Association of severe postpartum hemorrhage and development of psychological disorders: Results from the prospective and multicentre HELP MOM study.

OBJECTIVE: Post-partum hemorrhage (PPH) is the leading preventable cause of worldwide maternal morbidity and mortality. Risk factors for psychological disorders following PPH are currently unknown. HELP-MOM study aimed to determine the incidence and identify risk factors for psychological disorders following PPH. METHODS: HELP-MOM study was a prospective, observational, national, and multicentre study including patients who experienced severe PPH requiring sulprostone. The primary endpoint was the occurrence of psychological disorders (anxiety and/or post-traumatic disorder and/or depression) following PPH, assessed at 1, 3, and 6 months after delivery using HADS, IES-R, and EPDS scales. RESULTS: Between November 2014 and November 2016, 332 patients experienced a severe PPH and 236 (72%) answered self-questionnaires at 1, 3, and 6 months. A total of 161 (68%) patients declared a psychological disorder following severe PPH (146 (90.1%) were screened positive for anxiety, 96 (58.9%) were screened positive for post-traumatic stress disorder, and 94 (57.7%) were screened positive for post-partum depression). In multivariable analysis, the use of intra-uterine tamponnement balloon was associated with a lower risk to be screened positive for psychological disorder after severe PPH (OR = 0.33 [IC95% 0.15-0.69], p = 0.004, and after propensity score matching (OR=0.34 [IC95% 0.12-0.94], p = 0.04)). Low hemoglobin values during severe PPH management were associated with a higher risk of being screened positive for psychological disorders. Finally, we did not find differences in desire or pregnancy between patients without or with psychological disorders occurring in the year after severe PPH. DISCUSSION: Severe PPH was associated with significant psychosocial morbidity including anxiety, post-traumatic disorder, and depression. This should engage a psychological follow-up. Large cohorts are urgently needed to confirm our results. REGISTRATION: ClinicalTrials.gov under number NCT02118038.

Haemostatic support in postpartum haemorrhage: A review of the literature and expert opinion.

Postpartum haemorrhage (PPH) remains the leading cause of pregnancy-related deaths worldwide. Typically, bleeding is controlled by timely obstetric measures in parallel with resuscitation and treatment of coagulopathy. Early recognition of abnormal coagulation is crucial and haemostatic support should be considered simultaneously with other strategies as coagulopathies contribute to the progression to massive haemorrhage. However, there is lack of agreement on important topics in the current guidelines for management of PPH. A clinical definition of PPH is paramount to understand the situation to which the treatment recommendations relate; however, reaching a consensus has previously proven difficult. Traditional definitions are based on volume of blood loss, which is difficult to monitor, can be misleading and leads to treatment delay. A multidisciplinary approach to define PPH considering vital signs, clinical symptoms, coagulation and haemodynamic changes is needed. Moreover, standardised algorithms or massive haemorrhage protocols should be developed to reduce the risk of morbidity and mortality and improve overall clinical outcomes in PPH. If available, point-of-care testing should be used to guide goal-directed haemostatic treatment. Tranexamic acid should be administered as soon as abnormal bleeding is recognised. Fibrinogen concentrate rather than fresh frozen plasma should be administered to restore haemostasis where there is elevated risk of fibrinogen deficiency (e.g., in catastrophic bleeding or in cases of abruption or amniotic fluid embolism) as it is a more concentrated source of fibrinogen. Lastly, organisational considerations are equally as important as clinical interventions in the management of PPH and have the potential to improve patient outcomes.

The role of tranexamic acid in the management of postpartum haemorrhage.

