# Cost-effectiveness of screening and valaciclovir-based treatment strategies for first-trimester cytomegalovirus primary infection in pregnant women in France

C. Périllaud-Dubois, N. Hachicha-Maalej, C. Lepers, E. Letamendia, N.

Teissier, A. Cousien, J. Sibiude, S. Deuffic-Burban, C. Vauloup-Fellous, O.

Picone

► To cite this version:

C. Périllaud-Dubois, N. Hachicha-Maalej, C. Lepers, E. Letamendia, N. Teissier, et al.. Cost-effectiveness of screening and valaciclovir-based treatment strategies for first-trimester cytomegalovirus primary infection in pregnant women in France. Ultrasound in Obstetrics and Gynecology = Ultrasound in Obstetrics & Gynecology, 2023, 62 (4), pp.573-584. 10.1002/uog.26226 . inserm-04096700

HAL Id: inserm-04096700

https://inserm.hal.science/inserm-04096700

Submitted on 13 May 2023

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

# Cost-effectiveness of screening and valacyclovir-based treatment strategies for first-trimester cytomegalovirus primary infection in pregnant women in France

C. PÉRILLAUD-DUBOIS<fnref n="1" />,², N. HACHICHA-MAALEJ<fnref n="1" />#, C. LEPERS<fnref n="1" />#, E. LETAMENDIA³, N. TEISSIER⁴,⁵, A. COUSIEN<fnref n="1" />, J. SIBIUDE<fnref n="1" />,⁶, S. DEUFFIC-BURBAN<fnref n="1" />, C. VAULOUP-FELLOUS⁷,⁸† and O. PICONE<fnref n="1" />,⁶†

**KEYWORDS:** CMV; cost; cost-effectiveness; cytomegalovirus; effectiveness; first trimester; primary infection; screening; T1 PI; valacyclovir

## CONTRIBUTION

### What are the novel findings of this work?

In a cost-effectiveness analysis in France, the strategy of universal maternal screening for first-trimester cytomegalovirus (CMV) primary infection in conjunction with secondary prophylaxis with valacyclovir was cost-saving compared with current practice (25–50% systematic screening of pregnant women for first-trimester primary infection) and cost-effective compared with the absence of screening.

### What are the clinical implications of this work?

From a cost-effectiveness point of view, current maternal CMV screening practice in France is no longer acceptable. Universal CMV screening during pregnancy, in conjunction with valacyclovir treatment, is economically acceptable and should be offered routinely.

## ABSTRACT

**Objective** To assess the effectiveness, cost and cost-effectiveness of four screening strategies for first-trimester (T1) cytomegalovirus (CMV) primary infection (PI) in pregnant women in France.

**Methods** In a simulated pregnant population of 800 000 (approximate number of pregnancies each year in France), using costs based on the year 2022, we compared four CMV maternal screening strategies: Strategy S1, no systematic screening (current public health recommendations in France); Strategy S2, screening of 25–50% of the pregnant population (current screening practice in France); Strategy S3, universal screening (current medical recommendations in France); Strategy S4, universal screening (as in Strategy S3) in conjunction with valacyclovir in case of T1 PI. Outcomes were total cost, effectiveness (number of congenital infections, number of diagnosed infections) and incremental cost-effectiveness ratio (ICER). Two ICERs were calculated, comparing Strategies S1, S2 and S3 in terms of euros (€) per additional diagnosis, and comparing Strategies S1 and S4 in € per avoided congenital infection.

**Results** Compared with Strategy S1, Strategy S3 enabled diagnosis of 536 more infected fetuses and Strategy S4 prevented 375 congenital infections. Strategy S1 was the least expensive strategy (€98.3m total lifetime cost), followed by Strategy S4 (€98.6m), Strategy S2 (€106.0m) and Strategy S3 (€118.9m). In the first analysis, Strategy S2 was dominated and Strategy S3

Correspondence to: Dr C. Périllaud-Dubois, Virology Laboratory, Sorbonne Université, Hôpital Saint-Antoine, AP-HP, 184 Rue du Faubourg St Antoine, F-75012 Paris, France (e-mail: claire.dubois@aphp.fr)

#N.H.-M. and C.L. contributed equally to this study.

†C.V.-F. and O.P. contributed equally to this study.

Accepted: 31 March 2023

<footnote n="1">¹Université Paris Cité and Université Sorbonne Paris Nord, Inserm, IAME, Paris, France; ²Virology Laboratory, Sorbonne Université, Hôpital Saint-Antoine, AP-HP, Paris, France; ³Department of Neonatal Medicine, Université Paris-Saclay, Hôpital Antoine Béclère, AP-HP, DMU2 Santé des Femmes et des Nouveau-nés, Clamart, France; ⁴Department of Pediatric Otolaryngology, Robert Debré Hospital, AP-HP Nord, Paris, France; ⁵Université de Paris, INSERM U1141 NeuroDiderot, Inserm, Paris, France; ⁶Division of Obstetrics and Gynecology, Hôpital Louis Mourier, AP-HP Nord, Colombes, France; ⁷Université Paris-Saclay, INSERM U1193, Villejuif, France; ⁸Virology Laboratory, Université Paris-Saclay, Hôpital Paul-Brousse, AP-HP, Villejuif, France</footnote>
led to an additional €38 552 per additional in-utero
diagnosis, compared with Strategy S1. In the second
analysis, Strategy S4 led to an additional €893 per avoided
congenital infection compared with Strategy S1, and was
cost-saving compared with Strategy S2.

**Conclusions** In France, current screening practice for CMV PI during pregnancy is no longer acceptable in terms of cost-effectiveness because this strategy was dominated by universal screening. Moreover, universal screening in conjunction with valacyclovir treatment would be cost-effective compared with current recommendations and is cost-saving compared with current practice. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

INTRODUCTION

Congenital cytomegalovirus (cCMV) infection is the
leading congenital viral infection worldwide, with an
estimated incidence of between 0.2 and 1% of all live
births¹⁻³. It is a significant cause of sensorineural hearing
loss and neurodevelopmental sequelae, and, therefore,
a major public health issue⁴⁻⁷. Vertical transmission
of CMV can occur after maternal primary (PI) or
non-primary (NPI) infection, with the same fetal risk of
sequelae⁸. Maternal PI in the first trimester of pregnancy
(T1) is the main risk factor for cCMV infection with
long-term sequelae⁹⁻¹¹. Management of CMV PI during
pregnancy may soon change fundamentally, since recent
studies have shown acceptability, tolerance and benefit of
secondary prevention of cCMV infection by administering
valacyclovir to prevent vertical transmission¹²⁻¹⁵.

In France, where maternal CMV seroprevalence is
around 50%, approximately half of cCMV infections
are due to maternal PI and half to maternal NPI during
pregnancy<sup>16,17</sup>. The prevalence of cCMV infection is
estimated to be 0.4% of all live births, which represents
3200 infected neonates each year in France, of whom
500-700 will develop sequelae<sup>3,18</sup>. Currently, there are
several different recommendations concerning screening
for CMV during pregnancy: the French National Academy
of Medicine and French National College of Obstetricians
and Gynaecologists (CNGOF) support screening for
CMV (universal and targeted screening, respectively),
whereas the High Council of Public Health (HCSP)
recommends not to screen in pregnancy but to identify and
diagnose infected symptomatic neonates<sup>19-21</sup>. According
to a survey of a French public health institute<sup>22</sup>, an
estimated 25% of pregnant women are screened for CMV
in France, and almost 50% in the Paris area (current
practice). There is a lack of cost-effectiveness analyses
assessing the impact of universal maternal screening in
France, which makes it difficult to arbitrate between the
different recommendations.

The main objective of the current study, to guide future
recommendations, was to assess the effectiveness, cost and

cost-effectiveness of four maternal screening strategies for
T1 CMV PI in pregnant women in France.

METHODS

Study design

We built a deterministic decision-tree model to assess
effectiveness, cost and cost-effectiveness of different
screening strategies for maternal CMV infection and
cCMV infection, using the TreeAge Pro 2020 software
package (TreeAge Software, Inc., Williamstown, MA,
USA). We simulated a study population of 800 000
pregnant women in the French healthcare system
(the approximate number of pregnancies each year in
France)²³. We adopted a collective perspective, i.e. we
considered all resources involved in the provision of
overall care for maternal CMV and cCMV infections,
for the woman during pregnancy and for the infected
fetus/child for their entire life²⁴. The time horizon adopted
for the cost-effectiveness analysis was the life expectancy
of the child. The four maternal CMV screening strategies
considered were: no systematic screening (Strategy S1),
current screening practice (25–50% of pregnant women)
(Strategy S2), universal screening (Strategy S3) and
universal screening in conjunction with valacyclovir in
case of T1 PI (Strategy S4).

