Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic model

Larry Sawers; Martine Wallon; Laurent Mandelbrot; Isabelle Villena; Eileen Stillwaggon; François Kieffer

doi:10.1371/journal.pone.0273781

. 2022 Nov 4;17(11):e0273781. doi: 10.1371/journal.pone.0273781

Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic model

Larry Sawers ¹, Martine Wallon ^2,³, Laurent Mandelbrot ^4,^5,⁶, Isabelle Villena ^7,⁸, Eileen Stillwaggon ⁹, François Kieffer ^10,^*

Editor: Adriana Calderaro¹¹

PMCID: PMC9635746 PMID: 36331943

Abstract

Background

Toxoplasma gondii is one of the world’s most common parasites. Primary infection of the mother during pregnancy can lead to transmission to the fetus with risks of brain and eye lesions, which may cause lifelong disabilities. France instituted a national program based on monthly retesting of susceptible pregnant women to reduce the number of severe cases through prompt antenatal and postnatal treatment and follow-up.

Objective

To evaluate the ability of the French prenatal retesting program to reduce the lifetime costs of congenital toxoplasmosis.

Methods

We measured and then compared the costs and benefits of screening vs. not screening using decision-tree modelling. It included direct and indirect costs to society of treatment and care, and the lifetime lost earnings of children and caregivers. A probabilistic sensitivity analysis was carried out.

Findings

Total lifetime costs per live born child identified as congenitally infected were estimated to be €444 for those identified through prenatal screening vs €656 for those who were not screened. Estimates were robust to changes in all costs of diagnosis, treatment, and sequelae.

Interpretation

Screening for the prevention of the congenital T. gondii infection in France is cost saving at €212 per birth. Compared with no screening, screening every pregnant woman in France for toxoplasmosis in 2020 would have saved the country €148 million in addition to reducing or eliminating the devastating physical and emotional suffering caused by T. gondii. Our findings reinforce the conclusions of other decision-analytic modelling of prenatal toxoplasmosis screening.

Introduction

Toxoplasma gondii (T. gondii) is a protozoan parasite infecting approximately a third of all humans [1], with substantial differences in prevalence across the globe. Sources of human infection include the ingestion of cysts in raw or undercooked contaminated meat, or of oocysts present in cat feces or contaminated vegetables, fruits, soil, and water [1]. In case of primary infection with T. gondii during pregnancy, the risk of transmission is very low in the first trimester (2%-5%) and reaches 70% in the final weeks of pregnancy [2]. Spontaneous abortion may occur in case of early fetal infection. The probability of mild or subclinical disease is highest in infection acquired in the later stages of gestation [1, 3–5]. Sequelae of congenital toxoplasmosis (CT) include cerebral calcifications, hydrocephaly, cognitive and motor sequelae, retinochoroiditis, and visual and hearing impairment.

Prenatal screening programs are operated at a national scale in France, Austria, and Slovenia. Since 1985, all susceptible pregnant women in France are to be identified at their first prenatal visit, and since 1992, they are to be retested monthly until delivery. The objectives are to allow prompt treatment in case of seroconversion to prevent mother-to-child transmission and treatment of infected fetuses to reduce the likelihood and severity of injury [2, 6–14].

In recent decades, T. gondii seroprevalence has decreased sharply in industrialized countries [15–17]. In France, the seroprevalence in pregnant women fell from 54% in 1995 to 31.3% in 2016 [18], and the incidence of seroconversions during pregnancy decreased from 5.4 per 1,000 at-risk pregnancies in 1995 to 3.1 per 1,000 in 2016 with a prediction of 1.6 per 1,000 susceptible women by 2020 [19]. The cost of a screening program increases with the number of susceptible pregnant women to retest monthly. The declining seroprevalence challenges prenatal screening programs. Paradoxically, the success of maternal prenatal screening for T. gondii in France and Austria in reducing the number of children with disabling forms of CT has also undermined support in those countries for maintaining expensive prenatal screening programs [11, 20]. Two cost-benefit analyses (CBA) found prenatal retesting for toxoplasmosis to be cost saving, one with the hypothesis of applying the French screening protocol in the USA [21], and the other examining the Austrian screening protocol [20]. A cost-effectiveness study in 2019 compared neonatal to prenatal screening and found the French prenatal screening program to be cost effective [22].

To evaluate the ability of the monthly retesting program to reduce the lifetime costs of CT in the current epidemiological context, we performed a cost-benefit analysis (CBA) of prenatal screening in France. Our study was designed to facilitate comparison with two previous CBAs of toxoplasmosis screening.

Methods

Description of French toxoplasmosis screening and management protocol

Our modelling of maternal screening for toxoplasmosis is based on the protocol described by the National College of French Obstetricians and Gynecologists [11]. The first step in the screening process is testing pregnant women without previous documented immunization for anti-T. gondii IgG and IgM in the first trimester. Women whose serology is negative are informed about prevention of toxoplasmosis and are retested monthly until delivery [23]. To limit the passage of the parasite from mother to fetus, treatment is initiated as soon as a maternal infection is detected. Treatment includes spiramycin, or, after 14 weeks of gestation, pyrimethamine-sulfadiazine combination. Amniocentesis is offered at least 4 weeks from the presumed date of maternal infection and from 18 weeks of gestation. If the result of the PCR on the amniotic fluid is negative, spiramycin is continued until delivery. As the specificity of PCR on amniotic fluid is 100%, a positive result indicates that the fetus has CT and pyrimethamine-sulfadiazine is prescribed until delivery [24]. Prenatal ultrasound is performed monthly if the PCR result is negative and bimonthly if positive. In the event of severe fetal abnormalities, termination of pregnancy may be performed at the patient’s request after approval by a multidisciplinary prenatal diagnosis centre. All newborns undergo assessment at birth that include cerebral ultrasonography, an ocular examination, and testing of neonatal blood for anti-T. gondii IgM, IgA, and IgG antibodies. Infants with proven CT are treated with pyrimethamine and sulfadiazine (or sulfadoxine) for one year after birth and monitored in the long-term for neurological and ophthalmological complications. In the other children, the absence of infection is demonstrated by monitoring the clearance of maternal IgG before age one.

Modeling

We assumed full compliance with all procedures in the screening scenario and that all medications were well tolerated without serious adverse effects. In the no-screening scenario, we assumed that no subjects would be identified through individual screening, through testing in the context of maternal clinical signs of toxoplasmosis, or in the context of fetal ultrasound anomalies. We also assumed that children who are identified with CT in the no-screening scenario would still be treated for 12 months with no side effects just as in the screening scenario, even in cases of more severe or subclinical infection, and even if diagnosed several months or years after birth. Monitoring of infected children was assumed the same in both the screening and no-screening scenarios.

