Loïc Simon
email: simon.l@chu-nice.fr

Cynthia Trastour

Albert Soler

Fabienne Jeannet

Marie-Fleur Durieux

Karine Passebosc-Faure

Pierre Marty

Christelle Pomares

Karine Passebosc- Faure

A case of congenital toxoplasmosis-associated miscarriage with maternal infection four months prior to conception

Keywords: 1367, Figure count: 1, Table count: 1 Maternal toxoplasmosis before conception Toxoplasma gondii, congenital toxoplasmosis, preconception, miscarriage, fetal death

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

CASE REPORT

The intracellular parasite Toxoplasma gondii is responsible for toxoplasmosis, whose primary infection is asymptomatic in about 80% of cases in healthy people. Sometimes, mild symptoms may be present, including asthenia, cervical lymphadenitis, fever and biological mononucleosis syndrome. Newborns are at risk of congenital toxoplasmosis when the infection occurs during pregnancy. The tachyzoite form of the parasite can then be transmitted to the fetus by random breaks from placental foci. The risk of transmission is considered low when the maternal infection occurs at the beginning of pregnancy but it increases up to 70% at the end of pregnancy [START_REF] Wallon | Congenital Toxoplasma Infection: Monthly Prenatal Screening Decreases Transmission Rate and Improves Clinical Outcome at Age 3 Years[END_REF]. Conversely, severity of congenital infection is higher at the beginning compared to the end of pregnancy. Few congenital infections are described when women were infected before the date of conception. In the majority of cases, these infections can be explained by reactivation of a past infection during pregnancy in immunocompromised mothers [START_REF] Marty | Prenatal diagnosis of severe fetal toxoplasmosis as a result of toxoplasmic reactivation in an HIV-1 seropositive woman[END_REF]. Here, we report a case of fatal congenital toxoplasmosis with maternal infection dated four months before pregnancy in the absence of any specific immunosuppressive condition.

In February 2018, Ms. D., a 28-year-old G1P1 with no medical conditions and no foreign travel, presented with fatigue and enlarged cervical lymph nodes. After an evaluation by general physicians and ENT specialists, she was diagnosed with submaxillary lymphadenitis, confirmed by a cervical ultrasound. The biological workup, including a complete blood count with differential, was normal and did not show obvious sign of immunosuppression. The cytomegalovirus, Epstein-Barr Virus, Hepatitis B and C Virus, and HIV serological tests results were negative and rubella serology demonstrated immunity. As the lymphadenitis persisted, a T. gondii serology was performed the 4 th of April and was consistent with an acute infection dated beginning of February with presence of specific IgG, IgM and IgA (Table 1). IgG avidity was low, which was not relevant in helping to assume the age of the infection, as only high-avidity anti-Toxoplasma IgG antibodies is informative to exclude acute infection in the preceding 4 months. The last known negative T. gondii serology dated November 29, 2017: IgG = < 0.5 UI/mL; IgM index = 0.37 (ADVIA Centaur ® Toxo Assay). An ophthalmologic exam did not reveal any abnormality. No treatment was prescribed at that time.

Few months later, Ms. D. became pregnant. The first day of the last menstrual period was May 22, 2018 and the estimated date of conception was June 05, 2018. The first fetal ultrasound performed on August 17 during the first trimester demonstrated an embryo with a crown-rump length of 63.8 mm, consistent with a gestational age of 12 weeks and 4 days. All biometric measurements were between the 10 th and the 90 th percentiles and no morphological abnormalities were observed. On September 12, at 16 weeks and 2 days of pregnancy, a second obstetrical ultrasound highlighted fetal death that probably occurred few days after the first ultrasound according to the obstetrical measurements. Uterine curettage was performed the following day at the teaching hospital of Nice, France. Analysis of the products of conception by the laboratory of Parasitology-Mycology revealed a positive T. gondii PCR. Microsatellite genotyping performed on the PCR products by the National Reference Center for Toxoplasmosis, in Limoges, found a Type II T. gondii strain (TgH 23069A). Type II strains represent 95% of the circulating strains in France [START_REF] Ajzenberg | The rural-urban effect on spatial genetic structure of type II Toxoplasma gondii strains involved in human congenital toxoplasmosis, France, 2002-2009[END_REF][START_REF] Aubert | Molecular and biological characteristics of Toxoplasma gondii isolates from wildlife in France[END_REF][START_REF] Halos | An innovative survey underlining the significant level of contamination by Toxoplasma gondii of ovine meat consumed in France[END_REF]. Toxoplasma gondii PCR performed on the peripheral blood of Ms. D. was negative. Figure 1 summarizes the timeline of the events. After questioning Ms. D., we learned that the submaxillary lymphadenitis was still palpable when she became pregnant and during the pregnancy. To date, Ms. D. is doing well. She became pregnant again on April 2019 and gave birth to a healthy baby on December 31.

