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INTRODUCTION:
Amniotic fluid embolism is a serious complication of pregnancy
with a high mortality. Despite its rare occurrence, the syndrome
of amniotic fluid embolism (AFE) is well known to obstetricians.
Given its sudden and dramatic presentation and its often
devastating consequences, practitioners given the responsibility
of caring for the unfortunate woman with AFE remember the
experience in great detail for a long time thereafter. A leading
cause of maternal mortality in industrialized countries, AFE
remains an enigma. Understanding of its etiology and pathophysiology is incomplete, and the criteria used to make its
diagnosis are controversial. Furthermore, despite advances in
the care of critically ill patients, no management interventions
have been found to improve the survival or long-term outcome of
women with AFE. Gregory Locksmith’s recent account of this scary
condition gives vital insight in this matter and this article
draws vital points from the same with due appreciation.
Meyer first described the syndrome of AFE in 1926. It
became an established clinical entity in 1941 after Steiner and
Luschbaugh published a maternal mortality case series that
included eight women who had squamous cells and mucin,
presumably of fetal origin, within their pulmonary vasculature.
The authors postulated that these histologic findings formed the
basis of a clinical syndrome characterized by sudden shock and
pulmonary edema during labor that ultimately resulted in
maternal death.
The hundreds of case reports that have followed Steiner and Lush
Baugh’s landmark series have marginally increased understanding
of this syndrome. Because AFE is so uncommon, no single
institution has sufficient experience to assess risk factors,
determine the pathophysiology and clinical course, or evaluate
management strategies. Clark and co-workers established a
national registry for AFE to assist in understanding they
syndrome and published the results in 1995. The strength of the
report lies in its relatively large size (46 cases), its
stringent entry criteria, and its analysis of 121 different
clinical factors. The report confirmed the high mortality rates
associated with AFE but challenged several previously held
beliefs about the etiology, risk factors, and pathophysiology.
EPIDEMIOLOGY AND RISK FACTORS:
The incidence of AFE has been reported to range from 1 in 8000
to 1 in 80,000 deliveries. It is responsible for 10% of all
maternal deaths in the United States. The syndrome typically
occurs during labor, soon after vaginal or cesarean delivery, or
during second-trimester dilatation and evacuation procedures. In
the national registry 70% of the cases occurred during labor,
19% were recorded during cesarean delivery, and 11% occurred
after vaginal delivery. All of the cases noted during cesarean
section had their onset soon after delivery of the infant.
The analysis of the national registry did not find any maternal
demographic risk factors that predisposed gravid as to AFE.
Previous cases reports of AFE described the syndrome as commonly
occurring after long, hard, and tumultuous labor. These
descriptions led many investigators to believe that oxytocin use
and antecedent uterine hyperstimulation increased the risk for
AFE: however, the registry found that these two factors were no
higher among women diagnosed with AFE than in the general
population. Although uterine tetany often occurs concomitantly
with the initial syndrome of AFE, it is more likely a response
to profound tissue hypoxia rather than the cause of entry of
amniotic fluid into the maternal blood stream. Pang and Watts
recently studied the risk of CS done under spinal anesthesia and
suggested that this could be one of the risk factors. They
examined the sympathetic blockade as a basis of this risk.
However this requires to be carefully validated.
A factor that is consistently related to the occurrence of AFE
is a tear in the fetal membranes. Of the women included in the
national registry, 78% had ruptured membranes. Two thirds of
these women had artificial rupture and one third had spontaneous
rupture. In 13% of cases, maternal collapse occurred within 3
minutes of amniotomy or insertion of an intrauterine pressure
catheter. Placental abruption was confirmed in another 13% of
the women. These findings suggest that certain conditions may
permit exposure of fetal tissue to the maternal vasculature and
may increase the risk for AFE.
CLINICAL
MANIFESTATIONS:
Amniotic fluid embolism classically presents as the sudden onset
of dyspnoea and hypotension followed shortly by cardio
respiratory arrest. Women may exhibit cyanosis or mental status
changes from extreme hypoxemia. Arterial blood gas analysis
often demonstrates a dramatic gradient between the alveolar and
arterial partial oxygen pressure (PO2). In the analysis of
the national registry, the most common presenting signs were
seizure like activity (30%), dyspnoea (27%), fetal bradycardia
(17%), and hypotension (13%). The initial episode, if survived,
is usually followed by disseminated intravascular coagulation
(DIC) that can result in exsanguination. Hypo-perfusion of the
heart, lungs, and kidneys may start a vicious cycle culminating
in multi-organ system failure. Primary lung injury can lead to
adult respiratory distress syndrome (ARDS) and secondary
oxygenation deficiency. Permanent brain dysfunction can occur.
