

Risks of CMV during Pregnancy

The primary concern with CMV during pregnancy is transplacental transmission to the fetus, leading to congenital CMV (cCMV) infection. This can result in severe abnormalities and long-term sequelae.

Maternal Infection Types and Transmission: Maternal CMV infection can be classified as primary infection (PI), where the mother acquires the virus for the first time during pregnancy without pre-existing CMV-specific IgG antibodies, or non-primary infection (NPI), which refers to active CMV infection in pregnant individuals with pre-existing IgG antibodies, typically due to reactivation of an endogenous strain or reinfection with a different strain.

  • While NPI accounts for the majority of cCMV infections, especially in populations with high seroprevalence, the risk of intrauterine transmission is higher following a primary infection.
  • The rate of vertical transmission increases with gestational age: 5.5% for pre-conception, 21% for periconception, 36.8% for the first trimester, 40.3% for the second trimester, and 66.2% for the third trimester in cases of primary maternal infection.
  • However, severe cCMV-associated sequelae occur in early gestation infections (periconceptional or first trimester). The risk of long-term sequelae is primarily limited to maternal infection acquired in the first trimester of pregnancy.

Fetal and Neonatal Complications: cCMV infection is the most common non-genetic cause of sensorineural hearing loss (SNHL). It is also a leading cause of neurodevelopmental disabilities and congenital malformations in high-income countries.

  • Approximately 10–15% of infected newborns exhibit clinical signs at birth. Of these symptomatic infants, 30–40% are at risk of developing long-term neurological sequelae.
  • Even children who appear asymptomatic at birth are at risk for neurodevelopmental sequelae, with an estimated 10–15% developing long-term issues, most commonly hearing loss. SNHL can be progressive or fluctuating, sometimes appearing later in childhood.
  • Fetal sequelae can include:
    • Central Nervous System (CNS) abnormalities: These can be severe or mild, directly influencing fetal prognosis. Ventriculomegaly (lateral ventricles >15 mm) and microcephaly (head circumference >2 standard deviations below normal) are severe intracranial signs associated with a poor postnatal prognosis. Other CNS findings include high echogenicity in periventricular areas, hydrocephaly, increased cisterna magna, vermian hypoplasia, periventricular cysts, agenesis of the corpus callosum, lissencephaly, porencephaly, intracranial calcifications, choroid plexus cysts, subependymal cysts, and intraventricular synechiae.
    • Extracranial abnormalities: These may include fetal growth restriction (FGR) (9%), hyperechogenic bowel (13%), placentomegaly (>40 mm), ascites, pleural effusion, hydrops, skin edema, hepatomegaly (3.8%), splenomegaly (3.8%), and liver calcifications (1.2%).
    • Placental impairment can also lead to increased risk of miscarriage or intrauterine growth restriction.

Detecting maternal infection is a fundamental step, as it can predict fetal infection.

  • Screening and Confirmation Methods:
    • The most common method is serum antibody detection.
      • A primary infection is characterized by the presence of IgM antibodies in the serum, detectable as early as four weeks post-infection and potentially persisting for up to 20 weeks.
      • Diagnosis can be confirmed by viral DNA detection via PCR. Real-time PCR is the current standard and most frequently used diagnostic method due to its high performance, specificity, and sensitivity, and fewer limitations like contamination risk. PCR kits are also widely available, low-cost, and do not require special storage or transportation.
      • It is recommended to screen for specific antibodies (IgM and IgG) in the first trimester. If the patient is seronegative, further tests are necessary.
    • The IgG avidity test is crucial: low avidity (below 35–50%) indicates a recent infection, while high avidity (above 50–65%) indicates a past infection. Moderate to high avidity antibodies after 21 weeks of gestation can also indicate a primary maternal infection.
    • Confirmation of active maternal infection can also be done by detecting CMV in blood or other bodily fluids such as urine, saliva, and vaginal secretions. The presence of CMV DNA in blood is more frequent during primary infections, and urinary CMV excretion is associated with a high risk of fetal infection.
  • Challenges of Maternal Diagnosis:
    • It is often difficult to determine the exact timing of primary infection, as the virus can remain active for months or even years.
    • IgM tests can yield false positives due to cross-reactivity with other viruses (Epstein-Barr, herpes simplex, varicella-zoster) or autoimmune diseases.
    • Serology and PCR are often less informative in women with pre-existing immunity. CMV serology and PCR are not helpful for identifying women with pre-existing immunity at risk of giving birth to an infected neonate, with 0–25% IgM detection rate, 0–22% rise in IgG titers, and 24–66% positive DNAemia.

When maternal infection is suspected or confirmed, fetal evaluation is paramount.

  • Invasive Methods (Direct Virus Detection):
    • Amniocentesis is the reference prenatal diagnostic method to confirm fetal infection, as the infected fetus excretes the virus into the amniotic fluid via urine.
      • It should be performed between 17 and 20 weeks of gestation and at least 6 to 8 weeks after the suspected maternal infection to minimize false negatives. Some sources suggest at least 7 weeks after estimated date of primary infection and at least 21 weeks gestation.
      • The CMV viral load in amniotic fluid is directly proportional to fetal involvement and infection severity. A value greater than 10^5 genomic equivalents suggests a severe form of the disease, while a value below 10^3 likely excludes significant infection. However, one study noted that amniotic fluid CMV viral load and fetal liver tests were not associated with fetal symptoms in their series.
    • Chorionic villus sampling (CVS) is an emerging approach for earlier diagnosis in the first trimester, but it requires further studies for full validation.
  1. Prognostic Indicators and Challenges Accurate prediction of fetal disease and prognosis remains a challenge.
  • Timing of Maternal Infection: The severe anomalies occur when infection develops periconceptionally or early in gestation (first trimester). The risk of vertical transmission increases with gestational age, but the severity of sequelae is limited to  infections occurring in early in pregnancy. Long-term complications primarily follow maternal primary CMV infections acquired between 2 months before and 3 months after conception.
  • Biomarkers: Research on cytokine profiling in amniotic fluid has shown that increases in pro-inflammatory mediators (such as IP-10, IL-18, ITAC, TRAIL, CRP, MIG, and RANTES) are associated with infection and its severity. These proteins could serve as prognostic biomarkers. Fetal thrombocytopenia is also associated with severe fetal infection.
  • Postnatal Evaluation: Postnatal evaluation is also important, as many newborns may be asymptomatic at birth, and clinical anomalies may be diagnosed later when sequelae are permanent, particularly SNHL. SNHL develops in 42.9% and 6.6% of asymptomatic neonates with and without abnormalities on cerebral ultrasound and/or MRI, respectively.

In conclusion, despite advances in maternal and fetal diagnostic methods, managing fetal CMV infections remains complex. The focus is on early diagnosis and measures to reduce disease extent, including the potential use of immunoglobulins and antivirals. Hyperimmune globulin (HIG) is not recommended as an intervention option for the prevention of maternal-fetal HCMV transmission in primary HCMV infections based on a large randomized, controlled trial. However, oral valacyclovir at a dose of 8 g/day has shown promise in reducing vertical transmission rates, particularly for primary infections acquired periconceptionally or in the first trimester, with lower

FAQ

CMV infection in pregnancy can be primary, which is a first-time infection in a seronegative woman, or non-primary, which involves the reactivation of a latent virus or reinfection in a woman who already has immunity.

The risk of vertical transmission is higher in primary infections (30–40%) compared to non-primary infections (1–2%). In primary infections, the risk of transmission increases with gestational age, ranging from 5.5% in the preconception period to 66.2% in the third trimester. For non-primary maternal infections, the transmission rate is estimated to be low, generally less than 3.5%.

cCMV can lead to severe abnormalities if the primary maternal infection occurs periconceptionally or in the first trimester. It is the most common non-genetic cause of fetal sensorineural hearing loss (SNHL). About 17-20% of infected children may experience permanent sequelae. Approximately 30% of newborns are symptomatic at birth following maternal infection before 14 weeks of gestation, with SNHL occurring in 10-15% and more severe neurological damage (including intellectual disability or developmental delay) in 10-25%. Cranial anomalies like microcephaly and ventriculomegaly are linked to poor postnatal prognosis. Other symptoms at birth can include small for gestational age (SGA), hepatomegaly, splenomegaly, petechiae, chorioretinitis, and central nervous system (CNS) abnormalities. The overall risk of severe sequelae is lower after non-primary infection.

Maternal diagnosis primarily involves serum testing for CMV IgG and IgM antibodies. IgG avidity testing is also used to differentiate recent primary infection from past infection. In specific scenarios, PCR for CMV DNA in maternal blood can be performed, particularly if IgM is positive and IgG is negative. Maternal viremia at the time of amniocentesis indicates an increased risk of fetal infection.

Prenatal diagnosis involves maternal serum testing, confirmation of infection in amniotic fluid or fetal blood, and imaging techniques. Amniocentesis for PCR of CMV DNA is considered the gold standard and best available prenatal diagnostic tool, as the infected fetus excretes the virus into the amniotic fluid. It is typically performed after 16 weeks of gestation and at least 8 weeks after presumed maternal seroconversion to exclude false-negative results. Fetal blood analysis by cordocentesis can also be used, assessing fetal platelets and viral load. Emerging approaches like chorionic villus sampling (CVS) and virome DNA are being studied for earlier first-trimester diagnosis, but require further validation.

Ultrasound and magnetic resonance imaging (MRI) are crucial for assessing anomalies. While ultrasound helps predict prognosis, its sensitivity for prenatal diagnosis is low. MRI, offering higher resolution, complements ultrasound, especially transvaginal ultrasound for cephalic presentation. Although severe cerebral features on prenatal imaging indicate a poor outcome, a normal imaging finding does not exclude the risk of hearing loss at birth.

The amniotic fluid viral load is a key laboratory parameter for assessing postnatal outcomes. A high CMV viral load in amniotic fluid (> 1,300,000 copies/mL) is associated with a greater risk of imaging anomalies. Fetal blood parameters, including platelet count and viral load, have shown better predictive value for symptomatic status at birth or the later development of severe brain lesions compared to amniotic fluid CMV DNA load. Additionally, elevated levels of certain pro-inflammatory cytokines in amniotic fluid, such as IP-10, IL-18, ITAC, and TRAIL, are associated with cCMV infection and its severity.

Valacyclovir at a dose of 8 g/day has demonstrated effectiveness in preventing vertical transmission of CMV, especially when primary maternal infection occurs periconceptionally or in the first trimester. A meta-analysis showed that valacyclovir at this dosage can reduce vertical transmission by 70%. Early initiation of treatment is crucial for better efficacy. However, the quality of evidence supporting valacyclovir’s role in reducing the risk of congenital CMV infection and adverse perinatal outcomes has been assessed as very low.

