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8
PATHOPHYSIOLOGY OF POSTPARTUM HEMORRHAGE
AND THIRD STAGE OF LABOR
R.-U. Khan and H. El-Refaey
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POSTPARTUM HEMORRHAGE
such mechanisms are neural or neurohormonal. both to prevent and to treat postpartum hemor-
Two classes of hormones have been implicated rhage. At the same time, however, therapeutic
in third-stage uterine contractility, namely oxytocic agents used to augment labor are
oxytocin and prostaglandins. sometimes associated with uterine atony in
the third stage. In this latter circumstance, the
non-pulsatile administration of these agents
Oxytocin
may be leading to down-regulation of oxytocin
Interest in the role of oxytocin in the third stage receptors, as has been demonstrated in in vitro
has been partly motivated by the long-standing studies15. Despite the acknowledged therapeu-
experience with therapeutic oxytocin to prevent tic role of oxytocic agents in the third stage of
postpartum hemorrhage. Broadly speaking, labor, the true physiological role of oxytocin in
oxytocin causes increased uterine contractions the third stage remains unclear. It appears to
by acting on myometrial oxytocin receptors. have an inconsistent or paradoxical relationship
However, research has failed to show a clear with the third stage.
and simple relationship between physiological
oxytocin action and third-stage events for a
Prostaglandins
number of reasons. Oxytocin assays are notori-
ously unreliable, because the decidua synthe- Prostaglandins are potent stimulators of
sizes its own oxytocin. As a result, plasma levels myometrial contractility, acting via cyclic AMP-
do not reflect oxytocin concentrations at the mediated calcium release. The therapeutic use-
myometrium. Moreover, plasma oxytocin levels fulness of prostaglandin agents in postpartum
take no account of the density of myometrial hemorrhage lends credence to the possibility
oxytocin receptors, which has been shown to of a physiological role for prostaglandins in
participate in a complex control mechanism the third stage of labor. The prostaglandins
with oxytocin itself and other factors. Finally, involved in uterine contraction are produced in
oxytocinase, a plasma enzyme, denatures decidual tissue, placental tissue and fetal
oxytocin before it reaches its site of action11. membranes16. The uterotonic action of prosta-
During labor, oxytocin is released in a glandins does not depend on gestation. There
pulsatile manner, and both the pulse frequency are many classes of prostaglandin; the two
and duration increase12. Exactly what triggers classes implicated in uterine contraction are
the pulsatile oxytocin release is presently PGE2 and PGF2α.
unclear. Ferguson speculated that uterine Several observers have noted that large
stretching of the cervix stimulates oxytocin amounts of prostaglandin are released in the
release, leading to uterine contractions13. This third stage of labor. In an elegant experiment,
phenomenon so far has not been demonstrated Noort and colleagues measured plasma levels of
in humans, but there may be significant pres- prostaglandin metabolites during and up to 48 h
sure changes on adjacent pelvic organs and the after labor17. PGF2α levels reached their maxi-
vagina which result in neurological stimulation. mum and started to decline within 10 min after
A pulse of oxytocin does not necessarily placental separation (Figure 2). The subsequent
correspond to a uterine contraction, and some rapid decline in these levels suggested that the
women do not experience a rise in plasma prostaglandins arise from either necrosis/cellu-
oxytocin after the delivery of the baby14. More- lar disruption at the placental site, or from the
over, it is not necessary to have an oxytocin fetal membranes. The latter are known to be a
pulse in order to deliver the placenta and major source of prostaglandins. In vitro experi-
achieve hemostasis. Additional methods of con- ments have shown that intrapartum amniotic
trol must be involved. Whereas it is known that fluid triggers prostaglandin synthesis in fetal
myometrial oxytocin receptor density increases membranes. The ‘active agent’ in the amniotic
during pregnancy and labor, the precise con- fluid remains unknown16; however, these obser-
trols of this up-regulation are unknown15. vations are thought to reflect the active role of
For many years, synthetic oxytocic agents prostaglandins in securing hemostasis by way of
have been successfully used in the third stage myometrial contraction in the third stage.
