Gallego Hernanz Mp

Tourani Jm

MD Blandine Rammaert
email: blandine.rammaert.paltrie@univ-poitiers.fr

Observational study of vaccination in cancer patients: how can vaccine coverage be improved? Étude observationnelle sur la vaccination chez les patients atteints de cancer : comment améliorer la couverture vaccinale ?

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

INTRODUCTION

The World Health Organization (WHO) targets vaccination coverage rates for vaccinepreventable diseases ≥95% according to age. The only exception is for the influenza virus, for which the vaccination rate should reach 75% [START_REF] Morini | Etude de la politique vaccinale de la France bilan et enjeux[END_REF]. However, the WHO recommends antipneumococcal vaccine only for immunocompromised patients [START_REF] Oms | Recommandations de l'OMS pour la vaccination systématique -tableaux récapitulatifs[END_REF]. Patients presenting with cancer should benefit from vaccines as they are exposed to a heightened risk of invasive pneumococcal diseases (IPD) and influenza illness, leading to an increased risk of morbimortality [START_REF] Garcia-Vidal | Clinical and microbiological epidemiology of Streptococcus pneumoniae bacteremia in cancer patients[END_REF][START_REF] Cooksley | Epidemiology and outcomes of serious influenza-related infections in the cancer population[END_REF][START_REF] Kunisaki | Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses[END_REF][START_REF]Influenza (Seasonal)[END_REF]. In 2005 the overall incidence rate of IPD in adults with acquired immune deficiency, such as solid or hematological cancer, ranged from 300.4 to 503.1 cases/100,000 persons compared with 8.8 cases/100,000 persons in healthy adults [START_REF] Kyaw | The influence of chronic illnesses on the incidence of invasive pneumococcal disease in adults[END_REF]. A 2013 review confirmed that IPD risk in this population was 5 to 23 times higher than in the general population and that influenza illness was responsible for numerous complications [START_REF] Mauskopf | The burden of influenza complications in different high-risk groups: a targeted literature review[END_REF].

Influenza-attributable mortality rate ranged between 11% and 33% in immunocompromised patients treated with chemotherapy compared with 10% in the general population [START_REF] Kunisaki | Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses[END_REF].

Heavily immunosuppressed patients with solid cancer are at greater risk of developing pneumonia with subsequent high mortality [START_REF] Chemaly | A multicenter study of pandemic influenza A (H1N1) infection in patients with solid tumors in 3 countries: Early therapy improves outcomes[END_REF]. The level of immunosuppression depends on the age, type of malignancy, and chemotherapy regimen [START_REF] Mackall | T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review[END_REF]. Little data is available on immune deficiency persistence after the end of chemotherapy. Quantitative and qualitative T and B cell depletion continues months after chemotherapy administration. Therefore, French authorities implemented guidelines on vaccination for immunocompromised patients so as to reach the WHO objectives for vaccine coverage [START_REF] Hcsp | Vaccination des personnes immunodéprimées ou aspléniques[END_REF]. Diphtheria-tetanuspoliomyelitis (dTP) and anti-hepatitis B virus (HBV) vaccines are now recommended for use in the general population and vaccine boosters are specifically recommended three months after the end of chemotherapy in patients with solid cancer, and six months after chemotherapy in patients with hematological malignancy who undergo additional immunosuppressive chemotherapy. Anti-pneumococcal vaccination is based on a combined strategy: injection of 13-valent pneumococcal polysaccharide conjugate vaccine (PCV) followed at least two months later by 23-valent polysaccharide unconjugated vaccine (PPV).

Although this vaccination has to be initiated preferably before the chemotherapy, it can be continued during treatment. Inactivated influenza vaccine is recommended during autumn at least two weeks before the predictable epidemic periods for all immunocompromised patients.

Vaccination remains a good strategy to decrease the infection risk and hospitalization rate [START_REF] Beck | Influenza vaccination for immunocompromised patients: systematic review and meta-analysis by etiology[END_REF]. In the PRISMA study, flu vaccination prevented 78% of deaths and 87% of hospitalizations for 1,778 high-risk patients aged over 65 years [START_REF] Hak | Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: the PRISMA study[END_REF]. A recent review among immunosuppressed adults with cancer suggested lower mortality and better infectionrelated outcomes after influenza vaccination [START_REF] Bitterman | Influenza vaccines in immunosuppressed adults with cancer[END_REF]. Since the introduction of pneumococcal vaccines, IPD incidence decreased from 20 to 8/100,000-population year between 2009 and 2014 in the immunocompromised population including patients undergoing chemotherapy for cancer, even with insufficient coverage [START_REF] Sangil | Impact of vaccination on invasive pneumococcal disease in adults with focus on the immunosuppressed[END_REF]. However, in the general as well as the immunocompromised population, vaccination rates clearly fail to meet the goal set by the WHO, on which national goals are based [START_REF] Loubet | Attitude, knowledge and factors associated with influenza and pneumococcal vaccine uptake in a large cohort of patients with secondary immune deficiency[END_REF][START_REF]Données de couverture vaccinale des maladies à prévention vaccinale[END_REF]. For immunocompromised patients with autoimmune disease, solid organ transplantation, or hematological malignancy, vaccination rates against IPD and influenza are 49% and 59%, respectively [START_REF] Loubet | Attitude, knowledge and factors associated with influenza and pneumococcal vaccine uptake in a large cohort of patients with secondary immune deficiency[END_REF]. Little data is presently available on vaccination coverage rate for patients with malignancies.

The aim of our study was to assess vaccination coverage and factors associated with appropriate vaccination in oncology and hematology patients.

METHODS

Study design and population

This monocentric observational study was constructed as a survey among patients with solid cancer or blood malignancy, followed in a French university hospital. Patients over 18 years were included when they came in consultation, as outpatients to the day hospital or in weekly hospitalization. Patients unable to answer to the questionnaire because of any incapacity and those coming for the first time for a diagnostic procedure were excluded from the study. Stem cell transplanted patients were also excluded because they have a specific vaccination follow up.

Data collection

Medical secretaries distributed a questionnaire to all those patients at the administrative registration in September and October 2016. After being informed, participants were asked to answer 16 multiple-choice questions for an overall estimated time of 5 minutes, alone and during their waiting time. The questionnaire was anonymous. Collected data was age, sex, underlying malignancy, time to diagnosis, chemotherapy administration, pursuit or withdrawal of chemotherapy, opinions about vaccination, flu vaccinations of their relatives, previous vaccinations since diagnosis of cancer (without any precise date) against influenza, pneumococcus, HBV, and dTP. Another question concerned the most trustworthy person to deliver vaccination information and the need for more information on the subject. The main criterion of assessment was the number of patients who had been vaccinated since their cancer diagnosis. Physicians collected completed questionnaires.