In some countries like France, pregnant women are tested in the early weeks of gestation for the presence of specific IgG and IgM against T. gondii. When the first serology is negative, a monthly prenatal screening is performed. This approach allows prompt initiation of treatment of the mothers who seroconvert and of infected fetuses along with being cost-effective [START_REF] Wallon | Congenital Toxoplasma Infection: Monthly Prenatal Screening Decreases Transmission Rate and Improves Clinical Outcome at Age 3 Years[END_REF][START_REF] Binquet | The cost-effectiveness of neonatal versus prenatal screening for congenital toxoplasmosis[END_REF]. In our case, T. gondii infection, proven by the association of symptomatology and specific serology, occurred four months before conception. Per protocol, no further treatment or evaluation was performed and there should have been no consequences on the pregnancy.

Toxoplasma gondii was transmitted to the fetus long after the estimated date of infection. Similar cases are rare in the literature and to our knowledge, this is the first description of proven fetus infection with such a long period of time between mother infection and conception [START_REF] Marty | Prenatal diagnosis of severe fetal toxoplasmosis as a result of toxoplasmic reactivation in an HIV-1 seropositive woman[END_REF][START_REF] Villena | Prenatal diagnosis of congenital toxoplasmosis transmitted by an immunocompetent woman infected before conception. Reims Toxoplasmosis Group[END_REF][START_REF] Dollfus | Congenital toxoplasma chorioretinitis transmitted by preconceptionally immune women[END_REF][START_REF] Pons | Congenital toxoplasmosis: transmission to the fetus of a pre-pregnancy maternal infection[END_REF][START_REF] Desmonts | Congenital toxoplasmosis. 5 cases of mother-to-child transmission of pre-pregnancy infection[END_REF][START_REF] Boumahni | Maternal toxoplasmosis before conception and chorioretinitis in twin sisters[END_REF][START_REF] Vogel | Congenital toxoplasmosis transmitted from an immunologically competent mother infected before conception[END_REF][START_REF] Marty | Congenital toxoplasmosis and preconceptional maternal ganglionic toxoplasmosis[END_REF][START_REF] Chemla | Preconception seroconversion and maternal seronegativity at delivery do not rule out the risk of congenital toxoplasmosis[END_REF]. The presence of enlarged cervical lymph nodes seems to be the common feature in similar situations of pregnant women without immunosuppressive pathology [START_REF] Villena | Prenatal diagnosis of congenital toxoplasmosis transmitted by an immunocompetent woman infected before conception. Reims Toxoplasmosis Group[END_REF][START_REF] Desmonts | Congenital toxoplasmosis. 5 cases of mother-to-child transmission of pre-pregnancy infection[END_REF][START_REF] Boumahni | Maternal toxoplasmosis before conception and chorioretinitis in twin sisters[END_REF][START_REF] Vogel | Congenital toxoplasmosis transmitted from an immunologically competent mother infected before conception[END_REF]. We might wonder if an iterative release of parasites from the lymph nodes may have been responsible, in our case and the others, for fetus infection. Moreover, when primary infection is symptomatic, there could be a prolonged parasitemia, promoting transmission to the fetus. Our patient was not treated at the time of diagnostic but treatment with spiramycin before conception have been performed in other cases and failed to prevent infection of the fetus [START_REF] Marty | Prenatal diagnosis of severe fetal toxoplasmosis as a result of toxoplasmic reactivation in an HIV-1 seropositive woman[END_REF][START_REF] Villena | Prenatal diagnosis of congenital toxoplasmosis transmitted by an immunocompetent woman infected before conception. Reims Toxoplasmosis Group[END_REF][START_REF] Dollfus | Congenital toxoplasma chorioretinitis transmitted by preconceptionally immune women[END_REF][START_REF] Boumahni | Maternal toxoplasmosis before conception and chorioretinitis in twin sisters[END_REF]. Currently, there are no official recommendations about the preconceptional toxoplasmosis care. We agree with Villena et al. [START_REF] Villena | Prenatal diagnosis of congenital toxoplasmosis transmitted by an immunocompetent woman infected before conception. Reims Toxoplasmosis Group[END_REF] on advocating a pregnancy-free interval of at least six months after proven toxoplasmosis infection. In addition, specific monitoring, by regular ultrasound and prenatal diagnosis, in pregnant immune women with adenopathy should be recommended. Effective treatment of symptomatic toxoplasmosis in women with a desire for pregnancy could be advisable too.