Mild side effects such as nausea or headache have been reported by 21% of women. Mild to moderate acute renal failure, which resolved after discontinuing the drug, was reported in 2% of cases. The Center for Reference on Teratogenic Agents (CRAT) and the French National Agency for Medicines and Health Products Safety (ANSM) state that published data and post-marketing surveillance have not shown any teratogenic or toxic effects for the fetus or newborn.

Behavioral measures are crucial to reduce maternal seroconversion. Pregnant individuals should be educated on hygiene practices such as avoiding kissing toddlers on the mouth, not sharing food or utensils, washing hands after changing diapers, and avoiding contact with infected urine or saliva. This education can significantly lower the risk of maternal infection.

Early gestational age at maternal infection is a primary determinant of postnatal adverse outcomes in fetuses with congenital CMV infection. The risk of adverse fetal effects only exists if fetal infection occurs between 2 months prior concention and up to 12 weeks’ of conception. Sequelae from maternal primary infections are primarily limited to those acquired in the first trimester of pregnancy.

Early diagnosis of potential fetal infection is crucial for mitigating fetal sequelae. Identifying the infection early can reduce parental psychological burden and allow for consideration of interventions to decrease fetal involvement.

Postnatal evaluation is essential because many newborns might be asymptomatic at birth, and clinical anomalies, such as sensorineural hearing loss, may only be diagnosed later when they become permanent. Newborn hearing screening is particularly important, as CMV is a leading cause of hearing loss, which can be progressive and fluctuating. Early identification and intervention for hearing impairment can significantly improve outcomes.

For suspected cCMV infection in neonates, a PCR assay using urine, or saliva samples is recommended over culture, as it is faster and does not require expensive tissue culture. Saliva PCR is highly reliable for newborn screening. Dried blood spots (DBS) can also be used for retrospective diagnosis and assessing viral load.

Antiviral therapy (valganciclovir) is generally reserved for symptomatic neonates with cCMV at birth, characterized by conditions such as microcephaly, intracranial calcifications, abnormal cerebrospinal fluid index, chorioretinitis, or SNHL. For these symptomatic infants, 12 months of oral valganciclovir has shown effectiveness for hearing and neurodevelopmental outcomes. However, there is no evidence of benefit for antiviral therapy in asymptomatic infants. Treatment is not routinely recommended for neonates with mildly symptomatic disease, those born prematurely (under 32 weeks gestational age), or infants older than 30 days due to insufficient evidence.

The fetus becomes infected when the placental barrier fails to contain viral replication, usually within 2-3 months after maternal infection. Placentitis, characterized by a thick and heterogeneous placenta, can be observed. The infected placenta can act as an amplifying reservoir for the virus. CMV infection can also lead to placental insufficiency, which may result in fetal pathologies.

PROBLEMS AND SOLUTIONS

  • Description: An estimated 80% to 95% of pregnant women with a primary CMV infection show no symptoms or only mild, influenza-like symptoms, which means the disease often goes unsuspected and undiagnosed early in gestation.
  • Solution: Perform CMV serology as early as possible in the first trimester, with a retest between 14 and 16 weeks if seronegative, to precisely identify primary infection. Early diagnosis is critical for intervention and prognosis.
  • Description: The presence of IgM antibodies can persist for up to 20 weeks after primary infection, and rapid increases in IgG avidity can lead to false diagnoses of recent infection. This complicates the accurate timing of primary maternal infection, which is crucial for fetal prognosis. Serology and PCR tests are also often misleading for non-primary infections.
  • Solution: Follow current guidelines for CMV serology, including IgG avidity testing. Low avidity (less than 35–50%) indicates recent infection, while high avidity (more than 50–65%) indicates past infection. When the type and timing of maternal infection are unknown, perform serology retrospectively on a stored first-trimester serum, and have serology reviewed by a clinical virologist for accurate timing.
  • Description: While amniocentesis is the gold standard for fetal infection diagnosis, it is an invasive procedure with inherent risks. There is also a reported 8% rate of negative results from amniocentesis and potive in saliva at birth, due to delayed placental transmission or a viral load too low to be detectable.
  • Solution: Perform amniocentesis for PCR CMV DNA detection after 17 weeks of gestation and at least 8 weeks after the presumed date of primary maternal seroconversion. Counselling should include the possibility of false-negative results and the importance of continued monitoring. Newer approaches like chorionic villus sampling (CVS) and cell-free DNA are emerging for earlier diagnosis but require further validation.
  • Description: Prenatal imaging (ultrasound and MRI) findings can be difficult to assess, are not always specific for CMV, and may not appear until after 20 weeks of gestation. Importantly, normal prenatal imaging does not exclude the risk of long-term sequelae, as approximately half of the cases with CMV-associated sequelae did not have abnormal prenatal imaging.
  • Solution: Conduct serial focused fetal ultrasound assessments every two weeks until delivery and perform fetal brain MRI in the third trimester (e.g., at 32 weeks). MRI provides complementary information for assessing cortical and extracortical anomalies crucial for prognosis. For a more comprehensive prognostic assessment, combine targeted ultrasound with amniotic fluid viral load and fetal blood parameters (platelet count and viral load).
  • Description: Randomized controlled trials have consistently shown no benefit of hyperimmune globulin (HIG) in preventing vertical CMV transmission or modifying the course of primary CMV infection during pregnancy. While valacyclovir shows promise in reducing transmission, its direct beneficial effect on the outcome of an already infected fetus is less definitively established.
  • Solution: Do not use hyperimmune globulin (HIG). Instead, administer oral valacyclovir at a dose of 8 g/day as early as possible after diagnosis of primary infection in the periconceptional period or first trimester, and continue until amniocentesis. This treatment has been shown to reduce vertical transmission rates by 70% and neonatal infection rates by 70%, and reduce termination of pregnancy by 80% due to severe fetal findings. Monitor for side effects such as nausea, headache, and acute kidney injury, advising adequate hydration to mitigate renal toxicity.
  • Description: Approximately 10–15% of infants who are asymptomatic at birth will develop long-term sequelae, with sensorineural hearing loss (SNHL) being the most common, which can be progressive and fluctuating. These sequelae often manifest later in life and may be missed by initial clinical examinations.
  • Solution: Ensure close audiological and neurodevelopmental evaluations postnatally, including repeated hearing tests (BERA), physical examinations, and blood tests, even for seemingly asymptomatic infants. Timely interventions are crucial for improving overall outcomes, especially for hearing impairment.
  • Description: Current recommendations for antiviral treatment (valganciclovir/ganciclovir) in newborns are primarily for symptomatic congenital CMV, especially with Central Nervous System (CNS) involvement. There is “no evidence of the benefit of antiviral therapy in asymptomatic infants”, and treatment is not routinely recommended for mildly symptomatic infants or those under 32 weeks gestational age or over 30 days old.
  • Solution: Initiate oral valganciclovir treatment for a duration of 6 months in newborns diagnosed with symptomatic congenital CMV infection, particularly those with CNS involvement or isolated SNHL, within the first month of life. This has been shown to improve audiological and neurodevelopmental outcomes. Closely monitor absolute neutrophil counts (weekly for the first 6 weeks, then monthly) and transaminase levels (monthly) during treatment due to potential side effects.
  • Description: Despite advancements in diagnosis, it remains challenging to precisely determine the extent of fetal disease and predict permanent long-term sequelae. More reliable biomarkers are needed to predict the risk of late-onset sequelae, especially in asymptomatic infants.
  • Solution: Continue research into identifying new prognostic markers in amniotic fluid, such as cytokine profiling (e.g., increased soluble IP-10, IL-18, ITAC, and TRAIL), which have shown associations with fetal infection and its severity. Until more accurate predictors are validated, comprehensive postnatal follow-up, including long-term audiological and neurodevelopmental assessments, is crucial, as clinical anomalies can be diagnosed when sequelae are permanent.