We used TreeAge Pro Suite 2021 software (TreeAge Software, Inc., Williamstown, MA, US) to construct a decision-analytic model. Our CBA is built on two decision-analytic models, the retesting program currently operated in Austria, and a hypothetical program in the United States adapted from the French program [21]. We adapted those decision trees to use as templates for our modelling. The most important difference between the Austrian and French protocols is that the former has 4 serological tests 8 weeks apart while the latter has 8 serological tests 4 weeks apart. The protocol of management used in France has changed in important ways since 2011 when the US study was carried out and our decision tree reflects these improvements, particularly regarding prenatal diagnosis and treatments [25]. Images of the decision tree appear in the S1 File. They show the probabilities of all possible outcomes due to CT (green circles at chance nodes) and the costs associated with each outcome (red triangles at terminal nodes). Each outcome has a conditional probability equal to the sum of the probabilities along each branch. The formulas at the terminal nodes for each outcome provide the current cost of testing, surveillance, and medications, and costs of all direct injury costs (such as remedial education) and all indirect injury costs (such as lost earnings due to impairment).

Clinical probabilities

Probabilities of clinical outcomes were gathered from published estimates in both the context of no-screening (Table 1) and screening (Table 2). Examples include the probability of primary infection during pregnancy and the probabilities of pediatric clinical long-term outcomes due to congenital toxoplasmosis (CT) such as mild visual impairment. Table 1 shows the probabilities in the decision tree with the no-screening option while Table 2 shows the probabilities in the decision tree with the screening option. The order of the variables in the tables follows the structure of the decision tree. At the top of the table are located the variables of the beginning of the tree. At the bottom of the table are the variables at the end of each branch. At each intermediate node, the sum of the probabilities equals 1. The order of the variables in the table follows the structure of the tree. At the top of the table are located the variables of the beginning of the tree. At the bottom of the table are the variables at the end of each branch.

Table 1. Probabilities with no-screening option.

Variable	Probabilities (range)	Reference
Primary infection in pregnancy	0.0016	[7, 8, 18]
CT	0.39 (0.31–0.47)	[26]
Fetal death due to CT	0.0135	[8]
No CT	0.06	[26]
Visual injury	0.48	[26–29]
Of which Mild	0.09	[26–29]
Visual and cognitive injury	0.45 (0.40–0.55)	[5, 26, 28]
Of which Mild	0.39 (0.33–0.45)	[5, 26, 28]
Visual, cognitive, and hearing injury	0.01	[5, 26, 28]

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Table 2. Probabilities with screening option.

	date of maternal primary infection
Probabilities	12 Weeks	16 Weeks	20 Weeks	24 Weeks	28 Weeks	32 Weeks	36 Weeks^*	Newborn ^*	Postnatal ^*	References
Maternal IgG (+) (Seroprevalence)	0.313									[18]
IgG(+) IgM(+) Primary Maternal Infection	0.0016									[18]
Confirmation test (+)	0.9									[1]
Fetal death due to CT	0.02	0.0025	0	0	0	0	0	0	0	[30]
Fetal loss from amniocentesis	0.003 (0.0011–0.0049)	0.003	0.003	0.003	0	0				[31]
Amniocentesis (-)	0.90	0.873	0.785	0.638	0.514	0.450				[8, 24, 32]
False negative of amniocentesis (CT if amniocentesis (-))	0.05	0.05	0.05	0.05	0.10	0.15				[8, 24, 32]
Asymptomatic CT if amniocentesis (-)	0.70	0.70	0.75	0.775	0.79	0.79	0.795	0.795	0.795	[8, 24, 32]
Visual injury if CT with amniocentesis (-)	0.20	0.20	0.20	0.20	0.20	0.20	0.20	0.20	0.20	[2, 12, 14, 33, 34]
Visual and cognitive injury if CT with amniocentesis (-)	0.10	0.10	0.05	0.025	0.01	0.01	0.005	0.005	0.005	[2, 12, 14, 33, 34]
Asymptomatic CT if amniocentesis (+)	0.50	0.5	0.70	0.75	0.795	0.795				[2, 12, 14, 33, 34]
Visual injury if CT with amniocentesis (+)	0.30	0.30	0.25	0.20	0.20	0.20				[2, 12, 14, 33, 34]
Visual and cognitive injury if CT with amniocentesis (+)	0.20	0.20	0.05	0.05	0.005	0.005				[2, 12, 14, 33, 34]

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*Probability without amniocentesis and with confirmatory testing

Economic costs

Two types of costs are considered in the analysis, The first is the cost of treatment, which includes medication and testing during the mother’s pregnancy and in the year following her child’s birth. These are presented in Table 3. The second type of costs considered in the analysis are injury costs. They include remediation (for example, the costs of hearing aids for those with hearing damaged by CT, costs of remedial education for children with mild or severe cognitive impairment due to CT, or lifetime earnings loss due to disability caused by CT.

Table 3. Test and medication costs.

Variable Name in Tree	Descriptions	Current Value in 03/2021	Source (code)
MatIgGMTest	Maternal IgG + IgM test	€10.8	a (40B)
Amnio	Amniocentesis with PCR on amniotic fluid	€40.5	a (150B)
MatCBC	CBC during maternal treatment	€6.75	a (25B)
ObstetricUltra	Prenatal diagnostic ultrasound	€100.2	b (JQQMO18)
RxNegPCR	Maternal treatment with negative PCR on amniotic fluid (spiramycin for 4 months) [23]	€207.72	^C
RxPosPCR	Maternal treatment with positive PCR on amniotic fluid (spiramycin for one month, then pyrimethamine, sulfadiazine and folinic acid for 3 months) [23]	€195.19	^C
InfIgGMTest	Infant IgG + IgM test	€10.8	a (40B)
WestBlotTest	Western Blot test (comparison test of IgG and IgM profiles of mother and child)	€86.4	a (320B)
PedCranialUltra	Cerebral ultrasound	€37.8	b (AAQM002)
Fundus	Funduscopy	€48.36	b (BGQP004)
PedRx	Pediatric treatment 12 months	€3124.49	C
PedCBC	CBC during pediatric treatment	€6.75	a (25B)

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Source: a. www.codage.ext.cnamts.fr B value €0.27

b. https://www.aideaucodage.fr/ccam

c. https://www.vidal.fr/medicaments/

Some of these costs such as medications and tests are purchased and used within a few months or a single year. Other costs persist for years, for example lifetime earnings loss for patients who are never able to work (measured from average age of those first entering the paid labor force to the average age at retirement). Health economists in the United States routinely assume that a euro received tomorrow is worth 3% less (that is, discounted annually by 3%) than a euro received today. Other costs of other injuries may last only a few years. An example is the cost of remedial education when the child is young or the lost wages of a parent who stays at home to care for an injured child. A description of how these costs were measured is presented in S1 File.

