Bibliographic and Educational Resources in Fetal Medecine

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Systematic Serological Screening for Cytomegalovirus (CMV) in early Pregnancy in France

Dr Marianne Leruez-Ville

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Pr Yves Ville

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Overview

The management of Cytomegalovirus (CMV) infection during pregnancy has been a complex public health challenge in France, marked by evolving scientific understanding and differing policy recommendations. This synthesis will outline the historical context of CMV screening in early pregnancy in France, discuss the role of valacyclovir, and detail the significant shift brought about by the Haute Autorité de Santé (HAS) decision of June 5, 2025.

Cytomegalovirus is the most common congenital infection, affecting 0.5% to 2% of all live births and representing the main non-genetic cause of congenital sensorineural hearing loss and neurological damage. In France, congenital CMV (cCMV) infection occurs in approximately 0.39% of births and 0.43% of fetuses. While often asymptomatic or mild in the mother, primary maternal infection (PIM), particularly in the periconceptional period and first trimester, carries the highest risk of severe neurosensory sequelae in the infant, affecting up to 40-50% of infected neonates after first-trimester infection. Maternal infection occurring after 14 weeks’ of gestation is not a risk for CMV-related sequelae in the infected children. Severe sequelae concern 1 to 6 per 100,000 newborns in France.

Historically, French health authorities, including the Agence Nationale d’Accréditation et d’Évaluation en Santé (ANAES) in 2004 and the Haut Conseil de la Santé Publique (HCSP) in 2018 and 2023, consistently did not recommend systematic CMV screening during pregnancy. The rationale for this position was primarily based on:

  • Absence of proven effective antiviral treatment: There was a lack of robust evidence for a validated antiviral treatment capable of preventing mother-to-fetus transmission or the neurosensory complications in the fetus.
  • Unfavorable benefit-risk ratio: The potential benefits of systematic screening were not deemed to outweigh the risks, including the anxiety generated by seroconversion diagnoses and the risks associated with invasive diagnostic procedures like amniocentesis.
  • Insufficient data on valacyclovir efficacy and risks: While valacyclovir emerged as a potential treatment, its prolonged use at high doses during pregnancy raised concerns about efficacy and fetal outcomes, with data not conclusive enough to support widespread use.

Instead of systematic screening, the focus in France was on promoting hygiene measures to prevent maternal CMV infection, as these were considered effective. However, information about these measures only reached about 16% of women in 2021. In addition all positive studies in this matter were conducted in women aware of their serological status in early pregnancy.

Despite these official non-recommendations, anecdotal evidence and studies indicated a growing trend of CMV screening in France. In 2011, 25% of pregnant women were screened for CMV, increasing to 31.7% in 2023. This screening occurred as a result of maternal request, medical choices as well as in cases of maternal clinical or biological signs (like hepatic cytolysis), known exposure, or suggestive fetal ultrasound findings (such as intrauterine growth restriction or cerebral anomalies). This fragmented practice led to regional disparities in care, with higher screening rates observed in areas like Île-de-France (44% in 2011, 9.8 per 10,000 accouchements for valacyclovir prescription) compared to others.

Valacyclovir, an antiviral drug, has been central to the debate on CMV screening. Until recently, there was no marketing authorization (AMM) for valacyclovir in the prevention of vertical CMV transmission. The HCSP (2023) maintained that the efficacy and risks of prolonged, high-dose valacyclovir on fetal outcomes were largely unknown, thus not supporting a favorable benefit-risk ratio for routine use.

However, key studies began to alter this perspective:

  • The Shahar-Nissan et al. randomized controlled trial (2020) was a pivotal publication. It demonstrated that oral valacyclovir at a dosage of 8 g/day, administered from the diagnosis of primary infection up to amniocentesis, significantly decreased vertical transmission rates from 29.8% to 11.1% in pregnant women with primary infection in the periconceptional period or first trimester. This study provided the first randomized controlled evidence of its efficacy in preventing vertical transmission.
  • Subsequent meta-analyses, such as those by Chatzakis et al. (2024), on individual data and D’Antonio et al. (2023) based upon articles reports, further supported the conclusion that valacyclovir treatment reduces the vertical transmission of CMV.
  • Several observational studies (e.g., Faure-Bardon, Egloff, Zammarchi, Amir) also provided evidence supporting valacyclovir’s efficacy and good tolerance in preventing cCMV following maternal primary infection.

Regarding safety, the Centre de Référence sur les Agents Tératogènes (CRAT) reported no specific teratogenicity signals for valacyclovir administered at high doses during pregnancy from 2007 to 2023, based on the follow-up of 970 treated women. While rare adverse effects like acute renal failure or thrombopenia were noted, these were generally reversible and manageable with appropriate monitoring and hydration. However, the long-term effects of valacyclovir exposure on the fetus still require more extensive research.

Analysis of French SNDS (National Health Data System) data revealed that valacyclovir prescription for suspected CMV infection during pregnancy increased between 2022 and 2023. These prescriptions were predominantly made by hospital physicians and concentrated in specific regions, highlighting a disparity in care provision across France.

The landscape for CMV screening in France underwent a monumental change with the HAS decision of June 5, 2025. This re-evaluation was mandated by Article 44 of the 2023 Social Security financing law, which empowered the State to implement a systematic CMV screening program in pregnant women, subject to a favorable HAS opinion.

The HAS conducted a comprehensive, multidimensional analysis to inform its decision, reviewing the HCSP report, extensive scientific literature (including randomized controlled trials, observational studies, and meta-analyses), modeling test performance, assessing economic implications, analyzing ethical considerations, and integrating data from the SNDS, alongside feedback from experts, learned societies, and patient associations.

The HAS ultimately recommended the implementation of a national systematic screening program for CMV in all pregnant women whose serological status is negative or unknown. This marks a direct reversal of previous French health authority recommendations.

The HAS’s decision was based on several key considerations:

  • Significant Potential Burden: The acknowledged importance of CMV as a cause of severe neurosensory sequelae in newborns, coupled with the prevalence and vertical transmission rates, underscored the public health concern.
  • Established Valacyclovir Efficacy (Hypothesis now “Founded”): Based on the Shahar-Nissan trial and subsequent observational studies and meta-analyses, the hypothesis of valacyclovir’s efficacy in reducing vertical CMV transmission is now considered “founded” by HAS. This efficacy could potentially lead to a reduction of 586 to 2,054 cCMV cases and 511 to 617 cases of severe sequelae annually if screening were universal.
  • Reassuring Safety Profile of Valacyclovir: The available data, including from the CRAT, indicated no particular teratogenicity signals for high-dose valacyclovir during pregnancy, although long-term effects still warrant continued vigilance.
  • Benefits of Serological Status Knowledge: Knowing one’s serological status, especially if seronegative, has been shown to encourage pregnant women to adopt more stringent hygiene measures, which can reduce the risk of primary infection.
  • Consensus on Serological Test Interpretation Algorithms: Standardized algorithms for interpreting IgG, IgM, and IgG avidity tests exist and are recognized by European groups (ECCI) and the French National Reference Center for Herpesviruses (CNR Herpèsvirus).
  • Addressing Current Practice Inequities: The observed widespread, yet heterogeneous, practice of CMV screening and off-label valacyclovir prescription in France highlighted significant disparities in care. Implementing a systematic national program aims to harmonize practices and ensure equitable access to prevention and management across the territory.
  • Positive Economic Evaluations: Several cost-effectiveness analyses, including a French study by Périllaud-Dubois et al. (2023), suggest that systematic screening followed by valacyclovir treatment can be cost-effective, potentially leading to long-term savings by reducing expenses associated with severe cCMV complications.
  • Ethical Acceptability: While ethical dilemmas exist regarding balancing beneficence/non-maleficence with patient autonomy, expert and user association feedback indicated that with clear, informed communication and proper professional training, these concerns could be managed. Patient associations, in particular, largely supported systematic screening on condition of robust information provision and professional education.

The HAS also stipulated that this new systematic screening measure would be re-evaluated after three years to assess its relevance and consider its continuation. Furthermore, HAS recommended continued research to address remaining uncertainties, including updating national epidemiological data, studying valacyclovir’s long-term safety on a larger scale, assessing its effect on fetal/neonatal complications, and evaluating the overall performance of the testing sequence. The importance of developing tailored and comprehensive information for pregnant women regarding the benefits, risks, and persistent uncertainties of screening was also highlighted.

Prior to the HAS 2025 decision, there was no international political consensus on systematic CMV screening in pregnancy although a European experts’ consensus was reached in 2024 in favor of universal screening. Only Italy (since December 2023), Greece (since 2020), and Israel systematically recommend screening with subsequent valacyclovir treatment for positive cases. Other countries like the UK, Germany, and Canada have not adopted universal screening, often relying on targeted screening based on clinical or sonographic signs. Australia stands in between, advocating serological screening in pregnant women with a first child less than 3 years old. This divergence reflected the earlier lack of consensus on valacyclovir’s proven efficacy. The HAS decision positions France among the countries endorsing systematic screening, leaning on the accumulating evidence for valacyclovir’s effectiveness.

The HAS decision of June 5, 2025, represents a pivotal moment in French public health policy regarding CMV infection in pregnancy. Moving from a long-standing position of non-recommendation, HAS now advocates for systematic national screening, underpinned by growing evidence for valacyclovir’s efficacy in reducing vertical transmission, reassuring safety data, established diagnostic protocols, and a commitment to addressing existing inequities in care. This shift reflects an evolving understanding of the disease, the availability of therapeutic options, and the imperative to provide comprehensive information and equitable care to all pregnant women. While acknowledging persistent uncertainties, particularly regarding long-term outcomes and the need for ongoing research, France is now set to implement a more proactive and standardized approach to mitigate the impact of congenital CMV infection.

FAQ

On June 5, 2025, the French National Authority for Health (HAS) issued a recommendation for the implementation of systematic national screening for Cytomegalovirus (CMV) during pregnancy, targeting all pregnant women with a negative or unknown serological status as early as possible and throughout the first trimester of pregnancy. This measure will be re-evaluated after three years of implementation.

Previously, French health authorities (ANAES in 2004, HCSP in 2018 and 2023) did not recommend systematic CMV screening due to the perceived lack of effective treatment and an unfavorable benefit/risk ratio. The 2025 HAS re-evaluation was prompted by new scientific data, particularly concerning the potential efficacy of valaciclovir, and the increasing informal adoption of screening and treatment practices in France.

CMV is a common DNA virus belonging to the herpesviridae family, with humans as its only known reservoir. While often asymptomatic in infected individuals, it can be transmitted from mother to fetus (vertical transmission) during pregnancy. When fetal infection occurs in the first trimester, this congenital infection can lead to severe sequelae in the newborn, including sensorineural hearing loss and neurological damage.

In France, CMV seroprevalence among women aged 15 to 49 was estimated at 60% in 2010. The infection affects 1% to 4% of pregnant women.