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1000
750
PGF2 (pg/ml)
500
250
0
I II III 1 2 3 4 5 6 12 24 36 48
Time
Figure 2 Plasma PGF2α levels (pg/ml; mean ± standard equivalent of the mean). (I) In early labor and at
full dilatation; (II) at delivery of the fetal head; (III) at placental separation and up to 48 h after placental
separation (Noort et al., 198917)
The interaction between prostaglandins and Before and after delivery, subtle changes take
endogenous or therapeutic oxytocin in the third place in both coagulation factors and fibrino-
stage is not well understood. Numerous animal lysis agents. Plasma concentrations of clotting
experiments have demonstrated interactions factors increase not only during pregnancy but
between prostaglandins and oxytocin at luteo- also after delivery, which suggests a hyper-
lysis, initiation and maintenance of pregnancy, coagulable state20. However, after placental
and possibly at onset of labor18. However, ther- separation, the fibrinolytic potential of the
apeutic oxytocic agents used in the third stage maternal blood also increases, and this tends to
do not appear to have a significant effect on reduce the potential of blood to clot21.
prostaglandin metabolite concentrations19. Fur- These conflicting changes are difficult to rec-
ther studies are required to better understand oncile and are further complicated by changes
from where the prostaglandins arise, and what in platelet activity before and after delivery.
controls their release. However, there are indications that an inflam-
In the next few years, it is likely that matory response arises at the placental bed after
misoprostol, a prostaglandin E1 analogue with placental delivery22. Such a response would pro-
uterotonic properties, will play an increasing mote local coagulation. This finding is impor-
role in the management of the third stage, as it tant in terms of evolutionary advantage, because
is both cheaper and more thermostable than it allows prevention of hemorrhage at the pla-
existing agents. cental site, while elsewhere (particularly in deep
pelvic and leg veins) thrombi are less likely to
persist, due to the increased fibrinolysis.
Coagulation
von Willebrand disease (factor VIII defi-
Many standard obstetric text books provide ciency) is an important example of a coagulo-
only the vaguest of suggestions that coagulation pathy which can result in increased risk of
at the placental site represents an important postpartum hemorrhage. This is especially true
hemostatic mechanism. Whilst this is certainly in the disease variant featuring factor VIIIc defi-
true, the exact pathway(s) involved are unclear. ciency. In many ways, von Willebrand disease
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POSTPARTUM HEMORRHAGE
mimics a platelet adhesion dysfunction, and time. Whilst uterine atony is responsible for
indeed the only aspect of hematological 75–90% of primary postpartum hemorrhage,
hemostasis after placental delivery which can be traumatic causes of primary postpartum hemor-
emphasized with any certainty is the formation rhage (including obstetric lacerations, uterine
of platelet plugs at arterioles. Postpartum inversion and uterine rupture) comprise about
hemorrhage rates in von Willebrand’s disease 20% of all primary postpartum hemorrhage (see
are in excess of 15%, and it has been suggested Chapter 9). Significant but less common causes
that this hemorrhage is largely preventable by of postpartum hemorrhage include congenital
minimizing maternal trauma at delivery and giv- and acquired clotting abnormalities, which
ing prophylactic treatment with desmopressin comprise around 3% of the total24. Uterine
(DDAVP)23. atony is responsible for the majority of primary
In summary, the hemostatic mechanisms postpartum hemorrhage originating from the
during and after placental separation probably placental bed. Although the most important
involve the contraction of muscle sheaths around risk factor is a previous history of atonic post-
the spiral arteries, leading to platelet plug forma- partum hemorrhage (relative risk 3.3)25, many
tion, retraction of the uterus causing mechanical other important risk factors often found in
occlusion of arterioles facilitating platelet plug combination.