In any individual patient, the hemodynamic, pulmonary, or
hematological disturbances can dominate the presentation or be
entirely absent. Kim and colleagues have demonstrated occlusion
of branch retinal arterioles in the process of embolism.
The physiologic disturbance responsible for the extreme hypoxia
is not well characterized but may be an initial and transient
pulmonary vasospasm. An increase in pulmonary vascular
resistance has not been well documented in humans. In a goat
model, Hankins and co-workers demonstrated an initial and
transient rise in pulmonary and systemic vascular resistance
along with myocardial depression. These disturbances were
especially prominent when the injectate included meconium.
Because this initial hemodynamic response is transient, it may
resolve before instruments and monitors can be set in place to
document it in clinical situations.
Systemic hypotension is the most prominent hemodynamic
alteration documented in humans and results principally from
severe left sided heart failure. The etiology of the depressed
cardiac function is unclear. Proposed mechanisms include a
direct depressant effect of amniotic fluid elements on the
myocardium and myocardial ischemia resulting from coronary
artery vasospasm or global hypoxia. In the report on the
national registry, 40 of the patients (87%) sustained cardiac
arrest, 12 of whom were successfully resuscitated. Four other
women experienced serious dysrhythmias without frank arrest.
The coagulopathy that is part of the AFE syndrome ranges from
minor disturbances in laboratory coagulations studies to severe
DIC. Any or all of the following hematologic laboratory
abnormalities may be present: elevated fibrin split products of
D-dimer products, decreased fibrinogen, thrombocytopenia, and
prolonged partial thromboplastin and prothrombin times. The
exact incidence of coagulopathy with AFE is unknown, but it is
common among those who survive the initial event. On rare
occasions, it is the only manifestation present. The incidence
of coagulopathy in the analysis of the national registry was
83%.
The etiologic mechanism of the coagulopathy is obscure, In vitro
studies and animal models have yield inconclusive results. The
mechanism may be similar to that proposed for the coagulopathy
related to severe placental abruption. In this model, the
maternal immune system recognizes fetal antigens that have
gained entrance to the maternal blood stream. The fetal
antigens, possibly trophoblastic tissue, exert potent
thromboplastin like effects, initiating the extrinsic pathway of
the clotting cascade. Amniotic fluid contains pro-coagulants
that may be capable of initiating intravascular clotting.
Maternal survival rates associated with AFE range from 20% to
40%. In the AFE registry, the overall survival rate was 39%,
with 15% of patients surviving neurologically intact. A total of
28 patients in the finding were that the dismal maternal outcome
seemed to be independent of the clinical setting or the
treatment rendered. No difference in survival was noted between
registries patients diagnosed in tertiary care centers versus
rural hospitals. Even with recent advances in critical care, the
prognosis is not substantially better than the reported years
ago. Most patients in the registry died of refractory
cardiopulmonary arrest. In six patients, life support was
withdrawn after the diagnosis of brain death. Other causes of
death reported to be associated with AFE are exsanguination,
ARDS, and multiple organ failure.
The results of the national registry suggest that cardiac
arrest, meconium-stained amniotic fluid, and the presence of a
dead fetus before the event may be associated with a relatively
poor prognosis. Of the six women who did not sustain cardiac
arrest, four (67%) survived and two (33%) maintained baseline neurologic function. Eight registrants had meconium staining
noted before the event, two of whom also had a dead fetus. None
of these women survived neurologically intact. A trend was also
noted between meconium-stained fluid and a shorter time from
initial symptoms to cardiac arrest. Although none of these
associations were statistically significant, they suggest that
substances in meconium or occurring with a dead fetus may be
particularly inclined to initiate a more severe reaction.
In the national registry, 22 to 28 patients (79%) who became
symptomatic while the fetus was alive in utero delivered
surviving neonates: half of these fetuses were
neurologically intact. Usually, the infant demonstrates a
profound respiratory acidosis at birth. Arterial cord blood was
available for analysis for 11 neonates in the registry who were
delivered after maternal collapse. All samples demonstrated a pH
of less than 7.0. The mean pH was 6.79 and the low was 6.4
Interestingly, all of the infants who had cord blood analysis
performed survived neurologically intact despite severe acidosis
at birth.