The risk of severe sequelae for the fetus is highest when the mother acquires a primary infection (PIM) during the periconceptional period or in the first trimester of pregnancy. For PIMs in the first trimester, the risk of complications in the newborn is estimated between 51% and 57% if vertical transmission occurs. When fetal infection occurs after 14 weeks’, there is no risk of CMV-related sequelae

Valaciclovir, an antiviral medication, has shown efficacy in reducing the rate of vertical transmission of CMV from mother to fetus, particularly after primary maternal infection acquired periconceptionally or in the first trimester. Although it does not have marketing authorization (AMM) for this specific indication in France, its presumed efficacy was a key factor in the HAS 2025 recommendation.

  1. A dosage of 8 g/day of valaciclovir is typically used. It should be administered as early as possible after diagnosis of primary maternal infection and continued until the amniocentesis result. A preferential scheme of 2g four times a day is recommended to reduce the risk of renal side effects. Valaciclovir should be stopped when the result of amniocentesis for CMV-PCR is negative at 17 weeks’.

Data collected up to October 21, 2024, indicate no safety signal or teratogenicity observed with valaciclovir use during pregnancy, based on follow-up of 970 treated pregnant women between 2007 and 2023.

Diagnosis primarily relies on serological tests (IgG, IgM, and IgG avidity). If IgM and IgG are positive, an IgG avidity test helps to date the infection. PCR testing on maternal blood can also be used in some situations.

  1. Amniocentesis with PCR on amniotic fluid is the reference test for fetal diagnosis, usually performed from 17 weeks of gestation and at least 6 weeks after maternal infection. If the fetus is infected, follow-up typically includes serial ultrasound and Magnetic Resonance Imaging (MRI) of the fetus.

Amniocentesis carries a low risk of complications, with the risk of miscarriage estimated at less than 0.1%. The HAS acknowledges the “expected increase in the number of amniocenteses and associated risks” as a downside of systematic screening.

Even before the 2025 HAS recommendation, about one-third of pregnancies in France already benefited from CMV screening. The new recommendation aims to harmonize practices and care offerings across the national territory, addressing the observed regional disparities.

  1. As of June 2025, systematic CMV screening for pregnant women is not universally adopted globally. Only Italy, Greece, and Israel recommend systematic screening. Other countries like the UK, Netherlands, Norway, Switzerland, Brazil, US, Canada, Germany, and Sweden do not recommend universal screening, though some may have targeted screening.

Recent cost-effectiveness studies, including one French study, suggest a potential for systematic screening followed by valaciclovir treatment to be cost-effective. However, the conclusions of international studies are more nuanced, and uncertainties remain regarding the efficiency and budgetary impact in France.

The HAS identifies several benefits, including:

    • Knowledge of serological status: Allows reinforcement of hygiene measures for seronegative women.
    • Availability of effective treatment: Valaciclovir reduces vertical transmission, thus decreasing the number of children born with sequelae.
    • Intervention in appropriate therapeutic window: Integrating screening into mandatory first-trimester exams.
    • Reduction of renal insufficiency risk: Proper hydration and sequenced valaciclovir intake can prevent this reversible side effect.
    • Equity: Harmonizes care across the territory.
    • Protection of the infant and right to information for families.

The HAS acknowledges persistent uncertainties, including:

    • Updated national epidemiological data (maternal seroprevalence, frequency and severity of complications).
    • Long-term safety of valaciclovir at high doses and on a larger scale.
    • Efficacy of valaciclovir in reducing the risk and severity of sequelae (studies primarily focused on vertical transmission).
    • Global performance of the test sequence (IgG, IgM, avidity).
    • Uncertainty about the efficiency and budgetary impact of systematic screening in France.
    • Expected increase in amniocenteses and associated risks.
    • Potential for increased anxiety among pregnant women.

Patient associations, such as “Pour les yeux d’Émilie” and “Chanter, Marcher et Vivre,” and “La Fondation pour l’audition” generally support systematic screening, emphasizing the protection of the future baby, the right to information for pregnant women, and the reduction of territorial disparities. However, one association expressed conditional support, stressing the need for perfectly transmitted information to avoid confusion and ensure free choice.

The ethical considerations include the principle of autonomy (informed choice based on complete information), beneficence (offering a response to positive screening results through treatment), and non-maleficence (potential for anxiety, risk of amniocentesis, and long-term effects of valaciclovir). The “routinization” of screening could potentially lead to a delegation of autonomy by pregnant women.

The HAS recommends further studies to address the remaining uncertainties, including:

    • Updated national epidemiological data.
    • Long-term safety of valaciclovir on a larger scale.
    • Effect of valaciclovir on the frequency and severity of fetal/neonatal complications.
    • Overall performance of the test sequence (IgG, IgM, IgG avidity).
    • Studies on the perception of benefits and risks of systematic screening from social and human sciences perspectives.

The HAS recommends integrating CMV screening into the list of mandatory medical examinations during the first-trimester visit, as outlined in articles R. 2122-1 and R. 2122-2 of the Public Health Code. This aims to ensure intervention within the adequate therapeutic window.

Bibliography

Chatzakis C, Shahar-Nissan K, Faure-Bardon V, Picone O, Hadar E, Amir J, 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.

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.

Favre G et al.Cytomegalovirus universal screening in early pregnancy: truth is a tendency. Letter to the Editor Ultrasound in Obstetrics & Gynecology, 2025

Haut Conseil de la santé publique. Dépistage systématique de l’infection à cytomégalovirus pendant la grossesse. Collection Avis et Rapports. December 2023.

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.

Faure-Bardon V et al. Quantification of maternal and fetal valaciclovir exposure in a pharmacokinetic study of cytomegalovirus-infected pregnant women treated to prevent vertical transmission J Antimicrob Chemother https://doi.org/10.1093/jac/dkae470

Ville Y. Editorial American Journal of Obstetrics & Gynecology Maternal Fetal Medicine. 2021.

Haute Autorité de santé. Feuille de route: Évaluation de la pertinence d’un dépistage systématique de l’infection à cytomégalovirus au cours de la grossesse 2025, January 29

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. [Online]

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 [Online]

Haute Autorité de santé. Méthode de l’étude sur la délivrance de valaciclovir contre l’infection à CMV pendant la grossesse à partir des données du SNDS. 2024, November 19 [Online]

Objectives of the Study: The core objective was to evaluate the efficacy of oral valacyclovir at a dosage of 8 grams per day (8 g/d) in reducing the rate of vertical CMV transmission. A critical secondary objective was to scrutinize the maternal safety profile of this high-dose valacyclovir when administered for this specific indication. CMV is recognized as the leading cause of congenital infection and non-genetic sensorineural hearing loss, with the potential for severe outcomes, especially when primary maternal infection occurs early in pregnancy.

Methodology Employed: The meta-analysis was meticulously conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for IPD meta-analyses. It was officially registered with the International Prospective Register of Systematic Reviews (PROSPERO), under the identifier CRD42022370458.

  • Participant and Intervention Criteria: The study included pregnant women with confirmed PIM acquired during the periconceptional period or the first trimester of pregnancy. A pivotal inclusion criterion was that these women must have received oral valacyclovir at a dosage of 8 g/d. Their cases also had to include results from an amniocentesis, performed for the prenatal diagnosis of congenital CMV (cCMV). Amniocentesis needed to be conducted at least 6 weeks following the documented maternal infection and from 17 weeks of gestation onward to ensure optimal diagnostic reliability. The study also incorporated data on the short- and long-term outcomes of the fetuses and neonates born to these women.
  • Search Strategy: A comprehensive, pre-defined search strategy was applied across multiple electronic databases, including MEDLINE, Scopus, the Cochrane Central Register of Controlled Trials, and the US Registry of clinical trials (www.clinicaltrials.gov), in addition to gray literature. No restrictions were imposed on publication date or language. Search terms included “valacyclovir,” “secondary prevention,” “CMV,” “cytomegalovirus,” “congenital CMV infection,” and “primary CMV infection”. To ensure accuracy and minimize bias, two authors independently performed the search, resolving disagreements through discussion or a third author’s involvement. Measures were also taken to prevent the inclusion of duplicate or overlapping samples, prioritizing larger studies in such instances.
  • Outcome Measures Defined:
    • The primary outcome was the rate of vertical transmission of CMV, determined by polymerase chain reaction (PCR) analysis of amniotic fluid obtained via amniocentesis.
    • Secondary outcomes included:
      1. The presence of positive CMV infection at birth.
      2. Instances of pregnancy termination due to CMV-associated central nervous system (CNS) findings or multiorgan involvement identified via ultrasound or magnetic resonance imaging (MRI).
      3. A thorough assessment of any maternal side effects experienced from valacyclovir administration.

Key Findings and Implications: The meta-analysis yielded significant conclusions regarding the efficacy and safety of high-dose valacyclovir.

  • Reduced Vertical Transmission: The administration of 8 g/d of oral valacyclovir was found to lead to reduced rates of vertical CMV transmission. This beneficial effect was specifically observed in pregnancies where the mother acquired a primary CMV infection during the critical periconceptional period or the first trimester. Previous research indicates that PIMs in the first trimester are particularly associated with severe sequelae, including neurological and auditory issues.
  • Reduced Severe Forms: Beyond transmission rates, the treatment also contributed to reduced rates of severe forms of CMV infection, suggesting a protective effect on fetal outcomes. Congenital CMV infection can result in severe long-term sequelae such as sensorineural hearing loss, neurodevelopmental impairment, and other neurological issues like microcephaly, ventriculomegaly, or parenchymal calcifications. The impact on quality of life and language development has also been noted.
  • Maternal Safety: From a maternal safety perspective, high-dose oral valacyclovir was deemed a safe treatment option. The study reported that severe side effects, or indeed any side effects, were uncommon among the treated mothers. Other sources corroborate this, noting that severe adverse effects are rare, though minor issues like headache, nausea, or abdominal pain may occur. While there is a theoretical risk of renal toxicity, it is uncommon, and adequate hydration is important. The typical dosage of valacyclovir for other indications is lower (1.5-3 g/day), but 8 g/day is used for CMV prevention in transplant patients.

Broader Context and Challenges: While the Chatzakis (2024) IPD meta-analysis suggests promising results for early valacyclovir intervention, the broader landscape of CMV management in pregnancy presents complexities.