In the last decades, tranexamic acid (TXA) has emerged as an essential tool in blood loss management in obstetrics. TXA prophylaxis for postpartum haemorrhage (PPH) has been studied in double-blind, placebo-controlled, randomized clinical trials (RCTs). Given the small observed preventive effect, the systematic use of TXA for vaginal and/or caesarean deliveries remains controversial. The result of a pharmacokinetic modelling suggests that relative to intravenous administration, intramuscular administration may be an equally effective alternative route for preventing PPH and may enable access to this drug in low-resource countries. Prophylaxis is currently studied in high-risk populations, such as women with prepartum anaemia or placenta previa. TXA effectively reduces blood loss and PPH-related morbidity and mortality during active PPH, as demonstrated by high-grade evidence from large RCTs. The drug has a good safety profile: in most cases, only mild gastrointestinal or visual adverse events may be observed. TXA use does not increase the risk of serious adverse events, such as venous or arterial thromboembolism, seizures, or acute kidney injury. The TRACES in vivo analysis of biomarkers of TXA's antifibrinolytic effect have suggested that a dose of at least 1 g is required for the treatment of PPH. The TRACES pharmacokinetic model suggests that because TXA can be lost in the haemorrhaged blood, a second dose should be administered if the PPH continues or if severe coagulopathy occurs. Future pharmacodynamic analyses will focus on the appropriateness of TXA dosing regimens with regard to the intensity of fibrinolysis in catastrophic obstetric events.

Tranexamic acid dose-response relationship for antifibrinolysis in postpartum haemorrhage during Caesarean delivery: TRACES, a double-blind, placebo-controlled, multicentre, dose-ranging biomarker study.

BACKGROUND: The optimal dose of tranexamic acid to inhibit hyperfibrinolysis in postpartum haemorrhage is unclear. Tranexamic Acid to Reduce Blood Loss in Hemorrhagic Cesarean Delivery (TRACES) was a double-blind, placebo-controlled, randomised, multicentre dose-ranging study to determine the dose-effect relationship for two regimens of intravenous tranexamic acid vs placebo. METHODS: Women experiencing postpartum haemorrhage during Caesarean delivery were randomised to receive placebo (n=60), tranexamic acid 0.5 g (n=57), or tranexamic acid 1 g i.v. (n=58). Biomarkers of fibrinolytic activation were assayed at five time points, with inhibition of hyperfibrinolysis defined as reductions in the increase over baseline in D-dimer and plasmin-antiplasmin levels and in the plasmin peak time. RESULTS: In the placebo group, hyperfibrinolysis was evidenced by a mean increase over baseline [95% confidence interval] of 93% [68-118] for D-dimer level at 120 min and 56% [25-87] for the plasmin-antiplasmin level at 30 min. A dose of tranexamic acid 1 g was associated with smaller increases over baseline (D-dimers: 38% [13-63] [P=0.003 vs placebo]; plasmin-antiplasmin: -2% [-32 to 28] [P=0.009 vs placebo]). A dose of tranexamic acid 0.5 g was less potent, with non-significant reductions (D-dimers: 58% [32-84] [P=0.06 vs placebo]; plasmin-antiplasmin: 13% [18-43] [P=0.051]). Although both tranexamic acid doses reduced the plasmin peak, reduction in plasmin peak time was significant only for the 1 g dose of tranexamic acid. CONCLUSIONS: Fibrinolytic activation was significantly inhibited by a dose of intravenous tranexamic acid 1 g but not 0.5 g. Pharmacokinetic-pharmacodynamic modelling of these data might identify the best pharmacodynamic monitoring criteria and the optimal tranexamic acid dosing regimen for treatment of postpartum haemorrhage. CLINICAL TRIAL REGISTRATION: NCT02797119.

Accuracy and trending ability of finger plethysmographic cardiac output monitoring in late pregnancy.