Do’s and Don’ts

  • Do:
    • Perform CMV serology as early as possible in the first trimester, with a retest between 14 and 16 weeks if seronegative, to precisely identify primary infection.
    • Administer oral valacyclovir at a dose of 8 g/day as soon as possible after diagnosis until amniocentesis. Studies have shown that this dosage can reduce vertical CMV transmission by 70% in primary infections acquired periconceptionally or in the first trimester, and decrease neonatal infection rates by 70%. It has also been associated with an 80% reduction in termination of pregnancy due to severe fetal findings.
    • Counsel both parents to avoid contact with body fluids from infected individuals, especially toddlers, from before conception until 14 weeks. This remains a primary prevention strategy.
    • Monitor for potential side effects of valacyclovir, such as nausea and headache (reported by 20% of women), and acute kidney injury (reported in 2.1-3.17%), and advise on adequate hydration to mitigate renal toxicity.
    • Offer amniocentesis after 17 weeks of gestation and at least 8 weeks after the presumed date of primary infection to confirm fetal CMV infection. Amniocentesis is considered the gold standard for fetal diagnosis.
    • If fetal infection is confirmed, plan for serial focused fetal ultrasound assessments and magnetic resonance imaging (MRI) in the third trimester to gather complementary information for prognosis.
  • Don’t:
    • Do not use hyperimmune globulin (HIG) to prevent congenital CMV infection. Randomized controlled trials have not found any benefit in reducing vertical transmission.
    • Do not delay the initiation of valacyclovir treatment as prompt action is crucial for its effectiveness.
  • Do:
    • Continue maternal valacyclovir therapy at 8 g/day until delivery, if the woman agrees and is tolerating the medication. One study indicated this could significantly increase the proportion of asymptomatic neonates at birth.
    • Perform serial focused fetal ultrasound assessments every two weeks until delivery to monitor for any developing anomalies.
    • Conduct a fetal brain MRI in the third trimester (e.g., at 32 weeks) as it provides crucial complementary information for prognosis and to assess for cortical and extracortical anomalies. Severe cerebral abnormalities strongly indicate a poor prognosis.
    • Counsel parents that even with normal ultrasound and MRI, there is still a residual risk (around 17%) of unilateral sensorineural hearing loss (SNHL) and mild neurodevelopmental abnormalities, especially following first-trimester infection.
    • Consider fetal blood sampling at 20 weeks to assess platelet count and CMV DNA level. Fetal thrombocytopenia can be a marker of severe fetal infection, and increased pro-inflammatory cytokines in amniotic fluid are associated with severity.
    • Engage with an expert team to discuss antenatal treatment and management strategies for the confirmed fetal infection.
  • Don’t:
    • Do not provide absolute reassurance of a completely healthy outcome based solely on normal initial imaging findings, as late-onset or subtle issues like SNHL can still manifest.
    • Do not use hyperintense signal white matter (HSWM) as a grading criterion for fetal brain MRI in prenatal counseling; rely on anatomical findings instead.
  • Do:
    • Initiate antiviral treatment, preferably with valganciclovir, within the first month of life. This is critical for improving audiological and neurodevelopmental outcomes.
    • Administer valganciclovir for a duration of 6 months. This longer course has shown improved hearing outcomes at 12 and 24 months and better neurodevelopmental scores at 24 months compared to shorter durations.
    • If the infant cannot take oral medication or in very severe cases, ganciclovir can be used intravenously, but switch to oral valganciclovir as soon as possible.
    • Inform parents about the risks and benefits of antiviral treatment.
    • Discuss the case with a Pediatric Infectious Diseases expert and offer enrollment in the International CCMV Registry.
    • Ensure close audiological and developmental evaluations are conducted, including physical examination, blood tests (full blood count, liver function), hearing tests (otoacoustic emissions/automated auditory brainstem response), fundoscopic examination, and neonatal transcranial ultrasound examination. Brain MRI should be offered for abnormal transcranial ultrasound or clinical findings.
    • Treat chorioretinitis for 6 months, as it is typically associated with other symptoms and/or CNS involvement.
    • Monitor absolute neutrophil counts weekly for the first 6 weeks, then at 8 weeks, and monthly thereafter for the entire treatment duration. Also, monitor transaminase levels monthly.
  • Don’t:
    • Do not delay the initiation of antiviral treatment beyond the first month of life, as its efficacy is time-sensitive.
    • Do not expect antiviral treatment to eliminate CMV shedding completely. Viruria often returns within two weeks after treatment cessation.
    • Do not solely rely on cranial imaging abnormalities as definitive prognostic indicators, as studies have been inconclusive regarding a direct association between imaging abnormalities, symptomatic disease, and hearing loss.
    • Do not perform a lumbar puncture for the diagnosis or assessment of cCMV, even in symptomatic infants.
  • Do:
    • Initiate antiviral treatment, specifically valganciclovir, for 6 months. Treatment is recommended for infants with cCMV and isolated hearing loss.
    • Ensure close audiological and developmental evaluations are performed, with timely interventions. Early identification and intervention for hearing impairment are highly effective.
    • Inform parents about the risks and benefits of the antiviral treatment.
    • Discuss the case with a Pediatric Infectious Diseases expert and offer enrollment in the International CCMV Registry.
    • Monitor absolute neutrophil counts weekly for 6 weeks, then at 8 weeks, and then monthly for the duration of treatment, and transaminase levels monthly.
  • Don’t:
    • Do not assume that an asymptomatic newborn will remain free of long-term sequelae. An estimated 10-15% of asymptomatic infants with cCMV develop long-term sequelae, with hearing loss being the most common.
    • Do not overlook the possibility of progressive and fluctuating SNHL in children with asymptomatic congenital CMV infection.
  • Do:
    • Explain that while the risk of vertical transmission from a non-primary maternal infection (NMPI) is low (likely less than 3.5%), it can still contribute significantly to the overall burden of long-term sequelae in the population due to CMV’s high prevalence.
    • Reinforce education on behavioral interventions to limit CMV exposure, as this remains the primary prevention method. This includes advising both parents to avoid contact with body fluids, particularly from young children.
  • Don’t:
    • Do not rely on routine CMV serology and PCR tests to determine if a woman with pre-existing immunity is at risk for transmitting CMV to her fetus, as these tests are not informative for this specific purpose.
    • Do not routinely recommend anti-HCMV antiviral treatment during pregnancy for non-primary infections, as current studies and routine recommendations primarily apply to primary maternal infections.

Bibliography

Chatzakis C, Shahar-Nissan K, Faure-Bardon V, Picone O, Hadar E, Amir J, Egloff C, Vivanti A, Sotiriadis A, Leruez-Ville M, Ville Y.
The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. An individual patient data meta-analysis. Am J Obstet Gynecol. 2024;230(2):109-117.e2.

Haute Autorité de santé.
Évaluation de la pertinence d’un dépistage systématique de l’infection à cytomégalovirus (CMV) au cours de la grossesse 2025, June 5.

Leruez-Ville M, Foulon I, Pass R, Ville Y.
Cytomegalovirus infection during pregnancy: state of the science. Am J Obstet Gynecol. 2020;223(3):330–349.e1.

Ville Y.
Advocating for cytomegalovirus maternal serologic screening in t he first trimester of pregnancy: if you do not know where you are going, you will wind up somewhere else. American Journal of Obstetrics & Gynecology MFM, Volume 3, Issue 4, 100356

Haute Autorité de santé. Évaluation de la pertinence d’un dépistage systématique de l’infection à cytomégalovirus (CMV) au cours de la grossesse – Annexes. 2025, June 5

Chatzakis C, Sotiriadis A, Dinas K, Ville Y. Neonatal and long-term outcomes of infants with congenital cytomegalovirus infection and negative amniocentesis: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2023;61:158–167.

The study specifically focused on infections acquired during the periconceptional period or the first trimester of pregnancy, as these are the crucial periods associated with a higher risk of serious long-term sequelae for the fetus.

  1. Objective The primary objective of this meta-analysis was to evaluate whether oral valacyclovir, administered at a dose of 8 g/day, could substantially reduce the rate of vertical CMV transmission in pregnant women who had a primary CMV infection periconceptionally or in their first trimester. A secondary objective was to assess the maternal safety profile of this high-dose valacyclovir regimen.
  2. Methods The study was designed as an IPD meta-analysis, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and was registered with the International Prospective Register of Systematic Reviews (CRD42022370458).
  • Study Selection and Inclusion Criteria:
    • Design: Randomized controlled trials (RCTs) and quasi-randomized studies were included.
    • Intervention: Studies had to involve the administration of 8 g/day of oral valacyclovir to pregnant women.
    • Participants: Pregnant women with primary CMV infection acquired periconceptionally or during the first trimester of pregnancy. This specific focus is critical given that the risk of major sequelae is largely limited to maternal infection in the first trimester of pregnancy.
    • Diagnosis of Fetal Infection: Included studies must have performed and reported results from amniocentesis for prenatal diagnosis of congenital CMV (cCMV).
    • No restrictions were placed on publication date or language.
  • Data Sources and Search Strategy: Electronic databases (MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, US registry of clinical trials) and gray literature were searched until March 2023. The search used various combinations of terms related to valacyclovir, secondary prevention, and CMV infection. Two independent reviewers assessed study eligibility and resolved discrepancies through consensus.
  • Data Collection: Anonymized individual patient data were obtained directly from the corresponding authors of eligible studies. This comprehensive data included:
    • Gestational age at maternal primary infection, at treatment initiation, and at amniocentesis.
    • Details of the valacyclovir regimen and duration of treatment.
    • Results of amniocentesis and presence of CMV infection at birth.
    • Information on maternal side effects and termination of pregnancy (TOP) due to CMV-associated severe fetal findings on ultrasound or MRI.
  • Risk of Bias Assessment: The methodological quality of the included studies was rigorously assessed using specific tools: RoB 2 for RCTs and ROBINS-I for non-randomized studies. All three studies included in the meta-analysis were classified as having a low risk of bias.
  • Outcome Measures:
    • Primary Outcome: The rate of vertical transmission of CMV, determined by a positive CMV PCR result in amniotic fluid, collected at or after 17 weeks’ gestation and at least 6 weeks after maternal infection.
    • Secondary Outcomes:
      • Positive CMV infection at birth.
      • Termination of pregnancy due to CMV-associated central nervous system (CNS) findings or multiorgan involvement on prenatal imaging (ultrasound or MRI).
      • Maternal side effects related to valacyclovir administration.
  • Statistical Analysis: A one-stage IPD meta-analysis was employed, using a generalized linear mixed model clustered by individual trials. Subgroup analyses were performed to separately evaluate the effects of valacyclovir for periconceptional versus first-trimester infections.

III. Results The meta-analysis included three studies with a total of 527 pregnant women. Among these, 218 women received valacyclovir (8 g/day), while 309 received placebo or no intervention. The mean maternal age was 32.2 years, and the mean gestational age at seroconversion was 3.68 weeks (0.2 weeks for periconceptional cases and 7.9 weeks for first-trimester cases).

  • Primary Outcome – Vertical Transmission (Amniocentesis):
    • In the placebo/no intervention group, 25.5% (76/298) of amniocenteses were positive for CMV.
    • In the valacyclovir group, only 11.1% (24/217) of amniocenteses were positive for CMV.
    • The adjusted odds ratio (aOR) for valacyclovir treatment was 0.34 (95% CI, 0.18–0.61), indicating a substantial reduction in vertical transmission.
    • Gestational age at the initiation of treatment was a significant predictive factor (OR, 1.28; 95% CI, 1.05–1.57), demonstrating that earlier treatment initiation was associated with lower rates of vertical transmission.
  • Secondary Outcomes:
    • CMV Infection at Birth:
      • In the placebo/no intervention group, 41.1% (90/219) of neonates tested positive for CMV at birth.
      • In the valacyclovir group, 19.2% (34/177) of neonates tested positive for CMV at birth.
      • The aOR for valacyclovir treatment was 0.30 (95% CI, 0.19–0.47).
    • Maternal Side Effects:
      • Among 139 women who received valacyclovir, 20.8% reported nausea and 20.8% reported headache.
      • Acute kidney injury occurred in 2.1% (3 women), which resolved upon treatment cessation.
      • The overall prevalence of severe side effects was notably low at 2.1%.
    • Termination of Pregnancy (TOP) due to Severe Fetal Findings:
      • In the placebo/no intervention group, 4.5% (14/309) of women terminated their pregnancies due to severe CMV-associated fetal findings.
      • In the valacyclovir group, only 0.9% (2/218) terminated their pregnancies for these reasons.
      • The aOR for valacyclovir treatment was 0.23 (95% CI, 0.22–0.24), indicating a significant reduction in TOP due to severe fetal findings.
  • Subgroup Analyses (Periconceptional vs. First-Trimester Infection):
    • Periconceptional Infection: Valacyclovir significantly reduced positive amniocentesis rates (14.6% vs. 6.5%; aOR, 0.34) and neonatal infection rates (22.9% vs. 9.5%; aOR, 0.30). The impact on TOP for severe findings was not statistically significant in this subgroup (1.9% vs. 1.6%; aOR, 0.62).
    • First-Trimester Infection: Valacyclovir significantly reduced positive amniocentesis rates (36.7% vs. 17.0%; aOR, 0.35) and neonatal infection rates (57.9% vs. 30.5%; aOR, 0.30). Notably, none of the 94 women in the valacyclovir group terminated their pregnancy due to severe fetal findings, compared to 7.1% in the control group (aOR, 0.55).
  1. Discussion and Conclusion This IPD meta-analysis provides compelling evidence that oral valacyclovir at a dose of 8 g/day is highly effective in the secondary prevention of congenital CMV infection following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. The study demonstrates a significant reduction in both vertical transmission rates (as assessed by amniocentesis and neonatal positivity) and the incidence of terminations of pregnancy due to severe fetal manifestations of CMV.