Treatment strategy with trimethoprim-sulfamethoxazole (already used for T. gondii infection in immunocompromised patients) could be a good alternative to spiramycin. A double-blind, randomized clinical trial by Alavi et al. [START_REF] Alavi | Treatment of toxoplasmic lymphadenitis with co-trimoxazole: double-blind, randomized clinical trial[END_REF] showed the benefits of a treatment by trimethoprim-sulfamethoxazole (= cotrimoxazole) at 48 mg/kg/day for 1 month on the healing of lymphadenitis and the decrease of anti-T. gondii IgM level. Moreover, it is also important to encourage practitioners to examine women with miscarriage for the presence of enlarged lymph nodes. In case of lymphadenitis, the diagnosis of toxoplasmosis should be discussed. The role of T. gondii in unexplained miscarriages has been rarely assessed and is probably underestimated. According to the review by Giakoumelou et al. [START_REF] Giakoumelou | The role of infection in miscarriage[END_REF], the link between miscarriages and congenital toxoplasmosis was poorly studied. In this review, the study populations ranged from 100 to 326 women with a history of miscarriage. The analyses performed were often limited to serological tests or T. gondii PCR in mothers' blood and these assays are not those which make it possible to diagnose a congenital toxoplasmosis. Prevalence of toxoplasmosis ranges from 20% to 70% worldwide and more powerful studies about the potential role of T. gondii in miscarriages are needed to better prevent fetus infection. This case report highlights the fact that a symptomatic acute infection by T. gondii should be considered differently than an asymptomatic one. A period of six months should be considered between the symptomatic infection and the pregnancy, in order to prevent unexplained miscarriage.

FIGUREFigure 1 :

 1 FIGURE

TABLETable 1 .

 1 Biological resultsIgG avidity (Architect®, Abbott Laboratories): ≥ 60% → past infec0on > 4 months ago IgM (Architect®, Abbott Laboratories): negative < 0.50 ; equivocal 0.50 -0.59 ; positive ≥ 0.60 IgA (Platelia™, Bio-Rad): negative < 0.8 ; equivocal 0.8 -1 ; positive ≥ 1

	Assay performed	11/29/2017 04/04/2018 08/18/2018 09/07/2018 09/13/2018 09/24/2018 11/14/2018
	IgG (IU/mL)	< 0.5 a	194.9	732.3	1362.3	n/a	1350.9	1096.2
	IgG avidity	n/a	5.04%	38.10%	n/a	n/a	n/a	n/a
	IgM (index)	0.37 b	15.38	4.74	3.04	n/a	3.87	5.01
	IgA (index)	n/a	4.2	3	n/a	n/a	n/a	n/a
	PCR (products of conception)	n/a	n/a	n/a	n/a	Positive	n/a	n/a
	PCR (patient's blood)	n/a	n/a	n/a	n/a	n/a	Negative	n/a
	IgG (Architect®, Abbott Laboratories): negative < 1.6 ; equivocal 1.6 -2.9 ; positive ≥ 3

a IgG (ADVIA Centaur®, Siemens): negative < 6.4 ; equivocal 6.4 -9.9 ; positive ≥ 10 b IgM (ADVIA Centaur®, Siemens): negative < 0.9 ; equivocal 0.90 -0.99 ; positive ≥ 1 n/a: not available