PURPOSE: Individuals in late pregnancy are at risk of significant hemodynamic variations, especially during Cesarean delivery. Although non-invasive monitoring might enable the early detection of variations in cardiac output (CO), clinical validation is lacking. METHODS: In a prospective, single-center study, we measured CO simultaneously with finger plethysmography and transthoracic echocardiography in 100 third-trimester pregnant individuals in the supine and left lateral decubitus (LLD) positions. RESULTS: A Bland-Altman analysis revealed a mean (standard deviation) bias of 1.36 (1.04) L·min-1 in the supine position (95% limits of agreement, -0.68 to 3.4 L·min-1; percent error, 26.6%), indicating overestimation by finger plethysmography. The intra-class correlation coefficient was 0.43 (95% confidence interval [CI], 0.33 to 0.51). Regarding the changes in CO induced by the supine-to-LLD transition, the concordance rate in a four-quadrant plot was 98.3% (95% CI, 91.1 to 99.9%). CONCLUSION: Our study showed a poor reliability of finger plethysmography for static measurement of CO. Nevertheless, finger plethysmography had a reasonably high concordance rate for the detection of CO changes secondary to positional changes in late-pregnant individuals. STUDY REGISTRATION DATE: www. CLINICALTRIALS: gov (NCT03735043); registered 8 November 2018.

RéSUMé: OBJECTIF: Les personnes en fin de grossesse sont à risque de variations hémodynamiques importantes, en particulier pendant un accouchement par césarienne. Bien que le monitorage non invasif puisse permettre la détection précoce des variations du débit cardiaque (DC), la validation clinique de ce type de monitorage fait défaut. MéTHODE: Dans une étude prospective monocentrique, nous avons mesuré le DC simultanément avec la pléthysmographie au doigt et l'échocardiographie transthoracique chez 100 femmes au troisième trimestre de leur grossesse en décubitus dorsal et en décubitus latéral gauche (DLG). RéSULTATS: Une analyse de Bland-Altman a révélé un biais moyen (écart type) de 1,36 (1,04) L·min­1 en décubitus dorsal (limites d'agrément à 95 %, -0,68 à 3,4 L·min­1; pourcentage d'erreur, 26,6 %), indiquant une surestimation lorsque mesuré par pléthysmographie au doigt. Le coefficient de corrélation intraclasse était de 0,43 (intervalle de confiance [IC] à 95 %, 0,33 à 0,51). En ce qui concerne les changements de DC induits par la transition du décubitus dorsal au décubitus latéral gauche, le taux de concordance dans un diagramme à quatre quadrants était de 98,3 % (IC 95 %, 91,1 à 99,9 %). CONCLUSION: Notre étude a montré une faible fiabilité de la pléthysmographie au doigt pour la mesure statique du DC. Néanmoins, la pléthysmographie au doigt avait un taux de concordance raisonnablement élevé pour la détection des changements de DC secondaires aux changements de position chez les patientes en fin de grossesse. www.clinicaltrials.gov (NCT03735043); enregistrée le 8 novembre 2018.

Pharmacokinetics of Curative Tranexamic Acid in Parturients Undergoing Cesarean Delivery.

The aim of this study was to evaluate the population pharmacokinetics of tranexamic acid (TXA) administered intravenously at a single dose of 0.5 or 1 g in parturients undergoing active hemorrhagic cesarean delivery and to evaluate the influence of patient variables on TXA pharmacokinetics. Subjects from three recruiting centers were included in this PK sub-study if randomized in the experimental group (i.v TXA 0.5 g or 1 g over one minute) of the TRACES study. Blood samples and two urinary samples were collected within 6 h after TXA injection. Parametric non-linear mixed-effect modeling (Monolix v2020R1) was computed. The final covariate model building used 315 blood and 117 urinary concentrations from seventy-nine patients. A two-compartment model with a double first-order elimination from the central compartment best described the data. The population estimates of clearance (CL), central volume of distribution (V1), and half-life for a typical 70 kg patient with an estimated renal clearance of 150 mL/min (Cockroft-Gault) were 0.14 L/h, 9.25 L, and 1.8 h. A correlation between estimated creatinine clearance and CL, body weight before pregnancy, and V1 was found and partly explained the PK variability. The final model was internally validated using a 500-run bootstrap. The first population pharmacokinetic model of TXA in active hemorrhagic caesarean section was successfully developed and internally validated.