The findings underscore the critical importance of early initiation of valacyclovir treatment, as earlier intervention was consistently associated with better preventative outcomes. This reinforces the recommendation for early maternal CMV serology in pregnancy. The observed side effects were mostly mild (nausea, headache) or, in the case of acute kidney injury (2.1%), resolvable, confirming the overall safety profile of high-dose valacyclovir for mothers. The authors also highlight that discontinuing valacyclovir after a negative amniocentesis is a safe practice, as late fetal infections (those occurring after the first trimester, post-amniocentesis) are not associated with long-term sequelae.

The strength of this study lies in its design as an IPD meta-analysis, utilizing data exclusively from randomized or quasi-randomized trials classified as low risk of bias. This approach allowed for robust statistical power to detect effects even for less common events like severe side effects, and to account for confounding factors such as the timing of treatment initiation. This study’s findings are a significant contribution to evidence-based counseling and management strategies for pregnancies complicated by primary CMV infection, particularly given the substantial burden of congenital CMV infection and its potential for serious long-term effects on children.

The DGS specifically sought clarification on the clinical benefit (SMR) distinction across trimesters, the role of valaciclovir, and identification of specific at-risk sub-populations (e.g., young mothers with first young child).

Context and Disease Burden

CMV is a common DNA virus, with humans as its reservoir, transmitted through various bodily fluids. While often asymptomatic or causing mild symptoms in infected individuals, primary CMV infection (PIM) acquired in utero can lead to severe sequelae in newborns, including hearing impairment and neurodevelopmental delays. In France, these severe complications affect approximately 1 to 6 newborns per 100,000 births annually. The risk of vertical transmission is estimated at 21% during the periconceptional period and 36.8% in the first trimester. About 90% of newborns with congenital CMV (cCMV) are asymptomatic at birth, but 10% may develop sequelae, mainly hearing loss, within the first six years.

Historically, French public health recommendations, from ANAES (2004) to HCSP (2018, 2023), did not recommend systematic CMV screening during pregnancy. This stance was based on the lack of proven efficacy of antiviral treatments to prevent mother-to-fetus transmission or sequelae, and an unfavorable benefit-risk ratio. However, evolving scientific knowledge, increasing clinical practice diffusion of screening and treatment, and societal expectations prompted this re-evaluation.

Therapeutic and Screening Landscape

Currently, no antiviral medication holds marketing authorization (AMM) specifically for preventing PIM during pregnancy. Despite this, valaciclovir is increasingly used in clinical practice for this indication. The French Centre de Référence sur les Agents Tératogènes (CRAT) notes that extensive data exist on valaciclovir use in the second and third trimesters for curative treatment, and no teratogenic effect has been identified for first-trimester exposure, regardless of dosage. High-dose valaciclovir (8 g/day) necessitates adequate hydration and monitoring of maternal renal function to prevent acute kidney injury, which can be mitigated by splitting the daily dose into four administrations.

Internationally, systematic CMV screening for pregnant women does not have a global consensus. As of June 2025, Italy, Greece, and Israel are the only countries that recommend systematic screening with subsequent valaciclovir treatment for positive cases. Other countries, such as Australia, Canada, the United Kingdom, and Germany, either propose targeted screening or do not recommend systematic screening. The lack of consensus often stems from persistent uncertainties regarding valaciclovir’s efficacy in preventing fetal transmission and the long-term safety of the fetus.

HAS Evaluation Methodology

The HAS’s evaluation employed a multidimensional approach:

  • Analysis of the HCSP 2023 report: Identified areas needing updating, especially on valaciclovir efficacy and ethical considerations.
  • International recommendations panorama: Reviewed global screening practices.
  • Diagnostic test performance: Evaluated the reliability of serological tests (IgG, IgM, avidity).
  • Efficacy of preventive hygiene measures: Assessed interventions to prevent maternal PIM.
  • Re-evaluation of valaciclovir efficacy and safety: Focused on studies published after 2020, including a meta-analysis using a sophisticated hierarchical normal-normal model (NNHM) to combine randomized and observational data. This model aims to rigorously integrate external data, providing a robust estimate. Maternal safety data was also collected from national databases (BDM, CRAT).
  • Economic evaluation: Assessed cost-effectiveness of screening and treatment strategies based on recent studies.
  • Analysis of French practices: Utilized national health data (SNDS) for 2022-2023 to map CMV serology testing and valaciclovir prescription patterns.
  • Ethical analysis: Explored ethical considerations using the four principles of Beauchamp and Childress (beneficence, non-maleficence, autonomy, and justice).
  • Stakeholder consultation: Engaged patient associations, professional bodies, and experts for their perspectives.

Key Findings of the Evaluation

  1. Valaciclovir Efficacy: While valaciclovir lacks AMM, HAS’s re-analysis, using a robust statistical method combining the Shahar-Nissan randomized trial with four observational studies, demonstrated a significant effect of valaciclovir (8g/day) in reducing vertical transmission of CMV (Odds Ratio between 0.33 and 0.39). This finding is considered robust. However, the long-term safety and effects on fetal/newborn complications (frequency and severity) remain uncertain and require large-scale, robust studies.
  2. Valaciclovir Safety: Data from 2007-2023 on approximately 970 treated pregnant women shows no signal of teratogenicity. Maternal tolerance is generally good, though high doses require monitoring for acute renal insufficiency, which is usually reversible.
  3. French Practices: An analysis of SNDS data revealed a progressive increase and diffusion of valaciclovir prescriptions for CMV during pregnancy between 2022 and 2023, with 79% of initial prescriptions made by hospital physicians. There is significant regional heterogeneity, with higher rates in Île-de-France and Pays de la Loire. Approximately one-third of pregnancies are currently undergoing CMV screening in France. These practices are currently outside of regulated frameworks (AMM or compassionate use authorization).
  4. Medico-Economic Aspects: A recent French study (Perillaud-Dubois et al., 2023) suggests a benefit from systematic screening, but international studies are more nuanced. HAS noted that current models have limitations, such as not fully capturing the temporal dimension of events and the long-term costs of sequelae. While systematic screening might have significant initial costs, it could be economically relevant in the long term by reducing expenses related to congenital CMV complications.
  5. Ethical Considerations: The ethical analysis, based on Beauchamp and Childress’s principles, highlighted several issues. Key concerns include ensuring informed consent due to inherent uncertainties regarding the unpredictable outcomes of mother-to-fetus transmission and unknown long-term effects of valaciclovir. There is also a risk of “routinization” of screening, potentially leading to pregnant women delegating their autonomy to healthcare providers. The HAS emphasizes the need for transparent and comprehensive information to allow informed decision-making.
  6. Stakeholder Views: Patient associations were largely favorable to systematic screening, provided clear information is given and healthcare professionals are adequately trained. The Fondation pour l’audition, for instance, strongly advocated for screening due to CMV being a leading non-genetic cause of congenital deafness. Professional bodies, like the CNP-MIT, expressed that it seems reasonable to offer valaciclovir, but stressed the need for further research to address remaining uncertainties. Experts debated the HCSP’s previous conclusions, with some advocating strongly for systematic screening.

HAS Recommendation

Based on its comprehensive evaluation, the HAS made the following recommendation: The HAS recommends implementing a systematic national screening program for CMV infection for all pregnant women whose serological status is negative or unknown. This measure will be re-evaluated after three years of implementation to assess its relevance and consider its continuation.

The HAS also emphasizes the need for further studies to address persistent uncertainties concerning:

  • National epidemiological data (maternal seroprevalence, frequency, and severity of neonatal and childhood complications).
  • Long-term safety of valaciclovir on a larger scale.
  • The effect of valaciclovir on fetal/newborn infections (frequency and severity of complications).
  • The overall performance of the test sequence (IgG, IgM, IgG avidity).

The recommendation also acknowledges the expected increase in amniocenteses and associated risks following systematic screening. It underscores the importance of transparent and comprehensive information for pregnant women regarding the benefits, risks, and remaining uncertainties of screening.

The authors highlight cCMV as the most common congenital infection and the leading non-genetic cause of sensorineural hearing loss (SNHL) and neurological damage, emphasizing its significant public health burden. It accounts for up to 10% of all cerebral palsy cases and 8-21% of all congenital SNHL at birth, with this increasing to 25% by age four due to late-onset hearing loss.

Epidemiology and Transmission: CMV is ubiquitous, with seroprevalence in women of childbearing age ranging from 50% to 85% in Western Europe and the United States, increasing with age and lower socioeconomic status. Primary maternal infection (MPI) during pregnancy occurs in approximately 1-2% of pregnancies in these regions. Risk factors for MPI include being young and having at least one child, particularly toddlers who shed the virus for prolonged periods. Women seronegative at their first pregnancy and conceiving within two years face a significantly higher risk of MPI and related sequelae in subsequent infants.

The transplacental transmission rate after MPI is around 32%. While early reports suggested increased transmission with advancing gestation (26% in first, 28% in second, 65% in third trimester), long-term sequelae are primarily limited to maternal infections acquired in the first trimester. Infections occurring in the second or third trimester have not been reported to cause long-term sequelae in over 100 children in large studies. Maternal non-primary infection (MNPI) also contributes to cCMV burden, accounting for approximately 48-90% of cases in some settings, and can also lead to sequelae, though the risk of vertical transmission is generally lower compared to MPI (likely <3.5%).

Clinical Outcomes and Prognosis: About 20% of infected neonates experience neurodevelopmental impairment or permanent sequelae. Symptomatic neonates at birth, constituting about 10% of infected infants, have a higher risk of sequelae (40-58%), while even initially asymptomatic neonates face a 13.5% risk, mainly SNHL. The spectrum of disease, including hearing loss, is similar after MPI and MNPI. The critical prognostic factor is the gestational age at maternal infection, with long-term sequelae almost exclusively associated with first-trimester infections. Severe brain involvement detected early in pregnancy typically leads to a poor prognosis. Children with isolated SNHL are now recognized as symptomatic. Subtler problems in language development, concentration, and quality of life may also manifest at school age.

Diagnosis:

  • Maternal: Serological testing (IgG and IgM) is crucial, especially before 14 weeks of gestation, to identify MPI around conception. IgG avidity testing helps differentiate acute (low avidity, within 3 months) from past infections (high avidity). However, serology is not useful for women already immune before pregnancy.
  • Fetal: CMV DNA detection in amniotic fluid (AF) via PCR is the gold standard for prenatal diagnosis, as infected fetuses excrete the virus in urine. Amniocentesis is typically performed from 17 weeks gestation, at least 6-8 weeks after documented maternal seroconversion. Prenatal ultrasound and MRI are used to identify fetal abnormalities, which can range from subtle to severe, particularly in the brain. While ultrasound’s sensitivity for predicting neonatal symptoms is around 25%, serial targeted ultrasound and MRI in known infected fetuses have a >95% sensitivity for brain anomalies. Nevertheless, a normal ultrasound or non-severe findings at diagnosis can still miss cases that develop severe symptoms later in pregnancy (around 7% uncertainty). Fetal blood analysis, specifically platelet count and viral load, significantly enhances prognostic accuracy. A combination of ultrasound and fetal blood parameters can increase the negative predictive value for any symptoms at birth to 100%.
  • Neonatal: CMV PCR on saliva or urine collected within 3 weeks of birth is the recommended method for neonatal diagnosis. IgM testing in neonates has low sensitivity and is not recommended for diagnosis.