  • Effectiveness of Treatment: The Chatzakis (2024) study stands as an IPD meta-analysis supporting valacyclovir’s role in secondary prevention. Other studies and meta-analyses, while sometimes suggesting efficacy, have highlighted limitations, such as small sample sizes, lack of randomization, or focus on transmission rather than long-term sequelae. A significant point of discussion is whether a reduction in vertical transmission directly translates to a reduction in severe long-term sequelae in the child, which has not been definitively demonstrated by all studies.
  • Screening Debates: Despite the potential for intervention, no country officially recommends universal CMV screening during pregnancy. This is primarily due to several factors:
    • Low Incidence of Severe Outcomes: While individual outcomes can be severe, the population-level incidence of serious sequelae from cCMV in high-income countries like France is relatively low (1 to 6 severe sequelae per 100,000 newborns).
    • Test Reliability and Interpretation Challenges: While serological tests (IgG, IgM, and avidity) are generally reliable, interpreting positive IgM results can be complex, often requiring additional tests and specialized expertise to differentiate recent PIM from past infections or false positives. Universal screening could lead to a high number of false positives, causing unnecessary anxiety and further investigations.
    • Narrow Therapeutic Window: The optimal window for effective intervention with valacyclovir is very short, requiring PIM detection before 13 weeks of gestation to allow for sufficient treatment duration before amniocentesis. This tight timeframe makes widespread, timely intervention challenging in routine clinical practice.
    • Acceptability and Patient Burden: Universal screening involves multiple steps, including initial serology, confirmation tests, potential amniocentesis, and prolonged high-dose treatment. This process can be burdensome and anxiety-provoking for expectant parents, potentially leading to increased requests for medical terminations of pregnancy (IMG), even in cases with low risk of severe fetal involvement.
    • Ethical Considerations: Ethical principles of autonomy (informed choice), beneficence (doing good), non-maleficence (avoiding harm), and justice (fair distribution of resources) are central to the debate. Without a clearly proven and widely accessible highly effective intervention for sequelae, and given the potential for increased anxiety and unnecessary procedures, the ethical balance remains precarious.
    • Cost-Effectiveness: Studies on the cost-effectiveness of universal CMV screening have not reached a consensus, with some suggesting it may not be cost-effective compared to current practices, especially given the costs of follow-up and management of false positives.

Conclusion: The Chatzakis et al. (2024) IPD meta-analysis provides strong evidence that high-dose valacyclovir can reduce the rate of vertical CMV transmission and severe outcomes following PIM in the periconceptional period or first trimester, with a good maternal safety profile. However, the broader discussion by health authorities like the High Council of Public Health (HCSP) in France (2023) highlights that despite such advancements in treatment, universal CMV screening during pregnancy is not yet recommended. This is largely due to remaining uncertainties regarding the overall benefit-risk balance of a widespread screening program, particularly concerning long-term fetal outcomes, the psychological burden on parents, and the practicality and cost-effectiveness of implementation at a population level. Further research, including large-scale randomized trials focusing on the reduction of severe sequelae, is still considered essential.

Cytomegalovirus: A Significant Public Health Challenge Human Cytomegalovirus (CMV), a member of the Herpesviridae family, is highly species-specific, with humans being its sole host. It is acquired through mucosal sites (community exposure) or blood-borne transmission (transfusion or transplantation). The virus is characterized by cell-mediated spread following a replication phase and is found in various body fluids (urine, saliva, vaginal secretion, semen, breast milk) during primary infection and reactivation, making seropositive individuals a reservoir. Crucially, CMV is identified as the most common congenital infection, impacting 0.5% to 2% of all live births, and stands as the primary non-genetic cause of congenital sensorineural hearing loss (SNHL) and neurological damage. Furthermore, it is a major cause of congenital malformations in high-income countries and contributes significantly to neurological disability, accounting for up to 10% of all cerebral palsy cases and 8-21% of congenital SNHL at birth, a figure that can increase to 25% by four years of age due to late-onset hearing loss.

Maternal Infection Types and Diagnostic Approaches Congenital CMV infection can result from either maternal primary infection (PIM) or non-primary infection (reactivation or reinfection). The most significant risk for severe sensorineurological morbidity in the fetus is associated with PIM acquired during the first trimester of pregnancy, with up to 40-50% of infected neonates developing sequelae. Serological testing plays a critical role in identifying maternal infection. Performing serological tests (IgG, IgM, and IgG avidity) before 14 weeks of gestation is essential to detect primary infection occurring within approximately three months around conception. However, these tests are not informative for women already immune before pregnancy. In Europe and the United States, PIM in the first trimester is frequently observed in young parous women with children under three years old.

Fetal Diagnosis: Imaging and Amniocentesis When congenital CMV is suspected, typically due to suggestive findings on prenatal ultrasound, further diagnostic steps are taken. Amniocentesis, performed from 17 weeks of gestation, is the standard for fetal diagnosis. Prenatal ultrasound findings that may raise suspicion include:

  • Fetus being small for gestational age (SGA).
  • Echogenic bowel, which appears with echogenicity similar to the spine even when ultrasound gain is turned down.
  • Presence of various effusions (e.g., ascites, pericardial or pleural effusion).
  • Hepatosplenomegaly and liver calcifications.
  • Placentomegaly, characterized by a thick (>40mm) and heterogeneous placenta.
  • Oligo- or polyhydramnios.
  • Cerebral anomalies such as microcephaly, hydrocephaly, and ventriculomegaly. The source also mentions abnormal midline, posterior fossa, and cerebellum findings. While routine ultrasound sensitivity for predicting neonatal symptoms is limited (around 25%), serial targeted ultrasound and magnetic resonance imaging (MRI) of known infected fetuses show a high sensitivity (>95%) for detecting brain anomalies.

Prevention Strategies Prevention of CMV infection in pregnancy focuses on both primary measures and, for specific cases, secondary interventions.

  • Primary Prevention: Involves hygiene counseling for expectant parents to avoid contact with body fluids from infected individuals, particularly toddlers, from before conception until 14 weeks of gestation.
  • Vaccine Development: Candidate vaccines have been explored, but the review indicates that they have not yet provided more than 75% protection for over two years against CMV infection.
  • Passive Immunization: Cytomegalovirus hyperimmune globulins (HIG) have been investigated to reduce the risk of vertical transmission. However, two randomized controlled trials showed no clear benefit.

Antenatal and Neonatal Treatment Medical therapies have emerged, particularly for secondary prevention of vertical transmission and for treating symptomatic neonates:

  • Valaciclovir: The review highlights its potential in reducing vertical transmission. A randomized controlled trial of 90 pregnant women showed that valaciclovir, given from the diagnosis of primary infection up to amniocentesis, decreased vertical transmission rates from 29.8% to 11.1%.
    • A phase II open-label study further demonstrated that oral valaciclovir at a high dose of 8 grams per day (8 g/d), administered to pregnant women with a mildly symptomatic fetus, was associated with a higher proportion of asymptomatic neonates (82%) compared to an untreated historical cohort (43%).
    • This 8 g/d regimen of valaciclovir achieved expected concentrations in both maternal and fetal blood during the second trimester. Pharmacokinetic studies have shown specific median (range) parameters for the maternal compartment (AUCmat 570.2 (297.6–1282.4) µmol.h/L, Cminmat 9.6 (0.3–38.6) µmol/L, Cmaxmat 40.7 (27.1–87.9) µmol/L) and in amniotic fluid (AUCAF 562.4 (293.6–1229.2) µmol.h/L, CminAF 21.2 (9.3–48.8) µmol/L, CmaxAF 25.4 (13.4–52.8) µmol/L). The high dose of 8g/day was chosen initially because it was effective in preventing CMV disease in CMV-negative renal transplant patients receiving a CMV-positive graft, with the underlying hypothesis that preventing vertical transmission could be a similar scenario, with the fetus acting as the host and the mother as the graft.
    • No maternal, fetal, or neonatal adverse effects were reported in over 60 treated women during this phase II trial, which involved treatment for a median of 90 days from 25 weeks gestation until delivery. While this trial indicated the plausibility of valaciclovir’s efficacy, it noted that a higher level of evidence was required. Our conversation history indicates that a later individual patient data (IPD) meta-analysis by Chatzakis et al. (2024) provides this higher level of evidence, supporting that high-dose valacyclovir can reduce vertical CMV transmission and severe outcomes following primary maternal infection in the periconceptional period or first trimester, with a good maternal safety profile. This later study also reports that severe or any side effects were uncommon. However, despite these promising findings, universal CMV screening during pregnancy is not officially recommended in most countries, including France, due to ongoing uncertainties regarding the overall benefit-risk balance of widespread screening programs, the psychological burden on parents, and the practicality and cost-effectiveness of implementation.
  • Valganciclovir: For symptomatic neonates, valganciclovir treatment is likely to improve hearing and neurological symptoms, although the optimal extent and duration of treatment remain a subject of debate.

Conclusion: Reevaluating Public Health Strategies The Leruez-Ville et al. (2020) review concludes that congenital CMV infection represents a significant public health challenge, causing substantial neurological disability and SNHL globally. Given the evolving understanding of diagnosis and both pre- and postnatal management, the authors recommend that health care providers should reevaluate existing screening programs in early pregnancy and at birth. This reevaluation is critical to integrate new knowledge and improve outcomes for affected infants.

The authors identify CMV as the leading cause of congenital infection and non-genetic sensorineural hearing loss (SNHL). They highlight the well-established potential severity of maternal primary infection, especially when acquired in early pregnancy. The global prevalence of congenital CMV (cCMV) is around 0.7%, with 15% to 20% of affected neonates developing long-term sequelae. In high-income countries, approximately half of infected neonates acquire the infection after maternal primary infection (PIM), and the other half after non-primary infection (reactivation or reinfection). Most neurological and SNHL damage stems from maternal infection occurring before 14 weeks of gestation. The article notes that 20-30% of children exposed in utero to CMV following maternal seroconversion in early pregnancy will develop neurological sequelae.

While acknowledging that primary prevention through hygiene counseling is challenging to implement effectively on a large scale, Favre et al. (2025) argue that its impact could be significantly enhanced if pregnant women were aware of their serological status. They strongly assert that secondary prevention, following maternal seroconversion, is both feasible and effective. Currently, universal serological screening for CMV in early pregnancy has been implemented in countries like Italy and Greece based on expert recommendations, although France has not yet adopted such a policy, despite the issue being under scrutiny.

The authors point out that CMV’s prevalence is notably higher than other common congenital pathogens and, unlike other infections which have declined, CMV’s worldwide prevalence has not decreased over the past 60 years. Primary CMV infection can affect up to 10% of seronegative parous women, especially those with a child aged 2-3 years, a demographic identified as exceptionally high-risk.

In France, prenatal diagnosis typically involves amniocentesis following either maternal seroconversion or the detection of suggestive fetal features during routine antenatal ultrasound examinations. These suggestive features include:

  • Intrauterine growth restriction (IUGR).
  • Echogenic bowel.
  • Various effusions.
  • Hepatosplenomegaly and liver calcifications.
  • Placentomegaly.
  • Oligo- or polyhydramnios.
  • Cerebral abnormalities such as ventriculomegaly, microcephaly, hydrocephaly, abnormal midline, posterior fossa, and cerebellum findings. While there has been an increase in amniocenteses performed due to such ultrasound findings, the detection rate of cCMV remains modest, around 3%. The authors contend that this trend, while reflecting increased awareness, often leads to unnecessary fetal sampling due to the inherently poor sensitivity of routine ultrasound in predicting symptomatic neonatal outcomes (around 25%). Maternal CMV serology, if systematically performed, could effectively detect primary maternal CMV infection early, potentially reducing these unwarranted procedures.