Raising awareness to prevent, recognise and manage acute pain during caesarean delivery: The French Practice Bulletin.

The incidence of acute pain during caesarean section varies between studies, with a reported rate ranging between 0.5%-17% for spinal anaesthesia and 1.7%-20% for epidural anaesthesia. Leaders from the French Club anesthésie-réanimation en obstétrique (CARO) convened to provide a clinical framework and practice bulletin to prevent, recognise and treat acute pain during caesarean section. First, a steering group agreed on 5 themes guiding quality of anaesthesia care for caesarean section: (1) appropriate neuraxial anaesthesia and testing of the surgical block prior to incision (PREVENTION); (2) appropriate organisation around decision to delivery time (COMMUNICATION); 3) appropriate management of pain before and/or after skin incision (RECOGNITION & RESPONSE); (4) appropriate prevention, identification and management of post-traumatic stress disorder (SCREENING, PREVENTION AND MANAGEMENT OF COMPLICATIONS); (5) management of medico-legal issues (MITIGATION). Then, an interdisciplinary multi-professional taskforce composed of obstetric anaesthesiologists, obstetricians, neonatologists, psychiatrists, midwifes, nurse anaesthetists, lawyers and patients, developed 23 statements that contribute to optimise care for caesarean section under neuraxial anaesthesia, of which 10 were deemed key recommendations. A decision-tree was built to optimise prevention, communication, recognition, response and management. The aim of this practice bulletin, which was endorsed by 6 societies, is to raise awareness on the risks associated with severe acute pain during caesarean section and to provide best clinical practices; pain during caesarean is not acceptable and should be prevented and managed by all stakeholders.

French recommendations for the management of systemic sclerosis.

Systemic sclerosis (SSc) is a generalized disease of the connective tissue, arterioles, and microvessels, characterized by the appearance of fibrosis and vascular obliteration. There are two main phenotypical forms of SSc: a diffuse cutaneous form that extends towards the proximal region of the limbs and/or torso, and a limited cutaneous form where the cutaneous sclerosis only affects the extremities of the limbs (without passing beyond the elbows and knees). There also exists in less than 10% of cases forms that never involve the skin. This is called SSc sine scleroderma. The prognosis depends essentially on the occurrence of visceral damage and more particularly interstitial lung disease (which is sometimes severe), pulmonary arterial hypertension, or primary cardiac damage, which represent the three commonest causes of mortality in SSc. Another type of involvement with poor prognosis, scleroderma renal crisis, is rare (less than 5% of cases). Cutaneous extension is also an important parameter, with the diffuse cutaneous forms having less favorable prognosis.

Post-partum relapse in women with multiple sclerosis after neuraxial labour analgesia or neuraxial anaesthesia: A multicentre retrospective cohort study.

BACKGROUND: The proportion of women with multiple sclerosis experiencing a relapse in the post-partum period after neuraxial labour analgesia or neuraxial anaesthesia remains uncertain. This study aimed to assess the association between neuraxial labour analgesia or neuraxial anaesthesia and the occurrence of relapse during the first three months post-partum. METHODS: In this retrospective cohort study, cases of women with a diagnosis of multiple sclerosis delivering between January 2010 and April 2015 were analysed. Demographic, anaesthetic and obstetric characteristics, occurrence and number of relapses in the year preceding pregnancy, during pregnancy, and the first three post-partum months, were recorded. Logistic regression analyses were performed for the identification of factors associated with the occurrence of post-partum relapse. RESULTS: A total of 118 deliveries in 104 parturients were included, these were 78 (66%) vaginal deliveries and 40 (34%) caesarean deliveries. Neuraxial analgesia was provided in 50 deliveries, and neuraxial anaesthesia in 46 deliveries; no neuraxial anaesthesia or analgesia was administered in remaining 22 deliveries. Post-partum relapse occurred in 31 women (26%). There was no association between obstetric or anaesthetic characteristics and post-partum relapse. Both the occurrence and number of relapses prior to and during pregnancy, and the time between last relapse and delivery, were significantly associated with post-partum relapse in univariate analysis. The occurrence of relapse within the year preceding the pregnancy was the sole independent factor associated with post-partum relapse. CONCLUSION: Neuraxial procedures were not associated with increased rate of post-partum relapse; only disease activity prior to pregnancy was predictive of post-partum relapse.