Pathophysiology and Neuropathogenesis: CMV causes neurodevelopmental sequelae, including mental retardation, cerebral palsy, and SNHL. The virus is neuropathic, preferentially infecting neural stem cells, which can inhibit their differentiation into neurons and astrocytes, potentially leading to structural and migratory abnormalities in the developing brain. Extensive necrosis in severely affected brains is associated with viral inclusions and inflammatory infiltrates. CMV infection of placental cells can also contribute to pathogenesis by altering placental formation, potentially leading to placental insufficiency, intrauterine growth restriction, and other fetal outcomes. Animal models, particularly guinea pig and rhesus macaque, are critical for understanding disease mechanisms and testing interventions, as their fetal infection pathogenesis closely mimics human cCMV.

Interventions and Management:

  • Primary Prevention:
    • Hygienic Measures: Avoiding contact with body fluids (saliva, urine, tears) from infected individuals, especially toddlers, from preconception until 14 weeks of gestation is recommended. Educational interventions, such as films and brochures, have improved hygiene adherence among pregnant women.
    • Screening: The article highlights that most European countries do not have routine serology screening in pregnancy, but there is an increasing recognition of its relevance, with some studies showing it to be cost-effective, especially when combined with valacyclovir treatment. Systematic maternal CMV serology in the first trimester is recommended as sequelae are limited to infections acquired during this period. Early serology allows for retesting seronegative women every 4 weeks until 14-16 weeks.
    • Vaccines: Several vaccine candidates are in early-phase clinical trials, including enveloped virus-like particle (eVLP) vaccines and mRNA vaccines expressing CMV gB and pentameric complex. These aim to prevent maternal and congenital CMV infection.
  • Secondary Prevention (to prevent vertical transmission after maternal infection):
    • Valacyclovir: Oral valacyclovir (8 g/day) administered as early as possible after diagnosis of MPI in the periconceptional period or first trimester, and continued until amniocentesis, significantly reduces vertical transmission rates. A meta-analysis confirmed a 70% reduction in vertical transmission and neonatal infection rates, with earlier treatment initiation being more effective. Side effects are minimal, primarily nausea, headache, and rarely, reversible acute kidney injury. Cessation of treatment after a negative amniocentesis is safe, as a negative PCR ensures absence of long-term sequelae.
    • Hyperimmune Globulin (HIG): Two randomized controlled trials did not find a benefit for intravenous HIG (100 IU/kg monthly) in preventing vertical transmission. However, a case-control study suggested possible benefit with higher doses (200 IU/kg biweekly) for very recent first-trimester infections, but this needs further confirmation. The European Congenital Infection Initiative (ECCI) recommends against HIG administration at doses of 100 IU/kg every 4 weeks.
  • Antenatal Treatment (for infected fetus):
    • Valacyclovir: A phase II open-label study demonstrated that oral valacyclovir (8 g/day) given to pregnant women with a moderately symptomatic infected fetus was associated with a significantly higher proportion of asymptomatic neonates (82%) compared to an untreated historical cohort (43%). Fetal blood viral loads decreased and platelet counts increased significantly with treatment. This dosage was well tolerated with high adherence. For women with confirmed fetal infection, discussion with an expert team regarding antenatal valacyclovir treatment (8g/day) may be considered.
  • Neonatal Treatment (for symptomatic neonates):
    • Valganciclovir/Ganciclovir: For newborns with significant CMV-related symptoms at birth, including CNS involvement or isolated SNHL, antiviral treatment with valganciclovir (or ganciclovir if enteral medication is not possible) is recommended for 6 months. Treatment should start as soon as possible, ideally before one month of age, though starting between 1-3 months may also be beneficial. Treatment is likely to improve hearing and neurological symptoms. Six weeks of treatment is recommended for isolated persistent thrombocytopenia. Routine treatment for isolated intrauterine growth restriction (IUGR) is not recommended.

Conclusion: The article concludes that cCMV infection presents a major public health challenge. Given the advancements in diagnosis and pre- and postnatal management, the authors advocate for reevaluating screening programs in early pregnancy and at birth to allow for earlier and more informed decision-making regarding prevention and treatment strategies.

The editorial highlights several key areas where medical advancements have provided tools to combat cCMV:

  • Prevention of Vertical Transmission: Ville asserts that maternal treatment with oral valacyclovir at a dosage of 8 grams per day (8 g/d), when administered early in the fetal period, has been shown to decrease vertical transmission by 70%. This intervention, he suggests, “should be implemented as early as possible after maternal infection”. The rationale for this dosage, according to this and other sources, stems from its established effectiveness in preventing CMV disease in CMV-negative renal transplant patients receiving CMV-positive grafts, viewing the fetus as a host and the mother as a graft.
  • Reliable Diagnostic Tools: The editorial emphasizes the availability of reliable prenatal diagnostic tests. Amniocentesis with PCR amplification of viral DNA in the amniotic fluid is presented as a “reliable diagnostic test”. Furthermore, chorionic villus sampling (CVS) is mentioned as an alternative that could offer the same diagnostic performance “2 months earlier”. These facilities, including laboratory and fetal medicine networks, are stated to be “available in high- and middle-income countries”.
  • Treatment of Infected Fetuses: Beyond preventing transmission, Ville points to progress in treating already infected fetuses. He states that “prenatal treatment of infected fetuses decreases the occurrence of symptoms at birth and at 2 years of age“. This suggests a capacity to mitigate the severity of outcomes for infants found to be infected prenatally.
  • Cost-Effectiveness Considerations: While advocating for universal screening, Ville acknowledges that “the cost effectiveness of CMV serology screening in pregnancy should be modeled in each country”. This implicitly recognizes that economic considerations are a factor in implementing widespread screening programs.

However, despite Ville’s strong advocacy and the described medical progress, other sources provide crucial context and express significant caution regarding a generalized approach. The French Haut Conseil de la Santé Publique (HCSP), in its December 2023 report, explicitly maintains its recommendation against systematic CMV screening during pregnancy. This is primarily due to several unknowns, including the “unknown efficacy and risks of prolonged high-dose valacyclovir treatment on fetal outcomes”. The HCSP notes methodological weaknesses in key randomized trials, such as Shahar-Nissan et al. (2020), arguing that the primary outcome of vertical transmission might not be the most pertinent, as the critical concern is the prevention of severe neuro-sensory sequelae in the child, for which data are still lacking. Concerns about maternal acute kidney injury (AKI), particularly with the 4g/12h valacyclovir regimen, have also been raised. The HCSP concludes that available data “do not allow a conclusion of a favorable benefit-risk ratio” for CMV screening in pregnant women compared to current management. Furthermore, no country currently recommends generalized CMV screening for pregnant women. The HCSP also emphasizes that current treatments lack sufficient evidence of efficacy and safety for widespread use in a screening program. Even the Leruez-Ville et al. (2020) review, co-authored by Y. Ville, while noting valacyclovir’s effect on fetal viremia and asymptomatic outcomes in a phase II study, stated that “a higher level of evidence is required” for its efficacy.

In conclusion, Ville’s editorial forcefully advocates for the immediate adoption of comprehensive CMV prenatal management, asserting that the existing tools are sufficient to make a significant difference. He believes that waiting for absolute certainty would mean perpetual inaction. However, this optimistic view is tempered by the more cautious and evidence-demanding stance of health authorities like the HCSP, who argue that the current body of evidence does not yet support universal screening due to persistent uncertainties regarding long-term efficacy on severe outcomes and the safety profile of high-dose valacyclovir for both mother and fetus.

Context and Public Health Burden of CMV

CMV is a ubiquitous DNA virus, with humans as its sole reservoir, primarily transmitted through bodily fluids. While often asymptomatic or leading to mild symptoms in adults, primary CMV infection (PIM) acquired during pregnancy can lead to severe sequelae in newborns, including hearing impairment and neurodevelopmental delays. Approximately 90% of newborns with congenital CMV (cCMV) are asymptomatic at birth, but about 10% of these will develop complications, mainly hearing loss, within the first six years of life. In France, serious complications affect 1 to 6 newborns per 100,000 births annually. The risk of vertical transmission is estimated at 21% during the periconceptional period and 36.8% in the first trimester. Despite the potential severity of individual cases, the overall population impact was previously considered modest.

Historically, French public health bodies, including ANAES (2004) and HCSP (2018, 2023), did not recommend systematic CMV screening during pregnancy. This stance was based on the lack of proven efficacy of antiviral treatments to prevent mother-to-fetus transmission or sequelae, and a perceived unfavorable benefit-risk ratio. However, the landscape has evolved with new research, increasing clinical adoption of screening and treatment, and growing societal demand for intervention.

Comprehensive Evaluation Methodology

The HAS’s evaluation employed a multidimensional approach, meticulously detailed across these annexes:

  • Analysis of the HCSP 2023 Report: This involved a qualitative analysis of the HCSP’s work, verifying its conformity with HAS and WHO methodological standards for screening program evaluation and identifying areas needing update, particularly on valaciclovir efficacy.
  • Panorama of International Recommendations: A review of national and professional guidelines published between 2020 and 2025 was conducted to identify global CMV screening practices and their reliance on the Shahar-Nissan trial findings.
  • Diagnostic Test Performance: Evaluation of the reliability of serological tests (IgG, IgM, avidity) and interpretation algorithms.
  • Efficacy of Preventive Hygiene Measures: A systematic review assessed interventions aimed at preventing maternal PIM.
  • Re-evaluation of Valaciclovir Efficacy and Safety: This was a major component, focusing on studies published after 2020. A key aspect was a Bayesian meta-analysis using a hierarchical normal-normal model (NNHM) (developed by Röver and Friede in 2020) to rigorously integrate data from randomized and observational studies. Maternal safety data was also collected from national databases (BDM, CRAT).
  • Economic Evaluation: Assessed the cost-effectiveness of screening and treatment strategies based on recent studies, including a specific French study.
  • Analysis of French Practices: Utilized national health data (SNDS) for 2022-2023 to map CMV serology testing and valaciclovir prescription patterns across regions and prescribers.
  • Ethical Analysis: Explored ethical considerations using the four principles of Beauchamp and Childress (beneficence, non-maleficence, autonomy, and justice).
  • Stakeholder Consultation: Engaged patient associations, professional bodies, and experts to gather their perspectives.