The fetal survival rate after maternal cardiac arrest was 68% in
the registry, with half of survivors having normal neurologic
outcomes. The registry showed a correlation between short
cardiac arrest to delivery interval and neurologically intact
survival, but the numbers were too small to demonstrate
statistical significance.
PATHOGENESIS:
Animal and laboratory experiments have improved understanding of
the pathophysiology of AFE. In most of these investigations,
observations have been made of the physiologic effects of
amniotic fluid or other fetal substances in animal models.
Although the results conflict, most of the series demonstrate
adverse hemodynamic effects of this condition. Occasionally,
amniotic fluid injection resulted in death of the animal. The
results of these studies need to be interpreted with caution
because the experimental conditions often varied from true
clinical situations. The injections used in some of the studies
contained varying degrees of particulate matter. Some injections
were filtered, whereas others were particulate-enriched. On
occasion, the amniotic fluid source came from a different
species from the one being studied. Many of the models were
nonpregnant.
Although the results from any animal model experiment can never
be extrapolated directly to humans, the results of the animal
studies and the apparent association among AFE and abruptio
placentae, intrauterine pressure catheter placement, and
amniotomy suggest that this syndrome is initiated by maternal
exposure to fetal tissue. Although AFE was previously postulated
to result from forcible entry of a large volume into the
maternal blood stream under pressure, the majority of evidence
does not support this contention. The presence of uterine
contractions is also not a prerequisite for the occurrence of
AFE. AFE has occurred during first-trimester suction curettage
abortion, a time when the total volume of amniotic fluid is
relatively low. Therefore, the AFE syndrome could result from
simple exposure to even small volumes of fetal tissue, could
result from simple exposure to even small volumes of fetal
tissue, which under the right circumstances, trigger a severe
physiologic reaction.
Tissue factor (TF) is known to be present in a high
concentration in amniotic fluid. The main question of this study
is whether tissue factor pathway inhibitor (TFPI), a natural
inhibitor of TF, is present in amniotic fluid. Uszynski M and
colleagues recently studied 28 women with normal pregnancy
course, and at the first stage of termed labour. Fifteen
non-pregnant women were the control group. TF and TFPI were
studied by an immuno-enzymatic method (ELISA). The level of TFPI
in amniotic fluid was 38.7% of that in blood plasma
(16.81+/-5.34ng/ml versus 43.41+/-18.70ng/ml, P<0.001), while
the level of TF in amniotic fluid was 44.8 times higher than in
blood plasma (9995.93+/-8533.11pg/ml versus 252.66+/-28.84pg/ml,
P<0.001). They concluded that (i) amniotic fluid contains TFPI
(ii) It is reasonable to assume that the intrusion of amniotic
fluid into the blood stream may influence the plasmatic TFPI-TF
equilibrium resulting in intravascular blood coagulation. This
study can have a far-reaching bearing on the understanding of
the pathology of AFE.
Some evidence indicates that fetal tissue transfers to the
maternal blood stream frequently in the absence of the clinical
symptoms of AFE. Perhaps, AFE is initiated only after an
immunologic barrier has been breached by fetal antigens to which
the pregnant woman is susceptible, In fact, the pathogenic, hemodynamic, and laboratory manifestation of the AFE syndrome
are similar to those of anaphylactic and septic shock. All of
these disorders involve the entrance of a foreign substance into
the circulation, the release of endogenous mediators, and
profound myocardial depression resulting in hypotension and
reduced cardiac output. Consumptive coagulopathy, a common
consequence of septic shock, is one of the hallmarks of the AFE
syndrome. Interestingly, Clark and co-workers noted that 41% of
the patients in the AFE national registry had a history of
either drug allergy or atopy. One of the conclusions drawn by
the investigators in the national registry analysis was that the
pathophysiologic events noted in the subjects were more
consistent with septic shock and anaphylactic shock than with an
embolic process, and it was proposed that the term amniotic
fluid embolism be changed to anaphylactic syndrome of pregnancy.
Despite the similarities between these disorders, important
differences exist. Fever, which is a hallmark of sepsis, is not
a typical manifestation of AFE. An urticarial rash often
develops in patients sustaining anaphylactic reactions, whereas
cutaneous manifestations are not part of the AFE syndrome.
Furthermore, bronchospasm and upper airway swelling are
hallmarks of most anaphylactic reactions. Although five patients
in the national registry were noted to be difficult to ventilate
and although wheezes were auscultator in another patient,
obstructive ventilatory defects are not considered to be part of
the AFE syndrome. An anaphylactic reaction generally results
from re- exposures to an antigen to which an individual has
previously been sensitized, whereas AFE occurs in primigravidae
as well as well as in multi-gravidas.