Ethics

Participation in the survey was anonymous and voluntary. Since answering was voluntary, the study was not submitted to an ethics committee according to French policy. The French Data Protection Authority (French acronym CNIL), which is responsible for protection of individual data in France, approved the panel and its procedures. The study was declared in their database, with no need of approval request number.

Statistical analysis

Sample size calculations determined that 130 participants were needed per group for the primary endpoint. In anticipation of non-exploitable questionnaires at a rate of 5%, the sample size increased to 200 per group to ultimately analyze patients who had received chemotherapy and to compare patients in both groups.

Descriptive statistics were used to summarize all demographic and clinical characteristics of patients. Continuous variables were presented as mean and standard deviation (SD) or as median with range. Number and percentage were determined for categorical data. Variables with a p-value <0.25 in the univariate analysis were included for the multivariate analysis, after assessment of log-linearity. Bivariate interactions with a p-value <0.25 were included.

Finally, odds ratio (OR) and their 95% confidence interval (95%CI) were estimated using a logistic regression multivariate analysis with a stepwise-descending selection procedure, removing first the interactions and then the variables with a p-value >0.05. The Hosmer-Lemeshow test confirmed the validity of the model. Susceptibility analysis with multiple imputations (n=5) was performed due to missing data.

RESULTS

Population characteristics

A total of 1,600 questionnaires were distributed (Figure 1). Among 671 (41.9%) respondents, the M/F sex ratio was 0.9 (Table 1). Half of the participants (336; 50.1%) were aged >65 years. They were divided into two groups: 232 (34.6%) were treated for hematological malignancy and 439 (65.4%) for solid cancer. A total of 501 patients (74.7%) received or had received chemotherapy. The main hematological malignancies included lymphoproliferative diseases, multiple myeloma, and acute leukemia. The three main localizations of solid cancers were the breast, digestive tract, and lung (Table 1).

Vaccination in the cancer population

Since cancer diagnosis 39.7% (n=267) of patients declared that they had received at least one vaccination: 148 in oncology and 119 in hematology (34.6% vs 52.9%, p-value <0.0001, respectively). To estimate the global adherence to vaccination, we analyzed the proportion of cancer patients vaccinated against a vaccine used in the general population (i.e., dTP) based on patients' declarations. The question of appropriate immunization regimen for HBV or pneumococcal prevention was not asked. dTP vaccination was up to date in 57.6% (n=387) of patients, similarly in both groups. Only 27.4% (n=184) were vaccinated against HBV, a non-mandatory vaccine, with similar rates in hematology and oncology patients.

Reported pneumococcal vaccination rate was 7.2% (n=48): 5.1% in the oncology unit and 11.4% in the hematology unit (p=0.01). Flu vaccination had been performed in 28.6% (n=192) of patients, 47% (n=137) being aged over 65. The relatives of 173 patients (25.8%) were vaccinated against the flu (Table 2).

In the subgroup of 501 patients receiving chemotherapy, 40.5% (n=203) had been vaccinated since the cancer diagnosis, 19.9% (n=44) being aged <65 years. Pneumococcal and influenza vaccination rates were similar to that of the whole studied population, reaching 7.9% and 33.5%, respectively.

Vaccination perception of patients

A total of 423 patients (64.7%) had a good or very good opinion of vaccination as a whole. These patients were more vaccinated than those with a less favorable opinion (48.2% vs 33.7%; p<0.001). Family members of patients with a favorable opinion were also more vaccinated (38% vs 24%; p=0.005). Two thirds of the patients (66.6%) wished to improve their knowledge about vaccination. The most trustworthy person to deliver this information was considered to be the family physician for 36.2% of patients (n=166/458) or the oncologist for 56.8% (n=260/458).

Factors associated with vaccination

The results of the univariate and multivariate analyses are presented in Table 3. In the multivariate analysis, factors associated with a higher vaccination rate in the global population of the study were: age ≥65 years (OR 4.5 [2.9-7.0]; p<0.0001), information received from family physician (OR 12.9 4).

DISCUSSION

Our study provides an overview of vaccination coverage in a population presenting with malignancy. Although clear guidelines about vaccination of immunocompromised patients already exist, only a limited number of studies about vaccination rates in this population is available. Our study reported that cancer patients are largely under-vaccinated against the main frequent and threatening diseases, namely IPD, pneumococcal pneumonia, and the flu. With 7.9% and 33.5% of pneumococcal and flu vaccine coverage, respectively, the population of our study receiving chemotherapy is less vaccinated compared with previous literature reports. In the study by Loubet et al., the vaccination rate was higher for pneumococcus (72%) and for the flu virus (39%) in patients receiving chemotherapy, albeit far from the WHO target, even in a biased population of people belonging to patients associations [START_REF] Loubet | Attitude, knowledge and factors associated with influenza and pneumococcal vaccine uptake in a large cohort of patients with secondary immune deficiency[END_REF]. Other studies reported even lower rates from 25% to 30% for influenza vaccines in immunocompromised patients with cancer [START_REF] Loulergue | Low influenza vaccination rate among patients receiving chemotherapy for cancer[END_REF][START_REF] Fiore | Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007[END_REF]. In our study, vaccine uptake was nevertheless better for the flu than for pneumococcus. The French vaccine policy encourages flu vaccination in all patients aged over 65 years and in at-risk patients [START_REF] Hcsp | Actualisation de la liste des sujets éligibles à la vaccination contre la grippe saisonnière[END_REF].

Every patient aged ≥65 years receives a voucher from the public health insurance for free influenza vaccine irrespective of the underlying condition. This policy may explain the high rate of flu vaccine coverage in our study in the population aged ≥65 years with cancer.

Various issues have arisen regarding HBV vaccination. The low rate of HBV vaccination (27.4%) might be partially due to the negative perception of HBV vaccination in France [START_REF] Moyroud | Negative perceptions of hepatitis B vaccination among attendees of an urban free testing center for sexually transmitted infections in France[END_REF].