Key Findings Detailed in the Annexes

  1. Valaciclovir Efficacy: While valaciclovir lacks specific marketing authorization (AMM) for preventing PIM during pregnancy, HAS’s re-analysis, employing a robust statistical method that combined the Shahar-Nissan randomized trial with four observational studies (Faure-Bardon et al., Egloff et al., Amir et al., Zammarchi et al.), demonstrated a significant effect of valaciclovir (8g/day) in reducing vertical transmission of CMV. The odds ratio (OR) was consistently estimated between 33 and 0.39, indicating a substantial reduction in transmission risk. This finding is considered robust due to the sophisticated statistical modeling used. However, the long-term safety and effects on fetal/newborn complications (frequency and severity) remain uncertain and require large-scale, robust studies.
  2. Valaciclovir Safety: Data from 2007-2023, encompassing approximately 970 treated pregnant women in France, showed no signal of teratogenicity. Maternal tolerance is generally good, although high doses necessitate monitoring for acute renal insufficiency, which is usually reversible.
  3. French Practices: An analysis of SNDS data revealed a progressive increase in valaciclovir prescriptions for CMV during pregnancy between 2022 and 2023, with 79% of initial prescriptions made by hospital physicians. There is significant regional heterogeneity in prescription rates, with higher usage observed in Île-de-France and Pays de la Loire. CMV serology testing is also widespread, with approximately one-third of pregnancies undergoing such screening in France. These practices currently operate outside of a regulated framework (AMM or compassionate use authorization).
  4. Medico-Economic Aspects: While a recent French study (Périllaud-Dubois et al., 2023) suggests a benefit from systematic screening, international studies are more nuanced and models often have limitations, such as not fully capturing the temporal dimension of events or the long-term costs of sequelae. The annexes note that current economic models have not reached a consensus on the cost-effectiveness of systematic screening, but acknowledge that while it might incur significant initial costs, it could be economically relevant in the long term by reducing expenses related to congenital CMV complications.
  5. Ethical Considerations: The ethical analysis, based on Beauchamp and Childress’s principles, highlighted the importance of informed consent due to inherent uncertainties regarding unpredictable outcomes of mother-to-fetus transmission and unknown long-term effects of valaciclovir. There is a risk of “routinization” of screening, potentially leading to pregnant women delegating their autonomy to healthcare providers. The annexes emphasize the need for transparent and comprehensive information to allow informed decision-making.
  6. Stakeholder Views: Patient associations were largely favorable to systematic screening, provided clear information is given and healthcare professionals are adequately trained. The Fondation pour l’audition, for example, strongly advocated for screening due to CMV being a leading non-genetic cause of congenital deafness. Professional bodies, like the CNP-MIT, expressed that it seems reasonable to offer valaciclovir but stressed the need for further research to address remaining uncertainties. Experts debated previous conclusions, with some advocating strongly for systematic screening.

HAS Recommendation (as supported by the annexes)

Based on its comprehensive evaluation, the HAS recommends:

  • Implementing a systematic national screening program for CMV infection for all pregnant women whose serological status is negative or unknown.
  • This measure will be re-evaluated after three years of implementation to assess its relevance and consider its continuation.

The HAS also explicitly calls for further studies to address persistent uncertainties concerning:

  • National epidemiological data (maternal seroprevalence, frequency, and severity of neonatal and childhood complications).
  • Long-term safety of valaciclovir on a larger scale.
  • The effect of valaciclovir on fetal/newborn infections (frequency and severity of complications).
  • The overall performance of the test sequence (IgG, IgM, avidity IgG).

The recommendation also acknowledges the expected increase in amniocenteses and associated risks following systematic screening. It underscores the critical importance of transparent and comprehensive information for pregnant women regarding the benefits, risks, and remaining uncertainties of screening, ensuring their informed choice.

The Enduring Burden of Congenital Cytomegalovirus Infection: The letter emphasizes that cCMV is the leading cause of congenital infection globally, affecting approximately 0.5–2% of all live births worldwide. It is also recognized as the primary non-genetic cause of sensorineural hearing loss (SNHL), accounting for about one-third of congenital hearing loss cases and 8–21% of all congenital SNHL at birth, a figure that increases to 25% by the age of four due to late-onset hearing loss. Beyond auditory impairments, cCMV is a major cause of neurological damage, contributing to up to 10% of all cerebral palsy cases.

The severity of cCMV infection is highly variable, ranging from asymptomatic presentations to severe neurological disabilities or even perinatal death. Sequelae, including neurodevelopmental impairment, are almost exclusively linked to maternal primary infections (MPI) acquired before 14 weeks of gestation. Around 20–30% of children exposed in utero following maternal seroconversion in early pregnancy will develop neurological sequelae. Specifically, about 30% of newborns are symptomatic at birth, with 10–15% experiencing SNHL and 10–25% suffering more severe neurological damage, including intellectual disability or developmental delay. Even in neonates who appear asymptomatic at birth, there remains a significant risk of long-term sequelae, estimated at around 13.5%, primarily due to progressive hearing loss. The cumulative impact is substantial, with an estimated 30,000 cases resulting in related disabilities annually in the United States and a similar number in the European Union, alongside overall mortality and sequelae rates of 0.5% and 17–20%, respectively. A critical point highlighted is that cCMV is the only congenital infection whose worldwide prevalence has not decreased over the past 60 years. Furthermore, primary CMV infection poses a particular risk to seronegative women who have a child aged 2–3 years, with infection rates reaching up to 10% in this demographic.

Current Management Practices and Identified Gaps: The authors note that while the potential severity of primary maternal infection in early pregnancy is well-established, practical challenges render primary prevention measures, such as hygiene counseling, less effective, particularly if initiated late in pregnancy (e.g., at 11–12 weeks) when crucial windows of vulnerability have already passed. Currently, prenatal diagnosis of cCMV in France involves amniocentesis for CMV genome PCR, performed either after documented maternal seroconversion or when suggestive fetal abnormalities are observed on routine ultrasound examinations. These suggestive findings include intrauterine growth restriction, microcephaly, echogenic bowel, hepatosplenomegaly, placentomegaly, oligohydramnios or polyhydramnios, and various cerebral anomalies such as ventriculomegaly, abnormal midline structures, or posterior fossa and cerebellar abnormalities. Amniocentesis is typically recommended at or after 21 weeks of gestation, and at least 6 weeks following the presumed date of maternal primary infection, though recent studies suggest reliability from 17 weeks if performed at least 8 weeks post-MPI. A negative CMV PCR result in amniotic fluid following a timely amniocentesis generally assures the absence of long-term sequelae.

However, the authors point out significant limitations in the current approach:

  • Lack of Universal Screening: While Italy and Greece have implemented universal serological screening for CMV in early pregnancy based on expert recommendations, France and most other European countries have not, though the issue is currently under scrutiny.
  • Limited Prognostic Information: The number of pregnancy terminations related to fetal CMV infection has remained stable and notably low before 20 weeks of gestation, a period when only fetal CMV infection status is available without comprehensive prognostic information. This uncertainty hinders informed parental decision-making regarding potential pregnancy termination, even when severe fetal findings are identified later.
  • Incomplete Protection and Awareness: Serological testing is not informative for women who are already immune before pregnancy. Moreover, the fact that only about 10% of infected fetuses are symptomatic at birth complicates early prognosis and decisions regarding prenatal treatment. Crucially, normal prenatal imaging findings (ultrasound or MRI) do not rule out the development of SNHL and minor neurodevelopmental abnormalities in children born with cCMV.

Arguments for Universal Screening and Early Intervention: The letter strongly advocates for universal screening based on several key arguments:

  • Empowering Pregnant Women and Ensuring Equity: Universal screening would address the current disparity where many women are unaware of their CMV risk, thus empowering them to make informed decisions. It would uphold the principle of horizontal equity, ensuring that all pregnant women receive equal access to information about severe fetal CMV, allowing them to consider pregnancy termination if permitted by national laws.
  • Efficacy of Valacyclovir in Secondary Prevention: The emergence of effective antiviral treatment, specifically valacyclovir, for secondary prevention of vertical transmission strengthens the case for early screening.
    • Recent randomized controlled trials and quasi-randomized studies have demonstrated that oral valacyclovir at a dose of 8 g/day significantly reduces the vertical transmission rate of CMV by 70–71% in women with primary CMV infection acquired periconceptionally or during the first trimester of pregnancy. This reduction is observed for both periconceptional and first-trimester infections.
    • The meta-analysis cited indicates that valacyclovir also reduces the rate of neonatal infection (adjusted odds ratio, 0.30).
    • Significantly, valacyclovir treatment has been shown to reduce the rate of termination of pregnancy due to CMV-associated severe fetal findings by 77% (adjusted odds ratio, 0.23).
    • The efficacy of treatment is highly dependent on early initiation, with earlier commencement leading to better prevention outcomes.
    • Prior research, including a phase II study, supported these findings, demonstrating that high-dose valacyclovir administered to women with moderately symptomatic infected fetuses increased the proportion of asymptomatic neonates from 43% in an untreated historical cohort to 82% in the treated group. This study also indicated that fetal blood viral loads decreased and platelet counts increased significantly between treatment initiation and birth, suggesting a direct antiviral effect.
  • Favorable Safety Profile and Adherence: High-dose valacyclovir (8 g/day) has demonstrated an exceptionally good safety profile for mothers, with minimal side effects such as nausea or headache (reported in about 20% of women) and rare instances of mild to moderate acute kidney injury (2.1%), which typically resolved upon treatment cessation. The risk of acute kidney injury can be further mitigated by fragmenting the daily administration (e.g., 2g four times daily) and ensuring adequate hydration. Despite the high pill burden (16 pills a day), adherence to treatment was consistently high (>90%).
  • Cost-Effectiveness: Research has demonstrated that universal screening for first-trimester CMV infection is cost-effective and even cost-saving when combined with timely valacyclovir treatment.

Conclusion and Call to Action: In summary, the authors assert that the scientific understanding of cCMV has significantly advanced, particularly regarding the efficacy of antiviral treatment in preventing vertical transmission following primary maternal infection. They advocate that the benefits of early and accurate maternal diagnosis through serological tests, combined with the proven efficacy and safety of valacyclovir, are compelling enough to warrant a shift towards universal CMV screening in early pregnancy. This would not only enhance risk management and prevention strategies but also allow for refined personalized postnatal care based on risk assessments, ensuring targeted interventions for affected families. The letter serves as a crucial call to action for public health authorities and healthcare professionals to re-evaluate existing screening policies and implement a more proactive approach to mitigate the severe consequences of congenital CMV infection.

Podcast

Fictional clinical cases

Clinical Scenario: Ms. Evelyn R., a 28-year-old primigravida, is at 8 weeks of gestation. She reports a mild, flu-like illness (fatigue, low-grade fever) about 3 weeks ago, after her 2-year-old nephew developed a similar illness. She has no prior known history of CMV infection.