Our aim is to measure these costs from the perspective of society as a whole regardless of which person, institution, or medical insurance system paid for the treatment or injury costs. In the interest of simplicity, we assume 100% compliance with the protocol that we are testing. For example, we assume that if amniocentesis is medically recommended, that the mother complies with the recommendation. We further assume there are no side effects to medications or procedures. Tables 3 and 4 summarize costs that were included in the decision-tree analysis and the sources used to measure those costs. Table 3 reports the cost of spiramycin and pyrimethamine and sulfonamides, and the costs of tests performed to diagnose infections and complications and to monitor side effects of treatment. Table 4 summarizes costs that arise from injuries and impairments to persons with CT, their families, and the economy regardless of who pays. Examples include care for patients with cognitive and visual impairment and earnings loss of patients with CT and of their caregivers. Estimates of costs are derived from the literature for France (adjusted to the price level in 2020).

Table 4. Costs due to impairments.

Impairment name in tree	Description of Impairments	Cost of impairment
CognitiveMild	Treatment for mild cognitive impairment	€54,124
CognitiveSevere	Treatment for severe cognitive impairment	€406,634
HearingMild	Treatment for mild hearing impairment	€22,343
SpecEdBlind	Special school for severe visual impairment	€91,993
SpecEdCognitiveMild	Special school for mild cognitive impairment	€74,967
SpecEdCognitiveSevere	Special school for severe cognitive impairment	€747,175
VisualMild	Treatment for mild visual impairment	€272,684
ChildEarnLoss	Earnings loss for severe cognitive impairment	€564,858
ParentEarnLoss	Earnings loss of caregiver	€28,262
VisualSevere	Income loss + non-medical costs of severe visual impairment	€590,374
VSL	Value of a statistical life	€5.58 million

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Source: (S1 File): Measuring costs of impairment at terminal nodes in decision tree

The decision tree we used to calculate the cost savings from maternal screening for toxoplasmosis can be found in S1 File. The costs and the probabilities of incurring those costs are shown along each branch of the tree. The image of the entire decision tree (S1 Fig) gives the viewer a sense of the complexity of the estimations produced by the decision tree analysis, but the numbers and words on each branch are too small to decypher without magnification. Accordingly, in the S1 File we also include separate images of the 9 major branches of the decision tree that together form the decision tree (S2–S10 Figs). The last image shows the simplified tree after 4 of 5 identical branches of the tree were omitted (S11 Fig).

We used an incremental tornado diagram (see Fig 1) to test the robustness of our results to variations in costs. The tornado diagram is an array of one-way sensitivity tests ordered by the ability of each variable to affect cost savings produced by prenatal screening. We performed a sensitivity analysis using an Incremental Tornado Diagram varying all costs by ±20%. The model was based on previously obtained data from the literature, so no informed consent was possible or required.

The x-axis of the diagram shows cost saving per birth produced by prenatal screening. The horizontal bars show the variation in the expected per-birth value of cost saving from screening resulting from changing the range of values for each cost parameter by plus 20% and minus 20%.

Results

S1 File. show the decision tree after calculation of the no-screening option and the screening option. Without screening, the lifetime societal costs of CT sequelae plus treatment of toxoplasmosis for twelve months would have been €656 per birth in 2020 while the costs with screening were €444. Thus, screening saved €212 per birth. There were an estimated 700,000 births in France in 2020 [35]. Assuming every pregnant mother was screened according to protocol in 2020, the cost saving would have approached €148 million in France that year.

Of the costs examined in the incremental tornado diagram (Fig 1), variations in the probability of maternal primary infection had the greatest effect on cost saving from prenatal screening. Varying it by plus or minus 20% changed cost saving by 30.5%. The cost of treatment for mild visual impairment was the next most important variable. Changing it by ±20% led to a 14% change in estimated cost saving produced by prenatal screening. The third most important variable in affecting estimated cost saving from prenatal screening was the cost of special education for those with severe cognitive impairment. A ±20% change in those costs led to a 12% change in estimated cost saving. Increasing or decreasing all other variables by 20% led to estimated cost saving changing by less than 10%. Most of the variables had a trivial impact on cost saving from screening. For two-thirds of the 24 variables in the tornado analysis with the least impact, a 20% increase or decrease in value led to a change in cost saving from screening by less than 5%.

The one-way sensitivity analysis in Fig 2 examines changes in the incidence of primary maternal infection. This variable in the tornado diagram has the greatest impact on reducing screening costs and is the only parameter that can change the optimal strategy. The breakeven point shown in Fig 2 is 0.0005504 (5.504 per 10,000), indicating that the incidence of primary maternal infection would have to fall by nearly two thirds for a no-screening strategy to become less costly than the actual screening strategy. No other variable had a breakeven point.

Discussion

To reduce the lifetime consequences of congenital Toxoplasma infection, two preventive strategies are considered, prenatal and neonatal. The prenatal strategy combines education and serological testing of susceptible pregnant women, with three objectives: to avoid maternal infection, to recognize infection promptly, and to detect and treat before birth any congenital infection. The prenatal approach relies on the hypotheses, sustained by indirect evidence, that early maternal treatment reduces the risk of mother-to-child transmission [2], and that congenital infection treated prenatally is associated with a lower risk of severe lesions [13]. France has organized this prenatal strategy at a national level, including fully reimbursed retesting, every month, which makes it the most comprehensive program worldwide.

The aim of our study was to estimate whether this program is cost saving despite the declining seroprevalence and incidence of maternal and fetal infections. The model was based on population-based published outcomes and direct and indirect costs for society.

Our main finding is that monthly retesting is cost saving for French society since it reduces the number of severe cases of CT. We estimate that without prenatal screening, the cost of treating CT and dealing with long term functional consequences would be €656 per birth. Prenatal screening reduced the cost to €444, generating savings of €212 per birth. If no pregnant woman in France was screened for toxoplasmosis in 2020, the societal costs would have been €460 million.