For young adults, immunocompromised or not, HBV vaccination coverage is insufficient with a rate of only 55.3% [START_REF] Hustache | Hepatitis B vaccination status in an atrisk adult population: long-term immunity but insufficient coverage[END_REF][START_REF] Roblot | Vaccination coverage in French 17-year-old young adults: an assessment of mandatory and recommended vaccination statuses[END_REF]. This vaccine is nonetheless recommended in cancer patients as in the general population, with the same objective of 95% vaccination rate. It has been demonstrated that acute infections in patients with cancer receiving chemotherapy are more likely to become chronic with rates around 18-26%, compared with 5-10% in adults over 50 years [START_REF] Ariza-Heredia | Practical review of immunizations in adult patients with cancer[END_REF]. The mortality due to HBV is likewise higher in those patients than in the general population [START_REF] Ariza-Heredia | Practical review of immunizations in adult patients with cancer[END_REF].

Our study underscored a low vaccination rate for cancer patients. There is not enough data on vaccine coverage in immunocompromised patients or in people with chronic conditions at increased risk of vaccine-preventable diseases. Available evidence suggests that this population is often under-vaccinated even in developed countries [START_REF] Ariza-Heredia | Practical review of immunizations in adult patients with cancer[END_REF]. Two reasons may explain these low rates. First of all, vaccine immunogenicity in immunocompromised patients is questionable, as there is currently no consensus data on the period and the quality of the immune response on chemotherapy [START_REF] Loulergue | Low influenza vaccination rate among patients receiving chemotherapy for cancer[END_REF]. In a recent review, Vollaard et al.

reported that the majority of patients with solid tumors were able to achieve a timely, protective immunological response regardless of the chemotherapy schedule, similar to healthy controls [START_REF] Vollaard | Influenza vaccination in adult patients with solid tumours treated with chemotherapy[END_REF]. Further studies are however needed to address the issue of who should be vaccinated, with which other vaccines, with how many doses, and when during the chemotherapy. There is also a lack of vaccine knowledge leading to doubts about their adverse events and potential post-vaccine diseases [START_REF] Doherty | Vaccination of special populations: Protecting the vulnerable[END_REF], although there is no such risk if recommendations are followed. Moreover, the influence of the anti-vaccine lobbies remains present in France [START_REF]Rapport de la concertation citoyenne sur la vaccination[END_REF], notwithstanding a real decrease in morbidity and mortality in cancer population due to vaccination [START_REF] Hak | Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: the PRISMA study[END_REF][START_REF] Sangil | Impact of vaccination on invasive pneumococcal disease in adults with focus on the immunosuppressed[END_REF][START_REF] Torre | Influenza and Pneumococcal Vaccination in Hematological Malignancies: a Systematic Review of Efficacy, Effectiveness, and Safety[END_REF]. However, two thirds of our patients wished to improve their knowledge about vaccination, and the same proportion had a good opinion about vaccination.

Our study also suggested reasons for the lack of vaccine uptake and how to improve vaccination coverage in the cancer population. The most significant factor associated with vaccination consists in the information delivered by the family physician. Even with oncologists as the most trustworthy persons according to patients, there was no significant association with vaccination. One could hypothesize that in our study oncologists are not the persons who usually deliver vaccine information or prescription. Despite available national guidelines, family physicians and specialists are not sufficiently informed about vaccine recommendations [START_REF] Loulergue | Low influenza vaccination rate among patients receiving chemotherapy for cancer[END_REF]. Involving family physicians directly by means of oncologists could help improve vaccination coverage. Furthermore, favorable opinions about vaccination were linked to higher vaccination rates. This factor was previously demonstrated for the flu and pneumococcal vaccines in immunocompromised patients [START_REF] Nichol | Influenza vaccination. Knowledge, attitudes, and behavior among high-risk outpatients[END_REF][START_REF] Nichol | Factors associated with influenza and pneumococcal vaccination behavior among high-risk adults[END_REF]. To conclude, given the current vaccination controversies, more pedagogy about vaccine efficacy and safety is clearly needed.

There are several limitations to our study. All patients did not return the questionnaire, leading to a selection bias. We did not have access to socio-demographic data of nonresponders, which could have ruled out the presence of a selection bias, by comparison with responders' data. However, we had a good rate of response, exceeding 40%, when 15-20% are needed in a survey [31]. The other possible confounding factor could stem from the fact that it was impossible to individually check each patient's vaccine status and time of vaccine uptake. Our data was only declarative as we performed a monocentric study with no use of medical records. Although serological results would have helped us to identify vaccinated patients, patients' answers to the survey questionnaire was only used. A questionnaire administered to the medical team would have given complementary information.

The questionnaire did not ask for precise vaccination timing since the diagnosis of cancer. Thus, dTP vaccination rather reflects the global vaccine status than the vaccine status since cancer diagnosis. Therefore, dTP vaccination appears as an independent factor associated with vaccination (OR 2.6 [1.5-4.3]; p=0.0003). However, the study shows that vaccine coverage in cancer patients remains globally insufficient for pneumococcus and the flu.

Conclusion

Cancer patients -even elderly ones -are rarely vaccinated despite specific recommendations. Ways to improve the vaccination coverage in onco-hematology patients are: (i) targeted information campaigns directed at patients and physicians about the efficacy, safety, and benefits of vaccines, (ii) information given to and/or training of family physicians, (iii) reinforcement of links between family physicians and oncologists.

  [5.5-30.1]; p<0.0001), being treated for an hematological malignancy (OR 2.0 [1.3-3.1], p<0.008), and a positive opinion about vaccination (OR 2.0 [1.3-3.1]; p=0.003). In the multivariate analysis, for the subgroup of patients receiving or having received chemotherapy, age ≥65 years (OR 4.8 [3.0-8.0]; p<0.0001), information received from family physician (OR 11.6 [4.6-29]; p<0.0001), up-to-date dTP vaccination (OR 2.6 [1.5-4.3]; p=0.0003), and positive opinion about vaccination (OR 2.0 [1.2-3.3]; p=0.007) were associated with a higher rate of vaccination (Table

  insufficient demographic data -18: no data for primary endpoint -20: no malignancy -8: auto or allograft -1: first visit 671 inclusions: -439 in oncology -232 in hematology

Figure 1 . 1 .

 11 Figure 1. Flowchart of the study Figure 1. Diagramme de flux de l'étude

Table 1 .