Model outcomes

To determine costs for the model, we assumed that
interventions were implemented in 2022. They were
compared in terms of effectiveness, total cost and
incremental cost-effectiveness ratio (ICER). We defined
effectiveness outcomes as follows: number of fetal cCMV
infections, number of terminations of pregnancy (TOP),
number of fetal diagnoses and number of infected
children, with and without sequelae. The total cost of
an intervention included direct medical lifetime costs
associated with maternal CMV and cCMV screening,
diagnosis, treatment for the entire cohort of pregnant
women with T1 PI infection, and direct medical costs
for care of infected children during their lifetime. The
cost-effectiveness analysis was divided into two parts.
The first analysis compared S1, S2 and S3 in terms
of euros (€) per additional diagnosis (ICER<sub>1A</sub> in €
per additional *in-utero* diagnosis and ICER<sub>1B</sub> in € per
additional *in-utero* or neonatal diagnosis), to evaluate the
value of universal screening during pregnancy. The second
analysis compared S1 and S4 in terms of € per avoided
congenital infection (ICER<sub>2</sub>), to evaluate the value of
screening in conjunction with treatment by valacyclovir
to prevent vertical transmission.

All future costs were discounted at a rate of 2.5%
per year for the first 30 years and thereafter, from
30 years to 80 years, this rate decreased linearly to
1.5%, as recommended by the French National Health
Authorities²⁴.
## Model structure (Figures 1 and S1)

During pregnancy, women are at risk of CMV infection; fetuses and children born to these women are at risk of cCMV and sequelae. Seronegative women are at risk of T1, second-trimester (T2) or third-trimester (T3) PI, and seropositive women are at risk of NPI throughout pregnancy. In our model, both PI and NPI were considered for management and costs of infection, but only T1 PI was considered for screening during pregnancy, because only PI is amenable to screening and there is disagreement regarding the risk of sequelae after T2 or T3 PI¹¹.

## Definitions

In our model, we distinguished between screening for T1 PI, maternal diagnosis of CMV infection and neonatal diagnosis of cCMV infection. According to the model, screening for T1 PI (including periconceptional PI) includes CMV serology (immunoglobulin (Ig) G and IgM with or without IgG avidity) performed early in pregnancy and, in case of a seronegative result, a second serology at 14 weeks of gestation is offered. Maternal diagnosis of PI is made during pregnancy when there are fetal ultrasound abnormalities along with prospective, with or without retrospective, CMV serology. NPI and T2/T3 PI were only considered in the model for maternal diagnosis as neither is amenable to screening. In both of these scenarios (maternal screening and maternal diagnosis), in case of CMV PI or detection of ultrasound abnormalities related to CMV, management of the pregnant woman is implemented (including amniocentesis and specific ultrasound monitoring)²⁵. Neonatal diagnosis of cCMV infection (by salivary and/or urinary polymerase chain reaction (PCR) analysis) is performed in case of maternal

CMV PI or ultrasound abnormalities/neonatal signs related to CMV (according to the French HCSP).

## CMV screening strategies (Table 1 and Figure S1)

Screening strategy S1 reflected current recommendations in France (according to the French HCSP)¹⁹, not to screen for CMV during pregnancy, but to perform maternal diagnosis following detection of fetal ultrasound abnormalities related to CMV, and to perform neonatal diagnosis following detection of fetal ultrasound abnormalities or neonatal signs related to CMV.

Screening strategy S2 reflected current French practice, offering T1 PI screening to 25–50% of pregnant women²². Under this strategy, for women who are not offered screening, maternal diagnosis is recommended following detection of fetal ultrasound abnormalities related to CMV and neonatal diagnosis is recommended following detection of fetal ultrasound abnormalities or neonatal signs related to CMV. Maternal diagnosis of T2/T3 PI or of NPI in any trimester is possible following detection of fetal ultrasound abnormalities related to CMV, and neonatal diagnosis is possible following observation of fetal or neonatal signs related to CMV.

Screening strategy S3 was universal screening for T1 PI, reflecting current medical recommendations in France. Maternal diagnosis of T2/T3 PI or NPI in any trimester is possible following detection of fetal ultrasound abnormalities related to CMV, and neonatal diagnosis is possible following observation of fetal or neonatal signs related to CMV.

Screening strategy S4 was universal screening, as in Strategy S3, and treatment with valacyclovir in every case in which T1 PI was identified¹². Maternal diagnosis of T2/T3 PI or NPI in any trimester is possible following

<figure><img src="image_4.png" /><figcaption>**Figure 1** Schematic representation of model to assess effectiveness, cost and cost-effectiveness of different screening strategies for maternal cytomegalovirus (CMV) and congenital infection. For all strategies, seronegative pregnant women had a risk of first-trimester (T1) or second-/third-trimester (T2/T3) primary infection (PI) and seropositive pregnant women had a risk of non-primary infection (NPI). We used clones to duplicate the model structure, i.e. description of different tree branches in case of T1 PI was also applied for other maternal CMV infections or in different strategies. Parameters and probabilities of events varied in tree branches according to maternal infection and were stratified according to strategy. For live neonates, possibility of neonatal diagnosis depends on maternal infection and on strategy. TOP, termination of pregnancy.</figcaption></figure>
<table><caption>**Table 1** Strategies of model to assess effectiveness, cost and cost-effectiveness of different screening approaches for maternal and congenital cytomegalovirus (CMV) infection</caption><thead><tr><th rowspan="2">Strategy</th><th rowspan="2">Brief description</th><th colspan="4">T1 PI</th></tr><tr><th>Maternal screening</th><th>Prenatal treatment</th><th>Fetal diagnosis</th><th>Neonatal diagnosis</th></tr></thead><tbody><tr><td>S1</td><td>No systematic screening</td><td>No</td><td>No</td><td>Only if US abnormalities</td><td>Only if prenatal US abnormalities or neonatal signs</td></tr><tr><td>S2</td><td>Current practice: 25-50% maternal screening for T1 PI</td><td>Yes: 25-50% of cases<br/>No: 50-75% of cases</td><td>No</td><td>Yes: 25-50% of cases<br/>Only if US abnormalities: 50-75% of cases</td><td>Yes: 25-50% of cases<br/>Only if prenatal US abnormalities or neonatal signs: 50-75% of cases</td></tr><tr><td>S3</td><td>Universal screening for T1 PI</td><td>Yes: 100% of cases</td><td>No</td><td>Yes: 100% of cases</td><td>Yes: 100% of cases</td></tr><tr><td>S4</td><td>Universal screening for T1 PI + valacyclovir if T1 PI</td><td>Yes: 100% of cases</td><td>Valacyclovir 8 g/day<br/>(100% of cases)</td><td>Yes: 100% of cases</td><td>Yes: 100% of cases</td></tr></tbody></table>

Differences investigated between strategies were only with respect to first-trimester (T1) CMV primary infection (PI). In case of second- or third-trimester PI or non-primary infection, neither screening nor prenatal treatment is offered. Fetal diagnosis is offered only if ultrasound (US) abnormality is detected, and neonatal diagnosis is offered only in case of US abnormality or neonatal signs.

detection of fetal ultrasound abnormalities related to CMV, and neonatal diagnosis is possible following observation of fetal or neonatal signs related to CMV.

We assumed that guidelines on hygiene counseling to prevent maternal CMV infection during pregnancy²⁶, as has been recommended in France since 2004, were applied equally in each strategy²⁷.

### Key model assumptions

Regarding maternal CMV and cCMV infections, we made the following assumptions. Both women with PI and those with NPI are at risk for cCMV infection, with the same fetal risk overall and risk of sequelae⁸. In seronegative women, the incidence of T1 PI is 0.46% and the incidence of T2/T3 PI is 0.26%²⁸. The transmission rate to the fetus after maternal T1 PI is 36.8%, after T2 PI is 40.3% and after T3 PI is 66.2%⁹. Seropositive women are at risk of NPI that could occur in T1, T2 or T3, but neither the incidence rate of maternal CMV infection nor the rate of transmission to the fetus is identifiable. A global incidence of 0.4% cCMV infection was applied to all seropositive women to account for potential NPI with fetal transmission at any point in the pregnancy³,⁸,¹⁸. We assumed that prospective diagnosis of maternal NPI is unreliable²⁹.

Regarding management of pregnancies, we made the following assumptions. After diagnosis of fetal infection by amniocentesis, specific ultrasound monitoring is performed and the TOP rate after detection of T1 PI depends on the presence of ultrasound abnormalities (TOP rate, 42% with and 23% without US abnormalities)²⁵. The rate of TOP after detection of NPI with abnormal ultrasound findings is unknown, but we applied a linear distribution to estimate this parameter from the available published data for PI (Table 2). After birth, neonatal diagnosis is required in case of maternal infection or ante- or postnatal signs (as defined above). However, we assumed this is

performed in only 25-29% of cases due to lack of identification of these symptomatic neonates³. A positive CMV PCR analysis of neonatal saliva is always confirmed by PCR analysis of urine. If cCMV is diagnosed, specific follow-up is carried out and antiviral treatment with valganciclovir may be initiated³⁰.