Post-partum acute kidney injury: sorting placental and non-placental thrombotic microangiopathies using the trajectory of biomarkers.

BACKGROUND: Among the severe complications of preeclampsia (PE), acute kidney injury (AKI) is problematic if features of thrombotic microangiopathy (TMA) are present. Although a haemolysis enzyme liver low-platelets syndrome is considerably more frequent, it is vital to rule out a flare of atypical haemolytic and uraemic syndrome (aHUS). Our objective was to improve differential diagnosis procedures in post-partum AKI. METHODS: A total of 105 cases of post-partum AKI, admitted to nine different regional French intensive care units from 2011 to 2015, were analysed. Analysis included initial and final diagnosis, renal features, haemostasis and TMA parameters, with particular focus on the dynamics of each component within the first days following delivery. A classification and regression tree (CART) was used to construct a diagnostic algorithm. RESULTS: AKI was attributed to severe PE (n = 40), post-partum haemorrhage (n = 33, including 13 renal cortical necrosis) and 'primary' TMA (n = 14, including 10 aHUS and 4 thrombotic thrombocytopenic purpura). Congruence between initial and final diagnosis was low (63%). The dynamics of haemoglobin, haptoglobin and liver enzymes were poorly discriminant. In contrast, the dynamic pattern of platelets was statistically different between primary TMA-related AKI and other groups. CART analysis independently highlighted the usefulness of platelet trajectory in the diagnostic algorithm. Limitations of this study include that only the most severe cases were included in this retrospective study, and the circumstantial complexity is high. CONCLUSION: Trajectory of platelet count between admission and Day 3 helps to guide therapeutic decisions in cases of TMA-associated post-partum AKI. Our study also strongly suggests that during the post-partum period, there may be a risk of transient, slowly recovering TMA in cases of severe endothelial injury in women without a genetic mutation known to induce aHUS.

Staffing needs for unscheduled activity in obstetrics and gynecology.

INTRODUCTION: To determine a minimum threshold of medical staffing needs (obstetricians-gynecologists, anesthesiologists-resuscitation specialists, nurse-anesthetists, pediatricians, and midwives) to ensure the safety and quality of care for unscheduled obstetrics-gynecology activity. MATERIALS AND METHODS: Face to face meetings of French healthcare professionals involved in perinatal care in different types of practices (academic hospital, community hospital or private practice) who belong to French perinatal societies: French National College of Gynecologists-Obstetricians (CNGOF), the French Society of Anesthesia and Resuscitation Specialists (SFAR), the French Society of Neonatology (SFN), the French Society of Perinatal Medicine (SFMP), the National College of French Midwives (CNSF), and the French Federation of Perinatal Care Networks (FFRSP). RESULTS: Different minimum thresholds for each category of care provider were proposed according to the number of births/year in the facility. These minimum thresholds can be modulated upwards as a function of the level of care (Level 1, 2 or 3 for perinatal centers), existence of an emergency department, and responsibilities as a referral center for maternal-fetal and/or surgical care. For example, an obstetrics-gynecology department handling 3000-4500 births per year without serving as a referral center must have an obstetrician-gynecologist, an anesthesiologist-resuscitation specialist, a nurse-anesthetist, and a pediatrician onsite specifically to provide care for unscheduled obstetrics-gynecology needs and a second obstetrician-gynecologist available within a time compatible with security requirements 24/7; the number of midwives always present (24/7) onsite and dedicated to unscheduled care is 5.1 for 3000 births and 7.2 for 4500 births. A maternity unit's occupancy rate must not exceed 85 %. CONCLUSION: The minimum thresholds proposed here are intended to improve the safety and quality of care of women who require unscheduled care in obstetrics-gynecology or during the perinatal period.