A crucial argument for universal screening, from the perspective of pregnant women, is that it would alleviate the current situation where most women are unaware of their risk and thus unable to make informed decisions. Implementing systematic screening would uphold the principle of horizontal equity, ensuring that all pregnant women receive information about severe fetal CMV infection, enabling them to consider options like termination of pregnancy where legally permitted.

Regarding interventions, the article highlights the significance of early valaciclovir treatment, which has been shown to reduce the risk of sequelae in newborns by one-third. An individual patient data meta-analysis by Chatzakis et al. (2024) provides higher-level evidence, confirming that a dosage of 8 g/d of oral valacyclovir significantly reduced the vertical transmission rate of CMV (adjusted odds ratio, 0.34) and the rate of neonatal infection (adjusted odds ratio, 0.30) following primary maternal infection acquired periconceptionally or in the first trimester. This high-dose regimen was also found to be associated with a low incidence of severe side effects (2.1%). Pharmacokinetic studies have shown that this 8 g/d regimen achieves expected concentrations in both maternal and fetal blood. Importantly, no maternal, fetal, or neonatal adverse effects were reported in a phase II trial treating over 60 women for a median of 90 days with this dosage.

Furthermore, the authors state that research has demonstrated that systematic CMV screening for first-trimester CMV infection is cost-effective and even cost-saving when combined with timely valaciclovir treatment. This economic benefit, coupled with the potential to reduce severe long-term sequelae in children, underscores the compelling case for reevaluating current screening practices.

Key Aspects of CMV Infection and its Impact:

The report acknowledges that while CMV infection is often asymptomatic or mild, it can be potentially severe when acquired in utero, leading to serious sequelae in the fetus. Congenital CMV (cCMV) infection occurs in approximately 0.39% of live births and 0.43% of fetuses in France. Complications, including intrauterine death or moderate to severe anomalies (such as hearing loss), occur in about 10% to 18% of fetal infections. CMV is recognized as a major cause of congenital sensorineural hearing loss (SNHL) and neurological damage, accounting for 5% to 6% of childhood hearing loss cases.

From a public health perspective, the report states that while the impact of congenital CMV can be individually severe, its consequences are considered modest at a population level in terms of numbers. An estimated 1 to 6 severe sequelae per 100,000 newborns are attributed to cCMV in France. The incidence of maternal primary infection (PIM) and overall CMV seroprevalence in mothers appears to be decreasing. It’s noted that roughly half of cCMV cases follow maternal PIM, and the other half result from non-primary infections (reactivation or reinfection). Severe damage, particularly neurological and SNHL, is mostly associated with maternal infection occurring before 14 weeks of gestation.

Evaluation of Screening Criteria:

The HCSP conducted a systematic literature review from 2017 to late 2023, analyzing 294 relevant articles against established screening criteria from organizations like the WHO.

  • Primary Prevention (Hygiene Measures): The report emphasizes that hygiene measures are the only proven effective primary prevention strategy in the absence of a vaccine. However, the application of these measures is suboptimal in France; only 16% of women reported receiving advice on CMV prevention. Studies indicate that clear information can significantly reduce seroconversion rates. Key hygiene messages include avoiding sharing food, drinks, or utensils with young children, not putting a child’s pacifier in one’s mouth, and careful handwashing after contact with infected fluids. The report concludes that promotion of hygiene measures must be reinforced through new information campaigns targeting both professionals and families.
  • Reliability of Diagnostic Tests: Diagnosing PIM requires a combination of serological tests (IgG, IgM, IgG avidity), and sometimes viral load. Confirmation of fetal infection typically involves amniocentesis for PCR testing of amniotic fluid, ideally performed 6 to 8 weeks after maternal infection and from 17-20 weeks of gestation for maximum sensitivity (over 98%). While the intrinsic performance of these tests is good (96-100% sensitivity and specificity), the report highlights that universal screening would lead to a high number of false positives due to the low incidence of PIM in the general pregnant population. This would necessitate many additional, often unnecessary, confirmatory tests.
  • Efficacy and Safety of Therapeutic Interventions (Valacyclovir): The availability of valacyclovir has been a significant point of discussion. Only one randomized controlled trial (Shahar-Nissan et al.) was identified that compared valacyclovir (8g/day) to placebo for PIM in early pregnancy. This study showed a reduction in maternal-fetal transmission (Odds Ratio = 0.29 [0.09-0.90]) but did not demonstrate efficacy for periconceptional PIM (infections acquired before 5 weeks of gestation). Crucially, the trial’s primary outcome was vertical transmission, not the reduction of neurosensory sequelae in the child, for which no data have yet been published.

Safety concerns regarding high-dose valacyclovir are also raised. The 8g/day dosage is significantly higher than doses for other indications (1.5-3g/day). Acute kidney injury was reported in 1.7% to 4% of cases in various studies, necessitating weekly renal function monitoring and increased hydration. While current data on fetal toxicity from human pregnancies are largely reassuring, they are based on a limited number of exposures. The report concludes that no treatment has demonstrated sufficient efficacy and safety for routine systematic use in a screening program. It cautions against exposing a large number of fetuses to a treatment without proven efficacy and potential side effects.

  • Duration of the Pre-clinical Phase (Time Window for Intervention): Most maternal CMV infections are asymptomatic, making early detection challenging. For a theoretical treatment to be effective, PIM would need to be detected before 13 weeks of gestation to allow a minimum of 7 weeks of valacyclovir treatment before amniocentesis. However, in practice, it takes 3 to 5 weeks from contamination to the start of treatment, meaning only PIMs occurring between 5 and 8-10 weeks of gestation would fall within this narrow therapeutic window. This timeframe is considered too short and unreliable for a systematic screening program to be consistently effective.
  • Cost-effectiveness and Acceptability (Healthcare System & Patients): Modeling studies on the cost-effectiveness of universal CMV screening have not reached a consensus, with some indicating it would not be cost-effective. The implementation of systematic screening would also lead to a significant increase in workload for healthcare professionals and diagnostic centers, potentially straining resources.

From the patient’s perspective, a large majority of women are unaware of cCMV. The report notes that current information provided to pregnant women is often insufficient or poorly delivered. This lack of clear information, combined with the complexity of diagnostic results, can lead to increased anxiety and a rise in requests for pregnancy terminations (IVG/IMG), even in the absence of severe fetal findings. The number of IMG for infections (mostly CMV) has increased in France, reaching 8.64 per 100,000 births, which is significantly higher than the expected rate of severe sequelae.

Overall Conclusion and Recommendations:

The HCSP’s comprehensive review leads to the unequivocal conclusion that, based on current knowledge and the **lack of demonstrated efficacy of screening on cCMV sequelae, ** systematic screening for primary CMV infection in pregnant women cannot be recommended.

The report highlights that no other country currently recommends universal prenatal CMV screening. The main reasons for this stance include the relatively low frequency of severe pathology at a population level and, critically, the absence of a therapeutic intervention with proven efficacy in preventing sequelae. The observed increase in IMG rates following CMV diagnosis is also cited as a significant negative consequence of “spontaneous” screening.

The HCSP maintains its 2018 recommendation against systematic screening. Instead, it strongly recommends:

  • Strengthening efforts to promote hygiene measures for primary prevention of CMV infection among pregnant women and their families. This includes multi-support communication campaigns.
  • Developing further research to address existing uncertainties, specifically:
    • Randomized therapeutic trials to assess the effectiveness of treatments like valacyclovir on sequelae.
    • Health economic studies.
    • Longitudinal cohort studies comparing infected and non-infected women and children.
    • Epidemiological data updates on CMV in the general French population.
    • Social science studies on the perception of screening benefits and risks.
    • Pharmacovigilance studies on the adverse effects of high-dose valacyclovir in pregnant women and exposed children.
  • Accompanying the report’s publication with targeted communication to healthcare professionals and associations involved in maternal and child health.

Ultimately, the HCSP asserts that it is not currently possible to expose a large number of women and fetuses to a treatment that has not proven its efficacy, especially when potential side effects exist.

Background and Significance of cCMV: Congenital CMV infection is recognized as the most common congenital infection, with an incidence ranging from 0.2% to 2.2%. It is also the leading non-genetic cause of congenital deafness, accounting for approximately one-third of all cases. Furthermore, congenital CMV infection is a significant contributor to neurological defects, affecting around 8,000 infants annually in the USA. The vertical transmission rate after a primary maternal CMV infection during pregnancy is approximately 40%. The virus initially infects the placenta, which acts as a temporary barrier, but eventually crosses it to replicate in fetal kidney tubular epithelium and is then excreted into the amniotic fluid. This mechanism forms the basis for prenatal diagnosis via CMV DNA detection in amniotic fluid, a crucial step for managing pregnancy, including in-utero treatment and planning postnatal care.

Objectives of the Study: The primary objective of this individual patient data meta-analysis was to compare pregnancies with a negative amniocentesis result to those with a positive result regarding the frequency of fetal insults and long-term sequelae. The study specifically aimed to assess:

  • The rate of severe symptoms at birth, defined as neurological symptoms or multiorgan involvement.
  • The rate of severe sensorineural hearing loss (SNHL) and/or neurodevelopmental impairment at follow-up. The secondary outcome focused on the rate of pregnancy termination due to CMV-associated central nervous system (CNS) findings or multiorgan involvement observed on ultrasound or magnetic resonance imaging (MRI).

Methodology: The researchers conducted a systematic search of electronic databases including MEDLINE, Scopus, The Cochrane Library, and “gray literature” sources, with the last search performed in June 2022. The search was limited to observational studies published in European languages that reported amniocentesis results alongside neonatal and/or long-term outcomes of the offspring. Key search terms included “cytomegalovirus,” “congenital,” “fetal,” “maternal,” “amniocentesis,” “diagnosis,” and “symptomatic”.

Data extraction and quality assessment were performed independently by two authors, using the Newcastle–Ottawa Scale (NOS) to evaluate the methodological quality of non-randomized studies. The NOS assesses study quality across three broad groups: selection of study groups, comparability of groups, and ascertainment of exposure or outcome. For this study, all included studies received maximum stars for “selection of the non-exposed cohort” and “comparability” as all individuals shared the same exposure (maternal CMV infection).

Key Results: The systematic review and meta-analysis ultimately included seven observational studies after an initial yield of 14,783 potential studies. Five of these studies were prospective, and two were retrospective.