Regarding prevention of vertical transmission with valacyclovir, in the S4 strategy, we made the following assumptions. If T1 CMV PI is diagnosed, valacyclovir (8 g/day) is offered until amniocentesis (mean, 10 weeks of treatment) and biological follow-up is undertaken¹². In this strategy, valacyclovir is not offered in case of T2/T3 PI or NPI. There are no data in the literature to support a beneficial effect of valacyclovir on the fetal risk of sequelae if cCMV occurs despite administration of valacyclovir¹².

### Input parameters

All parameters (probabilities of occurrence and costs) are described and the relevant literature cited in Table 2 and Tables S1 and S2. It was assumed that management of pregnant women with T1 PI and their CMV-infected fetus is performed as recommended in a recent systematic review²⁵.

### Outcomes of infected children

All input probabilities regarding outcomes of infected children relied on data in the published literature reporting maternal infection with CMV²,⁴,⁵,⁸⁻¹¹,³¹,³². Outcome probabilities after maternal NPI were extrapolated from those concerning PI. Within the first 5 years after T1 CMV PI, 64.4% of liveborn have no sequelae, 23.2% develop early or delayed sensorineural sequelae, 10.3% have neurodevelopmental defects and 2.1% die. Within the first 5 years after T2/T3 CMV PI, 89.9% of liveborn have no sequelae, 10.0% develop early or delayed sensorineural
<table><caption>**Table 2** Input parameters (probabilities of occurrence and costs) for model to assess effectiveness, cost and cost-effectiveness of different screening strategies for maternal and congenital cytomegalovirus (CMV) infection</caption><thead><tr><th>Parameter</th><th>Base case</th><th>Min</th><th>Max</th><th>Source (ref)</th></tr></thead><tbody><tr><td>CMV seroprevalence</td><td>0.456</td><td>0.384</td><td>0.604</td><td>16,17</td></tr><tr><td>Maternal and congenital infection</td><td></td><td></td><td></td><td></td></tr><tr><td>Incidence of cCMV infection</td><td>0.004</td><td>0.0037</td><td>0.005</td><td>18</td></tr><tr><td>Incidence of maternal T1 PI</td><td>0.0046</td><td>0.0028</td><td>0.0053</td><td>26,28,47</td></tr><tr><td>Incidence of maternal T2/T3 PI</td><td>0.0026</td><td>0.0026</td><td>0.0046</td><td>28</td></tr><tr><td>Transmission rate after maternal T1 PI</td><td>0.37</td><td>0.21</td><td>0.4</td><td>9</td></tr><tr><td>Transmission rate after maternal T2/T3 PI</td><td>0.53</td><td>0.355</td><td>0.741</td><td>9</td></tr><tr><td>Maternal and congenital CMV infection management</td><td></td><td></td><td></td><td></td></tr><tr><td>Probability of occurrence of cCMV-related US abnormalities</td><td></td><td></td><td></td><td></td></tr><tr><td>If cCMV infection after maternal NPI diagnosed</td><td>0.34</td><td>0.27</td><td>0.42</td><td>10,48,49</td></tr><tr><td>If cCMV infection after maternal T1 PI diagnosed</td><td>0.45</td><td>0.35</td><td>0.55</td><td>25</td></tr><tr><td>If cCMV infection after maternal T2/T3 PI diagnosed</td><td>0.05</td><td>0</td><td>0.10</td><td>10</td></tr><tr><td>If no cCMV infection and maternal T1 PI diagnosed</td><td>0.048</td><td>0</td><td>0.1</td><td>25</td></tr><tr><td>If no cCMV infection (general population)</td><td>0.03</td><td>0.01</td><td>0.03</td><td>50</td></tr><tr><td>Performance of US to detect cCMV-related US abnormalities</td><td></td><td></td><td></td><td></td></tr><tr><td>If cCMV infection and maternal infection not diagnosed</td><td>0.48</td><td>0.43</td><td>0.53</td><td>51</td></tr><tr><td>If cCMV infection after maternal PI diagnosed</td><td>0.91</td><td>0.9</td><td>1</td><td>51</td></tr><tr><td>Performance of amniocentesis with CMV PCR</td><td></td><td></td><td></td><td></td></tr><tr><td>If abnormal US and seropositive woman</td><td>0.65</td><td>0.6</td><td>0.8</td><td>Expert*</td></tr><tr><td>If abnormal US and seronegative woman</td><td>0</td><td>0</td><td>0</td><td>Expert*</td></tr><tr><td>If abnormal US and maternal T1 PI diagnosed</td><td>0.96</td><td>0.8</td><td>1</td><td>25</td></tr><tr><td>If normal US and maternal T1 PI diagnosed</td><td>0.8</td><td>0.7</td><td>1</td><td>25</td></tr><tr><td>If abnormal US and maternal T2/T3 PI diagnosed</td><td>0.9</td><td>0.8</td><td>1</td><td>Expert*</td></tr><tr><td>If normal US and maternal T2/T3 PI diagnosed</td><td>0.6</td><td>0.5</td><td>0.7</td><td>Expert*</td></tr><tr><td>Performance of MRI</td><td></td><td></td><td></td><td></td></tr><tr><td>If positive amniocentesis after maternal T1 PI diagnosed</td><td>0.44</td><td>0.44</td><td>0.54</td><td>25,52</td></tr><tr><td>Number of CMV-related US examinations performed during pregnancy</td><td></td><td></td><td></td><td></td></tr><tr><td>If maternal T1 PI diagnosed and positive amniocentesis</td><td>10.5</td><td></td><td></td><td>25</td></tr><tr><td>If maternal T1 PI diagnosed and negative amniocentesis</td><td>3</td><td></td><td></td><td>Expert*</td></tr><tr><td>If maternal T1 PI diagnosed and no amniocentesis</td><td>8</td><td></td><td></td><td>25</td></tr><tr><td>If maternal T2/T3 PI diagnosed and positive amniocentesis</td><td>5</td><td></td><td></td><td>Expert*</td></tr><tr><td>If maternal T2/T3 PI diagnosed and negative amniocentesis</td><td>1</td><td></td><td></td><td>Expert*</td></tr><tr><td>If maternal T2/T3 PI diagnosed and no amniocentesis</td><td>3.5</td><td></td><td></td><td>Expert*</td></tr><tr><td>Pregnancy outcome if cCMV infection</td><td></td><td></td><td></td><td></td></tr><tr><td>TOP (only after positive amniocentesis)</td><td></td><td></td><td></td><td></td></tr><tr><td>With US abnormalities after maternal NPI diagnosed</td><td>0.325</td><td>0.23</td><td>0.42</td><td>25</td></tr><tr><td>With US abnormalities after maternal T1 PI diagnosed</td><td>0.42</td><td>0.4</td><td>0.5</td><td>25</td></tr><tr><td>With normal US after maternal T1 PI diagnosed</td><td>0.23</td><td>0.04</td><td>0.25</td><td>25</td></tr><tr><td>IUFD</td><td>0.0027</td><td>0.002</td><td>0.004</td><td>25</td></tr><tr><td>Fetal loss due to amniocentesis</td><td>0.001</td><td>0.001</td><td>0.005</td><td>53</td></tr><tr><td>cCMV-infected live neonate outcome</td><td></td><td></td><td></td><td></td></tr><tr><td>After maternal NPI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Asymptomatic neonate</td><td>0.75</td><td></td><td></td><td></td></tr><tr><td>Symptomatic neonate</td><td>0.25</td><td></td><td></td><td></td></tr><tr><td>After maternal T1 PI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Asymptomatic neonate</td><td>0.55</td><td></td><td></td><td></td></tr><tr><td>Symptomatic neonate</td><td>0.45</td><td></td><td></td><td></td></tr><tr><td>After maternal T2/T3 PI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Asymptomatic neonate</td><td>0.99</td><td></td><td></td><td></td></tr><tr><td>Symptomatic neonate</td><td>0.01</td><td></td><td></td><td></td></tr><tr><td>cCMV-infected live children outcome (5 years)</td><td></td><td></td><td></td><td></td></tr><tr><td>After maternal NPI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Without sequelae</td><td>0.819</td><td></td><td></td><td></td></tr><tr><td>With neurosensorial sequelae</td><td>0.149</td><td></td><td></td><td></td></tr><tr><td>With neurodevelopmental sequelae</td><td>0.027</td><td></td><td></td><td></td></tr><tr><td>Death</td><td>0.005</td><td></td><td></td><td></td></tr><tr><td>After maternal T1 PI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Without sequelae</td><td>0.644</td><td></td><td></td><td></td></tr><tr><td>With neurosensorial sequelae</td><td>0.232</td><td></td><td></td><td></td></tr><tr><td>With neurodevelopmental sequelae</td><td>0.103</td><td></td><td></td><td></td></tr><tr><td>Death</td><td>0.021</td><td></td><td></td><td></td></tr></tbody></table>