Effect of Oral Carbohydrate Intake During Labor on the Rate of Instrumental Vaginal Delivery: A Multicenter, Randomized Controlled Trial.

BACKGROUND: Carbohydrate intake during physical exercise improves muscle performance and decreases fatigue. We hypothesized that carbohydrate intake during labor, which is a period of significant physical activity, can decrease the instrumental vaginal delivery rate. METHODS: In a multicenter, prospective, randomized, controlled trial, healthy adult pregnant women presenting with spontaneous labor were assigned to a "Carbohydrate" group (advised to drink 200 mL of apple or grape juice without pulp every 3 hours) or a "Fasting" group (water only). The primary outcome was the instrumental vaginal delivery rate. Secondary outcomes included duration of labor, rate of cesarean delivery, evaluation of maternal hunger, thirst, stress, fatigue, and overall feeling during labor by numeric rating scale (0 worst rating to 10 best rating), rate of vomiting, and hospital length of stay. Statistical analysis was performed on an intention-to-treat basis. The primary outcome was tested with the "Fasting" group as the reference group. The P values for secondary outcomes were adjusted for multiple comparisons. The differences between groups are reported with 99% confidence interval (CI). RESULTS: A total of 3984 women were analyzed (2014 in the Carbohydrate group and 1970 in the Fasting group). There was no difference in the rate of instrumental delivery between the Carbohydrate (21.0%) and the Fasting (22.4%) groups (difference, -1.4%; 99% CI, -4.9 to 2.2). No differences were found between the Carbohydrate and the Fasting groups for the duration of labor (difference, -7 minutes; 99% CI, -25 to 11), the rate of cesarean delivery (difference, -0.3%; 99% CI, -2.4 to 3.0), the rate of vomiting (difference, 2.8%; 99% CI, 0.2-5.7), the degree of self-reported fatigue (difference, 1; 99% CI, 0-2), self-reported hunger (difference, 0; 99% CI, -1 to 1), thirst (difference, 0; 99% CI, -1 to 1), stress (difference, 0; 99% CI, -1 to 1), overall feeling (difference, 0; 99% CI, 0-0), and the length of hospitalization (difference, 0; 99% CI, -1 to 0). CONCLUSIONS: Carbohydrate intake during labor did not modify the rate of instrumental vaginal delivery.

Patient blood management in obstetrics: prevention and treatment of postpartum haemorrhage. A NATA consensus statement.

Patient blood management (PBM) is the timely application of evidence-informed medical and surgical concepts designed to maintain haemoglobin concentration, optimise haemostasis, and minimise blood loss in an effort to improve patient outcomes. The aim of this consensus statement is to provide recommendations on the prevention and treatment of postpartum haemorrhage as part of PBM in obstetrics. A multidisciplinary panel of physicians with expertise in obstetrics, anaesthesia, haematology, and transfusion medicine was convened by the Network for the Advancement of Patient Blood Management, Haemostasis and Thrombosis (NATA) in collaboration with the International Federation of Gynaecology and Obstetrics (FIGO), the European Board and College of Obstetrics and Gynaecology (EBCOG), and the European Society of Anaesthesiology (ESA). Members of the task force assessed the quantity, quality and consistency of the published evidence, and formulated recommendations using the system developed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group. The recommendations in this consensus statement are intended for use by clinical practitioners managing perinatal care of women in all settings, and by policy-makers in charge of decision making for the update of clinical practice in health care establishments.