An important step in learning more about the pathogenesis of AFE
is determining the roles of various cellular mediators. The
release of histamine, bradykinins, cytokines, prostaglandins
(PG), Leukotrines, thromboxane, and other mediators may trigger
the hemodynamic and hematologic alterations. Clark has
postulated that arachidonic acid metabolites may be responsible
for the physiologic disturbances seen in humans during AFE.
Azegami and colleagues injected rabbits with amniotic fluid
containing leukotriene activity and found that the animals often
died, whereas rabbits pretreated with an inhibitor of leukotriene synthesis survived. Work of Kitz, Miller and Lucas
suggest that PGF2 which is detectable in amniotic fluid only
during labor, has a prominent pathogenic role. They reproduced
clinical manifestations of AFE in cats after systemic injection
of PGF and amniotic fluid from women in labour, whereas the same
effects were not noted when the animals were injected with fluid
from women who were not noted when the animals were injected
with fluid from women who were not in labor.
Benson and colleagues recently evaluated the potential role of
immunologic mechanisms that involve mast cell degranulation
(anaphylaxis) or complement activation in the mechanism of
amniotic fluid embolism. They found that serologic
findings suggest a role for complement activation in the
mechanism of amniotic fluid embolism. Laboratory data from this
series did not implicate mast cell degranulation (anaphylaxis)
in the pathophysiology of the disease.
Endothelia, which are associated with many different pathophysiologic processes, may also be responsible for the
hemodynamic alterations seen in AFE. Endothelin is a potent
constrictor of human coronary and pulmonary arteries and of
human bronchi. Increased endothelia levels were noted in
experiments performed on rabbits and human endothelial cell
cultures after the administration of human amniotic fluid. This
increase was most prominent with meconium-stained fluid and was
not elicited in subjects injected with saline.
DIAGNOSIS:
The finding of fetal squames in the maternal pulmonary
circulation, once considered pathognomonic, is neither specific
nor sensitive for the diagnosis of AFE. Squamous cells have been
retrieved from the pulmonary vasculature of patients being
monitored for conditions other than AFE. Moreover, the
differentiation between maternal and fetal elements retrieved
from the maternal circulation is problematic. Various stains
such as Alcian blue, Atwood, Giemsa, Wright, oil red O, and
Sudan black may provide greater sensitivity for detecting fetal
debris than routine hematoxylin- eosin staining, however, data
concerning, the accuracy of any of these methods are lacking. Of
the 22 patients in the national registry on whom autopsy was
performed, 16 (73%) demonstrated cellular debris of presumed
fetal origin in the pulmonary vasculature. Histologic
examination of pulmonary artery catheter blood was performed in
eight patients, of whom four (50%) had fetal elements
identified.
A Japanese group has identified fetal mucin in the maternal
pulmonary vasculature using the monoclonal antibody TKH-2. This
technique may improve the ability to differentiate between fetal
and maternal elements; however, its accuracy has not been
determined. One prospective autopsy study demonstrated that four
of four patients with clinically diagnosed AFE had positive
TKH-2 immunoassaying of pulmonary vasculature sections.
Additionally, TKH-2 staining was negative in four of four women
who died of other causes during labour. Diagnosing AFE with
TKH-2 immunoassaying in living patients is possible using blood
from the maternal pulmonary circulation, however the results
from such specialized tests are unlikely to be available during
the acute episode or useful for clinical management.
In all circumstances, the diagnosis of AFE should be made on the
basis of clinical presentation and laboratory findings. Patients
must fulfill four clinical criteria based on physiologic signs,
laboratory values, and the clinical setting in the absence of
any other explanation for the manifestations observed. These
clinical criteria are as follows:
Acute hypotension or cardiac
arrest
Acute hypoxia
Coagulopathy
Absence of other explanations for the clinical manifestations
observed.
Onset during labour or within 30 minutes of delivery or surgical
abortion.
Other diagnoses to consider in a patient presenting with signs
and symptoms of AFE include hemorrhagic shock, placental
abruptions, sepsis, pulmonary embolism, aspiration of gastric
contents, and eclampsia. Less common conditions include
anaphylaxis, toxic reactions to anesthetic agents, myocardial
infarction, air embolism, and cerebral hemorrhage.