Continued over.
<table><caption>Table 2 Continued</caption><thead><tr><th>Parameter</th><th>Base case</th><th>Min</th><th>Max</th><th>Source (ref)</th></tr></thead><tbody><tr><td>After maternal T2/T3 PI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Without sequelae</td><td>0.899</td><td></td><td></td><td></td></tr><tr><td>With neurosensorial sequelae</td><td>0.100</td><td></td><td></td><td></td></tr><tr><td>With neurodevelopmental sequelae</td><td>0.001</td><td></td><td></td><td></td></tr><tr><td>Death</td><td>0.000</td><td></td><td></td><td></td></tr><tr><td>cCMV infected children with neurosensorial sequelae outcome</td><td></td><td></td><td></td><td>Expert*</td></tr><tr><td>Isolated vestibular syndrome</td><td>0.10</td><td></td><td></td><td></td></tr><tr><td>Unilateral hearing loss</td><td>0.30</td><td></td><td></td><td></td></tr><tr><td>Bilateral hearing loss</td><td>0.60</td><td></td><td></td><td></td></tr><tr><td>Maternal CMV screening/diagnosis</td><td></td><td></td><td></td><td></td></tr><tr><td>Rate of non-specific CMV-IgM</td><td>0.05</td><td></td><td></td><td>59</td></tr><tr><td>Positive predictive value of CMV-IgM</td><td>0.164</td><td></td><td></td><td>60</td></tr><tr><td>Neonatal CMV screening/diagnosis</td><td></td><td></td><td></td><td></td></tr><tr><td>Performance of CMV saliva PCR</td><td></td><td></td><td></td><td></td></tr><tr><td>If US abnormalities observed</td><td>1</td><td></td><td></td><td>19</td></tr><tr><td>If maternal PI diagnosed</td><td>1</td><td></td><td></td><td>19</td></tr><tr><td>If symptomatic neonate (without maternal screening)</td><td>0.29</td><td>0.25</td><td>0.29</td><td>3</td></tr><tr><td>In general population</td><td>0.05</td><td>0</td><td>0.25</td><td>Expert*<br>3</td></tr><tr><td>Positive predictive value of positive PCR in saliva</td><td>0.23</td><td></td><td></td><td></td></tr><tr><td>Valacyclovir intervention if maternal T1 PI diagnosed</td><td></td><td></td><td></td><td></td></tr><tr><td>Transmission rate</td><td>0.11</td><td>0.02</td><td>0.20</td><td>12</td></tr><tr><td>Performance of amniocentesis</td><td>0.90</td><td>0.80</td><td>1</td><td>25</td></tr><tr><td>Rate of infected neonate born after negative amniocentesis</td><td>0.125</td><td>0</td><td>0.20</td><td>12,25</td></tr><tr><td>Life expectancy</td><td></td><td></td><td></td><td></td></tr><tr><td>Infected neonate with neurosensorial sequelae</td><td>82</td><td>79</td><td>85</td><td>50</td></tr><tr><td>Infected neonate with neurodevelopmental sequelae</td><td>74</td><td>63</td><td>78</td><td>50</td></tr><tr><td>Costs</td><td></td><td></td><td></td><td></td></tr><tr><td>Costs for maternal and congenital screening/diagnosis</td><td></td><td></td><td></td><td>61,62</td></tr><tr><td>Serology CMV-IgG and -IgM</td><td>€22</td><td></td><td></td><td></td></tr><tr><td>Serology CMV-IgG avidity</td><td>€27</td><td></td><td></td><td></td></tr><tr><td>Systematic screening CMV serology</td><td>€35</td><td>€22</td><td>€37</td><td></td></tr><tr><td>CMV serology for diagnosis, according to maternal infection</td><td>€35</td><td>€23</td><td>€64</td><td></td></tr><tr><td>CMV PCR in saliva, with confirmation in urine</td><td>€41</td><td>€40</td><td>€41</td><td>3</td></tr><tr><td>Costs for maternal management</td><td></td><td></td><td></td><td></td></tr><tr><td>Fetal US</td><td>€100</td><td>€92</td><td>€100</td><td></td></tr><tr><td>Fetal MRI</td><td>€300</td><td></td><td></td><td></td></tr><tr><td>Amniocentesis + CMV PCR in amniotic fluid</td><td>€392</td><td></td><td></td><td></td></tr><tr><td>Vaginal delivery</td><td>€313</td><td></td><td></td><td></td></tr><tr><td>TOP</td><td>€100</td><td></td><td></td><td></td></tr><tr><td>Valacyclovir (/day)</td><td>€12</td><td>€11</td><td>€12</td><td></td></tr><tr><td>Renal function monitoring with valacyclovir (/week)</td><td>€7</td><td>€0</td><td>€7</td><td></td></tr><tr><td>Costs for infected child management</td><td></td><td></td><td></td><td>Tables S1 and S2</td></tr><tr><td>Child without sequelae</td><td></td><td></td><td></td><td></td></tr><tr><td>Diagnosed at birth: born asymptomatic after maternal NPI or T1 PI diagnosed</td><td>€3499</td><td>€3088</td><td>€4653</td><td></td></tr><tr><td>Diagnosed at birth: born asymptomatic after maternal T2/T3 PI</td><td>€2267</td><td>€1991</td><td>€3197</td><td></td></tr><tr><td>Diagnosed at birth: born symptomatic</td><td>€4466</td><td>€3635</td><td>€6039</td><td></td></tr><tr><td>Not diagnosed at birth</td><td>€0</td><td>€0</td><td>€0</td><td></td></tr><tr><td>Child with neurosensorial sequelae</td><td></td><td></td><td></td><td></td></tr><tr><td>Diagnosed at birth: born asymptomatic after maternal NPI or T1 PI diagnosed</td><td>€135 401</td><td>€120 964</td><td>€150 630</td><td></td></tr><tr><td>Diagnosed at birth: born asymptomatic after maternal T2/T3 PI diagnosed</td><td>€134 168</td><td>€119 867</td><td>€148 743</td><td></td></tr><tr><td>Diagnosed at birth: born symptomatic</td><td>€136 299</td><td>€121 444</td><td>€151 948</td><td></td></tr><tr><td>Not diagnosed at birth</td><td>€123 229</td><td>€121 441</td><td>€125 522</td><td></td></tr><tr><td>Child with neurodevelopmental sequelae</td><td></td><td></td><td></td><td></td></tr><tr><td>Diagnosed at birth: born symptomatic</td><td>€292 091</td><td>€258 281</td><td>€343 968</td><td></td></tr><tr><td>Not diagnosed at birth</td><td>€283 470</td><td>€252 862</td><td>€331 856</td><td></td></tr><tr><td>Death of child before age 5 years</td><td></td><td></td><td></td><td></td></tr><tr><td>Diagnosed at birth: born symptomatic</td><td>€104 015</td><td>€69 594</td><td>€138 906</td><td></td></tr><tr><td>Not diagnosed at birth</td><td>€102 882</td><td>€68 691</td><td>€137 073</td><td></td></tr></tbody></table>

<footnote>*Consensus of E.L., N.T. and O.P. cCMV, congenital cytomegalovirus; IUFD, intrauterine fetal death; max, maximum; min, minimum; MRI, magnetic resonance imaging; NPI, non-primary infection; PCR, polymerase chain reaction; PI, primary infection; ref, reference; T1, first trimester of pregnancy; T2/T3, second or third trimester of pregnancy; TOP, termination of pregnancy; US, ultrasound.</footnote>
sequelae, 0.1% have neurodevelopmental defects and 0% die. Within the first 5 years after NPI, 81.9% of liveborn have no sequelae, 14.9% develop early or delayed sensorineural sequelae, 2.7% have neurodevelopmental defects and 0.5% die.

The probabilities for performance of amniocentesis in case of ultrasound abnormalities and the numbers of ultrasound examinations were applied according to expert consensus. The definition of symptomatic status at birth is given in Appendix S1.

## Costs

We included direct medical lifetime costs associated with maternal CMV and cCMV screening, diagnosis, treatment (valacyclovir for pregnant women in Strategy S4 and valganciclovir for symptomatic neonates) and maternal and child care in France in 2022, evaluated using French national health insurance system fees³³ (Table 2). We included separately direct medical costs associated with screening/diagnosis and lifetime direct medical costs for care for infected children according to their clinical state. These two costs were added together to obtain total costs. Costs for screening/diagnosis included prenatal costs (e.g. serological testing, amniocentesis, ultrasound examinations, MRI, with and without valacyclovir) and costs for neonatal diagnosis (saliva with urine PCR). Lifetime direct costs for children included healthcare costs related to cCMV infection (e.g. specific follow-up, biological and imaging examinations, hearing monitoring, cochlear implant or hearing aids, rehabilitation, hospitalization). Experts (E.L., N.T., O.P.) determined these costs and we evaluated them with and without neonatal diagnosis, i.e. taking into account diagnosis wandering costs (Table S1). In the cost-effectiveness analysis, we made a conservative assumption that the willingness-to-pay (WTP) threshold in € per avoided congenital infection was equal to the estimated mean lifetime discounted direct cost of an infected child, €18 000 (Figure S2).