Table 1 :

 1 Biological resultsFigure1: Timeline of the events and important serological findings (serological results are expressed qualitatively according to the cut-offs of the tests described in Table1; GA: Gestational age; n/a: not available)


Ettore Recchi

Emanuele Ferragina

Emily Helmeid

Stefan Pauly

Mirna Safi

Nicolas Sauger

Jen Schradie

The "Eye of the Hurricane" Paradox: An Unexpected and Unequal Rise of Well-Being During the Covid-19 Lockdown in France

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

In the aftermath of the earthquake that hit Japan in 2011, which led to a tsunami and the Fukushima nuclear accident, researchers compared the levels of subjective well-being of young people to those from before the disaster. They were surprised by what they found: an improvement of overall morale, instead of an expected decline [START_REF] Uchida | Changes in hedonic and eudaimonic well-being after a severe nationwide disaster: The case of the Great East Japan Earthquake[END_REF]; see also [START_REF] Quarantelli | An Assessment of Conflicting Views on Mental Health: The Consequences of Traumatic Events[END_REF]. Similarly, through nationally representative panel data of French residents, we find that the perception of both health and well-being during the Covid-19 epidemic has improved in comparison to previous years. We name this counterintuitive phenomenon the "eye of the hurricane" paradox: the vast majority of individuals who are not infected by the virus may be seeing their general health and sense of subjective well-being in a more positive light than they normally would. There are, however, divergences across social groups that reflect socioeconomic inequalities. Particularly, manual workers deviate from the prevailing trend, as their level of self-reported health declines over the lockdown period.

Data and main indicators

Data for our analyses come from the first, second and third waves of a panel survey administered online and conducted during the lockdown from 1-8 April, 15-22 April and 29

April-6 May 2020 respectively. 1 The first survey took place exactly two weeks after the official start of the lockdown in France, which began on 17 March. Subsequent waves were carried out at two-week intervals, with the fourth and fifth waves coming after the official start of a progressive re-opening of France, which began on 11 May. During the lockdown period, schools and most shops were closed down, national and international travel was almost entirely cancelled, and individuals' freedom to leave their homes was limited to basic necessities.

Our survey waves build on ELIPSS, a probability-based panel launched in 2012. ELIPSS currently relies on a sample of 1400 residents of mainland France that was drawn from census data collected through face-to-face interviews during the initial stage for which the acceptance rate was greater than 25 percent. Weights have been computed to take into account design effects from the initial stage, bias due to acceptance rate during the enrollment phase, and poststratification on the basis of gender, age, education and region.

The main indicators we delve into for this research note are respondents' self-assessment of personal 'health', a composite indicator of subjective 'well-being', and a measure of lockdownrelated 'stress'. Self-assessed health is ranked on a five-point scale ranging from 'very bad' to 'very good'. To capture subjective well-being in a holistic way, we constructed an index combining panelists' responses to six different questions regarding how often they have felt 'nervous', 'low', 'relaxed', 'sad', 'happy' and 'stressed out' over the previous two-week period on a five-point scale from 'never' to 'always'. Negative feelings are inverted to enable the construction of an additive index, which was then normalized between 0 (lowest) and 1 (highest). 'Lockdown-related stress' was based on the response to the question 'Does the lockdown take a toll on you?' measured on a 0 to 10 point scale from 'not at all' to 'enormously'.