Risks:

  • Primary CMV infection (PIM) acquired peri-conceptionally or in the first trimester carries a significant risk of severe abnormalities in fetal development, known as congenital CMV (cCMV).
  • The risk of sequelae exists when maternal infection occurs before 14 weeks of gestation, with an estimated risk of 51-57% for fetuses infected during the first trimester.
  • CMV is the most common non-genetic cause of fetal sensorineural hearing loss (SNHL).

Prenatal Diagnosis:

  • Maternal serum testing is crucial to confirm and date the suspected primary infection. This includes testing for CMV IgG and IgM antibodies, along with an IgG avidity test.
  • A low IgG avidity would indicate a recent primary infection, confirming the suspicion.
  • If a primary infection is confirmed, amniocentesis is the gold standard for diagnosing fetal infection. It should be performed at least 8 weeks after the presumed date of maternal seroconversion and typically at 17 weeks of gestation. Early initiation of valacyclovir treatment is crucial.

Management:

  • Given the suspected primary infection in the first trimester, oral valacyclovir at a dose of 8 g/day (preferably 2g four times daily) should be considered and initiated as early as possible and continued until the amniocentesis. Studies show valacyclovir significantly reduces the vertical transmission rate of CMV following primary maternal infection acquired in the periconceptional period or first trimester.
  • Ms. R. should receive hygiene counseling to reduce the risk of further CMV exposure, such as avoiding contact with the body fluids of young children, particularly saliva and urine.
  • Plan for serial prenatal ultrasound scans and, if fetal infection is confirmed, a fetal magnetic resonance imaging (MRI) at around 32-33 weeks’ gestation, or earlier if abnormalities are suspected.

Clinical Scenario: Mrs. David S., 30 years old, presents at 10 weeks of gestation with confirmed primary CMV infection (recent seroconversion with low IgG avidity). She experienced significant maternal symptoms, including prolonged fever and lymphadenopathy.

Risks:

  • Primary CMV infection during the first trimester carries a high risk of vertical transmission (around 36.8%) and severe fetal consequences.

Prenatal Diagnosis:

  • Confirming the primary maternal infection with IgG, IgM, and avidity testing is crucial.
  • Once the maternal infection is confirmed and appropriately timed, amniocentesis is indicated to diagnose fetal infection, typically performed at 17 weeks of gestation and at least 8 weeks after seroconversion.

Management:

  • Immediate initiation of oral valacyclovir 8 g/day is recommended to reduce the rate of vertical transmission to the fetus. The efficacy of valacyclovir in reducing transmission is higher the earlier treatment starts.
  • Careful monitoring for maternal side effects, particularly acute renal failure, which is a rare but reported adverse event that resolves upon discontinuation of the drug.
  • If fetal infection is confirmed, serial prenatal assessment with ultrasound and MRI is vital for refining the prognosis and identifying potential sequelae. Counseling should prepare parents for possible termination of pregnancy (TOP) if severe fetal findings, especially cerebral anomalies, are detected. Valacyclovir treatment has been shown to reduce the rate of TOP due to severe fetal findings.

Clinical Scenario: Ms. Olivia M., a 32-year-old multipara, is diagnosed with a primary CMV infection at 20 weeks of gestation. Her initial ultrasound at 12 weeks was normal, and a recent scan at 20 weeks shows no obvious fetal anomalies.

Nothing to be done no prenatal diagnosis, no specific surveillance

Clinical Scenario: Mr. and Mrs. Peter H. are at 24 weeks of gestation. A routine ultrasound reveals fetal microcephaly and ventriculomegaly. CMV infection is suspected due to these findings.

Prenatal Diagnosis:

  • Immediate maternal serology (IgG, IgM, and avidity) is needed to confirm recent primary CMV infection. Only a negative serology would rule out maternal infection
  • Amniocentesis with CMV PCR is critical to confirm fetal infection.
  • A complementary fetal MRI is highly recommended to further assess the extent and severity of cerebral anomalies, as it offers a more detailed view than ultrasound alone.

Management:

  • If fetal CMV infection is confirmed, counseling should focus on the poor prognosis associated with severe brain anomalies. The prognosis for fetuses with moderate-to-severe fetal disease or CNS involvement is often poor, and such cases have typically been excluded from valacyclovir treatment trials.
  • Discussion should include the option of termination of pregnancy (TOP), as severe fetal cerebral lesions are known to have a dismal prognosis and are unlikely to be reversible with treatment.
  • Even if parents choose to continue the pregnancy, ongoing monitoring with serial imaging is important for assessing disease progression and preparing for postnatal management.

Clinical Scenario: Ms. Emily W., 29 years old, is at 21 weeks of gestation. Fetal CMV infection was confirmed by amniocentesis following a primary maternal infection in the first trimester. Her 21-week anatomy scan shows no gross anomalies, but there are concerns about potential subtle changes or late-onset issues.

Risks:

  • Confirmed fetal infection following first-trimester maternal primary infection carries a significant risk of sequelae, estimated at 51-57%.

Prenatal Diagnosis:

  • Fetal infection is confirmed by CMV PCR on amniotic fluid.
  • Serial prenatal assessment including ultrasound and MRI is crucial for refining the prognosis. Fetal blood analysis for prognostic markers may also be considered.

Management:

  • The role of valacyclovir therapy once fetal infection is established is still debated. While prenatal valacyclovir therapy appears promising in preventing vertical transmission, it is unclear whether it continues to exert a beneficial effect on fetuses with positive amniocentesis. Some studies suggest it is unlikely to improve prognosis once fetal infection is established. However, some trials (phase II open-label study) suggested oral valacyclovir (8 g/d) given to women with a mildly symptomatic fetus was associated with a higher chance of delivering an asymptomatic neonate (82% vs 43% historical cohort).
  • Detailed counseling is essential, explaining the current evidence on valacyclovir’s effect on already infected fetuses, the potential for long-term sequelae even with normal imaging, and discussing termination of pregnancy (TOP) as an option, especially if severe anomalies are detected.
  • Postnatal evaluation is vital for any newborn diagnosed with cCMV, even if asymptomatic at birth, as clinical anomalies may only appear later.

Clinical Scenario: Ms. Jessica A., 25 years old, is 6 weeks pregnant and her initial CMV serology is negative (non-immune). She is concerned about contracting CMV, as she works in a kindergarten.

Risks:

  • Being seronegative and having frequent or prolonged contact with young children (like in daycare settings) increases her risk of acquiring a primary CMV infection during pregnancy.
  • Primary infection during pregnancy can lead to severe congenital CMV.

Prenatal Diagnosis:

  • Baseline serology confirms her non-immune status.
  • Repeat serology should be performed to monitor for seroconversion, especially given her exposure risk. A retest between 14 and 16 weeks in seronegative women is recommended.

Management:

  • Comprehensive hygiene counseling is the cornerstone of prevention for seronegative pregnant women. This includes:
    • Washing hands frequently, especially after contact with children’s urine, saliva, or nasal secretions.
    • Avoiding sharing food, drinks, or eating utensils with young children.
    • Avoiding kissing young children on the mouth.
    • Not putting a child’s pacifier in her mouth.
    • Cleaning toys and surfaces that may have been contaminated with children’s fluids.
  • The benefit of knowing a negative serology result allows for a reinforcement of preventive hygiene measures, which can decrease the seroconversion rate.
  • If seroconversion occurs, follow management for primary maternal infection (Case 1).

Clinical Scenario: A newborn, Baby J., whose mother had a primary CMV infection during the first trimester, appears healthy at birth with no overt symptoms. However, due to the maternal history, congenital CMV is suspected.

Risks:

  • Many newborns with cCMV may be asymptomatic at birth, but clinical anomalies can be diagnosed later when sequelae become permanent.
  • Around 10% of fetuses with congenital CMV may develop symptomatic infection in the long term, and asymptomatic infections do not exclude permanent sequelae.
  • Long-term sequelae include sensorineural hearing loss (SNHL), intellectual disability, or developmental delay.

Prenatal Diagnosis (Past):

  • The mother’s history of primary CMV infection in the first trimester indicated a high risk for cCMV. Prenatal diagnosis methods, such as amniocentesis and imaging, would have been considered during pregnancy.

Management:

  • Postnatal evaluation is crucial to diagnose cCMV definitively. This involves CMV DNA detection via PCR from the newborn’s urine or saliva within the first 2-3 weeks of life. Dried blood spots can also be used for retrospective diagnosis.
  • If cCMV is confirmed, even in an asymptomatic newborn, regular follow-up is essential. This includes:
    • Audiological evaluations for SNHL, which can be progressive or fluctuating.
    • Neurological assessments for developmental delay or intellectual disability.
    • Ophthalmological examinations for chorioretinitis.
    • Other assessments for hepatosplenomegaly, thrombocytopenia, or elevated liver enzymes.
  • Antiviral treatment (valganciclovir) may be considered for symptomatic newborns to improve hearing and neurological symptoms, although the extent and duration of treatment are still debated. Even asymptomatic newborns with certain risk factors (e.g., high viral load) may be considered for treatment.

Course Outline:
CMV During Pregnancy: Risks and Prenatal Diagnosis

1. Significance of CMV Infection (5 minutes)

    • CMV is the most common congenital infection worldwide, affecting approximately 0.7% to 1% of all live births.
    • It is the primary non-genetic cause of sensorineural hearing loss (SNHL) and neurodevelopmental abnormalities in children.
    • Approximately 11% of infected newborns are symptomatic at birth, with 30% to 40% of these at risk of long-term neurological sequelae.
    • Permanent sequelae are observed in 17–20% of infected children. Many newborns may be asymptomatic at birth but can develop clinical anomalies later.
    • A recent major development in France is the HAS recommendation on June 5, 2025, for systematic national CMV screening during pregnancy, a significant shift in public health policy.
    • Learning Objectives: Understand the burden of congenital CMV infection and its impact on fetal and neonatal health, and acknowledge the evolving policy landscape.

2. CMV Biology and Epidemiology (5 minutes)

    • CMV is a ubiquitous DNA virus from the Herpesviridae family, with humans as its sole reservoir.
    • Maternal CMV infection types during pregnancy:
      • Primary Maternal Infection (PIM): Occurs in a seronegative woman. This is the main concern in pregnancy.
      • Non-primary Infection: Occurs in women with pre-existing immunity.
    • Risk of vertical transmission: Higher in primary infection (30–40%) compared to non-primary infection (<3.5%). This risk generally increases with gestational age at infection.
    • Risk factors for maternal primary infection: Contact with young children, especially in daycare settings.
    • Consequences of non-primary infections can include fetal sequelae, though the risk of severe outcomes is lower than in primary infections.

Maternal CMV Diagnosis (8 minutes)

    • Maternal CMV infection is commonly asymptomatic.
    • Diagnosis relies on maternal serum testing:
      • IgG and IgM antibodies: Presence of IgM and low IgG avidity typically indicates a recent primary infection.
      • IgG avidity test: Crucial for dating the infection; low avidity suggests an infection within the past 3-4 months. Intermediate avidity may require retesting.
    • Timing of serological testing: Needs to be performed as early as possible in the first trimester, with retesting between 14-16 weeks for seronegative women.
    • Role of PCR in maternal blood: Can be positive in some cases but is not definitively diagnostic for primary infection in all situations.