Our findings reinforce the conclusions of the cost-effectiveness analysis in 2019 that found prenatal screening according to the French protocol was cost effective compared with neonatal screening, at endpoints of one year and 15 years [22]. Our findings also agree with the two previous CBA of maternal screening for toxoplasmosis, despite differences in management of prenatal infections, retesting schedules, prevalence, and injury costs. The analysis in the low prevalence context of the United States in 2011 estimated that the screening program was cost saving and a sensitivity analysis estimated that it would still be the case for even lower prevalence [21]. The CBA of maternal toxoplasmosis screening in Austria found that prenatal screening for toxoplasmosis led to savings of €323 per birth in 2016 [20]. Adjusting for euro inflation between 2016 and 2020 and taking into account the lower estimates of prevalence in Austria narrowed the difference between the French and Austrian studies. The CBA in the US in 2011 and in France in 2021 assumed similar screening protocols and found similar level of costs for the screening option. After adjusting for inflation between 2011 and 2020, the cost of screening in the US of $390 was only 6.6% higher than the cost of the screening option in the French 2021 CBA analysis. The lower medical costs in France in 2020 than in the US in 2011 is partly explained by the 5-times higher cost of amniocentesis in the US in 2011 compared to France in 2021. Another part of the explanation reflects the technological improvements in diagnosis of CT in the decade after 2011. For example, the cost of obstetric ultrasounds (€100 each) in the French tree do not appear in the US tree. The medical regimen also changed between 2011 and 2020. Prenatal treatment with sulfadiazine and pyrimethamine is now given in second trimester maternal seroconversions as soon as the diagnosis is made and not only in case of positive amniocentesis and requires weekly CBC [11, 22]. Finally, the cost of pediatric treatment over one year for a child with CT was $210 in the US in 2011 and was €3,124 in France in 2021.

Costs for the no-screening scenario in the US CBA were greater by 75% ($1010 in 2011, equivalent to €1429 in 2021 after adjusting for inflation) than in our study (€656). This difference partially reflects the higher costs of medication but mostly results from the dramatically higher costs of caring for CT-related injuries, including remedial education, custodial care, hearing aids, eyeglasses, earnings loss by caregivers and those disabled by toxoplasmosis in the US [36, 37]. The arbitrarily higher estimate of the value of statistical life in the US combined with the higher probability of fetal death in the US CBA also help explain the difference in costs in the no-screening scenario. In summary, our CBA and the US and Austrian CBAs produce mostly similar conclusions. Dissimilar results from the three studies are explained by the substantial differences in the protocol used in each study and some costs of medicines, medical procedures, and injury costs.

A second important finding was the robust results for most parameters analysed in the sensitivity analysis. It includes prevalence of infection, which is a key finding at a time of falling prevalence in industrialized countries. Falling prevalence is also increasingly reported in developing countries in the few recent studies including valid comparisons over time [1].

Due to their common structure, our models shared several characteristics with the two other CBA models. The first is that probabilities of clinical outcomes were based on population-based reports, in the context of screening or no screening conversely and not on pre-set estimates of treatment efficacy. This allowed estimating the impact of prompt diagnosis and treatment interventions on reducing the number of severe cases of CT despite the lack of randomized controlled trials that compared screening to no screening. Experimental, parasitological, and clinical data indicate that prompt initiation of anti-parasitic treatment following maternal infection reduces the risk of placental transmission. Several recent studies from Europe and South America that adjust for the gestational age at the time of maternal infection (the major risk factor for transmission) observed lower rates of transmission with pyrimethamine-sulfadiazine than other or no prophylaxis [38]. A single RCT found a trend towards less transmission with pyrimethamine-sulfadiazine than spiramycin (18.5% vs. 30%, p = 0.147). This association was strengthened when the treatment was started within 3 weeks of seroconversion. The incidence of fetal cerebral ultrasound signs was significantly lower in the pyrimethamine-sulfadiazine group [39]. The benefits of anti-parasitic therapy for fetuses or neonates with CT are also strongly suggested by large observational studies, which show that prompt initiation of treatment with pyrimethamine and sulphonamides is associated with a decreased incidence of cerebral signs and symptoms as well as retinochoroidal lesions [12, 14]. However, no valid quantitative estimates are available to quantify the risk reduction from treatment. Binquet et al. made the choice to model the impact of treatment based on several assumptions of efficacy [22].

For the sake of simplicity and comparability with the two previous CBA studies, we also made the choice not to include the possibility for acute maternal infection to be detected by clinical signs; these are present in 20 to 30% of cases in immunocompetent adults but are non-specific and often identified only after seroconversion is diagnosed [1]. We also did not include the cost of the individual screening, which is increasingly performed worldwide at the initiative of patients at individual clinical practices or maternity hospitals or at the request of patients. These aggregated costs might have reduced the difference in costs and benefits between screening and no screening. There were, however, not found by Binquet et al. to modify their conclusion regarding the cost effectiveness of the monthly prenatal screening [22]. Similarly, we assumed 100% compliance with the screening, diagnosis, treatment procedures, and lack of side effects from treatment. There is no precise estimate of suboptimal adherence in the real world. In a study in one region of France in 2009, a quarter of the participants had their first test beyond the first trimester of pregnancy, 80% of participants had at least one between-test interval exceeding 35 days, and 60% of participants completed fewer than the recommended seven tests [40]. Non-compliance probably led to overestimating both the cost and benefits of screening in proportions that cannot be precisely estimated. Varying compliance from 50 to 100% however did not significantly affect the conclusion by Binquet et al. [22].

Also, we did not include indirect spillover benefits of serological retesting and health education on the overall outcomes of pregnancy, which could have increased the benefits associated with screening. Awareness of preventing infection through improved hand hygiene and food preparation could be reinforced by performing repeated blood tests. Finally, we did not model the psychological consequences of prenatal screening. Repeated monthly tests, amniocentesis, or uncertainties in the prognosis for fetuses with CT can be responsible for significant anxiety. Conversely, the psychological benefits of prenatal screening are also real since rapid treatment and precise information can be reassuring [41]. Costs of training clinicians and biologists should not be underestimated when implementing a screening program and would need to be included in a further stage of planning.

The simple structure of our tree will facilitate monitoring the impact of any additional preventive interventions or changes in the epidemiology of T. gondii. They will also help measuring the saving produced by using the point-of-care tests that have been validated as excellent and inexpensive and would reduce the logistical constraints of the French universal retesting program [42]. Our model could also be used as a simple decision-making tool for helping policy makers worldwide in simulating the benefits that implementing prenatal screening might have in their settings, according to local epidemiological and clinical findings, and costs. This approach would be of upmost interest in areas where Toxoplasma gondii is severe due to the presence of more virulent strains. It could also be used to help confirm the decision of not to screen made in several countries.

The finding that maternal screening is cost saving in both Austria and France–and would be in the US if implemented there–serves to reinforce confidence in ongoing prenatal toxoplasmosis screening programs. This also encourages efforts to implement prenatal screening programs in the US and elsewhere, particularly in countries where the incidence of toxoplasmosis is high, or the strains virulent, and where the socio-economic level allows access to prenatal diagnosis. Even in a country where prevalence is low and falling, prenatal screening may be needed, since we found that the breakeven point for prenatal screening was reached with a primary maternal infection rate much lower than the current French rate.