  • False-Negative Rate of Amniocentesis: The pooled false-negative rate of amniocentesis (defined as neonates shedding CMV in urine despite a negative amniocentesis result) was 0% (95% CI, 5.0–13.0%). This highlights that a negative amniocentesis does not entirely rule out vertical transmission.
  • Severe Neonatal Symptoms:
    • In fetuses with a negative amniocentesis result, the pooled rate of severe symptoms at birth was 0.0% (95% CI, 0.0–1.0%).
    • In fetuses with a positive amniocentesis result, this rate was 22.0% (95% CI, 11.0–38.0%).
    • The pooled odds ratio (OR) for severe neonatal symptoms following a negative vs. positive amniocentesis was 0.03 (95% CI, 0.01–0.10).
  • Severe SNHL and/or Neurodevelopmental Impairment:
    • For fetuses with a negative amniocentesis result, the pooled rate of severe SNHL and/or neurodevelopmental impairment at follow-up was 0.0% (95% CI, 0.0–1.0%).
    • For those with a positive amniocentesis result, this rate was 14.0% (95% CI, 7.0–26.0%).
    • The pooled OR was 0.04 (95% CI, 0.01–0.14).
  • Pregnancy Termination due to Severe Fetal Findings:
    • In fetuses with a negative amniocentesis result, the pooled rate of pregnancy termination due to CMV-associated CNS findings or multiorgan involvement on imaging was 0.0% (95% CI, 0.0–2.0%).
    • In fetuses with a positive amniocentesis result, this rate was 20.0% (95% CI, 10.0–36.0%).
    • The pooled OR was 0.03 (95% CI, 0.01–0.08).
  • Subgroup and Sensitivity Analyses:
    • A subgroup analysis focusing solely on pregnancies with primary CMV infection (n = 526) yielded very similar results. The pooled rate of severe symptoms at birth for negative amniocentesis was 0.0% (95% CI, 0.0–1.0%), compared to 19.0% (95% CI, 14.0–26.0%) for positive results. Similarly, the pooled rate of severe SNHL and/or neurodevelopmental impairment for negative amniocentesis was 0.0% (95% CI, 0.0–1.0%), compared to 16.0% (95% CI, 8.0–29.0%) for positive results.
    • A sensitivity analysis including only prospective studies also showed identical results to the main analysis for all three key outcomes (severe symptoms at birth, severe SNHL/neurodevelopmental impairment, and pregnancy termination).

Discussion and Interpretation: The study’s findings collectively indicate that a negative amniocentesis result in pregnant women with CMV infection strongly correlates with the absence of severe fetal insult and long-term sequelae in the child. This holds true even if vertical transmission of CMV has occurred, as evidenced by the 8.0% false-negative rate where CMV was detected postnatally despite a negative amniocentesis, yet without severe outcomes.

The authors explain that the placenta typically serves as a barrier, and CMV takes approximately 7 weeks from initial maternal contact to cause placental and subsequent fetal infection. The virus then replicates in fetal kidneys and is excreted into the amniotic fluid. This biological timeline underpins the recommendation by the International Society of Ultrasound in Obstetrics and Gynecology that amniocentesis should be performed at least 8 weeks after the initial maternal infection and ideally after 18–20 weeks of gestation to maximize diagnostic accuracy. While cases of neonatal cCMV infection following a negative amniocentesis exist, this meta-analysis demonstrates that these instances are not associated with severe clinical manifestations or adverse long-term neurosensory outcomes.

The robustness of these conclusions is supported by the consistent findings across subgroup analyses (primary CMV infection only) and sensitivity analyses (prospective studies only), indicating that these results are not significantly influenced by variations in study design or maternal infection type.

Conclusion: The authors unequivocally conclude that a negative amniocentesis result in pregnant women with CMV infection provides strong reassurance regarding the absence of severe fetal insult and long-term sequelae for the child. This implies that even if CMV transmission has technically occurred, as observed in cases with false-negative amniocentesis results, the likelihood of severe consequences for the child is negligible. This finding is significant for prenatal counseling and management, reinforcing the prognostic value of amniocentesis in stratifying risk and guiding decisions related to pregnancy continuation and intervention.

This study aims to provide crucial in vivo pharmacokinetic parameters, essential for optimizing therapeutic strategies and understanding the drug’s efficacy and safety in this sensitive population.

Background and Rationale for Valacyclovir Use: Congenital CMV infection remains the most common congenital infection and the leading non-genetic cause of sensorineural hearing loss (SNHL) [Summary of Chatzakis 2023, 10, 33]. It can lead to severe neurological defects and other long-term sequelae in affected infants [Summary of Chatzakis 2023]. The vertical transmission rate after a primary maternal CMV infection (CMV-MPI) can be substantial, around 40% [Summary of Chatzakis 2023]. Therefore, interventions aimed at preventing this transmission are of significant clinical interest.

Valacyclovir, an antiviral agent, has been investigated for its potential to prevent vertical transmission following CMV-MPI. The specific dosage of 8 grams per day (8 g/day), often administered in two 4-gram doses or four 2-gram doses, was initially chosen due to its demonstrated effectiveness in preventing CMV disease in CMV-negative renal transplant patients receiving CMV-positive grafts. The hypothesis supporting its use in pregnancy considers the fetus as a host and the mother as a graft, aiming to reduce maternal viral load, prevent vertical transmission, and mitigate fetal CMV infection and disease. Prior research indicated that valacyclovir 8 g/day could reduce transplacental passage of the virus by 70%. However, comprehensive pharmacokinetic data for this high dose specifically within pregnancy have been lacking.

Challenges and Knowledge Gaps Highlighted by Other Sources: The broader context of CMV management, as described by other sources, underscores the importance of this PK study. For instance, the French Haut Conseil de la Santé Publique (HCSP) report from December 2023 explicitly does not recommend universal CMV screening during pregnancy. A key reason cited is the unknown efficacy and risks of prolonged high-dose valacyclovir treatment on fetal outcomes. The HCSP report highlights several methodological weaknesses in the pivotal randomized trial by Shahar-Nissan et al. (2020), which suggested an efficacy of valacyclovir on vertical transmission. Specifically, the HCSP noted that the main outcome of that study (vertical transmission) was not the most pertinent, as the critical concern is the prevention of severe neuro-sensory sequelae in the child, for which data are still missing. Moreover, the HCSP raised concerns about the maternal safety profile of the 8 g/day dose, noting reports of acute kidney injury (AKI), particularly with a 4g/12h regimen. This pharmacokinetic study directly addresses the need for a better understanding of the drug’s exposure, a foundational element required to confidently evaluate its benefit-risk ratio.

Objectives of the Current Study: The primary objective of this population PK study was to quantify maternal and fetal valacyclovir exposure by establishing comprehensive pharmacokinetic parameters in vivo. By detailing how the drug behaves within the maternal and fetal compartments, the study aims to provide a better understanding of the therapy’s mechanism and to inform the refinement of optimal therapeutic management for maternal CMV seroconversions and fetal CMV infections during pregnancy.

Methodology: This was a population pharmacokinetic (popPK) study assessing the use of valacyclovir 8 g/day in CMV-infected pregnant women. The study participants were pregnant women with confirmed CMV-MPI. Maternal seroconversion was biologically verified at a national reference center using IgG, IgM, and IgG avidity testing. The timing of maternal infection was estimated using a standardized algorithm, defining periconceptional (approximately 3 months before conception) and first trimester (0-14 weeks of amenorrhoea) periods.

All participants received oral valacyclovir at a dose of 8 g/day. The administration regimen varied: 81.5% of patients received 2g every 6 hours (2g/6h), while 18.5% received 4g every 12 hours (4g/12h). Amniocentesis was performed at a median gestational age (GA) of 17.4 weeks (range 16.7–23.6 weeks), following a median treatment duration of 35 days (range 7–90 days). Fetal infection was assessed by CMV PCR on amniotic fluid samples. Notably, all ultrasound findings related to the placenta, amniotic fluid, and fetal weight (all eutrophic) were reported as normal for the study cohort.

Key Findings:

  • Vertical Transmission Rate: Despite maternal valacyclovir treatment, 12 out of 122 (9.8%) amniotic fluid samples were CMV PCR positive, indicating that vertical transmission had occurred. This rate is notable when compared to the 8.0% false-negative amniocentesis rate previously reported in cases where neonatal CMV infection occurred without severe outcomes [620, Summary of Chatzakis 2023].
  • Maternal Pharmacokinetic Parameters (Median and Range):
    • Area Under the Curve (AUCmat, 0–24 h): 570.2 µmol.h/L (range: 297.6–1282.4).
    • Minimum Concentration (Cminmat): 9.6 µmol/L (range: 0.3–38.6).
    • Maximum Concentration (Cmaxmat): 40.7 µmol/L (range: 27.1–87.9).
  • Amniotic Fluid Pharmacokinetic Parameters (Median and Range):
    • Area Under the Curve (AUCAF, 0–24 h): 562.4 µmol.h/L (range: 293.6–1229.2).
    • Minimum Concentration (CminAF): 21.2 µmol/L (range: 9.3–48.8).
    • Maximum Concentration (CmaxAF): 25.4 µmol/L (range: 13.4–52.8).
  • Comparison Between Transmitters and Non-Transmitters: The study did not find a clear difference in median maternal or fetal PK parameters (AUC, Cmin, Cmax) between pregnant women who transmitted the virus to their fetuses and those who did not. This suggests that the achieved drug exposure levels were similar irrespective of transmission outcome within the cohort.
  • Fetal Ultrasound Findings: All placental, amniotic fluid, and fetal weight assessments via ultrasound were reported as normal for the entire cohort. This finding, while not a direct PK result, provides reassuring clinical context regarding the absence of overt fetal insults in the studied population treated with valacyclovir.

Discussion and Implications: This study represents a significant contribution by providing the first in vivo quantification of valacyclovir PK parameters in both maternal and fetal compartments during pregnancy for the 8 g/day dose. This data is invaluable for understanding the systemic exposure of the drug in this specific population.

The observed 9.8% vertical transmission rate despite treatment indicates that valacyclovir, at the current dosing, does not completely eliminate the risk of transmission. This finding is particularly important when juxtaposed with previous research indicating that a negative amniocentesis (even if a false negative for transmission) correlates with a 0% rate of severe neonatal symptoms or long-term sequelae. While this PK study does not evaluate the clinical outcomes of these 9.8% transmissions, it emphasizes that even with therapeutic levels, some transmissions can still occur.

The finding that PK parameters did not significantly differ between transmitters and non-transmitters suggests that simply achieving a certain drug concentration within the measured ranges may not be the sole determinant of transmission prevention. This implies that other factors, such as viral load dynamics, maternal immune response, the exact timing of infection relative to treatment initiation, or variations in viral strains, might play a crucial role in vertical transmission. This insight is critical for refining future treatment protocols, potentially leading to more personalized or adaptive dosing strategies.

Furthermore, the data from this study provides a concrete basis for addressing the concerns raised by health authorities like the HCSP regarding the safety and efficacy of high-dose valacyclovir. While this PK study itself did not report on maternal adverse events, other sources have highlighted the risk of acute kidney injury (AKI) with the 8 g/day dose, particularly when administered in two large doses. The detailed PK data from this study will be essential for future modeling and clinical trials to determine optimal dosing regimens that maximize efficacy while minimizing maternal and fetal risks. The observation of normal ultrasound findings in the cohort provides some preliminary reassurance regarding the lack of immediate detectable fetal harm, although long-term follow-up of exposed children, as emphasized by the HCSP, remains critical.

