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.