Strengths and limitations
The main selection criterion was PPH following vaginal delivery requiring uterotonic prostaglandin administration as per French guidelines 17,24. The hypothesis was that patients with persistent PPH would present a significant decrease in plasma fibrinogen levels. We therefore expected that these patients would benefit from early fibrinogen supplementation, before their plasma fibrinogen level results became available. However, we could not to recruit enough patients with an ongoing coagulopathy (as shown by changes in plasma fibrinogen levels in Figure 2) and in whom fibrinogen concentrate was expected to be beneficial. We encountered similar issues to those reported in the Danish and UK studies 17,24 . This is partly due to the difficulty of including and obtaining informed consent from subjects with massive and rapid ongoing bleeding.
Moreover, the globally improved management of PPH, at least in developed countries, also explains why the FIDEL study failed to demonstrate any benefit from early systematic fibrinogen administration. Nowadays, management not only involves timely decision-making shared by obstetricians and anaesthesiologists, but also the early use of TXA and intrauterine balloon tamponade, routinely applied after prostaglandin administration 5,7,25,26. Following a pragmatic approach to optimize their security (including the possibility of administering rescue fibrinogen in both groups), all patients were treated with standard procedures as per guidelines and as decided by the investigators. We may have in fact correctly selected and randomized patients at risk for severe PPH, but at a very early stage. Postpartum haemorrhage was rapidly controlled and, in most cases, with no significant hemodynamic disorders, no coagulopathy, and subsequently normal fibrinogen levels. Very few invasive haemostatic procedures were required, and the quite common use of balloon tamponade in both groups (29%) may be regarded as an evolution of practices that dramatically reduces embolization and hysterectomy rates 27. This change occurred during the course of the FIDEL study.
Recruitment of potentially severe but rapidly controlled PPH (due to a strong incentive to include patients as early as possible), and optimized management are the main likely explanations for the absence of a fibrinogen supplementation effect. Our protocol did not include waiting for plasma fibrinogen assay results prior to IMP administration. By contrast, older studies reported substantial delays from inclusion to measurement of plasma fibrinogen prior to fibrinogen administration during which important blood loss and haemodilution occurred, and fibrinogen levels dropped significantly 9,11. We therefore failed to demonstrate a benefit from the “pre-emptive” administration of fibrinogen to patients at risk of severe PPH.