Conclusion: This pharmacokinetic study successfully established maternal and fetal valacyclovir exposure parameters at the 8 g/day dose in pregnant women with primary CMV infection. These novel in vivo data are fundamental for a deeper understanding of valacyclovir’s pharmacological behavior during pregnancy. The findings suggest that while high concentrations are achieved in both maternal and amniotic fluid compartments, the measured drug exposure alone does not fully differentiate between cases of vertical transmission and non-transmission. This study’s contribution is vital for informing future clinical trials and refining optimal therapeutic management strategies for congenital CMV, aiming to balance efficacy in preventing transmission and severe sequelae with the safety of the pregnant mother and fetus, addressing a key need identified by international health bodies.

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.

The DGS specifically sought clarification on three key points: the distinction of clinical benefit (service médical rendu, SMR) between the first trimester and other trimesters, the role of valaciclovir in the management strategy, and the identification of specific sub-populations that might benefit from intervention (e.g., young mothers with a first young child).

Context of CMV Infection in Pregnancy CMV is a ubiquitous DNA virus belonging to the Herpesviridae family, with humans as its reservoir. It can be transmitted naturally through bodily fluids like blood, saliva, nasal mucus, cervico-vaginal secretions, semen, urine, and breast milk. While often asymptomatic or causing minor clinical consequences in infected individuals, CMV infection can be significantly severe if acquired in utero, leading to serious sequelae in the newborn, such as hearing disorders or neurodevelopmental impairments. In France, these severe complications affect approximately 1 to 6 newborns per 100,000 births. The rate of sequelae, regardless of severity, can range from 29% when vertical transmission occurs periconceptionally (around the time of conception) to 40% when it occurs in the first trimester.

Current Therapeutic Landscape and Previous Recommendations As of 2025, no antiviral medication has marketing authorization (AMM) specifically for the prevention of primary maternal CMV infection (PIM) during pregnancy. Despite this, valaciclovir, an antiviral drug, is increasingly being used in clinical practice for this indication. The product characteristics (RCP) of valaciclovir state that data on its use during pregnancy are limited. However, the CRAT (Centre de Référence sur les agents tératogènes) notes that extensive data exist for valaciclovir exposure in the second and third trimesters for curative treatment, and no teratogenic effect attributable to valaciclovir has been identified in the first trimester, regardless of dosage. High-dose valaciclovir (8 g/day) requires adequate hydration and monitoring of maternal renal function.

Prior to this HAS evaluation, French public health recommendations (from ANAES in 2004, and the Haut Conseil de la santé publique – HCSP – in 2018 and 2023) did not recommend systematic CMV screening during pregnancy. This position was primarily based on the lack of proven efficacy of antiviral treatments for preventing mother-to-fetus transmission and/or its sequelae, and the unfavorable benefit-risk ratio of such screening. The HCSP’s 2023 report, even after considering the Shahar-Nissan (2020) randomized trial and meta-analyses (D’Antonio et al., 2023; Chatzakis et al., 2024), which suggested a reduction in vertical transmission, still maintained its non-recommendation. This was due to persistent uncertainties regarding the efficacy and risks of prolonged high-dose valaciclovir on fetal outcomes. The HCSP also highlighted that, at the time of their report’s finalization, no other country systematically recommended generalized CMV screening for pregnant women.

International Landscape of Screening Recommendations The international stance on systematic CMV screening remains varied. As of December 2023, Italy is the only country that recommends systematic CMV screening for pregnant women. This recommendation references the effectiveness of valaciclovir treatment based on a randomized controlled trial. In contrast, a preliminary literature review for this roadmap found no other countries with systematic screening recommendations. As of 2024, Australia and Canada propose targeted screening (e.g., based on ultrasound signs or maternal risk factors), while the United Kingdom and Germany do not recommend systematic screening. Some expert groups, like the European Congenital Cytomegalovirus Initiative (ECCI), suggest that screening relevance should be evaluated per country based on local epidemiology and cost-effectiveness.

Medico-Economic and Ethical Considerations Recent medico-economic evaluations (2022-2023) have explored the cost-effectiveness of systematic CMV screening with subsequent valaciclovir treatment. A French study from 2023 suggested a benefit from systematic screening. However, international studies have yielded more nuanced conclusions, with some suggesting cost-effectiveness while others do not, depending on the thresholds and modeling assumptions. The HAS report emphasizes that the conclusions of these studies are not directly transferable to France due to different evaluation criteria and cost structures.

Ethical considerations are central to the debate on systematic screening. The primary ethical interrogations include:

  • How to guarantee informed consent when information about the screening and its consequences (e.g., variable and unpredictable outcomes of materno-fetal transmission, long-term unknown effects of valaciclovir) is uncertain.
  • The risk of “routinization” of screening potentially leading to pregnant women delegating their autonomy to healthcare providers.
  • Ensuring the principle of beneficence and non-maleficence for the mother, fetus, and family, especially concerning the psychological well-being of the pregnant woman and minimizing decision-making conflicts regarding pregnancy continuation.
  • The potential increase in medical terminations of pregnancy (IMG) due to the identification of fetal infection, as observed in countries like Israel and Italy when screening was implemented outside recommendations.

HAS Evaluation Methodology The HAS evaluation for this roadmap builds upon the HCSP’s 2023 report and integrates new data and analyses. The comprehensive methodology includes:

  • A qualitative analysis of the HCSP 2023 report, identifying areas for update or further investigation, particularly regarding valaciclovir efficacy.
  • A panorama of international recommendations to understand global practices.
  • An evaluation of the performance of diagnostic tests for CMV.
  • An analysis of the effectiveness of preventive hygiene measures.
  • A re-evaluation of valaciclovir’s efficacy on vertical CMV transmission and its safety during pregnancy, focusing on studies published after 2020, including a rigorous statistical method (Röver and Friede’s hierarchical normal-normal model) to combine randomized trial data with observational studies.
  • An economic evaluation of screening and treatment strategies.
  • A study of French practices regarding CMV screening and valaciclovir prescription using national health data (SNDS) for 2022 and 2023, noting an increase and spread of valaciclovir prescriptions for CMV during pregnancy.
  • An in-depth ethical analysis of systematic screening, guided by the four principles of Beauchamp and Childress (beneficence, non-maleficence, autonomy, and justice).
  • Consultation with stakeholders, including patient associations (e.g., Fondation pour l’audition, CIANE, Chanter-Marcher-Vivre) and professional bodies, to gather their perspectives on hygiene measures, screening scenarios, and the associated benefits and challenges.

The HAS highlights that while valaciclovir treatment (8g/day) appears effective in preventing vertical transmission based on an enrichment analysis combining the Shahar-Nissan randomized trial with four observational studies, and has good maternal tolerance, its long-term safety and effects on fetal/newborn outcomes (frequency and severity of complications) remain uncertain and require further large-scale, robust studies.

The HAS recommends implementing a systematic national screening program for all pregnant women with negative or unknown serological status for CMV, with a re-evaluation after three years. This recommendation is based on the potential burden of CMV infection, the existence of a plausible and increasingly accepted treatment (valaciclovir) that reduces vertical transmission, and the need to address the existing disparities in practice. However, the HAS also stresses the need for further studies to address persistent uncertainties regarding national epidemiological data, long-term valaciclovir safety, its effect on fetal/newborn complications, and the overall performance of the testing sequence. Additionally, transparent and comprehensive information must be provided to pregnant women regarding the benefits, risks, and remaining uncertainties of screening.

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.

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.

Context and Rationale for the Study

CMV is a widespread virus that, while often asymptomatic, can cause severe, potentially disabling neurosensory sequelae in fetuses when acquired by the mother during pregnancy, particularly during primary infection. Historically, French health authorities, including ANAES (2004) and HCSP (2018, 2023), did not recommend systematic CMV screening during pregnancy. This stance was primarily due to the lack of strong evidence for effective antiviral treatments to prevent mother-to-fetus transmission or subsequent complications.

However, the landscape has been evolving. New scientific publications, particularly the Shahar-Nissan randomized trial published in 2020, suggested a potential benefit of valaciclovir in preventing vertical transmission. Furthermore, a new social security financing law and increasing clinical practices (despite no formal recommendation or marketing authorization for valaciclovir in this indication) prompted a re-evaluation by the Direction générale de la Santé (DGS). This specific methodology document addresses one of the DGS’s direct requests: to understand “the place of valaciclovir in the management strategy”. The study aimed to provide concrete data on how valaciclovir was actually being prescribed and dispensed for CMV during pregnancies in France, a practice that was already diffusing but without a regulated framework.

Objectives of the Study

The primary objective of this study was to assess the frequency of valaciclovir use in France for the treatment of primary CMV infection among women who gave birth in 2022 and 2023.

The secondary objectives aimed to provide a more detailed understanding of these practices, including:

  • Characterizing the prescribers of valaciclovir for CMV infection during pregnancy (e.g., their mode of practice, medical specialty, and geographical location).
  • Describing the diffusion of prescription practices across French territories and over time.
  • Identifying the gestational period at which valaciclovir treatment was initiated.

Methodology

  1. Study Design and Data Source:
    • This was an observational study based on medico-administrative databases.
    • The primary data source was the Système National des Données de Santé (SNDS), which includes comprehensive data from the Données de Consommation Inter-Régimes (DCIR) for medication dispensing in city pharmacies and the Programme de Médicalisation des Systèmes d’Information (PMSI) for hospital activities.
  1. Study Population:
    • Inclusion Criteria: All women who gave birth in France (including overseas departments and regions – DROMs: Martinique, Guadeloupe, Guyane, La Réunion, Mayotte) in 2022 and 2023, aged between 18 and 50 years, and who delivered in a Medicine-Surgery-Obstetrics (MCO) establishment.
    • Exclusion Criteria: To ensure data quality and relevance to CMV primary infection in viable pregnancies, the study excluded voluntary terminations of pregnancy (IVG), medical terminations of pregnancy (IMG) before 22 weeks of amenorrhea (SA), early spontaneous miscarriages, inconsistencies in multiple birth dates, and pregnancies associated with provisional or erroneous social security numbers. This was important as the number of IMG for CMV is generally low.
  1. Defining the Target Population (Valaciclovir for CMV):
    • A key methodological challenge was that the specific indication for medication prescriptions is not available in the SNDS. Therefore, direct identification of valaciclovir use specifically for CMV infection was not possible.
    • To overcome this, the study relied on a “high-dose” criterion: a treatment was considered to be for CMV primary infection if at least one valaciclovir dispensing during pregnancy was equal to or greater than 100 grams.
    • Rationale for the 100g Threshold: This threshold was chosen based on clinical practice, where high doses of valaciclovir (typically 8g/day) are used for CMV, contrasting with lower doses (1.5g to 3g/day) commonly used for other herpesvirus infections like Herpes Simplex Virus (HSV) or Varicella-Zoster Virus (VZV). The document includes a figure illustrating how this threshold helps distinguish between “low dose” (likely HSV/VZV) and “high dose” (likely CMV) groups.
  1. Data Collection and Variables:
    • The study identified valaciclovir dispensations from city pharmacies (hospital dispensations are generally not included, though hospital prescriptions dispensed in city pharmacies are).
    • For each identified pregnancy, the study collected the total quantity of valaciclovir dispensed and the number of dispensations.
    • Initiation of Treatment: Defined as the date of the first valaciclovir dispensation during pregnancy.
    • Gestational Period: Divided into trimesters, with the first trimester defined as the first 91 days of pregnancy (first 13 weeks).
    • Prescriber Characteristics: Including their mode of practice (liberal, hospital, or public health institution), medical specialty, and location (region, department).
    • CMV IgG Avidity Test: The study also sought to identify if an IgG avidity test (NABM code 1261), used to date CMV infection, was performed prior to valaciclovir dispensation, as a way to verify the 100g dose threshold’s ability to distinguish CMV cases.