## Sensitivity analysis

We first performed a series of one-way deterministic sensitivity analyses to evaluate the impact of assumptions

and data uncertainties on total costs, effectiveness and ICERs (ICER<sub>1A</sub>, ICER<sub>1B</sub>, ICER<sub>2</sub>). To do so, probabilities and costs were varied over a wide range using plausible ranges of values (Table 2). Next, we performed probabilistic sensitivity analyses (PSA), exploring the impact of the combined uncertainty of 20 parameters on the ICER results. These 20 parameters were identified as being the most sensitive with one-way deterministic sensitivity analyses (Figure S2); they were expressed as distributions for the PSAs: beta distributions for probability parameters and gamma distributions for cost parameters. We performed 10 000 Monte-Carlo simulations for the PSAs.

# RESULTS

## Model validity

We assessed the model's external validity by comparing external data from the literature¹⁹,²⁹,³⁴ with the results for Strategy S1 (no systematic screening) in our model. The model results were close to the external data (Table S3). For instance, we estimated 2776 live infected neonates in our model, compared with 2804 reported in the literature for the year 2022 in France (Table S3).

## Baseline analysis

### Effectiveness

The number of infected children, the number of TOPs, the number of diagnosed fetuses and the proportion of diagnosed and undiagnosed infected children according to their neonatal health status and according to the maternal screening strategy are presented in Tables 3, S4 and S5.

According to the model, in Strategies S1, S2 and S3, 2874 cCMV infections occurred, whereas 2499 infections occurred in Strategy S4. S4 was the only strategy which allowed avoidance of congenital infections (n = 375 avoided infections), which was expected because it is the only strategy that included a therapeutic intervention. Concerning the proportion of diagnosed infected fetuses

<table><caption>**Table 3** Results of baseline effectiveness analysis, showing cases of congenital cytomegalovirus (cCMV), expected termination of pregnancy (TOP) and diagnosed infected children with and without sequelae, according to screening strategy</caption><thead><tr><th>Strategy</th><th>cCMV<br>infection</th><th>TOP</th><th>Diagnosed<br>infected fetuses</th><th>Diagnosed infected<br>fetuses + neonates</th><th>Diagnosed infected<br>live children</th><th>Diagnosed infected live<br>children with sequelae</th></tr></thead><tbody><tr><td>S1: no systematic screening</td><td>2874</td><td>94</td><td>268/2874 (9.3)</td><td>534/2874 (18.6)</td><td>439/2776 (15.8)</td><td>204/579 (35.2)</td></tr><tr><td>S2: current practice:<br>25-50% maternal<br>screening for T1 PI</td><td>2874</td><td>153</td><td>469/2874 (16.3)</td><td>758/2874 (26.4)</td><td>613/2727 (22.5)</td><td>235/557 (42.2)</td></tr><tr><td>S3: universal screening for<br>T1 PI</td><td>2874</td><td>253</td><td>804/2874 (28.0)</td><td>1130/2874 (39.3)</td><td>876/2617 (33.5)</td><td>288/515 (55.9)</td></tr><tr><td>S4: universal screening for<br>T1 PI + valacyclovir if<br>T1 PI</td><td>2499</td><td>113</td><td>367/2499 (14.7)</td><td>756/2499 (30.3)</td><td>641/2383 (26.9)</td><td>170/398 (42.7)</td></tr></tbody></table>

Data are given as *n* or *n/N* (%). Denominators are total number of infected fetuses, infected fetuses + neonates, infected live children or infected live children with sequelae and numerators are those diagnosed in each group. PI, primary infection; T1, first trimester of pregnancy.
and/or neonates, Strategy S1 allowed diagnosis of 9.3% of cCMV fetuses and 18.6% of infected fetuses and neonates, Strategy S2 allowed diagnosis of 16.3% cCMV fetuses and 26.4% infected fetuses and neonates and Strategy S3 allowed diagnosis of 28.0% cCMV fetuses and 39.3% infected fetuses and neonates.

Concerning the number of TOPs, we estimated 94 TOPs for Strategy S1, 153 for Strategy S2, 253 for Strategy S3 and 113 for Strategy S4.

### Costs and cost-effectiveness

The base-case results of discounted costs are presented in Table 4. Strategy S1 was the least expensive strategy, with a total lifetime cost of €98 263 000. The total cost according to current practice (Strategy S2) was estimated to be €106 012 000. Strategy S3 was the most expensive strategy with €118 927 000 and Strategy S4 had total costs of €98 598 000.

In the first analysis, to assess the value of universal screening during pregnancy, Strategy S2 was dominated and Strategy S3 led to €38 552 per additional in-utero diagnosis, compared with Strategy S1 (Table 5).

In the second analysis, to assess the value of maternal screening in conjunction with treatment by valacyclovir to

prevent vertical transmission, Strategy S4 led to €893 per avoided congenital infection compared with Strategy S1, and was cost-saving compared with Strategy S2 (Table 6).

### Sensitivity analysis

Regarding ICER<sub>1A</sub> (Figure 2a), the cost-effectiveness acceptability curve shows that Strategy S2 is always dominated: S2 and S3 have the same ICER<sub>1</sub> but S3 is more effective. S3 would be cost-effective compared to S1 in more than 90% of simulations with a WTP threshold of over €60 000/additional in-utero diagnosis.

Regarding ICER<sub>2</sub> (Figure 2b), the cost-effectiveness acceptability curve shows that Strategy S4 is cost-effective compared with Strategy S1 in 69% of simulations at a WTP threshold of €18 000/avoided congenital infection. The CMV transmission rate after T1 PI with valacyclovir treatment and the probability of receiving valacyclovir were the two parameters for which ICER<sub>2</sub> was most sensitive (Figure 3): to keep ICER<sub>2</sub> below €18 000/avoided congenital infection (WTP), the transmission rate with valacyclovir should be below 16% (11% in the baseline analysis) and the probability of receiving valacyclovir above 77% (100% in the baseline analysis) (WTP at €120 000 in Figure S3).

<table><caption>Table 4 Base-case discounted cost analysis for congenital cytomegalovirus infection, according to screening strategy</caption><thead><tr><th>Strategy</th><th>Screening/diagnosis<br>discounted<br>cost (€)</th><th>Total<br>discounted<br>cost (€)*</th></tr></thead><tbody><tr><td>S1: no systematic screening</td><td>5 576 000</td><td>98 263 000</td></tr><tr><td>S4: universal screening for<br>T1 PI + valacyclovir if T1 PI</td><td>37 171 000</td><td>98 598 000</td></tr><tr><td>S2: current practice: 25–50%<br>maternal screening<br>for T1 PI</td><td>16 696 000</td><td>106 012 000</td></tr><tr><td>S3: universal screening<br>for T1 PI</td><td>35 229 000</td><td>118 927 000</td></tr></tbody></table>

<table><caption>Table 6 Base-case cost-effectiveness analysis to assess value of maternal screening in conjunction with treatment by valacyclovir to prevent vertical transmission of cytomegalovirus infection</caption><thead><tr><th>Strategy</th><th>Total<br>discounted<br>cost (€)*</th><th>Effectiveness<br>(avoided<br>congenital<br>infections (n))</th><th>ICER<sub>2</sub><br>(€/avoided<br>congenital<br>infection)</th></tr></thead><tbody><tr><td>S1: no systematic<br>screening</td><td>98 263 000</td><td>0</td><td>—</td></tr><tr><td>S4: universal screening<br>for T1 PI +<br>valacyclovir if T1 PI</td><td>98 598 000</td><td>375</td><td>893</td></tr></tbody></table>

<table><caption>Table 5 Base-case cost-effectiveness analysis to assess value of universal screening for cytomegalovirus infection during pregnancy</caption><thead><tr><th rowspan="2">Strategy</th><th rowspan="2">Total<br>discounted<br>cost (€)*</th><th colspan="3">In-utero diagnosis</th><th colspan="3">In-utero + neonatal diagnosis</th></tr><tr><th>Effectiveness<br>(diagnosis (n))</th><th>ICER<sub>1A</sub><br>(€/additional<br>diagnosis)</th><th>Dominance</th><th>Effectiveness<br>(diagnosis (n))</th><th>ICER<sub>1B</sub><br>(€/additional<br>diagnosis)</th><th>Dominance</th></tr></thead><tbody><tr><td>S1: no systematic<br>screening</td><td>98 263 000</td><td>268</td><td>—</td><td>—</td><td>534</td><td>—</td><td>—</td></tr><tr><td>S2: current practice:<br>25–50% maternal<br>screening for T1 PI</td><td>106 012 000</td><td>469</td><td>38 552</td><td>Dominated</td><td>758</td><td>34 594</td><td>Dominated</td></tr><tr><td>S3: universal screening<br>for T1 PI</td><td>118 927 000</td><td>804</td><td>38 552</td><td>€38 552/additional<br>diagnosis</td><td>1130</td><td>34 594</td><td>€34 594/additional<br>diagnosis</td></tr></tbody></table>

<footnote>*Total lifetime cost for all those diagnosed over the year (2022) in France. PI, primary infection; T1, first trimester of pregnancy.</footnote>

<footnote>*Total lifetime cost for all those diagnosed over the year (2022) in France. ICER, incremental cost-effectiveness ratio; PI, primary infection; T1, first trimester of pregnancy.</footnote>

<footnote>*Total lifetime cost for all those diagnosed over the year (2022) in France. ICER, incremental cost-effectiveness ratio; PI, primary infection; T1, first trimester of pregnancy.</footnote>
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

**Figure 2** Probabilistic sensitivity analysis of incremental cost-effectiveness ratio (ICER). Cost-effectiveness acceptability curves for: (a) ICER₁A (ICER for cost per additional *in-utero* diagnosis) and (b) ICER₂ (ICER for cost per avoided congenital infection). Willingness-to-pay (WTP) was assessed by evaluating the mean cost per congenitally infected child: *c.* 90% of asymptomatic children (mean, €3400) and *c.* 10% of symptomatic children (mean, €150 000) gives WTP = 0.9 × €3400 + 0.1 × €150 000 = €18 060. Thus, WTP threshold was fixed at €18 000/avoided congenital infection. Strategy S1 (—), no systematic screening; Strategy S2 (—), current screening practice (25–50% of pregnant women for first-trimester primary infection (T1 PI)); Strategy S3 (—), universal screening for T1 PI; Strategy S4 (— —), universal screening for T1 PI and valacyclovir treatment if T1 PI.