Conclusion

This analysis shows that prenatal screening and treatment for T. gondii infection following the French protocol result in substantial cost saving. Our results are robust to wide variations in parameter values, and they indicate that prenatal toxoplasmosis screening may be beneficial even in countries with low prevalence.

Supporting information

S1 File. Measuring the costs of impairment used at terminal nodes in the decision tree.

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S1 Fig. Image of entire decision tree with the 9 major branches: These 9 branches together show the probabilities of all possible outcomes due to congenital toxoplasmosis (green circles at chance nodes) and the costs associated with each outcome (red triangles at terminal nodes).

Each outcome has a conditional probability equal to the sum of the probabilities along each branch. The formulas at the terminal nodes for each outcome provide the current cost of testing, surveillance and medications, and costs of all direct injury costs (such as remedial education) and all indirect injury costs (such as lost earnings due to impairment) as shown in S1 Fig. Since the decision tree reproduced into a single image proved to be very difficult to read, we segmented the tree into its 9 main branches (S2–S10 Figs) and a simplified version of decision tree (S11 Fig).

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S2 Fig. No screening.

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S3 Fig. Screening and maternal seroconversion before 12 weeks.

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S4 Fig. Screening and maternal seroconversion between 12 and 16 weeks.

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S5 Fig. Screening and maternal seroconversion between 16 and 20 weeks.

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S6 Fig. Screening and maternal seroconversion between 20 and 24 weeks.

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S7 Fig. Screening and maternal seroconversion between 24 and 28 weeks.

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S8 Fig. Screening and maternal seroconversion between 28 and 32 weeks.

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S9 Fig. Screening and maternal seroconversion between 32 and 36 weeks.

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S10 Fig. Screening and maternal seroconversion after 36 weeks and no maternal seroconversion.

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S11 Fig. Simplified version of decision tree, omiting 4 of 5 identical tree branches.

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Data Availability

All relevant data are within the paper and Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

References

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PLoS One. doi: 10.1371/journal.pone.0273781.r001

Decision Letter 0

Jodie Dionne-Odom

10 Feb 2022

PONE-D-21-31899Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic modelPLOS ONE

Dear Dr. Sawers,

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

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Reviewer #1: Yes

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Reviewer #4: No

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5. Review Comments to the Author

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Reviewer #1: This is an excellent paper. The topic is highly relevant, the methodology is appropriate, it is well-written. I support publishing under few conditions.

Firstly, your results strongly depend on the costs. Even if the tornado diagram (+/- 20 %) indicates that the intervention remains cost-saving, there is still a major question about the costs. I would like to know much more about how you calculated the costs. At least I would like to see a detailed analysis of the underlying literature. How did you calculate the intervention cost? What part of the life-long cost are direct and indirect? How were indirect cost / opportunity cost calculated? and if you take them from literature: are they really comparable? What interest rate did you include? In other words: write much more about the costs.

Secondly, I had severe problems to read the decision-tree. It might be worthwhile to explain in the methods section at least the structure of the tree.

Thirdly, I assume you handle uncertainty by sensitivity analysis. But how exactly did you do that? Was some form of boot-strapping involved? Or how did you get the distribution of variables?

In other words: If you can describe more precisely what you most likely did anyhow, I will support publishing without doubt.

Reviewer #2: It would be helpful if the autors state that the 444 Euros is taking into account the number of live births, not that this is the cost for an individual pregnancy child with ct. Otherwise everything clear and worthwhile for readers to know.

Reviewer #3: The paper entitled « Prevention of congenital toxoplasmosis in France using prenatal screening: A decision analytic economic model” by Sawers et al. describes a cost-benefit analysis of prenatal screening for T. gondii in France. The experience drawn from this disease in treated children in France, a country with historically successful management of congenital toxoplasmosis, supports the value of prenatal screening. The authors show it to be cost-effective, in addition to reducing or eliminating the devastating outcomes caused by the parasite. The paper is well written and interesting to read. Some points need to be addressed to help in the rigor of the presentation of this manuscript.

- It would be useful to compare the cost-benefit of prenatal screening in France to countries that have rejected both prenatal and neonatal screening (e.g., UK, Denmark, and Sweden). Someone would argue that the reasons for this relate to the clinical harms associated with false-positive diagnoses, low and uncertain benefits of treatment, harms associated with treatment, and high costs of prenatal screening.

- Line 334, the authors state, “The finding that maternal screening is cost saving in both Austria and France – and would be in the US if implemented there – serves to reinforce confidence in ongoing prenatal toxoplasmosis screening programs.” This statement is not supported by the authors investigation. Prenatal screening is not routine in the US. It is hard to be implemented because of the low prevalence of the disease, high cost of screening, high fee for service health care providers, and a high proportion of the uninsured population.

-The authors need to present evidence for the effectiveness of alternative public health interventions, when implemented with prenatal screening.

- It would be useful to define the demographic characteristics (e.g., race, ethnicity, education level) of the women participated in this analysis.

- Given the growing number of virulent Toxoplasma in central and south America, how could the costs and benefits of prenatal screening and public health interventions be prioritized in these countries according to the risks of acquiring infection during pregnancy, the timing of infection, and the capacity of health care systems?

- Rewrite the sentence of 322-323. The evidence for treatment is not sufficiently robust. Data from Wallon et al. (2013) showed symptoms in congenitally infected children even when the mothers were treated during pregnancy.

- Figure 1a, b has low resolution and hard to read

- Line 318 sentence is unclear

- Line 107, word check

Reviewer #4: Important topic but

1-important confusion concerning the choice of the vocabulary (this study can not be a cost-benefit analysis as it is presented)

2-impossible to read the figures

3-there is an important ambiguity concerning the goal of the article (is it for the US or French decison makers?). The title needs to be modified.

4-I do not understand the fact to have 2 trees and 1 result.

**********

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Reviewer #1: Yes: Steffen Flessa

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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Attachment

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PLoS One. 2022 Nov 4;17(11):e0273781. doi: 10.1371/journal.pone.0273781.r002

Author response to Decision Letter 0

7 Apr 2022

Point-by-Point Responses to Reviewers: Rebuttal Letter

Response of authors to the Editor’s and reviewers’ queries and comments appear below in italics.

First, we want to thank you – the Editor and reviewers – for your help in improving our manuscript. We have responded to all of your comments. Your advice has helped us to submit a substantially improved manuscript to PLOS ONE.

The Academic Editor says, “If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results.”