Limitations of the Study

The methodology document acknowledges several limitations inherent to using medico-administrative data:

  • Absence of Clinical Data: The SNDS lacks detailed clinical information, such as the specific reason for consultation or the results of biological examinations. This means the study could infer CMV treatment based on dose, but not definitively confirm the clinical diagnosis or the presence of a primary infection.
  • Exclusion of Hospital-Dispensed Medications: Only valaciclovir dispensed in city pharmacies was included, potentially missing treatments initiated and entirely managed within hospitals.
  • Exclusion of Out-of-Hospital Births: The study population was restricted to women delivering in MCO establishments, excluding any out-of-hospital births.
  • Low Number of Specific IMGs: While IMGs for CMV are generally rare, the exclusion of IMGs before 22 weeks of amenorrhea based on administrative codes means that a very small number of cases relevant to severe fetal outcomes might have been missed.
  • Inconsistencies in Social Security Numbers: The exclusion of cases with incorrect or provisional social security numbers could lead to a slight underestimation of the treated population.
  • Approximation of Pregnancy Start Date: Pregnancy start dates are derived from administrative data, which can be an approximation.

Despite these limitations, the study’s design aimed to provide the most comprehensive picture possible of valaciclovir use for CMV in France given the available data. The findings from this methodological approach contributed to the HAS’s decision to recommend systematic CMV screening in pregnancy, particularly by demonstrating the existing, albeit unregulated, use of valaciclovir and providing insights into the evolving real-world practices.

Pros and Cons of Systematic CMV Screening in Pregnancy

  • Previous French Non-Recommendation: Historically, French health authorities, including ANAES (2004) and HCSP (2018, 2023), did not recommend systematic CMV screening. This stance was based on the perceived absence of effective treatment and an unfavorable benefit/risk ratio. The HCSP notably highlighted concerns about the unknowns regarding the efficacy and risks of prolonged high-dose valaciclovir on fetal outcomes.
  • Uncertainties Regarding Valaciclovir’s Impact on Sequelae Severity: While valaciclovir has shown efficacy in reducing vertical transmission, studies primarily focus on this outcome rather than directly demonstrating a reduction in the severity or frequency of long-term neurosensory sequelae in infected infants.
  • Increased Number and Risks of Amniocenteses: Systematic screening is expected to lead to an increase in the number of amniocenteses, which is the reference test for fetal diagnosis. Although the risk of miscarriage associated with amniocentesis is low (less than 0.5%), any increase in invasive procedures carries inherent risks.
  • Potential for Increased Maternal Anxiety: The diagnostic process, particularly uncertain or false-positive serology results, can generate significant anxiety for pregnant women, potentially disrupting the parent-child relationship throughout pregnancy and beyond.
  • Limited Benefit for Seropositive Women: CMV screening primarily targets primary infections. Women who are already seropositive (approximately 45.6% in France) may not directly benefit from screening, even though they can still transmit the virus through reinfection or reactivation.
  • Complexity of Serological Test Interpretation: Interpreting CMV serology (IgG, IgM, and IgG avidity) can be complex, and potential for false positives or uncertainties exists, requiring expertise for accurate diagnosis and counseling.
  • Ethical Dilemmas: Systematic screening raises ethical conflicts, particularly a dilemma between beneficence (potential prevention of sequelae) and non-maleficence (potential for anxiety, risk of amniocentesis, and unknown long-term effects of treatment). There’s also a challenge in ensuring true informed consent and patient autonomy, as the “routinization” of screening might lead to a passive acceptance of tests without full comprehension of implications.
  • Lack of Global Consensus: As of June 2025, systematic CMV screening for pregnant women is not universally adopted internationally. Only Italy, Greece, and Israel recommend systematic screening, while many other countries (e.g., UK, Germany, Canada, US) do not, citing various reasons including lack of proven effective treatment.
  • Uncertainty in Cost-Effectiveness and Budgetary Impact: While some studies are favorable, the overall efficiency and precise budgetary impact of systematic screening in France remain subject to nuance and uncertainty, with international studies drawing varied conclusions due to differing methodologies and assumptions.
  • Early Identification of Primary Maternal Infection (PIM): Serological testing, especially in the first trimester, is crucial for identifying PIM, which carries the highest risk of severe fetal complications. This allows for timely intervention.
  • Enabling Preventive Measures Through Serological Status Knowledge: Knowing a woman’s serological status, particularly if she is seronegative, can reinforce adherence to hygiene measures to prevent primary infection. Informed pregnant women are more likely to adopt these preventive behaviors.
  • Availability of an Effective Treatment (Valaciclovir): Valaciclovir at a dosage of 8 g/day has been shown to reduce the rate of vertical transmission of CMV from mother to fetus, especially after primary maternal infection acquired periconceptionally or in the first trimester. This, in turn, can decrease the number of children born with sequelae.
  • Safety Profile of Valaciclovir During Pregnancy: Data collected up to October 21, 2024, indicate no safety signal or teratogenicity observed with valaciclovir use during pregnancy. Maternal side effects were generally rare and benign, with acute renal failure being a reversible, isolated case. Proper hydration and a specific dosage regimen (2g four times a day) can further reduce the risk of renal side effects.
  • Facilitating Early Fetal Diagnosis and Management: In cases of suspected or confirmed maternal PIM, systematic screening allows for comprehensive follow-up including serial ultrasounds, fetal MRI, and amniocentesis for definitive fetal diagnosis. Early detection ensures intervention within the appropriate therapeutic window.
  • Promoting Equity in Healthcare Access: By implementing systematic screening, France aims to harmonize practices and care offerings across the national territory, addressing observed regional disparities where only about one-third of pregnancies currently benefit from CMV screening.
  • Empowering Pregnant Women and Families: Systematic screening provides all pregnant women with the opportunity to detect primary maternal CMV infection, upholding the principle of horizontal equity and offering families the right to information and informed decision-making regarding their pregnancy and the potential for a child with a disability.
  • Potential for Cost-Effectiveness: Recent cost-effectiveness studies, including a French study, suggest that systematic screening followed by valaciclovir treatment could be cost-effective and potentially cost-saving by reducing the long-term costs associated with managing congenital CMV complications.
  • Recognition of the Significant Burden of CMV Infection: HAS acknowledged the considerable impact of CMV during pregnancy, including the prevalence of maternal infections, the rate of vertical transmission, and the prevalence of severe neurosensory sequelae in newborns when transmission occurs. This burden was deemed substantial enough to warrant a change in policy.
  • Consensus on Serological Test Interpretation Algorithms: The existence of a harmonized and consensual logigram for interpreting serological tests (IgG, IgM, and IgG avidity) by leading European (ECCI) and French (CNR Herpèsvirus) expert groups was a crucial factor. This provides a clear framework for diagnostic pathways.
  • Demonstrated Benefits of Knowing Serological Status: HAS recognized that providing women with their serological status offers tangible benefits. For seronegative women, this knowledge empowers them to reinforce preventive hygiene measures, which has been shown to reduce the rate of primary infection.
  • Availability and Efficacy of Valaciclovir Treatment: This was a pivotal argument for the HAS. Despite valaciclovir not having a specific marketing authorization (AMM) for this indication in France, the HAS considered the accumulated evidence supporting its efficacy in reducing vertical transmission of CMV to the fetus. This perceived efficacy strengthens the justification for screening under the principle of beneficence, as it offers a concrete intervention to reduce adverse fetal outcomes.
  • Opportunity for Timely Intervention: Integrating CMV screening into the list of mandatory first-trimester medical examinations (as per articles R. 2122-1 and R. 2122-2 of the Public Health Code) ensures that primary infections are identified early enough to allow for intervention within the optimal therapeutic window.
  • Support from Patient Associations: The favorable opinions expressed by patient associations specializing in CMV and perinatal care strongly influenced the HAS’s decision. These associations emphasized the protection of the future baby and the right of families to be informed.
  • Endorsement from Professional Councils: The favorable opinion from the National Professional Council of Infectious and Tropical Diseases (CNP MIT) regarding the prescription of valaciclovir for first-trimester CMV infection also supported the HAS’s stance.
  • Positive Economic Appraisals: While acknowledging some nuances and uncertainties, recent cost-effectiveness studies, including a French one, generally supported the economic pertinence of systematic screening followed by treatment, indicating potential long-term savings by reducing costs associated with congenital CMV complications.
  • Addressing Inequities in Current Practices: The HAS observed a growing, yet heterogeneous, practice of CMV screening in France, with significant regional disparities. A systematic national program aims to harmonize practices and ensure equitable access to prevention and care across the country.
  • Simplifying Informed Consent: The availability of a treatment simplifies the information that needs to be given to women regarding the implications of screening and the collection of informed consent, which is essential for upholding the principle of autonomy.

In essence, the HAS’s 2025 recommendation reflects a re-evaluation of the benefit-risk balance, heavily swayed by emerging evidence of valaciclovir’s efficacy in preventing vertical transmission and the ethical imperative to provide comprehensive information and intervention options to all pregnant women.