formation, and the activation of both the clotting Failure of the uterus to contract may be
cascade and fibrinolysis. As of this writing, many associated with retained placenta or placental
of these events are vague assumptions rather than fragments, either as disrupted portions, or more
demonstrated fact, as third-stage physiology rarely a succenturiate lobe. The retained mate-
research has been grossly neglected. The fact rial acts as a physical block against strong uter-
that for decades effective treatments have been ine contraction, which is needed to constrict
available for postpartum hemorrhage in the placental bed vessels, but, in most cases, dys-
developed world has acted as a true disincentive functional postpartum contraction is the pri-
for novel work and ideas. It is tragic that the third mary reason for placental retention. It is more
stage of labor, the most dangerous moment of likely for the placenta to be retained in cases of
pregnancy, is so poorly understood. atonic postpartum hemorrhage, and so the con-
traction failure often becomes self-perpetuating.
The reasons for this contractile dysfunction are
PATHOPHYSIOLOGY OF
unknown. The exception is uterine fibroids,
POSTPARTUM HEMORRHAGE
where the source of distension cannot be
Although most of the physiological processes in removed by uterine contraction, and must
the third stage of labor remain unclear, they therefore cause the atony. However, the uterus
broadly help to explain the etiology of atonic does not even have to be distended during the
postpartum hemorrhage. In this section, the third stage for contractile dysfunction to occur.
etiology and accompanying pathophysiology Distension prior to delivery, which occurs with
will be discussed. multiple pregnancy and polyhydramnios, also
affects the ability of the uterus to contract
efficiently after delivery, and is thus another
Uterine atony
risk factor for atonic postpartum hemorrhage.
The most common cause of postpartum hemor- When postpartum hemorrhage occurs fol-
rhage is uterine atony, i.e. failure of the uterus lowing an antepartum hemorrhage, the scenario
to contract. Primary postpartum hemorrhage is particularly difficult since there have been two
due to uterine atony occurs when the relaxed episodes of blood loss. A rare but serious com-
myometrium fails to constrict these blood plication of abruption is extravasation of blood
vessels, thereby allowing hemorrhage. Since into the myometrium, known as a Couvelaire
up to one-fifth of maternal cardiac output, or uterus, which impairs the physiological uterine
1000 ml/min, enters the uteroplacental circula- contraction/retraction hemostatic process.
tion at term, postpartum hemorrhage is capable However, the relationship between the extra-
of exsanguinating the mother within a short vasation process and uterine dysfunction is
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POSTPARTUM HEMORRHAGE
the vicinity of the uterine scar with secondary because they tend to be relatively less
trophoblast invasion of the myometrium. Uter- amenable to medical treatment and sometimes
ine scarring is also known to be associated with necessitate radical surgical intervention, such as
an increased risk of scar dehiscence, febrile mor- hysterectomy.
bidity and other factors30. Thus the scar is clas- Whereas knowledge of the ultrastructure
sically considered to be a ‘weak area’. Scarring of placental bed musculature is lacking with
of muscle results in the normal tissue being regards to the upper segment, it is virtually non-
replaced by fibrous tissue. Intrauterine retrac- existent for the lower segment. New research
tion forces induced during labor tend to thin out into this area is urgently needed, because all
the lower segment, and these forces stretch the non-surgical therapeutic modalities for post-
scar to the point of rupture. Uterine rupture is partum hemorrhage involve enhancement of
not considered predictable31, but is more likely uterotonicity and, in the absence of sufficient
with each Cesarean section. Although poorly myometrium, they will simply not work. We
described in the literature, our personal clinical hypothesize that lower segment placentation/
experience suggests that, with each ensuing surgery leads to structural and thus functional
Cesarean section, the entire lower segment changes in the muscle histology. Thus, we
often seems to become thinner. Indeed, the envisage a new, clinically important class
lower segment may take on a translucent of postpartum hemorrhage, ‘lower segment
quality. This appearance is not limited to the postpartum hemorrhage’. This new subclass
scar itself. It is possible that the ‘weak scar’ will be best managed by new protocols which
in fact represents a generalized lower segment address the features specific to lower segment
weakness induced by previous surgery. involvement.
Clinical experience also suggests to us that it
is not enough to assume that postpartum hem-
orrhage is more common with lower segment References
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