Our Response: The research on which this paper is based is not an experiment conducted in a laboratory and so there are no laboratory protocols to deposit. This recommendation is not applicable to our submission.

When submitting your revision, we need you to address these additional requirements.

Our submission meets PLOS ONE's style requirements, including those for file naming. https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Our Response: We have paid close attention to these formatting guidelines.

2. Thank you for stating the following in your Competing Interests section:

No authors have competing interests

This information should be included in your cover letter; we will change the online submission form on your behalf.

Our Response: The authors have declared that no competing interests exist." We have already stated we have no competing interest. We are not sure what else you want us to do. We still have no competing interests.

In our original submission we noted we would provide repository information for our data at acceptance. Unfortunately, we have been confused by the words used here. The only repository we have is the Supporting Information Files attached to the article as separate files. Hence, there is no accession number or DOI. We have made changes to our Data Availability statement and describe these changes in cover letter in our resubmission. Our data are from publicly available sources and our calculations using those data are described in the article and its Supporting Information Files.

Our Response: The title page of the manuscript now follows the PLOS ONE style sheet.

Our Response: We have tried to follow these instructions. There are only two Supporting Information Files.

Reviewer's Responses to Questions and Comments to the Authors

Our reactions to the editor’s and reviewers’ comments are in italics.

1. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

Our Response: We believe that our manuscript is technically sound and that our conclusions are appropriately based on the data presented. As noted above, our manuscript does not report on a controlled experiment or a randomized controlled trial. Accordingly, we have no controls or sampling. However, our study is fully replicable. Indeed, our study replicates 2 earlier cost-benefit studies using a decision tree analysis of toxoplasmosis screening, both of which were published in PLOS NTDs.Our study design is replicable by others just as our paper replicates earlier studies.

Two reviewers report that our paper only partly meets the criteria for success listed in the above paragraph.That judgement makes sense if Reviewers #1 and #4 expected our work to include a controlled experiment, sampling, and/or a randomized controlled trial, none of which belong in our manuscript.

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data Policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

Our Response: The data used in producing our study is fully explained in the text of the article and in the Supplemental Information Files included in our submission. Is it possible that Reviewer #1 did not see the Supporting Information Files? (It appeared in the copy of the paper sent to reviewers on the very last page of the submission.) If he or she did not notice the Supplemental Information Files, then his or her response that underlying data in the manuscript are not fully available is no longer puzzling.

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: No

Our Response: Reviewer #4 notes that the manuscript we submitted was not intelligible and/or written in standard English. At any rate, without more specific criticisms, we have no way to react to this reviewer’s comment. We should point out that the lead author is a native English speaker who has published dozens of articles in distinguished academic journals and authored or edited five books issued by well-known publishing houses. We have carefully re-read the article and have corrected the few mistakes we found..

5. Review Comments to the Author

Reviewer #1

This is an excellent paper. The topic is highly relevant, the methodology is appropriate, it is well-written. I support publishing under few conditions..

Firstly, your results strongly depend on the costs. Even if the tornado diagram (+/- 20 %) indicates that the intervention remains cost-saving, there is still a major question about the costs. I would like to know much more about how you calculated the costs. At least I would like to see a detailed analysis of the underlying literature. How did you calculate the intervention cost? What part of the life-long cost are direct and indirect? How were indirect cost / opportunity cost calculated? and if you take them from literature are they really comparable? What interest rate did you include? In other words: write much more about the costs.

Our Response: The data used in producing our study are fully explained in the text of the article and in the Methodological Supplement (located in the Supporting Information File 1) included in our submission. The Supporting Information File has a six page single-spaced description of how we measured injury costs. The only way we can understand Reviewer #1’s response here is that he or she did not notice our Supporting Information Files on the last page of the original submission. For example, the reviewer asks “What interest rate did you include?” Nevertheless, several passages in the Supporting Information File 1 discuss different interest rates.

Secondly, I had severe problems to read the decision-tree. It might be worthwhile to explain in the methods section at least the structure of the tree.

Our Response: We have divided the image of the decision tree into 9 separate branches, each of which is easily read. These 9 files are now included in the Supplemental Information File 2. In the main text is an illegible version of the entire decision tree whose complexity is visually underscored.

Thirdly, I assume you handle uncertainty by sensitivity analysis. But how exactly did you do that? Was some form of bootstrapping involved? Or how did you get the distribution of variables? In other words: If you can describe more precisely what you most likely did anyhow, I will support publishing without doubt.

Our Response: A sensitivity analysis was performed using a tornado graph that compared the effects of changing the value of 24 explanatory variables by ± 20% on our output value. The explanatory variable with easily the most important impact on our output variable is the primary maternal infection prevalence. A second graph (Figure 3) shows that maternal screening is cost saving when the primary maternal infection rate is greater than .00055. These are our only sensitivity tests; no boot-strapping was utilized in our analysis.

Reviewer #2

It would be helpful if the authors state that the 444 Euros is taking into account the number of live births, not that this is the cost for an individual pregnancy child with ct. Otherwise, everything is clear and worthwhile for readers to know.

Our Response: Yes, the €444 was computed per child after taking into account all live births in France.

Reviewer #3

The paper entitled “Prevention of congenital toxoplasmosis in France using prenatal screening: A decision analytic economic model” by Sawers et al. describes a cost-benefit analysis of prenatal screening for T. gondii in France. The experience drawn from this disease in treated children in France, a country with historically successful management of congenital toxoplasmosis, supports the value of prenatal screening. The authors show it to be cost-effective, in addition to reducing or eliminating the devastating outcomes caused by the parasite. The paper is well written and interesting to read.

Some points need to be addressed to help in the rigor of the presentation of this manuscript.

It would be useful to compare the cost-benefit of prenatal screening in France to countries that have rejected both prenatal and neonatal screening (e.g.,). Some would argue that the reasons for this relate to the clinical harms associated with false-positive diagnoses, low and uncertain benefits of treatment, harms associated with treatment, and high costs of prenatal screening.

Our Response: The reviewer is raising an important point: to our knowledge, no standard medico- economic assessment in several countries has been published supporting the decision not to screen. It is true that screening tests might yield false negative or negative results and that drug prescription needs to respect rules. However in our experience, false positive tests results are less frequent than estimated and their impact can be strongly reduced by adequate diagnostic strategies and training, Moreover, we find treatment is well tolerated in mothers and their children. We would not otherwise prescribe them at such a large scale in France. We therefore call for using medico economic appraisal to make informed decision-based realistic estimates. We have added a sentence line 334 of the text. Ours is now the third cost-benefit analysis showing that the benefits of maternal screening exceed its cost.

