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Risk of serious maternal morbidity associated with cesarean supply and mother's age role: population trend score analysis


BACKGROUND: Short-term maternal complications of cesarean delivery remain uncertain due to confusion by sign. Our objective was to assess whether cesarean supply is associated with severe maternal or postpartum morbidity compared to vaginal delivery, both generally and by cesarean timing.

METHODS: We performed a case management analysis using data from EPIMOMS, a proposed study of population-based classes at 22 weeks of pregnancy or later from 6 regions in France in 2012–2013. Cases of serious maternal morbidity within-in-postpartum that were not due to a condition present were compared before being presented with randomly selected controls in a 1/50 ratio. Associations were estimated between severe distribution methods and morbidity on the mother in a sample that matched a trend score.

RESULTS: Among 182 300 deliveries, 1444 cases and 3464 controls were identified. The proportion of cesarean provision was significantly higher in cases than controls (36.0% v. 18.2%). In the trend analysis – a corresponding analysis, cesarean deliveries were significantly associated with an increased risk of severe serious maternal morbidity (cross-ratio ratio) [OR] 1.8, 95% confidence interval [CI] 1.5-2.2). This association increased with the age of the mother and was particularly evident for women aged 35 or over (adjusted OR 2.9, 95% CI 1.9–4.4). This increased risk was significant for cesarean deliveries during labor among women of all age groups and for those before labor only in women aged 35 or over (adjusted OR 5.1, 95% CI 2.3–11.0) ).

INTERPRETATION: Cesarean supply is associated with an increased risk of acute acute maternal morbidity than delivery by vagina, particularly in women aged 35 and over. Clinical decisions about the method of delivery should account for this excess risk accordingly.

The introduction of Cesarean is a useful intervention for mothers and newborn babies in many situations. However, its rates have increased over the last 20 years in most developed countries, where more than 1 in 5 women present by cesarean.1 The range of signs for delivery appears to have increased. cesarean has expanded considerably, with more cesarean deliveries likely to be committed for suspicious medical signs.2This increase requires an evaluation of its potential adverse consequences on maternal and newborn health.

The long-term obstetric risks associated with the presence of a scarring womb in a future pregnancy are well recognized, mainly in the womb and abnormal resistance.8.13 Conversely, conclusions about the relative relative maternal risks of cesarean and vaginal delivery remain unclear. A random trial has to be managed among women with no medical indication for cesarean delivery, at best, is questionable ethically. Observational studies can provide relevant information to address this, but their conclusions are likely to be limited due to signal limitations. That is, the fact that maternal morbidity can be the result of the state that is stated or justified supplying the cesarean rather than the surgical treatment itself can produce a connection t the appearance of maceans and maternal morbidity.

Earlier studies of the link between maternal mortality and method of delivery have shown an increased risk of maternal death associated with cesarean delivery against vaginal delivery.14,15 However, these studies were limited by their retrospective plan, the absence of maternal mortality and inadequate consideration of this caused confusion. Over the last 10 years, a number of observational studies have identified incompatible consequences of the link between cesarean and severe maternal morbidity, and their conclusions have also been limited by a number of methodological deficiencies: inadequate control for signal confusion, improper definition of serious serious maternal morbidity, retrospective designs that limit the quality and availability of data, non-population-based designs limit the prevalence of consequences and failure to distinguish between cesarean supply before or during labor. 1620

One of the objectives of the proposed EPIMOMS population study, specifically designed to study the morbidity of acute acute mothers, was to examine its association with cesarean delivery. Our objective here is to test for – and if it exists, to quantify – the link between severe maternal morbidity and postpartum and cesarean supply against the vagina, generally and according to the timing of cesarean delivery, before or during labor. This analysis focused in particular on the management of signal confusion, firstly by the careful selection of the women analyzed, with the exception of situations at high risk of confusion by sign, and then by the use of bias to control scores for residual confusion by sign.