 1 Characteristics of patients

	Tableau 1. Caractéristiques des patients
		Oncology	Hematology	Total
		n (%)	n (%)	n (%)
	Population	439 (65.4)	232 (34.6)	671
	Age >65 years	202 (46.0)	134 (57.8)	336 (50.1)
	Male gender	188 (42.8)	132 (56.9)	320 (47.7)
	Median duration of follow-up, months (min-	17 (0-356)	36,5 (0-365)	22 (0-365)
	max)
	Currently receiving chemotherapy	338 (77.0)	163 (70.3)	501(74.7)
	Chemotherapy received within the previous year 267 (61.4)	102 (44.0)	369 (55.0)
	Underlying malignancies
	Breast cancer	127 (29.0)	-	-
	Colorectal cancer	77 (17.5)	-	-
	Other digestive cancers	54 (12.2)	-	-
	Lung cancer	46 (10.3)	-	-
	Prostate cancer	34 (7.8)	-	-
	Gynecologic cancers	29 (6.7)	-	-
	Other urological cancers	16 (3.7)	-	-
	Other localizations	56 (12.9)	-	-
	Lymphoproliferative diseases	-	131 (56.0)	-
	Multiple myeloma	-	34 (15.0)	-
	Acute leukemia	-	15 (6.0)	-
	Myeloproliferative syndrome	-	34 (15.0)	-
	Other hematological cancers	-	18 (8.0)	-

Table 2 .

 2 Vaccines received by the study population Tableau 2. Vaccins reçus par la population à l'étude

	Total population	Oncology	Hematology	Total
		(n=439)	(n=232)	(N=671)	p value
	Patients vaccinated since cancer diagnosis	148 (33.7)	119 (51.2)	267 (39.7)	<.0001
	dTP vaccination
	-Within the last 10 years	245 (55.8)	142 (61.2)	387 (57.6)	0.17
	-More than 10 years before	133 (30.2)	66 (28.5)	199 (29.7)	0.61
	HBV vaccination	123 (28.0)	61 (26.3)	184 (27.4)	0.63
	Pneumococcal vaccination	22 (5.1)	26 (11.2)	48 (7.2)	0.01
	Flu vaccination	117 (26.7)	75 (32.3)	192 (28.6)	0.12
	Flu vaccination of family members	98 (22.3)	76 (32.7)	173 (25.8)	0.003


F Deleu

C Deneux-Tharaux

C Chiesa-Dubruille

A Seco

Marie-Pierre P Bonnet
email: marie-pierre.bonnet@aphp.fr

A retrospective analysis of French transfusion practices for women experiencing severe postpartum hemorrhage

Keywords: Postpartum hemorrhage, severe, Transfusion, Guidelines, Epidemiology

published or not. The documents may come

Introduction

Severe postpartum hemorrhage (SPPH) occurs in 1% of deliveries in high-resource countries and is the leading cause of severe maternal morbidity and mortality worldwide. [START_REF] Calvert | Identifying regional variation in the prevalence of postpartum haemorrhage: a systematic review and meta-analysis[END_REF][START_REF] Dupont | Incidence and management of postpartum haemorrhage following the dissemination of guidelines in a network of 16 maternity units in France[END_REF][START_REF]Global, regional, and national levels of maternal mortality, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015[END_REF] Individual risk factors are poor predictors of postpartum hemorrhage (PPH). [START_REF] Bateman | The epidemiology of postpartum hemorrhage in a large, nationwide sample of deliveries[END_REF] Consequently, interest has focused on care practices, since changes in management may affect maternal morbidity and mortality. [START_REF] Driessen | Postpartum hemorrhage resulting from uterine atony after vaginal delivery: factors associated with severity[END_REF] Blood transfusion is an essential component of SPPH management by maintaining the circulating blood volume and tissue oxygenation, and for hemostatic support. [START_REF] Chandraharan | Diagnosis and management of postpartum haemorrhage[END_REF] There are few prospective population-based studies on transfusion practices in SPPH.

Previous studies are monocentric [START_REF] Parker | A retrospective one-year single-centre survey of obstetric red cell transfusions[END_REF][START_REF] Butwick | Retrospective analysis of transfusion outcomes in pregnant patients at a tertiary obstetric center[END_REF] or retrospective based on hospital databases, [START_REF] So-Osman | Triggers and appropriateness of red blood cell transfusions in the postpartum patient--a retrospective audit[END_REF][START_REF] Patterson | Blood transfusion during pregnancy, birth, and the postnatal period[END_REF][START_REF] Cauldwell | Retrospective surveys of obstetric red cell transfusion practice in the UK and USA[END_REF][START_REF] Mhyre | Massive blood transfusion during hospitalization for delivery in New York State, 1998-2007[END_REF] while population-based studies focus on massive transfusion [START_REF] Green | The haematological features and transfusion management of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based study[END_REF] or are older. [START_REF] Bonnet | Transfusion practices in postpartum hemorrhage: a population-based study[END_REF] Population-based and prospectively-collected data could provide a snapshot of transfusion practices in SPPH, assist clinicians in decision-making and identify areas that are performed well or poorly.

International and national transfusion guidelines for SPPH differ depending on whether the bleeding is active or has been controlled. [START_REF] Abdul-Kadir | Evaluation and management of postpartum hemorrhage: consensus from an international expert panel[END_REF][START_REF]Transfusion de globules rouges en situation d'urgence hémorragique, d'anesthésie et de réanimationrecommandations de bonne pratique[END_REF][START_REF] Boulay | Anesthesic practices in patients with severe postpartum hemorrhage with persistent or worsening bleeding[END_REF] However, transfusion practices in obstetric hemorrhage have not been described according to the status of bleeding. The EPIMOMS study, a French population-based study of severe acute maternal morbidity performed in 2012 and 2013, provided prospective data on women with SPPH and detailed information about transfusion management and active or controlled bleeding. [START_REF] Korb | Risk of severe maternal morbidity associated with cesarean delivery and the role of maternal age: a population-based propensity score analysis[END_REF][START_REF] Madar | Severe acute maternal morbidity in twin compared with singleton pregnancies[END_REF] The objective of this retrospective study was to describe transfusion practices in women with SPPH based on data from a prospective population-based study. Women in whom transfusion started during active bleeding and those in whom transfusion started only after the control of bleeding were analyzed separately. The study evaluated the compliance with some specific components of transfusion management from contemporary French national guidelines, endorsed by the French National Agency for the Safety of Medicines and Health Products (ANSM) [START_REF]Transfusion de globules rouges en situation d'urgence hémorragique, d'anesthésie et de réanimationrecommandations de bonne pratique[END_REF]20 and by the National College of French Gynecologists and Obstetricians (CNGOF). [START_REF] Boulay | Anesthesic practices in patients with severe postpartum hemorrhage with persistent or worsening bleeding[END_REF][START_REF] Goffinet | Postpartum haemorrhage: recommendations for clinical practice by the CNGOF (December 2004)[END_REF]