Line 334, the authors state, “The finding that maternal screening is cost saving in both Austria and France – and would be in the US if implemented there – serves to reinforce confidence in ongoing prenatal toxoplasmosis screening programs.” This statement is not supported by the authors’ investigation. Prenatal screening is not routine in the US. It is hard to be implemented because of the low prevalence of the disease, high cost of screening, high fee for service health care providers, and a high proportion of the uninsured population.

Our Response: The reviewer is correct when explaining the difference between the US and other countries, but Stillwaggon’s et al.’s study shows that even with those differences, the potential benefits of prenatal screening would exceed by a substantial amount its cost. Research often tries to estimate what the future might bring, and that is what our study attempts to do.

The authors need to present evidence for the effectiveness of alternative public health interventions, when implemented with prenatal screening.

Our Response. Prenatal screening requires screening all pregnant women whose immunity status for Toxoplasma is unknown to identify those who are susceptible. This systematic identification of women at risk naturally leads to their education on how to avoid infection. This probably contribute to reducing the incidence of maternal infections and thus the number of severely infected children, (and might contribute to explaining the decreasing incidence in France,) but the effect size cannot be precisely estimated, in the absence of any ethical possibility to randomize the delivery of any preventive advice. Similarly, identifying women who seroconverted during delivery allows submitting their newborns systematically to extensive diagnostic work up, including those who show no symptoms. Treatment and follow up of all infected newborns probably contributes to their good overall functional prognosis. Education of women found to be non immunized is natural/ We could not do otherwise--it just goes together with screening. The same is true for screening newborns at birth--no one would even consider not doing it.

Nevertheless, the specific contribution of each single intervention is impossible to estimate precisely.

We would, however, point out that women who are informed of the risk of Toxoplasma infection might be likely to be more aware of other prevention measures. The higher incidence of listeriosis reported in a French area of higher prevalence for toxoplasmosis might be considered as an indirect evidence of these spillover benefits of screening..

It would be useful to define the demographic characteristics (e.g., race, ethnicity, education level) of the women participated in this analysis.

Our Response: Our study is not a trial or experiment, and it is not a study of a sample of women. Our data seek to measure costs and benefits for all women in France.

Given the growing number of virulent Toxoplasma in central and south America, how could the costs and benefits of prenatal screening and public health interventions be prioritized in these countries according to the risks of acquiring infection during pregnancy, the timing of infection, and the capacity of health care systems?

Our Response: We would be delighted if someone would carry out the proposed project, but it is far beyond our resources. It would need to take into account the specific epidemiological characteristics in each setting; prevalence of toxoplasmosis in pregnant women, incidence of maternal infection, incidence of congenital toxoplasmosis and risk of long term lesions. At any rate, the benefits of screening are likely to correlate with the severity of the disease that is prevented. Accordingly, we invite local policy makers to set priorities. We add a sentence Line 331.

Rewrite the sentence of 322-323. The evidence for treatment is not sufficiently robust. Data from Wallon et al. (2013) showed symptoms in congenitally infected children even when the mothers were treated during pregnancy.

Our Response: The “Wallon et al. study” provided evidence that starting treatment early reduces the risk and severity of congenital toxoplasmosis. The comparison did not compare treatment vs no treatment, but treatment started early vs. later. Screening pregnant women every month (to insure prompt detection and treatment) is a requisite for obtaining the full benefit of treatment. The efficiency of the French programs could certainly be improved by improving compliance with the monthly testing.

These aggregated costs might have reduced the difference in costs and benefits between screening and no screening. That, however, was not found by Binquet et al. They found maternal screening for toxoplasmosis to be cost effective.

Our response: to respond adequately to this query we would need to know what are the aggregated costs mentioned by the reviewer 4.

Figure 1a, b has low resolution and hard to read

Our response: Any image that encompasses the entire decision tree and is also readable would be a meter or more in height, that is, would not fit on a single page. Consequently, we include within the text of the article a single image of the entire tree which is almost entirely illegible but it gives the reader a sense of the complexity of our statistical analysis. Then, in the Supporting Information File 2 we include 9 separate images. Each one is an image of one of the nine major branches of the tree. The numbers and words on each of those branches are easily readable.

Line 318 sentence is unclear

Our response: Line 318 to line 324 acknowledges a simplification that we chose to make to exclude the possibility for acute maternal infection to be detected by clinical signs; these are present in 20 to 30% of cases in immunocompetent adults but are non-specific and often identified only after seroconversion is diagnosed.” We did this for the sake of allowing comparison with the previous CBA studies.

Line 107, word check

Our response: We fixed the “T” in line 110.

Reviewer #4

Important topic but

1-important confusion concerning the choice of the vocabulary (this study cannot be a cost-benefit analysis as it is presented)

Our Response: Two articles in a distinguished journal (Stillwaggon et al. and Prusa et al. in PLOS NTDs) have together been cited almost 200 times without receiving any criticism for describing our method as a cost-benefit analysis. Without your explanation for why you think our study is not a cost-benefit analysis we have no way to address your comment.

2-impossible to read the figures

Our Response. We agree. As noted above, we have reformatted the tree figures. We divided the main tree into 9 separate branches that are included in our Supporting Information File (S2). The figure of the entire tree is still illegible, but necessarily so: it is too big to fit on a single page. Nevertheless, each of the 9 sub-branches easily fit on a single page and are easily readable.

3-there is an important ambiguity concerning the goal of the article (is it for the US or French decision makers?).

Our Response: The goal of our article is to illustrate how medico – economic evaluation can help make informed decisions regarding the pursuit of ongoing screening programs for congenital toxoplasmosis or the implementation of new universal programs. Whether or not universal screening is appropriate has been debated for a long time, but the decreasing prevalence of toxoplasmosis in pregnant women further reinforces the need to answer this question objectively. We used data routinely collected in the context of the most comprehensive screening program to date and the largest number of pregnant women screened daily. Our results will inform French (and both Austrian and Slovenian) decision-makers that maternal toxoplasmosis screening is cost saving and so maintaining existing screening programs makes economic sense. The same demonstration has been made for the US. But we also expect that decision makers elsewhere with an interest in toxoplasmosis will be interested in our results and encouraged to perform an appraisal such as ours. Our model is a generalizable tool for all policy makers worldwide and not only for the French or American ones. Standardization of tools is a key issue to allow.

The title needs to be modified.

Our Response: We hope that the explanation given above will convince the reviewer that the study is not about US, but about the cost and benefits of a screening program such as the one that is currently used in France. We have modified the text (see previous paragraph) rather than the title. We would however be pleased to hear your suggestions for a different title for our article.

4-I do not understand the fact to have 2 trees and 1 result.