Population study

We designed an incompatible case management analysis within the EPIMOMS study, a proposed population-based study carried out in 6 French regions from May 1, 2012, through 30 November 2013. Recruitment was conducted over a year in each region at 119 o maternity units and 136 intensive care units (ICU) which accounted for 182 309 deliveries during the study period – ie, a fifth of those in France during the study period – with party characteristics. , hospitals and cesarean distribution rates are similar to the national profile.21 The EPIMOMS study includes a standard definition of acute acute maternal morbidity developed through a national Delphi process to gain expert consensus from experts, with the intention of characterizing maternal complications with severe health change and organ dysfunction. EPIMOMS multi-viteria definition combines diagnosis (severe obstetric hemorrhage, eclampsia, severe preeclampsia, pulmonary embolism, stroke and psychiatric disorder), organ dysfunction (hepatic, hematological, respiratory, cardiovascular, renal and neurological), and interventions (ICU reception) t and laparotomy after delivery) (the definition is detailed in Appendix 1, available at

Definition of cases and controls

Ultimately, we identified all women who had a serious morbidity event in the mother during pregnancy (after 22 weeks of pregnancy) or in the 42 days after birth and were included in the EPIMOMS study (n = 2540). We managed the identification of cases through the review of supply log books, hospital discharge data and laboratory files; we included additional cases after their clinicians in charge confirmed their competence.

For the current analysis, we banned women with severe maternal and antepartum morbidity and defined other exclusion criteria to focus on the population for which the second between cesarean and the introduction of the vagina exists. therefore women were excluded in situations where 1 method of delivery is used systematically. . Other exclusion criteria included obstetric conditions which developed during pregnancy which were symptoms and present before labor and were responsible for severe serious morbidity after the mother (eg, previa placenta responsible for severe postpartum hemorrhage,). or preeclampsia diagnosed during pregnancy and meeting serious criteria on maternal morbidity in the postpartum); and severe serious morbidity of the mother during labor which required emergency cesarean. The women who were left with severe serious intrapartum maternal morbidity or postpartum were the cases used for our analysis.

Compatible, in accordance with the EPIMOMS study protocol, of hospital supply files, we selected a 1/50 random sample of women who were supplying without serious serious maternal morbidity in the same regions during the same time period as # The management group. We determined the size of this control sample to show a relative risk of 1.5 or more for a feature present in 10% or more of the women with α = 0.05 and 1 – β = 0.9; with an expected incidence of severe serious maternal morbidity of 1% of deliveries, 2% of deliveries were required without severe serious maternal morbidity – yes, 1/50 – in the control group. Similar exclusion criteria were applied for the cases.

Define and measure exposures

For all women with severe serious morbidity on the mother and sample of the representative included in the EPIMOMS study, we collected data on the social and demographic characteristics of women, medical conditions and obstetrics, features and complications of pregnancy and supply. details of the course and management of the morbidity incident from medical records where these items were recorded prospectively as they occurred. We collected data on the characteristics of the maternity units in a specific questionnaire.

A method of presentation, the interest link, was studied in 2 ways. We distinguished between deliveries of the vagina and cesarean first. Then, to consider the timing of delivery of the cesarean, we created 3 groups: vaginal deliveries, cesarean deliveries before delivery and cesarean delivery during labor.

Statistical analysis

We compared the characteristics of cases and controls, based on χ2 or Fisher's correct tests for definite variables and Students p or Wilcoxon sets volume tests for continuous variables, as appropriate.

In order to manage for confusing factors that may influence the choice of delivery method and morbidity occurs within or after the lungs, we used a trend score approach. A woman's trend score was defined as her chances of introducing cesarean based on her individual chovariates measured before distribution. Details of the score and trend to match can be found in Appendix 2 (available at In the corresponding set, logistic regression was used to estimate the estimated equation of a pair to estimate cross ratios (ORs) and 95% confidence intervals to measure the link between the delivery method and serious maternal morbidity. We also carried out a sensitivity analysis weighted an inverse trend score (details of the method used are provided in Appendix 3, available at

We tested for relevant interactions clinically using terms of interaction between supply methods and considered the covariates. Because of a significant positive interaction with maternal age, we repeat the analysis after stratification by maternal age: <25 years, 25-29 years, 30-34 years and ≥ 35 years.

An analysis of a similar trend score was carried out when considering 3 methods of presentation: presentation by vagina, cesarean before delivery and cesarean during labor, with the vagina as the reference category, as explained in Appendix 4 (on available at doi: 10.1503 / cmaj.181067 / – / DC1) .22

Sensitivity analyzes

For testing the link between the distribution methods (2- or 3 group exposures) and severe maternal morbidity, we also used a multifaceted logistics regression model, based on ORs with 95% of Organizations. Cancer, adapting for prognostic covariates. We used multi-level modeling to consider the hierarchical structure of the data (women in maternity units) and the lack of observation of observations in maternity units.