Methods

The source population was extracted from the EPIMOMS study, a prospective observational population-based study of severe acute maternal morbidity, defined by expert consensus using a national Delphi process, and conducted during one year in 119 maternity units and 136 intensive care units of six French regions (April 2012 to November 2013; 182 309 deliveries). [START_REF] Korb | Risk of severe maternal morbidity associated with cesarean delivery and the role of maternal age: a population-based propensity score analysis[END_REF][START_REF] Madar | Severe acute maternal morbidity in twin compared with singleton pregnancies[END_REF] Caregivers prospectively identified women with severe acute maternal morbidity and the completeness of case ascertainment was validated by a review of delivery logbooks, birth registers, hospital discharge databases and laboratory records. Detailed information on sociodemographic characteristics, medical and obstetric history, antenatal care, delivery and obstetric hospitalization was collected from medical charts.

The study population included all the women from the EPIMOMS study who had SPPH, defined as a hemorrhage with at least one of the following criteria: blood loss >1500 mL, transfusion of four red blood cell (RBC) units or more, arterial embolization, conservative uterine surgery (arterial ligation or uterine compression sutures), hysterectomy, acute organ dysfunction (cardiovascular, respiratory, renal, hepatic or neurologic dysfunction), admission to an intensive care unit, acute severe postpartum anemia (hemoglobin (Hb) level <7 g/dL) in the absence of chronic anemia, acute thrombocytopenia <50.10 9 /L, disseminated intravascular coagulopathy (DIC), or maternal death. [START_REF] Korb | Risk of severe maternal morbidity associated with cesarean delivery and the role of maternal age: a population-based propensity score analysis[END_REF][START_REF] Madar | Severe acute maternal morbidity in twin compared with singleton pregnancies[END_REF] During the study period, 1655 women had SPPH (0.9% of deliveries, Fig. 1). For this analysis, women with congenital bleeding disorders or antepartum diagnosis of morbidly adherent placenta were excluded because specific transfusion strategies were planned in advance for those patients. Secondary SPPH, occurring more than 24 h after delivery, was excluded because its causes and management, including transfusion strategy, differ from primary PPH. The analysis was therefore restricted to women with primary SPPH for whom transfusion strategy was not anticipated (n=1495).

The time when bleeding was controlled (corresponding to the cessation of the bleeding as diagnosed by the clinicians) and the time when RBC transfusion was started were specifically collected in the EPIMOMS study. Women with SPPH were included in the "transfusion started during active bleeding" group if RBC transfusion started prior to the control of bleeding, and in "transfusion started after bleeding control" if RBC transfusion started after the time of bleeding control. Women transfused before and after bleeding control were classified in the group "transfusion started during active bleeding".

Maternal demographics, pregnancy, delivery and hospital markers of the severity of PPH (total blood loss; nadir Hb level; nadir plasma fibrinogen level; hemorrhagic shock as defined in the EPIMOMS study by a systolic blood pressure <90 mmHg for >60 min or unresponsive to plasma expansion); DIC as defined in the EPIMOMS study by a platelet count <50.10 9 /L and/or a prothrombin time <60% and/or a serum fibrinogen level <2 g/L; components of PPH management; and causes of SPPH such as placenta accreta, placenta previa, placental abruption, uterine rupture, amniotic fluid embolism, surgical causes, perineal trauma or episiotomy, placental retention, uterine atony, other causes and unidentified causes) were collected. If SPPH arose from multiple causes, only one was recorded in the order of priority mentioned above.

Transfusion practices were explored: type and total quantity of blood products administered, the intervals between the diagnosis of PPH and the start of RBC transfusion and between the first administration of RBC and of fresh-frozen plasma (FFP) or fibrinogen concentrate (FC), the FFP:RBC ratio administered within three hours of the first RBC transfusion, and last Hb level measured before transfusion.

At the time of the study, French national guidelines were available for transfusion in SPPH, as part of general guidelines on blood transfusion [START_REF]Transfusion de globules rouges en situation d'urgence hémorragique, d'anesthésie et de réanimationrecommandations de bonne pratique[END_REF]20 and as a specific section of obstetric guidelines on the management of PPH. [START_REF] Boulay | Anesthesic practices in patients with severe postpartum hemorrhage with persistent or worsening bleeding[END_REF][START_REF] Goffinet | Postpartum haemorrhage: recommendations for clinical practice by the CNGOF (December 2004)[END_REF] These guidelines were similar to those in Europe and North America at the time. [START_REF] Rossaint | Management of bleeding following major trauma: an updated European guideline[END_REF][START_REF]Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies[END_REF] The transfusion strategies differed according to the presence or absence of active bleeding. In adults with acute anemia not associated with active bleeding and without cardiovascular disease, the transfusion trigger was a Hb level <7 g/dL.

In adults with active bleeding, RBC were indicated if the patient was hemodynamically unstable and/or to keep Hb 7-10 g/dL, but were usually not indicated when the Hb concentration was >10 g/dL.

French guidelines advocate the monitoring of the plasma fibrinogen level both to predict the severity of PPH and to guide the administration of coagulation factors. In SPPH, FFP transfusion is recommended early using a FFP:RBC ratio between 1:2 and 1:1.

Administration of fibrinogen concentrate or FFP is also suggested if the plasma fibrinogen level is <2 g/dL. Non-compliance with French transfusion guidelines was considered to have occurred if there had been no RBC transfusion despite a Hb level <7 g/dL, RBC transfusion despite a Hb level >10 g/dL, early FFP and RBC transfusion with a FFP:RBC ratio lower than 1:2, absence of FFP or fibrinogen concentrate administration in women with a fibrinogen level <2 g/dL or DIC, and administration of fibrinogen concentrate to women with a fibrinogen level ≥2 g/dL.

The characteristics of the women, pregnancy, labor, delivery, the maternity unit, PPH severity, PPH management and causes of SPPH were collected and described separately for women with RBC transfusion started during active bleeding, women with RBC transfusion started after the control of bleeding, and women without a RBC transfusion. Transfusion practices and their compliance with French guidelines were described accordingly.

Values are expressed as n (%), means (SD), or medians (IQR) as appropriate. Analyses were performed using STATA version 13.1 (College Station, TX, USA).

The French Data Protection Authority and the French Advisory Committee on Information

Processing in Research in the field of Health approved the EPIMOMS study (CNIL 912210, CCTIRS 12.060). All the women were informed of anonymized data collection during the EPIMOMS study.