DISCUSSION

In this study, we aimed to evaluate the costs and
effectiveness of different strategies of maternal CMV
screening in T1. Our analysis provides sufficient evidence
to conclude that valacyclovir is efficient in reducing
vertical transmission of CMV after maternal T1 PI<sup>12-15</sup>.

In the first analysis, we studied the cost-effectiveness
of implementing universal maternal T1 PI screening.
We calculated that this implementation has an
ICER of €38 552/additional in-utero diagnosis or
€34 594/additional in-utero or neonatal diagnosis. Con-
sidering that these costs are already born by our society
in Strategy S2, these ICERs seem acceptable. We modeled

<figure><img src="image_7.png" /></figure>

**Figure 3** Two-way sensitivity analysis for incremental cost-effectiveness ratio (ICER<sub>2</sub>) (ICER for cost per avoided congenital infection). Two-way sensitivity on transmission rate after first-trimester maternal cytomegalovirus primary infection (T1 PI) and valacyclovir treatment and probability of receiving valacyclovir, with a willingness-to-pay threshold of €18 000/avoided congenital infection. ■, Strategy S1 (no systematic screening); □, Strategy S4 (universal screening for T1 PI and valacyclovir treatment if T1 PI).

that Strategy S3 would generate 100 more TOPs com-
pared with Strategy S2. According to French law, TOP is
considered only when the fetus is at high risk of severe
sequelae.

In the second analysis, we found that implementing
Strategy S4, i.e. universal maternal T1 PI screening with
valacyclovir treatment in case of T1 PI, would be more
effective with respect to the number of infections avoided
for an additional cost of €893/avoided congenital CMV
infection. This seems reasonable, especially as it is already
accepted for prenatal screening for other conditions (e.g.
toxoplasmosis, Down syndrome). In the PSA, Strategy S4
was cost-effective compared with Strategy S1 in 69% of
simulations at a WTP threshold of €18 000/avoided con-
genital infection. This WTP threshold was calculated as
the mean cost of a cCMV-infected child during their entire
life. This is a conservative point of view and the WTP
threshold to avoid a congenital infection could be higher
(Figure S3, WTP threshold at €120 000/avoided congen-
ital infection). Concerning total costs, Strategy S4 was
found to be cost-saving compared to Strategy S2. Strat-
egy S1 was the least expensive, but this is only a theoretical
strategy in France, as, currently, 25–50% of pregnant
women are offered CMV serology during pregnancy
(Strategy S2, current practice). Strategy S2 was a domi-
nated strategy. From a cost-effectiveness point of view,
this finding suggests that current maternal CMV screening
practice in France is no longer acceptable. Our model indi-
cated it to be more expensive than Strategy S4, leading to
a greater burden of cCMV infection considering the total
cost of cCMV-infected infants during their entire life.

Cahill et al.<sup>35</sup> and Albright et al.<sup>36</sup> each carried out
a cost-effectiveness analysis of maternal CMV screening
but their conclusions are not applicable to the French
healthcare system because they included treatment with
hyperimmunoglobulin to reduce vertical transmission of
CMV, but this is not readily available in France and
does not seem to be efficient in significantly reducing
vertical transmission³⁷,³⁸. In our model, the antenatal
costs and effectiveness (number of infected fetuses and
children diagnosed) were concordant with those of the
recent French study published by Seror *et al*.³⁴, who
focused on the costs and effectiveness of screening for
T1 CMV PI during pregnancy, in conjunction with
valacyclovir treatment. Additionally, the main input
of our study was to consider total costs of cCMV
infection and not just screening costs. We included all
of the postnatal costs of cCMV follow-up, regardless
of whether cCMV infection was diagnosed (including
wandering diagnostic costs). Fisher *et al*.³⁹ performed a
cost-effectiveness analysis to compare the strategy ‘T1 PI
screening and valacyclovir’ with the control strategy ‘no
systematic screening’ in the USA. They concluded that
the test-and-treat strategy was not cost-effective, with a
WTP set at $100 000/quality-adjusted life years (QALY).
Recently, the Japanese study from Aoki *et al*.⁴⁰ estimated
that systematic screening for T1 PI in conjunction
with valacyclovir would incur an additional cost of
$6604/QALY compared with the absence of screening for
CMV, and an additional cost of $7336/QALY compared
with targeted newborn screening for CMV. Unlike these
cost-effectiveness studies, we included in our model a
‘real-life’ French control and showed the test-and-treat
strategy (Strategy S4) to be cost-saving compared with
current practice (Strategy S2). Moreover, we took into
account all types of maternal infection, not only T1 PI,
in order to collect all costs related to cCMV infection.
In our model, we decided to focus on CMV screening
for PI in T1 because these cases are at the greatest
risk of neurodevelopmental and neurosensorial delay⁹,¹¹.
We chose not to consider screening for other maternal
infections, either because this was less pertinent clinically
(T2/T3 PI) or because it is not possible to do so (NPI)⁴¹.

Several studies have been conducted to evaluate
the feasibility of both universal and targeted neonatal
CMV screening³,⁴². Gantt *et al*.⁴³ and Chen *et al*.⁴⁴ each
conducted a cost-effectiveness analysis to assess neonatal
screening for cCMV infection and reported that this was
cost-effective. Moreover, Gantt *et al*.⁴³ showed that it
was cost-saving if the loss of productivity was taken into
account. In future cost-effectiveness studies, the relevance
of offering screening throughout pregnancy should be
estimated, as well as universal neonatal screening. Our
model is valid and it will be used shortly to investigate the
cost-effectiveness of neonatal screening with or without
maternal screening.

Our model has several limitations. Although a recent
meta-analysis highlighted the benefit of valacyclovir in
reducing vertical transmission¹⁵, only one randomized
study has been conducted and there is still uncertainty
concerning the future of valacyclovir in routine therapy.
For this reason, we stratified our analyses into two
arms: one without valacyclovir (Analysis 1) and one with
valacyclovir (Analysis 2). A second limitation is that our
model is specific to France and therefore may not be
relevant in other settings. Nonetheless, the efficiency of

Strategy S4 could be generalizable to high-income settings with similar healthcare system, seroprevalence, diagnosis and management practice. We decided not to consider prenatal treatment by valacyclovir of cCMV-infected symptomatic fetuses because it has only been tested in fetuses with moderate ultrasound signs and the reported benefit has still to be confirmed in larger studies⁴⁵. Moreover, our model was not designed to distinguish outcomes depending on the ultrasound abnormality. This is a limitation as we know that cerebral antenatal ultrasound signs are associated with increased risk (odds ratio, 8.02 (95% CI, 1.74–60.27)) of inner ear impairment⁴⁶.

Finally, our model focused only on effectiveness in
terms of diagnosis of cCMV, avoidance of congenital
infection and the number of TOPs, and did not
quantify effectiveness in terms of utility scores. In
future evaluations, we will include a quality-of-life
index to calculate the ICER of each strategy, as it is
usually recommended in cost-effectiveness analysis to
calculate ICER in €/QALY. Further studies are needed to
evaluate these screening strategies in other countries with
different cost and management strategies, particularly in
countries with different laws concerning TOP. This study
emphasizes that French public health policies need to
change to allow equity among women in France and to
decrease healthcare expenditure.

REFERENCES

1. Kenneson A, Cannon MJ. Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. *Rev Med Virol* 2007; 17: 253-276.

2. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. *Rev Med Virol* 2007; 17: 355-363.

3. Letamendia-Richard E, Périllaud-Dubois C, La Guillonnière L, Thouard I, Cordier A, Roque-Afonso A, Luca D, Benachi A, Vauloup-Fellous C. Universal newborn screening for congenital cytomegalovirus infection: feasibility and relevance in a French type-III maternity cohort. *BJOG Int J Obstet Gynaecol* 2022; 129: 291-299.

4. Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA. Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. *Pediatr Infect Dis J* 1992; 11: 93-99.

5. Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF. Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. *Pediatrics* 1999; 104 (1 Pt 1): 55-60.

6. Revello MG, Gerna G. Diagnosis and Management of Human Cytomegalovirus Infection in the Mother, Fetus, and Newborn Infant. *Clin Microbiol Rev* 2002; 15: 680-715.

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

8. Maltezou PG, Kourlaba G, Kourkouni E, Luck S, Blázquez-Gamero D, Ville Y, Lilleri D, Dimopoulos D, Karalexi M, Papaeangelou V. Maternal type of CMV infection and sequelae in infants with congenital CMV: Systematic review and meta-analysis. *J Clin Virol* 2020; 129: 104518.

9. Chatzakis C, Ville Y, Makrydimas G, Dinas K, Zavlanos A, Sotiriadis A. Timing of primary maternal cytomegalovirus infection and rates of vertical transmission and fetal consequences. *Am J Obstet Gynecol* 2020; 223: 870-883.e11.

10. Picone O, Vauloup-Fellous C, Cordier AG, Guitton S, Senat MV, Fuchs F, Ayoubi JM, Grangeot Keros L, Benachi A. A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome: Outcome of maternal CMV infection during pregnancy. *Prenat Diagn* 2013; 33: 751-758.

11. Faure-Bardon V, Magny JF, Parodi M, Couderc S, Garcia P, Maillotte AM, Benard M, Pinquier D, Astruc D, Patural H, Pladys P, Parat S, Guillois B, Garenne A, Bussières L, Guilleminot T, Stirnemann J, Ghout I, Ville Y, Leruez-Ville M. Sequelae of congenital cytomegalovirus (cCMV) following maternal primary infection are limited to those acquired in the first trimester of pregnancy. *Clin Infect Dis* 2019; 69: 1526-1532.

12. Shahar-Nissan K, Pardo J, Peled O, Krause I, Bilavsky E, Wiznitzer A, Hadar E, Amir J. Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial. *Lancet* 2020; 396: 779-785.
13. Faure-Bardon V, Fourgeaud J, Stirnemann J, Leruez-Ville M, Ville Y. Secondary prevention of congenital CMV infection with valaciclovir following maternal primary infection in early pregnancy. *Ultrasound Obstet Gynecol* 2021; 58: 576–581.

14. Egloff C, Sibiude J, Vauloup-Fellous C, Benachi A, Bouthry E, Biquard F, Hawkins-Villarreal A, Houhou-Fidouh N, Mandelbrot L, Vivanti AJ, Picone O. New data on efficacy of valaciclovir in secondary prevention of maternal-fetal transmission of CMV. *Ultrasound Obstet Gynecol* 2023; 61: 59–66.

15. D'Antonio F, Marincu D, Prasad S, Khalil A. Effectiveness and safety of prenatal valacyclovir for congenital cytomegalovirus infection: systematic review and meta-analysis. *Ultrasound Obstet Gynecol* 2023; 61: 436–444.

16. Antona D, Lepoutre A, Fonteneau L, Baudon C, Halfermeyer-Zhou F, LE Strat Y, Lévy-Bruhl D. Seroprevalence of cytomegalovirus infection in France in 2010. *Epidemiol Infect* 2017; 145: 1471–1478.

17. N'Diaye DS, Yazdanpanah Y, Krivine A, Andrieu T, Rozenberg F, Picone O, Tsatsaris V, Goffinet F, Launay O. Predictive factors of cytomegalovirus seropositivity among pregnant women in Paris, France. *PloS One* 2014; 9: e89857.

18. Leruez-Ville M, Magny JF, Coudere S, Pichon C, Parodi M, Bussières L, Guillememin T, Ghout I, Ville Y. Risk Factors for Congenital Cytomegalovirus Infection Following Primary and Nonprimary Maternal Infection: A Prospective Neonatal Screening Study Using Polymerase Chain Reaction in Saliva. *Clin Infect Dis* 2017; 65: 398–404.

19. HCSP. Prévention de l'infection à Cytomégalovirus Chez La Femme Encinte et Le Nouveau-Né. Rapport. 2018.

20. Chays A, Ville Y, Crepin G. Rapport 19-12. Audit foetale et infection par la Cytomegalovirus - Fetal audition et cytomegalovirus infection. *Bull Acad Natl Med* 2020; 5: 546–549.

21. Favre R, Picone O, Benachi, Jouannic JM, Salomon L, Winer N, Fuchs F, Groussoles M, Martinovic M. Avis du CNGOF sur le dépistage systématique en prénatal du CMV. Published online 21 February, 2018. https://static.cnsf.asso.fr/wp-content/uploads/2019/01/avis-CNGOF-sur-depistage-CMV-2018.pdf.

22. Richaud-Eyraud E, Brouard C, Antona D, La Ruché G, Tourdjman M, Dufourg MN, Lot F. Screening during pregnancy and at birth: recent epidemiological data. Infectious diseases screening during pregnancy: results from the ELFE survey in maternity units, France Métropolitaine, 2011. Bulletin épidémiologique hebdomadaire - Institut de veille sanitaire, 12 mai 2015. http://beh.santepubliquefrance.fr/beh/2015/15-16/2015_15-16_4.html.

23. Insee (Institut national de la statistique et des études économiques). Tableaux de l'économie française, édition 2020. https://www.insee.fr/fr/statistiques/4318291.

24. Choix méthodologiques pour l'évaluation économique à la HAS. Published online 2020, pp. 118. https://www.has-sante.fr/upload/docs/application/pdf/2020-07/guide_methodologie_evalutation_economique_has_2020_vf.pdf.

25. Péllard-Dubois C, Belhadi D, Laouénan C, Mandelbrot L, Picone O, Vauloup-Fellous C. Current practices of management of maternal and congenital Cytomegalovirus infection during pregnancy after a maternal primary infection occurring in first trimester of pregnancy: Systematic review. *PLOS ONE* 2021; 16: e0261011.

26. Vauloup-Fellous C, Picone O, Cordier AG, Parent-du-Châtelet I, Senat M, Frydman R, Grangeot-Keros L. Does hygiene counseling have an impact on the rate of CMV primary infection during pregnancy? Results of a 3-year prospective study in a French hospital. *J Clin Virol* 2009; 46: S49–S53.

27. Évaluation de l'intérêt du dépistage de l'infection à cytomegalovirus chez la femme encinte en France. *J Gynecol Obstet Biol Reprod (Paris)* 2005; 34: 170–174.

28. Picone O, Vauloup-Fellous C, Cordier AG, Parent du Châtelet I, Senat M, Frydman R, Grangeot-Keros L. A 2-year study on cytomegalovirus infection during pregnancy in a French hospital. *BJOG* 2009; 116: 818–823.

29. Leruez-Ville M, Ville Y. Épidémiologie et diagnostic virologique de l'infection congénitale à cytomegalovirus (CMV). *Bull Acad Natl Méd* 2020; 204: 126–136.

30. Kimberlin DW, Jester PM, Sánchez PJ, Ahmed A, Arav-Boger R, Michaels MG, Ashouri N, Englund JA, Estrada B, Jacobs RF, Romero JR, Sood SK, Whitworth MS, Abzoug MJ, Caserta MT, Fowler S, Lujan-Zilberman J, Storch GA, DeBiasi RL, Han JY, Palmer A, Weiner LB, Bocchini JA, Dennehy PE, Finn A, Griffiths PD, Luck S, Gutierrez K, Halasa N, Homans J, Shane AL, Sharland M, Simonsen K, Vanchiere JA, Woods CR, Sabo DL, Aban I, Kuo H, James SH, Pritchard MN, Griffin J, Giles D, Acosta EP, Whitley RJ. Valganciclovir for symptomatic congenital cytomegalovirus disease. *N Engl J Med* 2015; 372: 933–943.

31. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. *N Engl J Med* 1992; 326: 663–667.

32. Lipitz S, Elkan Miller T, Yinon Y, Weissbach T, De-Castro H, Hoffman C, Katorza E, Weisz B. Revisiting short- and long-term outcome after fetal first-trimester primary cytomegalovirus infection in relation to prenatal imaging findings. *Ultrasound Obstet Gynecol* 2020; 56: 572–578.

33. CCAM Online. [French Health Insurance website]. https://www.ameli.fr/accueil-de-la-cam/index.php.

34. Seror V, Leruez-Ville M, Özek A, Ville Y. Leaning towards Cytomegalovirus serological screening in pregnancy to prevent congenital infection: a cost-effectiveness perspective. *BJOG* 2022; 129: 301–312.

35. Cahill AG, Odibo AO, Stamilio DM, Macones GA. Screening and treating for primary cytomegalovirus infection in pregnancy: where do we stand? A decision-analytic and economic analysis. *Am J Obstet Gynecol* 2009; 201: 466.e1–7.

36. Albright C, Werner E, Anderson B. Universal cytomegalovirus screening in pregnancy: A cost-effectiveness analysis. *Am J Obstet Gynecol* 2015; 212: S307–S308.