Secondly, the link between the delivery method and the serious serious morbidity of the mother was tested by the underlying causal condition by differentiating morbidity due to severe obstetric sediments and morbidity due to other conditions by multi-level multi-functional logistic modeling.

Finally, we tested the link between the method of delivery (designed rather than the exact way in our main analysis) (designed by the cesarean v. The vagina) and serious severe morbidity on the mother multi-functional multi-functional logistic modeling. The proportion of women missing ranged from 0% to 9.3%, including 3761 (72%) of women with full data, whose characteristics were close to the girls with missing data (data not shown). We used multiple implant equations to impute missing data. We performed all analysis with assumed data and with un-calculated data (data not shown).

All tests were bilateral, with p values ​​of 0.05 or less denotes statistical significance. The STATA 13 (StataCorp LP) software was used to carry out the descriptive and multifaceted analyzes, and its “psmatch2” package for matching trend score.23.,24 We used “Twang” and “survey” packages for analysis with trend scores for multiple treatments and a “ggplot2” package to create graphics.25

Ethics approval

The study was approved by the National Data Protection Authority (Nationale de l 'Informatique et des Libertés'). [CNIL] number authorization. 912210, March 14, 2012).


Population study

Of the women who took part in this study, 1444 were cases and 3464 were controls (Figure 1). Among women with severe severe maternal morbidity, the primary underlying causal condition was severe obstetric hemorrhage, observed in 1231 (85.3%) women (Appendix 5, available at / / DC1). t The majority of severe obstetric haemorrhages were from an atonia womb (57.9%). Compared to the control group, women in the case group were much more often indigenous from Sub-Saharan Africa, older, unsuccessful or respectable with at least 1 previous cesarean, and living without a partner; they also had a higher body mass index and, more often than not, existing maternal conditions; more previous obstetric hemorrhages; in vitro fertilization; multiple pregnancy; anemia; pregnancy hypertension disorders; breeze presentations; premature deliveries; no prophylactic oxitocin after birth; and babies who were more for pregnancy age (Table 1).

Figure 1:
Figure 1:

Flow chart showing selection of cases and controls. Note: GW = conception week, SAMM = acute acute maternal morbidity.

Table 1:

Characteristics of cases (women with severe serious maternal morbidity within or postpartum) and controls (women who were supplied without severe serious maternal morbidity) t

The proportion of cesarean provision was significantly higher in cases than controls (36.0% v. 18.2%). Cesarean supplies were more prevalent in cases either before labor (14.5% v. 8.5%) or during labor (21.5% v. 9.5%).

Density score – corresponding analysis

Of the 1150 women who had cesarean deliveries, 917 (79.7%) could be matched with 917 (24.4%) of the 3758 women who were unclear. In the corresponding sample, cesarean supply was associated with an increased risk for acute acute maternal morbidity (adjusted OR 1.8, 95% CI 1.5–2.2).

At each age tier of the mother, the corresponding groups were balanced (Appendix 2B). Compared to vaginal supply, cesarean supply was associated with significantly higher risk for acute acute maternal morbidity in women aged 25 and over (25–29 per: adjusted OR 1.5, 95% CI 1.1 –2.2; 30–34 y: OR adjusted 1.6, 95% CI 1.2–2.3; ≥ 35 y: to be adjusted OR 2.9, 95% CI 1.9–4.4) (Figure 2).

Figure 2:
Figure 2:

Socialize between the supply of cesarean and severe maternal morbidity within or to postpartum by maternal age. Note: CI = confidence ratio =, OR = odds. * Variables for bias score: country of birth, non-partner living, mother's age, body mass index, smoker, existing medical condition, previous cesarean equality and supply, previous obstetric hemorrhage, previous pregnancy hypertension disorders, multiple pregnancy, in vitro fertilization, pregnancy during pregnancy, anemia in the third term, a breeze introduction, large for pregnancy age (LGA), age of pregnancy in delivery, maternity unit status; have been adapted for any prophylactic oxitocin after birth; utation 118 women with cesarean supply amounted to 118 women with vaginal supply. ‡ Adapted for country of birth, living without partner, age, body mass index, smoker, existing medical condition, previous cesarean equality and supply, previous obstetric haemorrhage, hypertension disorders before previous pregnancy, pregnancy multiple, in vitro fertilization, pregnant hypertension disorder, anemia in the third trimester, breech presentation, no prophylactic oxitocin after birth, LGA, pregnancy age at delivery, maternity unit status; after multiple multiplication. Women §225 with cesarean provision equivalent to 225 women with vaginal supply. 8298 women with a cesarean supply matched 298 women with vaginal supply. ** 226 women with a cesarean supply matched 226 women with vaginal supply.