Initial Work-up upon Confirmed Maternal Primary Infection (7 minutes)

    • Referral to a specialized center/Fetal Medicine Unit is recommended.
    • Ongoing pregnancy surveillance with regular ultrasound examinations.
    • Counseling is crucial: Discuss risks of transmission, potential sequelae, and available diagnostic and management options.

Fetal Transmission and Gestational Age (7 minutes)

    • Risk of severe sequelae is limited to maternal infection in the first trimester of pregnancy or the periconceptional period.
    • Highest risk of severe sequelae:
      • Periconceptional infection (4 weeks before to 6 weeks after last menstrual period): Risk of severe sequelae is approximately 70% if transmitted.
      • First-trimester infection: Risk of complications ranges from 20% to 57% if transmitted.
      • Risk significantly decreases in the second and third trimesters, with severe fetal infection being confinedunlikely after the first trimester.

Spectrum of Congenital CMV (cCMV) Sequelae (8 minutes)

    • Neurological sequelae: Microcephaly, hydrocephalus/ventriculomegaly, cerebral calcifications (especially periventricular), hyperechogenic periventricular halo, subependymal cysts, abnormal gyration.
    • Sensorineural Hearing Loss (SNHL): The most common and often progressive or fluctuating sequela. It can be unilateral or bilateral.
    • Vestibular symptoms
    • Other symptomatic manifestations at birth: Rash, jaundice, hepatosplenomegaly, thrombocytopenia, intrauterine growth restriction (IUGR).
    • Long-term outcomes: Many infected newborns may be asymptomatic at birth, but clinical anomalies can be diagnosed when sequelae are permanent. Postnatal evaluation is critical.

Amniocentesis: The Gold Standard (15 minutes)

    • Procedure: Involves collecting amniotic fluid for CMV DNA PCR testing.
    • Timing: Crucial for accuracy. Should be performed:
      • At least 6-8 weeks after the presumed date of maternal primary infection/seroconversion.
      • At 17 weeks of gestation. Performing it too early (less than 8 weeks post-infection or before 18 weeks gestation) increases the risk of false negatives.
    • Prognostic value of viral load in amniotic fluid: CMV DNA load in amniotic fluid has been shown to increase with gestational age. Biomarkers in amniotic fluid can predict the severity of congenital CMV infection.

Fetal Blood Sampling (Cordocentesis) (5 minutes)

    • Purpose: May be offered in cases of confirmed fetal infection (positive amniocentesis) to check for fetal platelet count and fetal CMV DNA viral load. These parameters can help refine the fetal prognosis.
    • When: Typically performed around 20 weeks gestation.

Role of Imaging in Fetal Assessment (5 minutes)

    • Prenatal diagnosis requires imaging techniques to assess cortical and extracortical anomalies.
    • Imaging findings can predict both fetal involvement and postnatal prognosis, but they are difficult to assess even for highly trained physicians.
    • Serial prenatal assessment is crucial for refining prognosis, especially for first-trimester infections.

Ultrasound (US) Findings (10 minutes)

    • Ultrasound is a primary tool, but its performance for detecting CMV is considered mediocre due to the late appearance of severe lesions during pregnancy.
    • Extracerebral findings: Fetal Growth Restriction (FGR) or Small for Gestational Age (SGA) (9%), hyperechogenic bowel (13%), placentomegaly (2-30.2%) and placental calcifications, ascites, pleural effusion, pericardial effusion, hydrops, skin edema (~1%), hepatomegaly (3.8-14%) and/or splenomegaly (3.8-20.9%), liver calcifications (1.2%), polyhydramnios (<1%), oligohydramnios (3.4%).
    • Cerebral findings: Ventriculomegaly (6.1%), hydrocephalus (3.6%), microcephaly (6%), cerebral calcifications (6.3%), hyperechogenic periventricular halo (3%), subependymal cysts (1.7%), abnormal gyration (<1%). Periventricular lesions
    • Limitations of US: A normal fetal brain ultrasound does not reliably predict a normal neurodevelopmental outcome in congenital CMV infection.

Fetal Magnetic Resonance Imaging (MRI) (5 minutes)

    • Complementary to ultrasound, especially useful for assessing cortical and extracortical anomalies.
    • Recommended around 30 weeks of gestation or earlier if US suspects brain lesions.
    • MRI can detect abnormalities not visible on ultrasound.

Historical and International Perspectives on CMV Screening (8 minutes)

    • Previous French Stance (Pre-2025): French health authorities (ANAES in 2004, HCSP in 2018 and 2023) consistently did not recommend systematic CMV screening during pregnancy. This was based on arguments such as the absence of a proven effective treatment for preventing mother-to-fetus transmission or severe complications, the difficulty in establishing fetal prognosis, the risks of amniocentesis, and potential maternal anxiety.
    • International Landscape:
      • Italy, Greece, and Israel are among the few countries that recommend systematic CMV screening during pregnancy, often with valacyclovir treatment in case of positive findings.
      • Most other countries, including the UK, Canada, Australia, New Zealand, Germany, and Sweden, do not recommend universal screening, frequently citing limitations in treatment efficacy or insufficient evidence.
      • Some countries adopt targeted screening based on maternal risk factors (e.g., contact with young children in daycare) or suggestive ultrasound findings.

HAS Recommendation of June 5, 2025: Systematic Screening in France (22 minutes)

    • Key Decision: On June 5, 2025, the French High Authority for Health (HAS) issued a recommendation to implement systematic national screening for CMV infection. This measure is for all pregnant women whose serological status is negative or unknown. It marks a significant departure from France’s previous policy.
    • Underlying Rationale (Multi-dimensional Analysis) for the Shift: The HAS decision was based on a comprehensive evaluation including updated scientific literature, economic analyses, ethical considerations, and real-world clinical practices.
      • Evolution of Scientific Knowledge and Treatment Efficacy: New data, particularly from the randomized controlled trial by Shahar-Nissan et al. (2020), demonstrated that valacyclovir significantly reduces the vertical transmission of CMV. This efficacy was further supported by subsequent observational studies (Faure-Bardon 2021, Egloff 2023, Amir 2023, Zammarchi 2023) and meta-analyses (Chatzakis 2024, D’Antonio 2023), showing a substantial reduction in transmission rates (e.g., from 30% to 11% in Shahar-Nissan’s trial). While uncertainties persist regarding valacyclovir’s direct effect on the severity of sequelae, the evidence for reducing transmission was deemed sufficient to justify screening.
      • Safety Profile of Valacyclovir: The HAS noted no signal of teratogenicity from high-dose valacyclovir (8 g/day) in 970 pregnancies followed between 2007 and 2023. While rare cases of reversible acute renal failure can occur, they are manageable with proper hydration and staggered doses.
      • Public Health Burden: Congenital CMV remains a significant public health issue, being the leading non-genetic cause of sensorineural hearing loss (SNHL) and neurodevelopmental abnormalities. A considerable proportion of infected children (17–20%) develop permanent sequelae.
      • Benefits of Serostatus Knowledge: Knowing one’s seronegative status empowers women to reinforce adherence to preventive hygiene measures, which have been shown to reduce the risk of maternal infection.
      • Addressing Inequities: The existing heterogeneous practices of CMV screening and treatment across France led to significant disparities in patient care. A national systematic program aims to reduce these inequalities and ensure equitable access to care.
      • Cost-Effectiveness: Recent economic evaluations, including a French study (Périllaud-Dubois et al., 2023), suggest that systematic screening followed by valacyclovir treatment can be cost-effective in the long term by reducing the substantial costs associated with severe congenital CMV complications. Most international studies also conclude cost-effectiveness, despite variations in methodology.
      • Ethical Considerations and Patient Perspective: The availability of an effective treatment (valacyclovir) significantly alters the ethical balance, bolstering arguments for beneficence (preventing severe sequelae) and facilitating informed consent and maternal autonomy in reproductive choices. Patient associations generally expressed favorable views towards systematic screening, emphasizing the right to information and prevention.
    • Implementation Modalities (Mandatory Screening):
      • Timing & Tests: Screening will be performed in the first trimester of pregnancy. It will include a sequence of IgM, IgG, and IgG avidity tests. This sequence will be integrated into the list of mandatory medical examinations for pregnant women.
      • Interpretation Algorithm: The algorithm validated by the CNR Herpèsvirus (French National Reference Center for Herpesviruses) will be adopted for interpreting serological results.
      • Provisional Clinical Management: Pending formal HAS guidelines, healthcare professionals are advised to refer to the CNR Herpèsvirus recommendations for the management and follow-up of women with confirmed maternal primary infection.
      • Accompanying Measures: The systematic screening program will be supported by:
        • Patient Information: Dissemination of clear information materials (potentially from HAS) to ensure free and informed consent, including reminders about preventive hygiene measures for seronegative women.
        • Professional Training: Extensive training programs for healthcare professionals are crucial to ensure homogeneous and compliant implementation across the national territory.
        • Diagnostic Tool Evaluation: Ongoing evaluation and updating of diagnostic test performance by the HAS.
        • Valacyclovir Precautions: Specific guidance on precautions, such as adequate hydration and staggered doses, to minimize potential adverse effects like acute renal failure.
    • Future Re-evaluation and Remaining Uncertainties: The systematic screening program will undergo a re-evaluation after three years of implementation. Its continuation beyond this initial period will be conditioned on the production of further scientific data to address remaining uncertainties, which include:
      • Updated national epidemiological data (maternal seroprevalence, frequency, and severity of neonatal/child complications).
      • Long-term safety of valacyclovir at a larger scale.
      • Valacyclovir’s effect on reducing the severity of sequelae in infected fetuses/newborns, as current studies primarily focus on transmission reduction.
      • Operational feasibility and budget impact of widespread implementation in France.
      • Expected increase in amniocentesis procedures and associated risks.

Postnatal Management (5 minutes)

    • Ganciclovir/Valganciclovir: Treatment for symptomatic cCMV in newborns, particularly with CNS involvement, has shown to be effective, especially if initiated within the first month of life for improved audiological and neurodevelopmental outcomes.
    • Long-term follow-up: Children with cCMV, even if asymptomatic at birth, require close audiological and developmental evaluations with timely interventions to improve overall outcomes.

Future Perspectives and Q&A (5 minutes)

    • Universal CMV screening in pregnancy: now recommended in France.
    • Vaccine development: Ongoing research includes an mRNA vaccine candidate in phase III trials, with results expected in 2026, which could offer a primary prevention strategy.
    • Remaining Research Needs: Large randomized controlled trials are still needed to fully establish the impact of prenatal valacyclovir on fetal structural anomalies, symptomatic infection severity, and neurocognitive impairment.
    • Open Discussion and Questions.