The goal of this trial is to determine if postpartum blood loss can be reduced by replenishing coagulation factor XIII (FXIII) at an early stage of postpartum hemorrhage (PPH).

Summary of current body of evidence:

• Morbidity and mortality due to PPH is rising.
• Current guidelines focus on replenishment of fibrinogen as an initial step in the treatment of PPH-related coagulopathy, despite non-conclusive evidence in all prospective trials.
• Trials from other specialties demonstrate a significant impact of FXIII on perioperative bleeding complications; a previous study at the University Hospital Zurich showed that pre-partum factor XIII activity had a strong association to postpartum blood loss.

Therefore, this nationwide, multi-center, randomized, controlled trial in multiple perinatal centers across Switzerland will be conducted. The goal is to determine if postpartum blood loss and PPH-related complications can be reduced by replenishing FXIII.

All participating women receive, according to the national guideline, 1g tranexamic acid (TXA) i.v. in case of PPH (measured blood loss [MBL] ≥ 500 mL) during the pre-study phase. Randomization takes place if bleeding continues and exceeds 700mL. The intervention group then receives FXIII (Fibrogammin®) according to approved dosage in addition to obstetric standard of care treatment for causes of PPH; the control group receives only standard of care treatment.

Postpartum hemorrhage (PPH) is a main reason for maternal mortality and morbidity. PPH, defined by the WHO as blood loss of 500 mL or more within 24 hours after delivery, causes about 30% of maternal deaths worldwide. The internationally observed trend towards increased PPH-related morbidity and mortality is disturbing and demands new strategies in the prevention and treatment of PPH.

Although the most frequent causes for severe PPH are believed to be uterine atony or retained placenta, virtually all cases of severe PPH lead to a disorder of the coagulation system which itself aggravates bleeding.

At the moment, most guidelines on coagulation management during PPH and expert opinions focus on the replenishment of coagulation factor I (fibrinogen) although three out of three randomized controlled trials with early or pre-emptive administration of fibrinogen during PPH were negative.

Based on earlier research, it was hypothesized that coagulation factor XIII (FXIII) might play a significant role in women with increased postpartum blood loss, because of its role in the establishment of blood clot stability and fibrinolytic resistance. This hypothesis was tested in a prospective diagnostic study involving 1300 parturient women at the University Hospital Zurich and showed that pre-partum factor XIII activity had a strong association to postpartum blood loss.

Therefore, this nationwide, multi-center, open-label, randomized controlled trial in major perinatal centers across Switzerland will be conducted. The goal is to determine if postpartum blood loss and PPH-related complications can be reduced by substitution of FXIII at an early stage of PPH.

Irrespective of the answer to the question whether FXIII is effective in the treatment of PPH, this trial will contribute to enhancing the comprehension of coagulopathy in the context of PPH

Inclusion Criteria:

• planned vaginal delivery
• singleton vital pregnancy
• gestational age at delivery >= 30+0 weeks
• maternal weight at admission for delivery <100 kg

Exclusion Criteria:

• Antithrombotic therapy in pregnancy (therapeutic dosage) until admission for delivery (LMWH, UFH)
• diagnosis of preeclampsia (ISSHP classification , eclampsia or HELLP syndrome),
• known history of deep vein thrombosis or pulmonary embolism,
• known diagnosis of bleeding disorder or thrombophilia,
• known thrombocytopenia during second half of pregnancy with thrombocytes < 100 G/L,
• known anemia during second half of pregnancy with Hb<80 g/L,
• known sickle cell disease,
• known malignant tumor(s),
• participation in another study with investigational drug within the 30 days preceding and during the present study,
• inability to follow the procedures of the study, e.g. due to language problems,
• known or suspected non-compliance, drug or alcohol abuse.

Exclusion criteria prior randomization

• Maternal fever ≥39.0°C
• unplanned cesarean delivery is performed,
• Measured Blood Loss remains < 700 mL after administration of 1g tranexamic acid .
• Postpartum hemorrhage due to occult bleeding (intra-abdominal, retroperitoneal, parametric),

The data sharing plan aims to ensure computational reproducibility of all published research findings obtained from data collected in this trial. Each publication will be accompanied by a dedicated compendium containing deidentified individual patient data necessary to independently reproduce the analyses presented in the corresponding publication. Such a compendium also contains information about the computer code that was used to generate figures, tables, and other statistical output. Distribution will be via a data repository following FAIR principles (such as zenodo.org).

At the time of publication

Access will be provided without limitations. Data will be provided to allow independent computational reproducibility of already published results.

The analysis of the primary outcome will be performed using blinded treatment arms.