Podcast

Powerpoint presentation:
Systematic Screening for Cytomegalovirus (CMV) in early Pregnancy in France

Slide 1: Systematic Cytomegalovirus (CMV) Screening During Pregnancy in France
  • A Major Shift in French Perinatal Health Policy
  • Focus on the Haute Autorité de Santé (HAS) Recommendation of June 5, 2025
  • Addressing the Most Common Congenital Viral Infection
  • Preventing Severe Long-Term Sequelae in Newborns
Slide 2: Understanding CMV: A Ubiquitous Virus
  • CMV is an ubiquitous DNA virus belonging to the Herpesviridae
  • Infected individuals are continuous viral reservoirs, excreting the virus in various bodily fluids (saliva, urine, breast milk, etc.).
  • Often asymptomatic in healthy individuals, but can cause severe illness in immunocompromised persons.
  • Maternal infection is a proxy for fetal infection since the virus can cross the placenta throughout the pregnancy
  • Viral variability allows for reinfections with different strains, adding complexity to management [Video Synthesis].
Slide 3: CMV During Pregnancy: Primary vs. Non-Primary Infection
  • Primary Maternal Infection (PIM): Seroconversion occurs during pregnancy, posing the highest risk of severe fetal complications when occurring between 8 weeks before and 12 weeks’ after conception.
  • Non-Primary Maternal Infection: Involves reactivation of a latent virus or more commonly reinfection with a different strain.
  • Vertical transmission rates vary: PIM transmission ranges from 20% to 70% depending on the trimester, while non-primary infection transmission is estimated at less than 3.5%.
  • Severe neurosensory sequelae are more common with PIM, and only when acquired in the first trimester.
 Slide 4: The Clinical Burden of Congenital Cytomegalovirus Infection
  • cCMV is the most common congenital infection worldwide, affecting 0.5% to 2% of live births [Video Synthesis].
  • It is the leading non-genetic cause of congenital sensorineural hearing loss.
  • 10% of asymptomatic newborns will develop sequelae within the first six years, primarily hearing loss and, less commonly, neurodevelopmental delays.
  • In France, CMVc leads to 1 to 6 cases of severe sequelae per 100,000 newborns annually.
Slide 5: Historical Context in France (Pre-2025): ANAES & HCSP
  • Since 2004, French health authorities (ANAES, then HCSP) have consistently advised against systematic CMV screening during pregnancy.
  • The last HCSP report (December 2023) maintained this position, citing unresolved uncertainties.
  • This stance highlighted concerns about valaciclovir efficacy and potential risks of widespread screening.
  • The HCSP emphasized the lack of a favorable benefit-risk ratio for systematic screening compared to current management.
Slide 6: Why Systematic Screening Was Not Recommended Previously in France
  • Absence of proven effective antiviral treatment to prevent mother-to-fetus transmission or reduce sequelae.
  • Limited data on long-term safety of high-dose valaciclovir for the fetus.
  • Concerns about potential maternal anxiety and the risk of increased medical terminations of pregnancy (IMG) due to uncertain diagnoses.
  • Lack of strong scientific evidence from randomized controlled trials supporting the benefit-risk ratio of screening.
Slide 7: Current Practices in France (Pre-HAS 2025)
  • In France, systematic CMV screening was not recommended, but a targeted approach was in place.
  • Targeted screening occurred in cases of maternal clinical/biological signs, known exposure, or suggestive fetal ultrasound findings (e.g., microcephaly, ventriculomegaly, echogenic bowel, hepatosplenomegaly).
  • Despite no formal recommendation, CMV screening was already diffusing, with about a third of pregnancies undergoing it in 2022-2023.
  • Valaciclovir was being prescribed in some hospital centers for PIM, despite not having market authorization (AMM) for this indication.
Slide 8: International Landscape
  • Until December 2023, no country officially recommended universal CMV screening for pregnant women, as stated by HCSP.
  • However, Italy and Greece had already implemented universal serological screening in early pregnancy, based on expert recommendations.
  • Other countries like Australia, New Zealand, Denmark, and Germany applied targeted screening based on risk factors or ultrasound findings.
  • The lack of international consensus was largely attributed to the uncertainty surrounding valaciclovir efficacy.
Slide 9: The Pivotal HAS Opinion: June 5, 2025
  • The Haute Autorité de Santé (HAS) issued a new recommendation on June 5, 2025, marking a significant change in France.
  • Systematic national screening for CMV is now recommended for all pregnant women with negative or unknown serological status.
  • This decision was based on a multidimensional analysis, including updated scientific literature and ethical considerations.
  • The HAS specifically addressed points of contention from previous HCSP evaluations, such as treatment efficacy and ethical implications.
Slide 10: Valaciclovir Efficacy: New Evidence Supporting its Role
  • The HAS review included a robust new meta-analysis (Chatzakis et al. 2024) combining the Shahar-Nissan trial (2020) with four additional observational studies.
  • This meta-analysis, using a sophisticated Bayesian hierarchical model, demonstrated a statistically significant protective effect of valaciclovir.
  • It showed a substantial reduction (at least half) in the risk of vertical CMV transmission, with odds ratios consistently between 0.40 and 0.49.
  • Valaciclovir at 8g/day, in 4 takes of 2g, until amniocentesis, significantly reduced both mother-to-child transmission and symptomatic congenital CMV at birth.
Slide 11: Valaciclovir Safety During Pregnancy: An Updated Overview
  • The HAS reviewed valaciclovir safety data from the French national drug database (BDM) and the Reference Center for Teratogenic Agents (CRAT).
  • No signal of teratogenicity has been identified between 2007 and 2023, based on the follow-up of 970 treated pregnant women.
  • Minor maternal side effects such as digestive issues or back pain were rare and generally benign. An isolated case of reversible acute renal failure was reported.
  • The European experts (ECCI) and SPILF also support valaciclovir administration (8g/day, 4 times 2g daily) as early as possible post-diagnosis until amniocentesis, to minimize renal side effects.
Slide 12: Ethical Framework: Balancing Benefits, Risks, and Autonomy
  • Beneficence: Systematic screening enables early intervention with valaciclovir to prevent severe sequelae.
  • Non-maleficence: The HAS carefully balanced potential benefits against risks like anxiety or invasive procedures.
  • Autonomy: Emphasis on providing comprehensive and impartial information to prospective parents for truly informed choices.
  • Justice: The screening program aims to ensure equitable access to screening and follow-up care across France, addressing potential disparities.
Slide 13: Economic Evaluation: A Favorable Cost-Effectiveness Ratio
  • Recent health economic evaluations, including 2 French study by Périllaud-Dubois et al. (2023), Seror et al (2023) favored systematic screening.
  • The French study simulated a population of 800,000 pregnant women, using a 0.46% PIM incidence in the first trimester.
  • Results indicated that systematic screening followed by valaciclovir treatment was cost-effective.
  • This favorable cost-effectiveness ratio contributed significantly to the HAS’s decision [Video Synthesis].
Slide 14: Current Practices & Regional Disparities in France
  • Significant diffusion of screening practices: In 2022-2023, nearly one-third of pregnancies in France were already undergoing CMV screening.
  • Valaciclovir prescriptions increased between 2022 and 2023.
  • Geographical heterogeneity persists: Screening and treatment are concentrated in hospital settings, particularly in Ile-de-France and Pays de la Loire.
  • These findings highlighted the existing disparities in access to CMV screening and treatment across the country.
Slide 15: International Alignment and Evolving Consensus
  • The HAS decision aligns France with Israel, Italy and Greece, which already practice universal CMV screening.
  • The new HAS recommendation reflects an evolving international perspective, driven by updated scientific evidence on valaciclovir efficacy [Video Synthesis, 282, 327].
  • The European Congenital Cytomegalovirus Initiative (ECCI) consensus of experts (2024) also recommends evaluating screening pertinence based on national epidemiology.
Slide 16: The Role of Amniocentesis in CMV Management
  • Amniocentesis, performed at least 6 weeks after maternal infection and from 17 weeks of gestation onward, is the reference test for fetal CMV diagnosis via PCR.
  • It allows for confirmation of fetal infection and helps guide management decisions.
  • The HAS decision acknowledged the anticipated increase in amniocentesis procedures following systematic screening.
  • While amniocentesis carries a slight risk of miscarriage, its role in confirming infection for potential treatment benefits is crucial [Video Synthesis].
Slide 17: Implementing Systematic Screening: The New Protocol
  • The HAS recommends integrating CMV serology into mandatory medical exams during the first trimester visit.
  • The protocol involves an initial IgG and IgM serology at 12 weeks of amenorrhea (SA).
  • If seronegative (IgG and IgM negative), a repeat test at 16-18 SA is recommended.
  • If IgG and IgM are positive, an IgG avidity test is used to date the infection; a repeat avidity test is needed if the result is intermediate.
Slide 18: Information and Counseling for Expectant Parents
  • Crucial emphasis on providing complete and unbiased information to future parents.
  • Counseling should cover the benefits, risks, and remaining uncertainties regarding CMV screening and treatment.
  • Information on preventive hygiene measures is vital for seronegative women to reduce PIM risk.
  • Parents must be fully informed to make truly informed choices about screening and subsequent management options.
Slide 19: Addressing Patient Anxiety: A Key Consideration
  • The HAS acknowledged concerns about increased anxiety among pregnant women due to screening, especially with positive results.
  • Patient associations emphasize that lack of information is more stressful than knowing the risks.
  • Providing clear, honest information on prognosis, treatment, and potential sequelae is deemed essential to mitigate anxiety.
  • The goal is to shift from anxiety stemming from uncertainty to empowered decision-making based on knowledge.
Slide 20: The Indispensable Role of Healthcare Professionals
  • Healthcare professionals, including gynecologists, general practitioners, and midwives, are crucial for disseminating information.
  • They must be trained and equipped to provide comprehensive and unbiased counseling regarding CMV screening and management.
  • The HAS highlights the need to develop adapted information materials for expectant mothers.
  • This systematic screening requires a harmonized approach across the national territory to ensure equity of care.

Slide 21: Future Research: Addressing Remaining Uncertainties

  • The HAS advocates for further studies to fully address existing uncertainties.
  • Key areas for future research include updated national epidemiological data on maternal seroprevalence, and frequency/severity of neonatal and childhood complications.
  • Long-term safety of valaciclovir at larger scales and its effect on fetal/newborn infections and sequelae need further investigation.
  • Comprehensive evaluation of the overall performance of the screening test sequence (IgG, IgM, IgG avidity) is also required.

Slide 22: Patient Advocacy: Unifying Voices for CMV Screening

  • Patient associations, such as “Chanter-Marcher-Vivre” and “Pour les yeux d’Émilie,” have been vocal advocates for systematic screening.
  • They emphasize the right to know for expectant parents and the profound impact of CMVc on affected families.
  • These groups highlight the need for better and earlier information on CMV prevention and the risks of transmission.
  • The Fondation pour l’Audition specifically advocates for screening to prevent hearing loss and ensure early intervention for affected children.

Slide 23: Navigating the Landscape: Challenges and Opportunities

  • Challenges:
    • Persistent uncertainties regarding long-term valaciclovir effects and precise sequelae reduction.
    • Potential for increased maternal anxiety and medical terminations of pregnancy.
    • Need for standardized information and counseling across all healthcare settings.
  • Opportunities:
    • Early identification and potential intervention to reduce CMVc sequelae.
    • Improved patient autonomy through informed decision-making.
    • Equitable access to screening and treatment across France.
    • Alignment with international best practices in public health.

Slide 24: Conclusion: A New Era for CMV Prevention in France

  • The HAS decision of June 5, 2025, marks a historical turning point for CMV prevention in France.
  • It signifies a move towards a proactive and systematic approach, grounded in evolving scientific evidence on valaciclovir efficacy and safety.
  • This recommendation aims to reduce the burden of severe neurosensory sequelae caused by CMVc.
  • It underscores the dynamic nature of medical science and the essential role of continuous re-evaluation to achieve the best patient outcomes [Video Synthesis].

Slide 25: Key Takeaways and Future Outlook

  • Systematic CMV screening is now recommended in France for all pregnant women with negative or unknown status at the first trimester.
  • Valaciclovir is recognized as an effective treatment for reducing vertical transmission in primary maternal infections.
  • Ongoing research and close monitoring of implementation, safety, and long-term outcomes are crucial.
  • Empowering pregnant women through clear, comprehensive information and counseling remains paramount.