37. Revello MG, Lazzarotto T, Guerra B, Spinillo A, Ferrazzi E, Kustermann A, Guaschino S, Vergani P, Todros T, Frusca T, Arossa A, Furione M, Rognoni V, Rizzo N, Gabrielli L, Klersc C, Gerna G. A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. *N Engl J Med* 2014; 370: 1316–1326.

38. Devlieger R, Buxmann H, Nigro G, Enders M, Jückstock J, Siklós P, Wartenberg-Demand A, Schüttrumpf J, Schütze J, Rippel N, Herbold M, Niemann G, Friese K. Serial monitoring and hyperimmunoglobulin versus standard of care to prevent congenital cytomegalovirus infection: a phase III randomized trial. *Fetal Diagn Ther* 2021; 48: 611–623.

39. Fisher SA, Miller ES, Yee LM, Grobman WA, Premkumar A. Universal first-trimester cytomegalovirus screening and valaciclovir prophylaxis in pregnant persons: a cost-effectiveness analysis. *Am J Obstet Gynecol* MFM 2022; 4: 100676.

40. Aoki H, Bitnun A, Kitano T. The cost-effectiveness of maternal and neonatal screening for congenital cytomegalovirus infection in Japan. *J Med Virol* 2023; 95: e28391.

41. Picone O, Grangeot-Keros L, Senat M, Fuchs F, Bouthry E, Ayoubi J, Benachi A, Vauloup-Fellous C. Cytomegalovirus non-primary infection during pregnancy. Can serology help with diagnosis? *J Matern Fetal Neonatal Med* 2017; 30: 224–227.

42. Fourgeaud J, Boithias C, Walter-Nicolet E, Kermorvant E, Couderc S, Parat S, Pol C, Mousset C, Bussières L, Guillememin T, Ville Y, Nkam L, Grimaldi L, Parodi M, Leruez-Ville M. Performance of targeted congenital cytomegalovirus screening in newborns failing universal hearing screening: a multicenter study. *Pediatr Infect Dis J* 2022; 41: 478–481.

43. Gantt S, Dionne F, Kozak FK, Goshen O, Goldfarb DM, Park AH, Boppana SB, Fowler K. Cost-effectiveness of universal and targeted newborn screening for congenital cytomegalovirus infection. *JAMA Pediatr* 2016; 170: 1173–1180.

44. Chen K, Zhong Y, Gu Y, Sharma R, Li M, Zhou J, Wu Y, Gao Y, Qin G. Estimated cost-effectiveness of newborn screening for congenital cytomegalovirus infection in China using a Markov model. *JAMA Netw Open* 2020; 3: e2032949.

45. Leruez-Ville M, Ghout I, Bussières L, Stirnemann J, Magny JF, Coudere S, Salomon LJ, Guillememin T, Aegerter P, Benoist G, Winer N, Picone O, Jacquemard F, Ville Y. In utero treatment of congenital cytomegalovirus infection with valacyclovir in a multicenter, open-label, phase II study. *Am J Obstet Gynecol* 2016; 215: 462.e1–10.

46. Chebib E, Maudoux A, Benoit C, Bernard S, Belarbi N, Parodi M, Picone O, Van Den Abbelee T, Wiener Vacher SR, Teissier N. Predictors of cochlovestibular dysfunction in children with congenital cytomegalovirus infection. *J Eur Pediatr* 2022; 181: 2909–2918.

47. de Vries JJC, van Zwet EW, Dekker FW, Kroes ACM, Verkerk PH, Vossen ACTM. The apparent paradox of maternal seropositivity as a risk factor for congenital cytomegalovirus infection: a population-based prediction model. *Rev Med Virol* 2013; 23: 241–249.

48. Leruez-Ville M, Stirnemann J, Sellier Y, Guillememin T, Dejean A, Magny JF, Coudere S, Jacquemard F, Ville Y. Feasibility of predicting the outcome of fetal infection with cytomegalovirus at the time of prenatal diagnosis. *Am J Obstet Gynecol* 2016; 215: 342.e1–9.

49. Enders M, Daiminger A, Exler S, Ertan K, Enders G, Bald R. Prenatal diagnosis of congenital cytomegalovirus infection in 115 cases: a 5 years' single center experience. *Prenat Diagn* 2017; 37: 389–398.

50. N'Diaye DS, Launay O, Picone O, Tsatsaris V, Azria E, Rozenberg F, Schwarzinger M, Yazdanpanah Y. Cost-effectiveness of vaccination against cytomegalovirus (CMV) in adolescent girls to prevent infections in pregnant women living in France. *Vaccine* 2018; 36: 1285–1296.

51. Leruez-Ville M, Guillememin T, Stirnemann J, Salomon LJ, Spaggiari E, Faure-Bardon V, Magny JF, Ville Y. Quantifying the burden of congenital cytomegalovirus infection with long-term sequelae in subsequent pregnancies of women seronegative at their first pregnancy. *Clin Infect Dis* 2020; 71: 1598–1603.

52. Kyriakopoulou A, Serghiou V, Dimopoulos D, Arista I, Psaltopoulou T, Dimopoulos A, Papaevangelou V. Antenatal imaging and clinical outcome in congenital CMV infection: A field-wide systematic review and meta-analysis. *J Infect* 2020; 80: 407–418.

53. Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. *Ultrasound Obstet Gynecol* 2015; 45: 16–26.

54. Buca D, Di Mascio D, Rizzo G, Giancotti A, D'Amico A, Leombroni M, Makatsarya A, Familiari A, Liberati M, Nappi L, Flacco ME, Manzoli L, Salomon LJ, Scambia G, D'Antonio F. Outcome of fetuses with congenital cytomegalovirus infection and normal ultrasound at diagnosis: systematic review and meta-analysis. *Ultrasound Obstet Gynecol* 2021; 57: 551–559.

55. Bartlett AW, McMullan B, Rawlinson WD, Palasanthiran P. Hearing and neurodevelopmental outcomes for children with asymptomatic congenital cytomegalovirus infection: A systematic review. *Rev Med Virol* 2017; 5: e1938.

56. Foulon I, Naessens A, Foulon W, Casteels A, Gordts F. Hearing loss in children with congenital cytomegalovirus infection in relation to the maternal trimester in which the maternal primary infection occurred. *Pediatrics* 2008; 122: e1123–1127.

57. Foulon I, Naessens A, Foulon W, Casteels A, Gordts F. A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. *J Pediatr* 2008; 153: 84–88.

58. Goderis J, De Leenheer E, Smets K, Van Hoecke H, Keymeulen A, Dhooge I. Hearing loss and congenital CMV infection: a systematic review. *Pediatrics* 2014; 134: 972–982.

59. Revello MG, Vauloup-Fellous C, Grangeot-Keros L, Helden J, Dickstein Y, Lipkin I, Mühlbacher A, Lazzarotto T. Clinical evaluation of new automated cytomegalovirus IgM and IgG assays for the Elecsys® analyser platform. *Eur J Clin Microbiol Infect Dis* 2012; 31: 3331–3339.

60. Péllard-Dubois C, Bouthry E, Jadoui A, Leng AL, Roque-Afonso AM, Vauloup-Fellous C. Positive predictive values of CMV-IgM and importance of CMV-IgG avidity testing in detecting primary infection in three different clinical settings. A French retrospective cohort study. *J Clin Virol* 2020; 132: 104641.

61. Nomenclature des actes de biologie médicale (NABM). http://www.codageext.cnants.fr/codit/nabm/index_presentation.php?p Site=AMELI.

62. Agence Technique de l'Information sur l'Hospitalisation. Référentiel de coûts MCO 2011: Agence Technique de l'Information sur l'Hospitalisation (ATIH). https://www.atih.sante.fr/mco/documentation?secteur=MCO.
SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:

<figure><img src="image_8.png" /></figure>

**Appendix S1 Definition of symptomatic congenital cytomegalovirus-infected neonate**

**Figure S1** Details of management of pregnant women according to screening strategy: (a) management in Strategy S1 (no systematic screening) and (b) management in Strategy S3 (systematic screening for first-trimester maternal cytomegalovirus primary infection).

**Figure S2** One-way sensitivity analyses for incremental cost-effectiveness ratio (ICERs). (a) Tornado diagram for ICER₁A (€/in-utero additional diagnosis), comparing Strategies S3 vs S2 or S1. (b) Tornado diagram for ICER₂ (€/avoided congenital infection), comparing Strategies S4 vs S1.

**Figure S3** Two-way sensitivity analysis for incremental cost-effectiveness ratio (€/avoided congenital infection). Two-way sensitivity on transmission rate after first-trimester maternal cytomegalovirus primary infection and valacyclovir and probability of receiving valacyclovir, with a willingness-to-pay threshold of €120 000/avoided congenital infection.

**Table S1** Detail of interventions involved in postnatal costs according to health condition of infected neonate/child

**Table S2** Detail of costs incurred in management of infected neonates/children

**Table S3** External validity of model

**Table S4** Details of diagnosed and undiagnosed infected children according to timing of maternal infection, children's health condition and strategy

**Table S5** Details of diagnosed infected children with sequelae according to sequelae and strategy