Results

Of the 1495 women with SPPH, 970 (64.9%) were transfused; 747 (50.0%) had RBC transfusion started during active bleeding and 223 (14.9%) had RBC transfusion started only after control of bleeding (Fig. 1).

The proportions of sub-Saharan African women, multiparous women, women with previous PPH, multiple pregnancy, emergency cesarean delivery, and women who did not receive prophylactic uterotonic drugs were higher among women with RBC transfusion started during active bleeding than among women transfused only after control of bleeding (Table 1). The proportions of women under 30 years of age, primiparous, having antepartum anemia, and having an operative vaginal delivery were higher among women transfused after control of bleeding than among women with RBC transfusion started during active bleeding.

Uterine atony was the commonest etiology of SPPH not only overall but also in each subgroup according to transfusion management (Table 2). Clinical and biologic markers of PPH severity and invasive procedures were frequently observed in women with RBC transfusion started during active bleeding (Table 2). Among these women, two-thirds received FFP, 43.9% received FC and 8.6% had a massive transfusion (≥10 RBC units) (Table 3a).

Among women with RBC transfusion started after control of bleeding, 5.4% received FFP and 4.0% FC.

Regarding non-compliance with guidelines, for women with SPPH and a nadir Hb <7 g/dL, 21.4% were not transfused (Table 3b), while in women with RBC transfusion started during active bleeding, 47.6% had a nadir Hb <7 g/dL. In this subgroup of women with transfusion started during active bleeding, the FFP:RBC ratio within the first three hours of RBC transfusion was <0.5 in 10.3% of women transfused with both RBC and FFP, and the plasma fibrinogen was ≥2 g/L in 37.4% of those who received FC. Among women with RBC transfusion started after control of bleeding, 13.0% had a nadir Hb between 7 and 10 g/dL.

Discussion

In women with severe postpartum hemorrhage, half had RBC transfusion started during active bleeding, 15% were transfused exclusively after bleeding control and 35% were not transfused. A fifth of the women with SPPH and a Hb level <7 g/dL were not transfused with RBC. Conversely, one in eight women with Hb level ≥7 g/dL and control of bleeding received RBC. Two-thirds of women with transfusion started during active bleeding were treated with FFP, including 80% with an FFP:RBC ratio between 1:2 and 1:1. Fibrinogen concentrate was also used in almost half of these women, but this included only a third of those with a plasma fibrinogen of <2 g/dL.

The characteristics of patients and transfusion practices in SPPH differed between women in whom transfusion was started during active bleeding and those transfused only after control of bleeding. Women transfused during active bleeding were more frequently from sub-Saharan Africa, multiparous and delivered by a cesarean. In addition, they received more diverse types of blood products and in larger quantities than women in whom transfusion was started after the control of bleeding. These results suggest the need to explore transfusion practices separately in these two different contexts.

The gap between clinical practice and the French transfusion guidelines suggests undertransfusion, as a fifth of the women with SPPH and a nadir Hb <7 g/dL were not transfused.

A restrictive transfusion strategy, considering RBC transfusion indicated for patients with a

Hb level <7 g/dL, is recommended in obstetric and non-obstetric settings. [START_REF] Rossaint | Management of bleeding following major trauma: an updated European guideline[END_REF][START_REF]Practice guidelines for perioperative blood transfusion and adjuvant therapies: an updated report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies[END_REF][START_REF] Munoz | Patient blood management in obstetrics: prevention and treatment of postpartum haemorrhage. A NATA consensus statement[END_REF] Severe maternal anemia is associated with increased maternal mortality and morbidity, and should be corrected. [START_REF] Daru | Risk of maternal mortality in women with severe anaemia during pregnancy and post partum: a multilevel analysis[END_REF] Our results show that this transfusion trigger and the need for RBC transfusion in SPPH with severe anemia should be regularly communicated to practitioners.

In the context of transfusion started during active bleeding, two-thirds of the women had a Hb level >7 g/dL at the start of transfusion, which is consistent with the 2004 French guidelines. [START_REF] Goffinet | Postpartum haemorrhage: recommendations for clinical practice by the CNGOF (December 2004)[END_REF] Half the women transfused during active bleeding had a nadir Hb <7 g/dL during their management, which may reflect the severity of PPH but also the clinical challenge of transfusion decision-making. In ongoing SPPH, maintenance of Hb levels between 7 and 10 g/dL is recommended but may be difficult to achieve. Monitors providing real-time perfusion indices, such as tissue oxygen saturation (StO2) measured by near-infrared spectroscopy, coupled with laboratory data, are probably the next frontier in the management of hemorrhagic shock. [START_REF] Duret | Skeletal muscle oxygenation in severe trauma patients during haemorrhagic shock resuscitation[END_REF] Delays in transfusing blood products are also possible, but this remains speculative in the absence of data showing that transfusions were specifically triggered after a Hb <7 g/dL had been confirmed. The administration of FFP was observed in 68.8% of women with SPPH and transfusion started during active bleeding, and in agreement with 2012 French guidelines it was used in a FFP:RBC ratio between 0.5 and 1 in 80% of these women. 20 Fixed FFP:RBC ratios for initial transfusion in major bleeding are extrapolated from the trauma and cardiovascular surgery literature, [START_REF] Rahouma | Does a balanced transfusion ratio of plasma to packed red blood cells improve outcomes in both trauma and surgical patients? A metaanalysis of randomized controlled trials and observational studies[END_REF] but there are few data on its use in SSPH and its relevance is currently challenged. [START_REF] Collis | Haemostatic management of obstetric haemorrhage[END_REF] The transfusion strategy based on FFP:RBC ratio greater than 1:2 in ongoing bleeding may not be appropriate for all clinical settings, in particular in the absence of coagulation factor deficiencies. Recent studies in major obstetric hemorrhage suggest that prothrombin time and activated partial thromboplastin time (as markers of coagulopathy) are poorly correlated with blood loss and are abnormal in a minority of women with very large blood losses. [START_REF] Green | The haematological features and transfusion management of women who required massive transfusion for major obstetric haemorrhage in the UK: a population based study[END_REF][START_REF] Gillissen | Coagulation parameters during the course of severe postpartum hemorrhage: a nationwide retrospective cohort study[END_REF] A systematic review including randomized controlled trials that compared the use of point-of-care thromboelastometry or thromboelastography with usual care, to guide transfusion strategy in bleeding patients, concluded that these devices reduced the proportion of patients transfused with RBC, FFP or platelets and may reduce mortality. [START_REF] Wikkelso | Thromboelastography (TEG) or rotational thromboelastometry (ROTEM) to monitor haemostatic treatment in bleeding patients: a systematic review with meta-analysis and trial sequential analysis[END_REF] However, this review did not include obstetric patients and its results were mainly based on elective cardiac surgery. There was a high risk of bias due to heterogeneity. Goal-directed coagulation factor therapy based on visco-elastic algorithms for the treatment of coagulopathy in SPPH should be evaluated further. [START_REF] Collins | Viscoelastometry guided fresh frozen plasma infusion for postpartum haemorrhage: OBS2, an observational study[END_REF] An increasing use of pro-hemostatic agents was seen in women transfused during active bleeding: both FC and tranexamic acid were administered to more than 40% of the women with a transfusion started during active bleeding. Changes in transfusion practice have anticipated changes in guidelines. [START_REF] Sentilhes | Postpartum hemorrhage: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians (CNGOF): in collaboration with the French Society of Anesthesiology and Intensive Care (SFAR)[END_REF] Fibrinogen concentrate was given before the first RBC unit in half the cases, which may be explained by its immediate availability while awaiting delivery of FFP or RBCs. It could also be explained by knowledge about publications that have highlighted the association between an early fall in plasma fibrinogen and progression to SPPH. [START_REF] Charbit | The decrease of fibrinogen is an early predictor of the severity of postpartum hemorrhage[END_REF][START_REF] Cortet | Association between fibrinogen level and severity of postpartum haemorrhage: secondary analysis of a prospective trial[END_REF] For women transfused after bleeding control, a minority was transfused when above the recommended transfusion triggers: 13% received RBC despite a Hb >7 g/d, and 5.4% received FFP and 4.0% FC. The use of FFP or FC after bleeding has been controlled is not in accordance with the French guidelines. 20 Clinicians may have used these products to correct biological abnormalities or out of concern about a recurrence of bleeding. The results highlight the need for improving postpartum anemia management in France and may be a comment on the limited guidelines with respect to patient blood management in obstetrics.