Therapeutic and pharmaco-biological, dose-ranging multicentre trial to determine the optimal dose of TRAnexamic acid to reduce blood loss in haemorrhagic CESarean delivery (TRACES): study protocol for a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide. Tranexamic acid (TA), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma. In ongoing PPH following vaginal delivery, a high dose of TA decreases PPH volume and duration, as well as maternal morbidity, while early fibrinolysis is inhibited. In a large international trial, a TA single dose reduced mortality due to bleeding but not the hysterectomy rate. TA therapeutic dosages vary from 2.5 to 100 mg/kg and seizures, visual disturbances and nausea are observed with the highest dosages. TA efficiency and optimal dosage in haemorrhagic caesarean section (CS) has not been yet determined. We hypothesise large variations in fibrinolytic activity during haemorrhagic caesarean section needing targeted TA doses for clinical and biological efficacy. METHODS/DESIGN: The current study proposal is a blinded, randomised controlled trial with the primary objective of determining superiority of either 1 g of TXA or 0.5 g of TXA, in comparison to placebo, in terms of 30% blood-loss reduction at 6 h after non-emergency haemorrhagic caesarean delivery (active PPH > 800 mL) and to correlate this clinical effect in a pharmacokinetics model with fibrinolysis inhibition measured by an innovative direct plasmin measurement regarding plasmatic TA concentration. A sample size of 342 subjects (114 per group) was calculated, based on the expected difference of 30% reduction of blood loss between the placebo group and the low-dose group, out of which 144 patients will be included blindly in the pharmaco-biological substudy. A non-haemorrhagic reference group will include 48 patients in order to give a reference for peak plasmin level. DISCUSSION: TRACES trial is expected to give the first pharmacokinetics data to determinate the optimal dose of tranexamic acid to reduce blood loss and inhibit fibrinolysis in hemorrhagic cesarean section. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02797119 . Registered on 13 June 2016.

TRAnexamic acid in hemorrhagic CESarean section (TRACES) randomized placebo controlled dose-ranging pharmacobiological ancillary trial: study protocol for a randomized controlled trial.

BACKGROUND: Evidence increases that a high or a standard dose of tranexamic acid (TA) reduces postpartum bleeding. The TRACES pharmacobiological substudy aims to establish a therapeutic strategy in hemorrhagic (H) Cesarean section (CS) with respect to the intensity of fibrinolysis by using innovative assays. METHOD/DESIGN: The TRACES trial is a multicenter, randomized, double-blind, placebo-controlled, TA dose-ranging study that measures simultaneously plasmatic and uterine and urine TA concentrations and the plasmin peak inhibition tested by a simultaneous thrombin plasmin generation assay described by Van Geffen (novel hemostasis assay [NHA]). Patients undergoing H CS (>800 mL) will receive blindly TA 0.5 g or 1 g or placebo. A non-hemorrhagic (NH) group will be recruited to establish plasmin generation profile. Venous blood will be sampled before, at the end, and then at 30, 60, 120, and 360 min after injection. Uterine bleeding will be sampled after injection. Urine will be sampled 2 h and 6 h after injection. The number of patients entered into the study will be 114 H + 48 NH out of the 390 patients of the TRACES clinical trial. DISCUSSION: To explore the two innovative assays, a preliminary pilot study was conducted. Blood samples were performed repeatedly in patients undergoing either a H (>800 mL) or NH (<800 mL) CS and in non-pregnant women (NP). H patients received TA (0-2 g). Dose-dependent TA plasmatic concentrations were determined by LC-MS/MS quantification. Plasmin generation and its inhibition were tested in vitro and in vivo using the simultaneous thrombin-plasmin generation assay (STPGA). The pilot study included 15 patients in the H group, ten patients in the NH group, and seven patients in the NP group. TA plasmatic concentration showed a dose-dependent variation. STPGA inter-assay variation coefficients were < 20% for all plasmin parameters. Inter-individual dispersion of plasmin generation capacity was higher in H and NH groups than in NP group. Profile evolution over time was different between groups. This preliminary technical validation study allows TRACES pharmacobiological trial to be conducted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02797119. Registered on 13 June 2016.