MANAGEMENT:
No form of therapy has been found to improve outcome
consistently in women with AFE: therefore care is supportive.
The initial management objective is to maintain adequate
oxygenation and vital organ perfusion. Cardiopulmonary
resuscitation is necessary for patients with cardiac arrest.
Oxygen should be provided at a high concentration (100%).
Patients who are unconscious require endotracheal intubation.
Volume replacement with isotonic crystalloid solution is a first
line therapy for maintaining blood pressure.
Patients who survive the initial insult are at high risk for
heart failure, ARDS, and DIC. Patients who demonstrate
persistent hypotension despite adequate volume expansion should
be treated with inotropic agents such as dopamine or dobutamine.
A rule or thumb for supporting critically ill obstetric patients
is to maintain systolic blood pressure above 90mm Hg, the PaO2
above 60 mm Hg, the arterial oxygen saturation above 90%, and
the urine output greater than 25 ml./hour. After the correction
of hypotension, fluid therapy needs to be guided gently to
achieve the optimal balance between maintaining blood pressure
and preventing pulmonary edema and ARDS. Information derived
from a pulmonary artery catheter usually is valuable in guiding
hemodynamic management.
The therapy for coagulopathy causing active bleeding is
replacement of blood components. Platelets, fresh frozen plasma,
cryoprecipitate, and packed red blood cells may all be necessary
to correct deficiencies. Occasionally, uterine atony develops
and results in hemorrhage. Intravenous oxytocin and
intramuscular PGF are the preferred therapeutic agents if this
condition arises. Kaneko and colleagues have used
hemodiafiltration for these cases getting good results.
The fetal condition often deteriorates in women in whom AFE
develops during pregnancy. After 24 weeks gestation, continuous
and watchful monitoring of fetal heart rate is essential.
Profound fetal academia often develops with maternal collapse,
and early delivery may improve the neonatal prognosis. The
performance of cesarean delivery in an unstable patient is
fraught with pitfalls therefore management must be
individualized. Although the primary responsibility of the
obstetricians is to ensure the health and life of the mother,
intervention on behalf of the fetus is appropriate in certain
instances.
If the patient with AFE sustains cardiac arrest, her chance of
neurologically intact survival is poor. Delivery may actually
improve the likelihood of success of the resuscitation.
Relieving uterine compression of the inferior vena cava may
improve cardiac output by increasing preload. Although never
demonstrated in practice, the theoretical maternal benefits and
probable neonatal benefits of immediate delivery seem to
outweigh the risks. Therefore, peri-mortem cesarean
delivery is recommended in pregnant women with AFE and cardiac
arrest.
Other therapeutic options have been proposed. Given the
pathophysiologic similarity with anaphylaxis, immunosuppression
and sympathetic nervous system augmentation have been proposed
as a therapy for AFE. This therapeutic approach has not been
tested, but given the likely catastrophic outcome, it seems
reasonable to try. Clerk and co-workers recommend giving 500 mg
of hydrocortisone sodium succinct intravenously every 6 hours
until improvement of the patient or death occurs. Epinephrine
may also be given. Because many women with AFE have cardiac
arrest, they are likely to have received epinephrine previously
during the resuscitation.
Recently Hsieh Y and colleagues used extra corporeal membrane
oxygenation and intra-aortic balloon counter pulsation as
life-saving therapy for a patient with amniotic fluid embolism.
They are very happy with the results and enthusiastically
suggest that extra corporeal membrane oxygenation and
intra-aortic balloon counter pulsation should be considered to
save the life of a patient with amniotic fluid embolism and left
ventricular failure unresponsive to medical therapy.
CONCLUSION:
Fortunately, AFE is rare. Because it occurs so infrequently and
because studies in animal models cannot reproduce accurately the
physiologic and clinical alterations noted in humans, its
pathogenesis remains an enigma. Based on clinical observations,
AFE is similar in presentation to septic and anaphylactic shock.
From these similarities, a theory has been proposed that the
clinical syndrome of AFE results when fetal antigens breach a
maternal immunologic barrier in susceptible mothers. Maternal
immunologic recognition subsequently triggers the release of
endogenous mediators that are responsible for dramatic
physiologic disturbances.
Most cases of AFE are associated with dismal maternal outcomes
and poor fetal outcomes regardless of the quality of care
rendered. Improved understanding of the molecular pathophysiology of AFE may lead to the development of preventive
measures and more effective and specific treatment. In the
meantime, its occurrence remains unpredictable and unpreventable
and its effects, for the most part, untreatable.
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