In distinguishing between the 3 modes of delivery, the risk for severe maternal morbidity was significantly higher with cesarean deliveries during labor at all maternal ages (<25 per year: adjusted OR 1.6, 95% CI 1.0 –2.9; 25–29 the: OR has been modified 2.0, 95% CI 1.3–3.1; 30–34 y: modified OR 2.5, 95% CI 1.6–3.9; To adjust OR 4.1, 95% CI 2.4–6.9). In contrast, the risk for severe maternal morbidity with cesarean deliveries prior to labor was significantly higher for women aged 35 and over (adjusted OR 5.1, 95% CI 2.3–11.0) (Figure 3 ).

Figure 3:
Figure 3:

Association between the introduction of cesarean (A) before and (B) during labor, and severe serious morbidity between mothers during the mother or postpartum according to the mother's age. Note: CI = confidence ratio =, OR = odds. * Variables for trend score: country of birth, living without partner, age, body mass index (BMI), current smoker, existing medical condition, previous cesarean equality and supply, previous obstetric hemorrhage, pregnancy hypertension disorders previous, multiple pregnancy, in vitro fertilization, hypertensive disorder during pregnancy, anemia in the third term, a breeze introduction, large for pregnancy age (LGA), pregnancy age in delivery and maternity unit status; have been adapted for any prophylactic oxitocin after birth; after multiple multiplication. † Adapted for country of birth, living without partner, age, BMI, current smoker, existing medical condition, previous cesarean equality and presentation, previous obstetric haemorrhage, previous pregnancy hypertension disorders, multiple pregnancy, fertility in vitro, pregnant hypertension disorder, third-term anemia, breech presentation, post-birth prophylactic oxytocin, LGA, pregnancy age at transition and maternity unit status; after multiple multiplication.

The sensitivity analysis with an inverse trend score weighting provided similar results (Appendix 3B).

Sensitivity analyzes

Analysis of multifunctional logistics regression models in the whole population provided broadly similar results to trend score estimates (Figures 2 and 3).

Analysis by category of primary causal condition showed that cesarean supply was associated with an increased risk of severe obstetric hemorrhage and also had a higher risk of serious serious maternal morbidity from other underlying causal conditions (Appendix 6, available at lookup / suppl / doi: 10.1503 / cmaj.181067 / – / DC1). Analysis with un-calculated data finds similar results (data not shown).

Analysis of the planned method of delivery showed that there was a greater risk of serious acute maternal morbidity associated with planned sewage, compared to proposed vaginal provision, only in women aged 35 and over (Appendix 7, available at suppl / doi: 10.1503 / cmaj.181067 / – / DC1).


In a proposed analysis based on the population's special focus on controlling confusion by sign, cesarean supply was to be independently linked with significantly higher risk of severe serious morbidity within or postpartum than supplied vagina. The strength of this society was adjusted further by the age of the mother. Excessive risk was particularly evident for women aged over 35 and existed for cesarean delivery before and during labor in this sub-group. The results were consistent for the different statistical methods used to take confusing factors and confuse by sign.

Our findings improve the volume of evidence showing that while the delivery of caesarean is usually a safe intervention, it remains an invasive surgical procedure with congenital intrinsic effects for women. This should be taken into account in the risk-benefit balance when selecting the method of delivery, together with the increased risk of adverse consequences in babies born by supplying cesarean in the short term and long term t .2628 Indeed, although the literature on this issue is contrary to one another, some recent studies have identified an increased risk of severe morbidity to the mother in women achieved by cesarean delivery, 17,Although a number of methodological constraints raised questions about their results: the retrospective design limits the quality and availability of data, and as a result could lead to the wrong character of women with severe maternal morbidity and timing of delivery. 39 and the limited number of people available. Additional restrictions have included inadequate consideration of signal confusion performed by selecting a low risk population; definition of severe severe morbidity of the mother to be limited to selected components of serious maternal morbidity, which does not allow a comprehensive study of serious maternal complications; and use data from hospital databases that do not allow the correct characterization of women or morbidity events.

Using proposed data and a robust methodology to avoid the bias of signage, we found that cesarean supply was independently associated with significantly higher risk of acute acute maternal morbidity than delivery of the vagina. Our main analysis was deliberately performed according to the actual method of delivery and not according to the proposed method of delivery, for various reasons. Firstly, from an explanatory or causal perspective, to isolate the inherent risk of serious maternal morbidity associated with cesarean supply, it is more relevant to carry out analysis by the method of delivery received. , which is the actual exposure. On the other hand, when the objective is to lead clinical practice in a specific context where there is a debate on which strategy to deliver should be chosen first, an analysis by the proposed method of delivery will be the answer. question. In addition, analysis by the proposed method of delivery in the general population of stakeholders will be greatly affected by the initial selection and proportion of women with cesarean planned provision, and then by selection and share of the t cesarean deliveries during labor (this last route of supply are those most at risk), highly dependent on obstetric practices. However, we also carried out a sensitivity analysis with the proposed method of delivery; his results were consistent with our main analysis, showing an increased risk of serious maternal morbidity associated with cesarean supply being designed in women aged 35 and over, a similar result to this t seen for cesarean delivery before labor. This was an expected finding, as most planned cesarean deliveries were performed before labor.

Another important consequence is that the risk of severe serious maternal morbidity associated with cesarean supply is adjusted by maternal age. In higher income countries, the mother's age at delivery has increased in recent decades; women aged over 35 make up a significant proportion of pregnancy – 17.0% in the US, 21% in France and England and 21.7% in Canada in 2016.2932 Compatible, cesarean delivery has risen, particularly in women aged over 35, with rates of around 30% in this older age group.33,34 The age of the older mother has been associated with existing conditions, more obstetric complications, resulting in increased maternal morbidity, and increased risk of moving from serious maternal morbidity to death.3538 We adapted for the known conditions that already existed in our analysis. However, precautionary changes to the role of organs due to aging may limit the potential of some women to recover from stress such as surgery and explain the effect of age on these maternal complications of cesarean delivery. Changes of this nature were reported in nonobstetric contexts, including sepsis or hemorrhagig shock resuscitation, and may reflect physiological inadequacies to respond to pathology with older people.39,40 In the obstetric setting, various studies have reported an increased risk of postpartum hepatorrge with a higher maternal age;,4145 pathophysiological data also supports this mechanism, including changes in myometrial agreement with maternal age, which could cause severe obstetric hemorrhage.46.,47

This study has a number of strengths. It was based on the study of a proposed population based cohort, allowing us to consider the diversity of women's habits and characteristics. The use of a standard and comprehensive definition of severe morbidity on the mother was based on a national consensus and the possibility of identifying women who met this definition restricting the risk of selective bias. for cases. The method we used to select the girls in the control group as a representative sample of the source cohort makes a selection bias unlikely for them too. The study plan allowed for the collection of solvents and possible confusing factors that were absent in studies carried out from hospital databases.17,18 The accuracy of the proposed data collection of the EPIMOMS study makes it possible to discriminate with cesarean prior to labor and cesarean during labor, which is known to offer a greater risk of serious maternal morbidity within-or postpartum.17 Finally , through a variety of statistical methods, we also considered the significance through an inherent sign in this type of observational study. We carried out a trend score analysis and made extensive adjustments for confusing factors to reduce the likelihood of attributing the inaccuracy of serious serious maternal morbidity within or postpartum to cesarean.


The main limitation of this study is its observational nature and therefore, despite the large number of people available, we cannot exclude the presence of unmeasured residual confusion, particularly for cesarean intrapartum. Furthermore, for mothers' conditions that were not excluded, there may not be an adjustment for existing complications or diseases before they were introduced as binary variables, or included these variables in the trend score, control & # 39 for confusion, if the severity is within existing conditions or categories the complications of pregnancy were heterogeneous, which could also lead to possible residual confusion, albeit marginal. However, the residual irritability of such appears to be unlikely to explain the strength of the society found here.

This study was conducted in France, which could limit the external validity of the results for other countries. However, the rate and supply practices of cesarean in France, as well as its overall rates of maternal mortality and serious morbidity, are similar to those in other countries with high resources.,33,34 Serious obstetric hemorrhage is the main underlying causal condition of severe maternal morbidity in-post or postpartum, although it is standard in all similar studies, 17,18 are even stronger in the current study because of the choice of cases of postnatal morbidity designed to limit signal confusion. However, we also found that the risk of serious serious maternal morbidity from other joint cases had increased with cesarean supply, indicating that cesarean maternity risks associated with bleeding are not limited.

Finally, the shortage of each of the other underlying causal conditions associated with severe maternal morbidity is limited in their association with cesarean.


We found that cesarean supply was associated with an increased risk of severe serious maternal morbidity than vaginal delivery, particularly in women aged 35 and over. This outcome has implications for clinical practice and will be useful in determining the method of delivery. Our discovery raises questions about the practices of some obstetricians who may consider caesarean deliveries to be identified by a higher maternal age, with the idea that there will probably be no more pregnancy. This practice should be adapted to avoid unnecessary disclosure of women over 35 years of age to the excessive risk of severe serious morbidity on the mother. Yn ogystal, pan fydd angen cyflwyno cesarean, dylai ein canfyddiad annog rhoddwyr gofal i baratoi&#39;n fwy rhagweithiol ar gyfer y morbidrwydd difrifol difrifol ar y fam a all ddeillio o hynny.


Mae&#39;r awduron yn diolch i gydlynwyr y rhwydweithiau amenedigol rhanbarthol cyfranogol: Alsace, Aurore, Auvergne, Basse-Normandie, MYPA, NEF, Paris Nord, 92 Nord, Lorraine; Chloé Barasinski, Sophie Bedel, Aline Clin D&#39;Amour, Laurent Gaucher, Isabelle Le Creff, Blandine Masson Carole Ramousset, Mathias Rossignol, Zelda Stewart, Dalila Talaourar, Yacine Toure, Nicole Wirth am eu cyfraniad at weithredu astudiaeth EPIMOMS yn eu rhanbarth; yr obstetregwyr, bydwragedd ac anesthetyddion a gyfrannodd at nodi achosion a dogfennaeth yn eu hysbyty; a&#39;r cynorthwywyr ymchwil a gasglodd y data.


  • Grŵp Astudio EPIMOMS: Bruno Langer, Rhwydwaith Amenedigol Naitre en Alsace; Corinne Dupont a René-Charles Rudigoz, Rhwydwaith Amenedigol Rhône-Alpes Aurore; Françoise Vendittelli, Rhwydwaith Amenedigol Auvergne; Gaël Beucher, Rhwydwaith Amenedigol Basse-Normandie; Patrick Rozenberg, Rhwydwaith Amenedigol MYPA, rhanbarth Ile de France; Lionel Carbillon, Naitre dans yw&#39;r rhan fwyaf o Rwydwaith Ffrancolaidd regionle-de-France; Elie Azria a Nathalie Baunot, Rhwydwaith Amenedigol Paris Nord; Catherine Crenn-Hebert a Gilles Kayem, 92 Rhwydwaith Amenedigol Nord, rhanbarth dele-de-France; Jeanne Fresson, Rhwydwaith Amenedigol Lorraine; Alexandre Mignon, Société Française dAnesthésie Réanimation; Sandrine Touzet, polyn Cyhoeddi Santé, Hospices Civils de Lyon; Marie-Pierre Bonnet, Marie-Hélène Bouvier-Colle, Anne Chantry, Coralie Chiesa-Dubruille, Catherine Deneux-Tharaux ac Aurélien Seco, tîm ymchwil Inserm EPOPé.

  • Diddordebau cystadleuol: Ni ddatganwyd dim.

  • Adolygwyd yr erthygl hon gan gymheiriaid.

  • Cyfranwyr: Catherine Deneux-Tharaux, François Goffinet and Diane Korb had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Catherine Deneux-Tharaux, François Goffinet, Sylvie Chevret and Diane Korb conceptualized the study and wrote the manuscript. Diane Korb and Aurélien Seco performed the statistical analysis. Catherine Deneux-Tharaux obtained funding and supervised the study. All of the authors contributed to the interpretation of the data, revised the manuscript critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

  • Funding: Supported by a grant from the National Research Agency and the Île-de-France Regional Health Agency.

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