Pregnancy and post-partum
red blood cells and plasma while no
information was described on tranexamic
acid and platelets. 25 Mallaiah et al
compared two periods: a massive
transfusion protocol blind strategy during
the first period versus the use of an
adapted dose of fibrinogen concentrate
targeted by point of care diagnosis of
hypofibrinogenemia during the second
period. They demonstrated a significant
reduction in the number of patients
requiring more than 6 RBC and in overall
blood product requirements, in maternal
morbidity but not on hysterectomy rate. 26
The first prospective, double-blind,
placebo-controlled, randomised study
available – the FIB-PPH trial 27 – failed to
show a difference between placebo and
fibrinogen in terms of transfusion rate
(21% compared with 22% in the placebo
group) in normo-fibrinogenaemic
patients (pregnancy and postpartum
reference values: 4.5–5.5g). In this trial,
patients were recruited in case of blood
loss due to manual removal of placenta
(≥500ml), manual exploration of the
uterus after placental delivery (≥1000ml),
or C-section (perioperative blood loss
≥1000ml). Patients were randomised to
receive a single uniform dose of 2g
fibrinogen or placebo systematically, that
is, independently to the laboratory- or the
point of care plasma fibrinogen level.
There were limitations to the FIB-PPH
trial: the patients enrolled were non-
severe and normofibrinogenemic; the
delay to administer the product was long
(more than one hour after the diagnosis)
and the population studied was mostly
surgical bleeding (C-section and genital
tract injury) as opposed to obstetrical
bleeding that leads to coagulation defects.
Bleeding probably stopped in a majority
of patients with a limited need for
transfusion and no need for invasive
procedures in both groups. The selection
of a non-severe population with a low rate
of transfusion was mostly due to the
difficulty in recruiting and obtaining
informed consents during an ongoing
bleeding; the primary endpoint took into
account only the transfusion rate but not
anaemia or haemoglobin drop in
non-transfused patients. Despite the
pioneering nature of the FIB-PPH trial,
the scientific questions on efficacy, safety,
timing and dose of fibrinogen concentrate
in ongoing severe PPH with
hypofibrinogenemia have not yet been
answered. 27
Collins et al have published
a randomised trial hypothesising that an
early fibrinogen replacement, guided by
thomboelastometric test, reduces
transfusion need and bleeding in severe
PPH. 28,29 They enrolled 55 women w ith
hypofibrinogenemia attested by a <12mm
FIBTEM A5 amplitude out of the 663
severe PPHs recruited. The 55 enrolled
patients were blinded to fibrinogen or
placebo. The median (25th–75th centile)
measured blood loss was 1450ml
(1200–1800ml) at enrolment and 1950ml
(1500–2285ml) when the studied
medication was infused. 29
The adjusted incidence rate ratio
(IRR) (95% CI) for the number of
allogeneic units transfused in the
fibrinogen group compared with placebo
was 0.72 (0.3–1.7; p=0.45). In pre-
specified subgroup analyses, subjects who
had a FIBTEM A5 <12mm at the time
of randomisation and who received
fibrinogen concentrate received a median
of 1 (0–4.5) PRBC and had an additional
300ml (100–350ml) blood loss whereas
those who received placebo also received
3 (0–6) units of allogeneic blood products
and had 700ml (200–1550ml) additional
blood loss (NS). There was one
thrombotic event in each group. 29
The authors concluded that infusion
of fibrinogen concentrate triggered by
FIBTEM A5 <15mm did not improve
outcomes in PPH. Pre-specified subgroup
analyses suggested that fibrinogen
replacement is not required if the
FIBTEM A5 is>12mm or Clauss
fibrinogen >2g/l, but an effect below
these levels cannot be excluded.
However, in this trial, as in the data
of Wikkelso et al, 27 the recruitment of the
coagulopathic patients was difficult and
women were excluded if they declined
transfusion, had prenatally diagnosed
placenta accreta, had undergone an
invasive procedure to control bleeding,
or if there was a clinical suspicion of
amniotic fluid embolism. Moreover,
despite a clear protocol design, the use of
FFP was encouraged in both groups and
tranexamic acid was given at
randomisation. This may be responsible
for a confounding effect on bleeding
reduction. 20,21
The ongoing double-blind, placebo-
controlled RCT – the FIDEL trial – aims
to assess the early administration of 3g
fibrinogen concentrates versus placebo in
more severe and ongoing PPH resistant to
the first-line uterotonics. 30 The
recruitment has been prolonged to
achieve inclusion of 462 patients and
a 90% beta risk. FIDEL is an efficacy trial.
The primary efficacy variable is a binary
composite endpoint (failure versus
success). Failure is defined when a patient
loses at least 4g/dl Hb, and/or requires
the transfusion of at least two units of
packed RBCs within 48 hours following
the administration of investigational
medicinal product. The Hb reference level
is defined as the last Hb value recorded
within the third trimester of pregnancy.
To avoid or minimise bias and/or centre
effect, the primary endpoint has been
defined independently of therapeutic
obstetrical interventions and/or clinical
practices such as surgical ligation or
embolisation. All centres currently use
a French guidelines’ algorithm for PPH
management. 31 The secondary objectives
of this trial are to evaluate PPH evolution,
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