The recent NATA patient blood management guidelines in obstetrics are a step forward as they recommend the administration of intravenous iron to women with postpartum Hb level of 6-9 g/L. [START_REF] Munoz | Patient blood management in obstetrics: prevention and treatment of postpartum haemorrhage. A NATA consensus statement[END_REF] This study has several strengths. We used a large population-based cohort of pregnant women with characteristics comparable to the national profile, [START_REF] Blondel | Trends in perinatal health in France from 1995 to 2010. Results from the French National Perinatal Surveys[END_REF] and the definition of SPPH was reproducible and easily applied. The prospective inclusion of women using predefined SPPH criteria ensured the completeness of the cases in the source population. The design allowed differentiation between women transfused during active bleeding and those exclusively transfused after control of bleeding. However, the study also has limitations. Despite detailed data having been collected on transfusion practice in SPPH, some data on timing of subsequent blood products administered (including platelet transfusions) were not recorded.

The time period between the last pre-transfusion Hb measurement after delivery and the onset of RBC transfusion was not standardized as data were extracted from an observational study. Also, we did not have access to hematological indices closest to the time of hospital discharge, so we could not determine the extent of anemia or hemostatic derangement among these patients in the early postpartum period. We did not have patient-centric information to assess whether patients with anemia were symptomatic. We were also unable to determine provider-specific transfusion decision-making and whether providers used other point-of-care technologies, such as visco-elastic testing in their transfusion decision-making.

In conclusion, our findings suggest that moderate variability exists in French transfusion practices during the acute period of bleeding and after arrest of bleeding for women with SPPH. Further research is needed to explore decision-making approaches to transfusion and to examine the degree to which these are influenced by national guidelines. Although standardizing practices may be challenging during the dynamic period of blood loss, there is a need to study the impact of patient blood management practices for the treatment of postpartum anemia after SPPH.

Declarations of interest: none.

identification and documentation in their hospital, and research assistants who collected the 305 data. 306 The total number of women may vary slightly from one characteristic to another because of missing data. a In exclusive categories. RBC: red blood cells. PPH: postpartum hemorrhage. Shock: Systolic blood pressure <90 mmHg of duration >60 min or unresponsive to plasma expansion. DIC: Disseminated intravascular coagulopathy defined by thrombocytopenia <50 x 10 9 /L or s. fibrinogen level <2 g/L or prothrombin ratio <60% The total number of women may vary slightly from one characteristic to another because of missing data. a Among women with RBC transfusion started during active bleeding and transfused with FFP (n=514). b Among women with RBC transfusion started during active bleeding and who received FC (n=328). RBC: red blood cells. Hb: hemoglobin. PPH: postpartum hemorrhage. FFP: fresh frozen plasma. FC: fibrinogen concentrate. The total number of women may vary slightly from one characteristic to another because of missing data. a Expressed as row percentage. b Expressed as column percentage. c Among women with RBC transfusion started during active bleeding and transfused with FFP (n=514). d Among women transfused with RBC and who received FC (N=337). e Among women transfused with RBC and who had a nadir fibrinogen <2g/L (n=247). f Among women transfused with RBC and who had a DIC (N=330). RBC: red blood cells. Hb: hemoglobin. PPH: postpartum hemorrhage. FFP: fresh frozen plasma. FC: fibrinogen concentrate. DIC: disseminated intravascular coagulopathy defined by thrombocytopenia <50 x 10 9 /L or fibrinogen level <2g/L or prothrombin ratio <60%.

Fig. 1 .

 1 Fig.1. Study population

Table 1 .

 1 Characteristics of women with severe postpartum hemorrhage, stratified by use of red blood cell transfusion.

		Deliveries
		n=182 309
	All severe postpartum hemorrhages (SPPH)
		n=1,655 (0.9% of deliveries)
			Inherited
			hemostasis
			disorder
			n=12
			Antepartum
			diagnosis of
			placenta accreta
			n=70
			Secondary SPPH
			n=61
			Missing data on
			primary or
			secondary type of
			hemorrhage
			n=13
		Primary SPPH
		n=1,499
			Missing data on
			transfusion n=4
		Primary SPPH with available data on
		transfusion therapy
		n=1,495 (0.8% of deliveries)
	RBC transfusion started during active	RBC transfusion started only after bleeding	No RBC transfusion
	bleeding n=747 (50.0% of SPPH)	controlled n=223 (14.9% of SPPH)	n=525 (35.1% of SPPH)

Table 2 .