Feeling good in hard times? Diverging trends in French society

Self-reported health

Whereas between 2017 and 2019 only 11 percent of respondents declared being in very good health, this proportion has more than doubled during the lockdown, following an initial jump at the beginning and a subsequent stabilization. However, this dramatic rise was not felt uniformly across French society. This is particularly the case among blue-collar workers for whom the proportion of those feeling good or very good has declined since the lockdown began (figure 1, top-left panel). To some extent, this may be related to their exposure to risk during the epidemic, as we also find that the incidence rate of Covid-19 is higher among manual workers, reaching 11.2 percent in our latest survey (early May), as opposed to 6.2 percent in the rest of the population. 2 The gap in self-assessed 'good/very good' health between blue-collar workers (55 percent) on the one hand and managers and farmers (90 percent) on the other is impressive. Farmers are the occupational category that fares the best, in continuity with surveys from the two preceding years. Overall, with the remarkable exception of manual workers, the rise in the level of self-reported good health is widespread and reflects the pre-existing hierarchy of working conditions among occupations.

Self-reported health is also stratified by household income (figure 1, top-right panel). Although it shrinks slightly (but not significantly) as the lockdown progresses, the gap between income groups remains relatively constant before and after the start of the lockdown. In sum, the epidemic seems to trigger health inequalities that are occupation-specific rather than incomerelated. Apparently, for low-income earners, health risks are concentrated among blue-collar workers. Other socioeconomic factors have an impact as well, given that good health is significantly less prevalent among the most financially vulnerable (i.e. people who say they cannot afford an unexpected €400 bill), women, older people and respondents living in smaller homes (after controlling for all other relevant variables, see Appendix). These effects have, however, remained stable over time --notably, before and after the lockdown.

Subjective well-being

Like general health, subjective well-being scores have been on the rise since the quarantine started. The rise is constant across household income levels. Although clerks exhibit a steep upswing, the generalized increase is less marked than that for general health (bottom-left panel, figure 1). Why such uniformity across social groups when it comes to subjective wellbeing? From a comparative perspective, the robustness of the welfare system may be a factor (France has the highest level of social spending among OECD countries), as the state granted rather generous unemployment benefits to full-time employees who were temporarily laid off (chomage partiel, at least 84% of former salary) during the crisis. Reading: The purple line in the top left panel shows that 90% of farmers report being in "good" or "very good" health in the latest 2020 survey. The left column plots time trends by occupation and the right column by tertiles of disposable household income. The upper row plots the share of respondents who report being in "good" or "very good" health and the lower row shows the evolution of the subjective well-being index on a 0-1 scale. This index is an average of six questions that touch upon feeling nervous, low, relaxed, sad, happy and lonely. The answers are normalized to be between 0 and 1, with 0 indicating the lowest and 1 the highest possible well-being level.

Inequalities do exist though. Subjective well-being is still significantly lower for the most financially vulnerable and for individuals living in smaller homes, once we control for all other relevant variables (as listed in the Appendix). Moreover, new regional disparities emerge during the lockdown. Controlling for the average level of subjective well-being in each survey (i.e., accounting for an overall change due to Covid-19) and the average level for each individual (e.g. accounting for low-income survey participants or residents in Paris being less happy in general), we show in figure 2 that residents in the Paris region experienced a sizeable and significant decrease in their subjective well-being score compared to the rest of the country (the drop amounts to around 7% of the overall average). Perhaps housing constraints and the paucity of green spaces in Paris exacerbate the negative impact of the sudden disappearance of the most attractive features of la capitale --its dynamic cultural, artistic and entertainment life. Without theatres, museums, cafes and street life, Paris may be more suffocating than your average French town. Under such conditions, the Simmelian blasé character of Parisians looks to have been shaken for once. ("Does the lockdown take a toll on you?" on a 0-10 scale). This measure has not changed significantly over the three waves of our survey. To some extent, we find that it reflects workhours and type of workplace (figure 3). The longer respondents' work-hours are, the stronger the sentiment is that the quarantine exhausts them. This is especially true for those who spend long working days at home in front of their computers or answering the phone. This flies in the face of arguments praising the advantages of home-working (e.g., [START_REF] Bloom | To raise productivity, let more employees work from home[END_REF], which may protect one from the virus but seems to entail psychological costs. Such costs are even higher for teleworkers who rarely went outside during confinement. For teleworkers who leave home only once a week or less, each additional hour of daily work means an increase of stress levels by around 4% compared to teleworkers who go out more frequently. Reading: The horizontal axis indicates the average number of hours worked per day, the vertical axis the position of respondents on a 0 to 10 scale in answer to the question: "Does the lockdown take a toll on you?". The average score for people working from home 0-1 hours per day is 4.3 and for those working outside is 4.8. The number of hours worked per day was measured in brackets: 0-1 hours, 1-2 hours, … up to 10 or more hours.

Conclusion

The Covid-19 pandemic sent shockwaves worldwide --not only because of the disease and its death toll, but also because of the resulting lockdown and its disruption of daily life. France was no exception. Nevertheless, the majority of people did not panic. Quite the contrary, they declared feeling healthier and having a better morale than beforehand. While instances of this phenomenon -have been observed in the aftermath of other socially disruptive events, only research conducted elsewhere during the worldwide Covid-19 crisis may tell us to what extent this may be a culturally-specific reaction. Likewise, only further survey waves once the pandemic is over will allow us to assess whether such a change is a temporary shock or the beginning of a new normal.

Despite the overall upswing, we also found inequalities that trouble the general picture. As regards self-reported health, the epidemic exacerbated health disparities between occupations, hitting the working class ('ouvriers') the hardest. This is reflected in the proportion of people both infected by the virus and reporting being in good or very good health by occupation --blue-collar respondents' level declined while that of all other occupations rose. As regards subjective well-being, significant deviations from the overall increase emerged for residents of Paris as opposed to the rest of France. Space-related factors seem to play a major role when it comes to psychological adjustment to such adverse conditions. This is also reflected, to some extent, in the level of self-reported stress attributed to the lockdown, which we found to be higher among those working long hours at home. We conclude with a caveat: in this brief research note we tracked the effects of the pandemic over the first six weeks of the nationwide lockdown. Such effects were not, on the whole, too alarming but were nonetheless unequal. This does not rule out the possibility that in the long term --depending on policy responses, macro-and meso-level contextual variations, and personal experiences of the disease --the Covid-19 pandemic will leave multiple scars on several social groups.

Figure 1 .

 1 Figure 1. Changes in self-assessed health and subjective well-being from Springtime 2017 to April 2020 among mainland French residents by respondents' occupation and household income

Figure 2 .

 2 Figure 2. Subjective well-being of residents in Paris compared to average French residents from 2017 into the lockdown

Figure 3 .

 3 Figure 3. Changes in lockdown-related stress levels among mainland French residents by respondents' main site of work

Further information about our preliminary findings are included in two policy briefs(Recchi et al

;[START_REF] Ferragina | Dans l'oeil du cyclone. La société française après un mois de confinement[END_REF].

These figures include both people who tested positive and those who believe that they suffered from Covid-19 but were not tested. Such estimates are well in line with those of epidemiological studies for France[START_REF] Salje | Estimating the burden of SARS-CoV-2 in France[END_REF][START_REF] Magal | Predicting the number of reported and unreported cases for the COVID-19 epidemic in South Korea[END_REF].

Acknowledgements

The CoCo project is funded by the French Agence Nationale de la Recherche (Flash Covid-19 call for projects). For further details: https://www.sciencespo.fr/osc/fr/content/faire-face-au-covid-19.html.

The ELIPSS panel benefits from the support of an ANR Grant for infrastructures (ANR-10-EQPX-19-01).

Appendix: Descriptive table of variables

Home size less than 20 m² 0.00 0.05 1.00 0.00 927

Home size between 20 and 39 m² 0.03 0.18 1.00 0.00 Home size between 60 and 79 m² 0.18 0.39 1.00 0.00 927

Home size between 80 and 100 m² 0.29 0.45 1.00 0.00 927

Home size more than 100 m² 0.42 0.49 1.00 0.00 927