Our Response: We have only one tree with nine branches. Our methodology is to compare the two main branches, one of which measures the benefits of prenatal testing and treatment and the other with no prenatal testing and treatment. The main branching is where the tree divides between screening and no screening and the ratio of the two gives us the principal measure of the economic advantage of screening over no screening.

6. PLOS authors have the option to publish the peer review history of their article. If published, this will include your full peer review and any attached files.

Our Response: We have no opinion about our peer review history.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Steffen Flessa

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

Attachment

Submitted filename: Response to reviewers.docx

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PLoS One. doi: 10.1371/journal.pone.0273781.r003

Decision Letter 1

Jodie Dionne-Odom

20 Apr 2022

PONE-D-21-31899R1Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic model

PLOS ONE

Dear Dr. Sawers,

You have addressed nearly all reviewer concerns and the manuscript is well-written. Only two issues remain:

1) I agree with reviewer #1 that additional information about the economic analysis assumptions should be added in the methods section of the main manuscript. This does not need to be extensive - a few sentences with the most relevant information will be helpful for readers with expertise in cost effectiveness analyses.

2) Figure 1 is too small to be legible. Please move it to supplemental materials with the larger snapshot images that are already in supplemental images.

Please submit your revised manuscript by Jun 04 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Jodie Dionne-Odom, MD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments (if provided):

The authors worked hard to address all of the reviewer concerns and the manuscript is well-written. Only two issues remain.

2) Figure 1 is too small to be legible. Please move it to supplemental materials with the larger snapshot images that are already in supplemental images.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: As I had commented already in the first review, this is a very good paper. My main concern was that the methodology is not clear. You entered lots of information into the Supporting Information Files. That was my main critique: it is in the wrong place. The methodology (e.g. interest rate) is so relevant that it MUST be in the main body of the text. This is standard in health economic papers. From my perspective, You cannot put most crucial elements of the methodology into an appendix or attachment.

However, I would leave this to the editors. If they think it is o.k., then it is fine with me.

Reviewer #3: (No Response)

Reviewer #4: (No Response)

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Steffen Flessa

Reviewer #3: Yes: KAMAL EL BISSATI

Reviewer #4: No

PLoS One. 2022 Nov 4;17(11):e0273781. doi: 10.1371/journal.pone.0273781.r004

Author response to Decision Letter 1

10 May 2022

We agreed to all of the comments made by the editor and reviewers and have responded appropriately by revising the text of the article.

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file.^{(12.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0273781.r005

Decision Letter 2

Adriana Calderaro

30 May 2022

PONE-D-21-31899R2Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic modelPLOS ONE

Dear Dr. Sawers,

The Auhors have addressed to all the comments and the manuscript results to be deeply improved, however only few reccomendations by the Reviewer#3 could further improve it in order to be better clear to the reader.

Please submit your revised manuscript by Jul 14 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Adriana Calderaro

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Reviewer #1: (No Response)

Reviewer #3: (No Response)

Reviewer #4: The two comments have been fully addressed by the authors. Thank you very much.

I know how complicated it is to export decision trees from the software Tree Age , but I think that a global view (even short and summarized) of the decision tree is missing. It would guide the reader to add all the figures (1b to 1i) in an entire tree. Moreover, when I opened the Supporting Information file, some figures were on a "portrait" format instead of landscape". This could be changed. Moreover, the authors provided formulas to calculate costs at the end of each arm but without any legend to understand the abbreviation of the variables used.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Steffen Flessa

Reviewer #3: No

Reviewer #4: No

PLoS One. 2022 Nov 4;17(11):e0273781. doi: 10.1371/journal.pone.0273781.r006

Author response to Decision Letter 2

13 Jul 2022

The editor requested three changes to our submitted manuscript. They were "I think that a global view (even short and summarized) of the decision tree is missing. It would guide the reader to add all the figures (1b to 1i) in an entire tree. Moreover, when I opened the Supporting Information file, some figures were on a "portrait" format instead of landscape". This could be changed. Moreover, the authors provided formulas to calculate costs at the end of each arm but without any legend to understand the abbreviation of the variables used." We have responded to all three requests for change in our submission by making the requested changes. Larry Sawers Corresponding Author

PLoS One. doi: 10.1371/journal.pone.0273781.r007

Decision Letter 3

Adriana Calderaro

16 Aug 2022

Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic model

PONE-D-21-31899R3

Dear Dr. Sawers,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Adriana Calderaro

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #3: Yes

**********

6. Review Comments to the Author

Reviewer #3: The authors have adequately addressed the reviewers' comments and I feel that this manuscript is now acceptable for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #3: Yes: KAMAL EL BISSATI

**********

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 File. Measuring the costs of impairment used at terminal nodes in the decision tree.

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S2 Fig. No screening.

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S3 Fig. Screening and maternal seroconversion before 12 weeks.

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S4 Fig. Screening and maternal seroconversion between 12 and 16 weeks.

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S5 Fig. Screening and maternal seroconversion between 16 and 20 weeks.

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S6 Fig. Screening and maternal seroconversion between 20 and 24 weeks.

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S7 Fig. Screening and maternal seroconversion between 24 and 28 weeks.

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S8 Fig. Screening and maternal seroconversion between 28 and 32 weeks.

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S9 Fig. Screening and maternal seroconversion between 32 and 36 weeks.

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S10 Fig. Screening and maternal seroconversion after 36 weeks and no maternal seroconversion.

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S11 Fig. Simplified version of decision tree, omiting 4 of 5 identical tree branches.

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Attachment

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Data Availability Statement

All relevant data are within the paper and Supporting Information files.

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PERMALINK

Prevention of congenital toxoplasmosis in France using prenatal screening: A decision-analytic economic model

Larry Sawers

Martine Wallon

Laurent Mandelbrot

Isabelle Villena

Eileen Stillwaggon

François Kieffer

Roles

Abstract

Background

Objective

Methods

Findings

Interpretation

Introduction

Methods

Description of French toxoplasmosis screening and management protocol

Modeling

Clinical probabilities

Table 1. Probabilities with no-screening option.

Table 2. Probabilities with screening option.

Economic costs

Table 3. Test and medication costs.

Table 4. Costs due to impairments.

Fig 1. Tornado diagram.

Results

Fig 2. Sensitivity analysis of the expected value of prenatal screening for toxoplasmosis vs no screening, according to the annual incidence of primary maternal infection.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Jodie Dionne-Odom

Roles

Author response to Decision Letter 0

Decision Letter 1

Jodie Dionne-Odom

Roles

Author response to Decision Letter 1

Decision Letter 2

Adriana Calderaro

Roles

Author response to Decision Letter 2

Decision Letter 3

Adriana Calderaro

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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