 2 Etiology and management of women with severe postpartum hemorrhage, stratified by use of red blood cell transfusion.

		Women receiving RBC	Women receiving RBC	Women not receiving RBC
		during active bleeding	after bleeding control
		(n=747)		(n=223)		(n=525)
		n	n	(%)	n	n	(%)	n	n (%)
	Cause of PPH a	747			223			525
	Uterine atony		335 (44.8)		66 (29.6)		198 (37.7)
	Placental retention		80 (10.7)		46 (20.6)		85 (16.2)
	Perineal wound or episiotomy		82 (11.0)		56 (25.1)		62 (11.8)
	Surgical cause		71	(9.5)		21	(9.4)		78 (14.9)
	Amniotic fluid embolism		14	(1.9)		0	(0.0)		0	(0.0)
	Uterine rupture		21	(2.8)		1	(0.5)		7	(1.3)
	Placental abruption		33	(4.4)		7	(3.1)		9	(1.7)
	Placenta previa		19	(2.5)		0	(0.0)		22	(4.2)
	Placenta accreta		32	(4.3)		1	(0.5)		5	(0.9)
	Others		14	(1.9)		7	(3.1)		4	(0.8)
	Unidentified		46	(6.2)		18	(8.1)		55 (10.5)
	Characteristics of PPH severity
	Total blood loss (mL)	588	1750 (1500,2200)	165	1000 (750,1500)	468	1500 (1100,1700)
	Nadir s. fibrinogen level (g/L)	670			140			338
	<1		61	(9.1)		2	(1.4)		3	(0.9)
	1-1.9		169 (25.2)		15 (10.7)		30	(8.9)
	≥2		440 (65.7)		123 (87.9)		305 (90.2)
	Hemorrhagic shock	747 104 (13.9)	223	12	(5.4)	525	21	(4.0)
	DIC	747 302 (40.4)	223	28 (12.6)	525	38	(7.2)
	Characteristics of PPH management
	Tranexamic acid	747 338 (45.2)	223	33 (14.8)	525 118 (22.5)
	Arterial embolization	747 138 (18.5)	223	10	(4.5)	525	27	(5.1)
	Conservative uterine surgery	747 173 (23.2)	223	1	(0.4)	525	67 (12.8)
	Peripartum hysterectomy	747	83 (11.1)	223	2	(0.9)	525	5	(1.0)
	Data presented as n (%), median [interquartile range]

Table 3a .

 3a Transfusion-related data for women with severe postpartum hemorrhage transfused with red blood cells during or after active bleeding.

		Women with RBC	Women with RBC
		during active bleeding	after bleeding control
			(n=747)			(n=223)
		n	n	(%)	n	n	(%)
	Characteristics of RBC transfusion
	Hb level before RBC transfusion (g/dL)	683			220
	<6.0		91	(13.3)		59	(26.8)
	6.0-6.9		141	(20.7)		123	(55.9)
	7.0-7.9		140	(20.5)		26	(11.8)
	≥8.0		311	(45.5)		12	(5.5)
	Time from PPH diagnosis to RBC transfusion	690 1h38 (52min,2h53)	200	32h (22h,58h)
	Total number of RBC units	743		3 (2,5)	221		2 (2,3)
	≥10 RBC units		64	(8.6)		0	(0.0)
	Characteristics of FFP transfusion
	FFP transfusion	747	514	(68.8)	223	12	(5.4)
	Time from RBC to FFP transfusion a	467	28min (4,59)
	Total number of FFP units a	511		3 (2,5)
	Characteristics of FC administration
	FC administration	747	328	(43.9)	223	9	(4.0)
	Time from RBC to FC administration b	290	-1min (-37,46)
	Total quantity of FC b (g)	319	3 (1.5,4.5)
	Platelets transfusion	747	132	(17.7)	223	5	(2.2)
	Data presented as n(%), median [interquartile range]

Table 3b :

 3b Anemia management and hemostatic support among women with severe postpartum hemorrhage

		Women receiving RBC during active	Women receiving RBC after bleeding	Women not receiving RBC
		bleeding	control
		(n=747)	(n=223)	(n=525)
		n	n (% a )	n	n (% a )	n	n (% a )
	RBC transfusion according to nadir Hb level
	Women with nadir Hb <7g/dL (N=697)		354 (50.8)		194 (27.8)		149 (21.4)
		n	n (% b )	n	n (% b )	n	n (% b )
	Management of acute anemia
	Nadir Hb (g/dL)	743		223		523
	<7		354 (47.6)		194 (87.0)		149 (28.5)
	7-10		360 (48.5)		29 (13.0)		312 (59.7)
	>10		29 (3.9)		0 (0.0)		62 (11.9)
	Hemostatic support
	FFP:RBC within the first 3 h of RBC transfusion c	368
	<0.5		38 (10.3)
	0.5 -1		296 (80.4)
	>1		34 (9.3)
	Fibrinogen level before FC administration d (g/L)	286		7
	<2		103 (36.0)		2 (28.6)
	≥2		107 (37.4)		1 (14.3)
	not measured		76 (26.6)		4 (57.1)
	Neither FFP nor FC transfusion despite fibrinogen <2g/L e 230	24 (10.4)	17	8 (47.1)
	Neither FFP nor FC transfusion despite DIC f	302	37 (12.3)	28	17 (60.7)

Acknowledgements

The authors thank the coordinators of the participating regional perinatal networks: Alsace, Aurore, Auvergne, Basse-Normandie, MYPA, NEF, Paris Nord, 92 Nord, Lorraine; Chloé Barasinski, Sophie Bedel, Aline Clin d'Amour, Laurent Gaucher, Isabelle Lecreff, Blandine Masson, Carole Ramousset, Mathias Rossignol, Zelda Stewart, Dalila Talaourar, Yacine Toure, Nicole Wirth for their contribution to the implementation of the EPIMOMS study in their region; the obstetricians, midwives, and anesthetists who contributed to case

Institute of Health and Medical Research (INSERM) and by the Regional Health Agency in

Ile de France (ARS Ile de France). This study was financially supported by grants from the French Society of Anesthesiology and Intensive Care (SFAR) and the French Society of Obstetric Anesthesia (CARO).

Funding

The EPIMOMS project (Severe maternal morbidity: measurement, determinants and quality of care) was funded by the French National Research Agency (ANR), by the French National

Appendix A

The following are members of the EPIMOMS study group: