REVIEW

CURRENT
OPINION Amniotic fluid embolism: update and review
Pervez Sultan a, Katherine Seligman b, and Brendan Carvalho b

Purpose of review
This article reviews our current understanding of amniotic fluid embolism (AFE), specifically the
pathogenesis, treatment strategies, potential diagnostic tests and future therapeutic interventions for AFE.
Recent findings
The incidence and case mortality of AFE varies widely because of heterogeneous diagnostic criteria and
varying reporting mechanisms across the world. Amniotic fluid embolism is thought to be caused by
abnormal activation of immunologic mechanisms following entry of fetal antigens into maternal circulation.
Mast cell degranulation and complement activation may play a role in this anaphylactoid or systemic
inflammatory response syndrome. Development of serum biomarkers and immune-histochemical staining
techniques to aid diagnosis and develop treatments are under development and evaluation. Treatment of
AFE is supportive and directed at treating cardiovascular, pulmonary, and coagulation derangements.
Treatment for coagulopathy (fresh frozen plasma, cryoprecipitate/fibrinogen concentrate, and
antifibrinolytics) should be initiated promptly. Recombinant factor VIIa may lead to increased mortality and
should not routinely be used. C1 esterase inhibitors may be a potential therapeutic option.
Summary
AFE is a devastating obstetric complication that requires early and aggressive intervention with optimal
cardiopulmonary resuscitation, as well as hemorrhage and coagulopathy management. Biomarkers offer
promise to aid the diagnosis of AFE, and immunomodulation may provide future therapeutic interventions
to treat this lethal condition.
Keywords
amniotic fluid embolism, anaphylactoid, pregnancy

INTRODUCTION underreporting (e.g. including maternal hemor-

Amniotic fluid embolism (AFE) or ‘anaphylactoid
syndrome of pregnancy’ [1] is a rare and devastating
obstetric condition, affecting women during labor,
&
delivery, or postpartum [2,3 ]. AFE has also been
described following trauma, cervical laceration, abor-
tion, amniocentesis, and manual removal of the
placenta. In this review, we aim to summarize the
current evidence surrounding the incidence, patho-
genesis, diagnosis, and treatment strategies for AFE.
INCIDENCE OF AMNIOTIC FLUID
EMBOLISM
The definition of AFE varies between countries and
registers throughout the world. Because of this var-
iability in diagnosis and reporting, the true inci-
dence of AFE is unknown. The incidence data of
& &
AFE [4 ,5–15,16 ,17,18] is summarized in Table 1.
National registers and pooled data analyses all have
potential limitations in estimating the incidence
because of inclusion and exclusion diagnostic
criteria that may lead to overreporting or
rhage, diagnostic criteria for more severe cases)
[19]. The incidence of AFE varies according to
reporting methodology used, with lowest estimated
incidence obtained through reviewed and validated
case identification, and highest rates obtained from
retrospective analysis of population discharge data-
bases [6]. Population-based registration studies and
death certificates overestimate AFE because cases are
not retrospectively reviewed to identify and reduce
false-positive diagnoses. Geographic differences in
AFE incidence are also apparent (e.g. North America
is three times higher than Europe) [7]. Accounting
for these limitations, an AFE incidence rate of
a
University College London Hospital, London, UK and bDepartment of
Anesthesia, Stanford University School of Medicine, California, USA
Correspondence to Brendan Carvalho, MBBCH, FRCA, Department of
Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive,
Stanford, CA 94305, USA. Tel: +1 650 861 8607; fax: +1 650 725
8544; e-mail: bcarvalho@stanford.edu
Curr Opin Anesthesiol 2016, 29:288–296
DOI:10.1097/ACO.0000000000000328

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 Amniotic fluid embolism Sultan et al.

[1,7,19,30,32]. Mortality is linked to the disease

KEY POINTS
 The incidence and case mortality of AFE varies widely
because of heterogeneous diagnostic criteria and
varying reporting mechanisms across the world.
 Treatment for coagulopathy (fresh frozen plasma,
cryoprecipitate/fibrinogen concentrate, and
antifibrinolytics) should be initiated promptly.
 Biomarkers offer promise to aid the diagnosis of AFE,
and immunomodulation may provide future therapeutic
interventions to treat this lethal condition.
&
approximately 1 in 40 000 has been proposed [3 ].
The incidence of AFE over time is difficult to assess
because of changing diagnostic criteria and report-
ing. There appears to be no temporal change in total
incidence of AFE in Canada [9] or the UK [4 ],
&
despite concurrent increases in potential risk factors
for the development of AFE [20–23] (Table 2
& &
[2,4 ,5,7,9,10,14,15,17–19,24–27,28 ]).
AMNIOTIC FLUID EMBOLISM-RELATED
MORBIDITY AND MORTALITY
The mortality associated with AFE is estimated to be
between 5 and 15% of all maternal deaths [7,29–31],
with case fatality and perinatal mortality rates
between 11–80 and 7–44%, respectively (Table 1)
&
presentation and severity [3 ], and as with incidence
data, AFE mortality data varies based on diagnostic
criteria and methods utilized for data collection.
Deaths because of AFE appear to have remained
& &
largely unchanged over recent decades [3 ,16 ,33],
despite improved clinician awareness and intensive
care of patients affected by this potentially cata-
strophic condition. Maternal mortality rates have
been quoted at 0.5–1.7 deaths per 100 000 deliveries
in developed countries and 1.8–5.9 per 100 000
deliveries in developing countries [7]. Among sur-
vivors, persistent neurological impairment has been
reported in-between 6 and 61% of women [1,32],
with significant morbidity including cerebral palsy
and ischemic encephalopathy also occurring in
infant survivors [34].
PATHOGENESIS OF AMNIOTIC FLUID
EMBOLISM
The pathogenesis and pathophysiology of AFE are
not fully understood. Early descriptions of AFE in
1926 describe physical obstruction of maternal pul-
monary circulation by fetal material contained
within amniotic fluid [35]. In 1941 after reviewing
the autopsies of 32 women dying from obstetric
shock during labor, Steiner and Lushbaugh [36]
noted squamous cells presumed to be fetal in origin
within the maternal pulmonary arterial circulation.
More recently, an immunological pathogenesis for

Table 1. Incidence data for amniotic fluid embolism

Study Country Incidence of AFEa Case fatality rates (%) Mortality rate per 100 000

Fitzpatrick et al. [4 ] UK (UKOSS) 1.7 (1.4–2.1) 19 (12–29) 0.3

&

Knight et al. [5] UK (UKOSS) 2.0 (1.5–2.5) 20 (11–32) 0.39

Knight et al. [6] UKb 1.9 (1.5–2.4) 19 (11–30) 0.6 (0.3–1.0)
Netherlandsb 6.1 (1.3–4.8) 11 (3–45) 0.4 (0.2–0.8)
USA 5.5 (5.5–5.5) 18 (17–21) 1.3
Canada 6.0 (5.3–7.1) 13 (8–19) 0.8 (0.5–1.2)
Australia 6.1 (5.2–6.9) 14 (9–19) 1.1 (0.7–1.4)
Conde-Agudelo and Romero [7] North America [8–10] 6.6 (6.0–7.19) 13–30 (all data) 1.0–1.7
(Pooled data)
Europe [11–13] 1.9 (1.7–2.0) – 0.5
(Pooled data)
Roberts et al. [14] Australia 3.3 (1.9–4.7) 35 (15–59) 1.2 (0.3–2.0)
Hogberg and Joelsson [15] Sweden 1.2 66 –
Kanayama and Tamura [16 ] Japan 5.0 24.3 –
&

Kramer et al. [17] Canada 3.2 27 0.8

Spiliopoulos et al. [18] USA 4.5 13.3 0.60

AFE, amniotic fluid embolism. UKOSS, United Kingdom Obstetric Surveillance System.
a
AFE incidences quoted as number per 100 000 deliveries with (95% confidence intervals) presented where available.
b
Validated case identification compared with other data obtained from medical coding within this study.

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Obstetrics and gynecological anesthesia
Table 2. Risk factors for the development of amniotic fluid embolism
Maternal factors Fetal factors
AMA > 35 years [4 ,19] Male sex [24]
&
Multiparity [25] Fetal distress [2,7,9,10,17]
Diabetes [2,9,10,17] Fetal macrosomia [15]
Ethnic minority [10,18] Polyhydramnios [15]
Intrauterine death [28 ]
& &
Multiple pregnancy [2,4 ,5,17]
& &
AMA, advanced maternal age.
this disease process has been proposed to explain
inconsistencies in pulmonary blood flow obstruc-
tion, and clinical symptoms such as coagulopathy
and neurological symptoms that are not typical in
pulmonary embolism [31]. Contemporary etiologi-
cal hypotheses suggest an abnormal activation of
humoral and immunological mechanisms, and the
release of vasoactive and procoagulant substances
following entry of fetal antigens and amniotic fluid
into the maternal circulation [7,37]. Fetal and amni-
otic fluid antigens likely stimulate complement acti-
vation, a process that may be expedited by
inflammation during labor and delivery. Sensitivity
may be further increased by damage associated mol-
ecular pattern molecules (DAMPs), complexes
released from injured tissues [19].
Intravascular injection of human amniotic fluid
contaminated by meconium can induce AFE in
rabbits and dogs [36]; however, large volumes of
autologous amniotic fluid introduced into the cir-
culation of monkeys appears to be benign [38]. In
addition, passage of fetal material into the maternal
circulation regularly occurs without causing any
damage to mother or fetus [39]. There may be a
maternal genetic mediated hypersensitivity to fetal
antigens increasing susceptibility to AFE. Fetal con-
tribution toward the disease is also evident; AFE is
more common in women carrying a male fetus and
with rhesus iso-immunization [1], and recurrent AFE
has not been reported in AFE survivors who have
subsequent pregnancies [7,33]. Severity in AFE pres-
entation is likely because of variations in antigen
exposure and individual response [1]. Further under-
standing is needed to identify processes that sensi-
tize or predispose some women to develop AFE
following utero-placental breech and maternal
exposure to fetal material. The development of an
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Obstetric factors
Amniocentesis [25]
Premature rupture of membranes [2,9,10,14,17,26]
Cervical laceration [27]
Labor induction or augmentation [2,4 ,5,9,10,14,17,24,26]
&
Uterine rupture [28 ]
Placenta previa [4 ,27]
Placenta accreta [28 ]
&
Placental abruption [27]
Preeclampsia [2,9,10,17,26]
Eclampsia [2,9,10,17]
Instrumental delivery [2,9,10,17]
Cesarean delivery [2,5,9,10,14,17,26,27]
animal model to replicate the human condition
of AFE is also required to advance our understanding
of this disease.
BIOMARKERS FOR AMNIOTIC FLUID
EMBOLISM
Mast cell degranulation appears to occur in
maternal lungs in fatal AFE cases unlike other
mortal pregnancy conditions [31]. There is also
a greater degree of mast cell degranulation in the
lungs of AFE fatal cases compared with traumatic
controls [40]. Whether mast cell degranulation is a
primary or secondary process resulting from
complement activation is uncertain. Mast cell
degranulation results in release of tryptase, hista-
mine, bradykinin, endothelin, leukotriene, and
arachidonic acid metabolites. Serum tryptase
levels in fatal cases of AFE have been found elev-
&
ated 7–10 times greater than controls [40,41,42 ];
however, one fatal AFE case with evidence of fetal
squames within the pulmonary tree, uterine
vessels, and brain had no increased peripheral
venous tryptase levels taken 1.5 h post-mortem
&
[43]. Busardo et al. [42 ] recently evaluated the
role of immune response relating to AFE, and
concluded that a post-mortem interval within
5 h of death is needed to optimize reliable serum
tryptase detection [44]. Increased tryptase
levels are also associated with anaphylaxis and
should be differentiated from AFE.
The role of complement in the activation of
respiratory distress in AFE was first described in
1982 [45]. Amniotic fluid has been shown to activate
complement in experimental models [46]. Comp-
lement acts through either the classical pathway or
indirectly by the release of anaphylactoid peptides.
Volume 29  Number 3  June 2016

Complement activation products C3a and C5a bind
to the high-affinity immunoglobulin E receptor
expressed on mast cell membranes, which deter-
mine their activation and degranulation [47].
Because immunoglobulin E is not thought to be
the initial mediator resulting in mast cell cascade,
the term anaphylactoid syndrome of pregnancy has
been used instead of amniotic fluid embolism [1,48].
Complement may potentially be a reliable diagnos-
tic biomarker. One fatal case of AFE reported lower
serum C3 and C4 levels than control levels [41],
suggesting complement activation [49]. However,
complement levels may decrease following birth
[39], and comparative levels in critically ill non-
AFE pregnant women have not been well elucidated.
Sialyl-Tn (STN) is a component of meconium
and mucin derived from amniotic fluid. The pres-
ence of STN in maternal serum in patients with
suspected AFE is a direct diagnostic test confirming
that amniotic derived mucin has crossed into the
maternal circulation [50,51]. Low C3 and C4 comp-
lement levels along with high STN have been associ-
ated with complement activation [49]. C5a receptor
staining has been used to aid demonstration of
complement activation [52]. Increased concen-
trations of ZnCP-1 and STN in addition to positive
immune-histochemical staining for C5a receptor
have been reported in stromal cells around pulmon-
ary capillaries and inflammatory cells within the
alveolus in a fatal case of AFE [53]. C1 esterase
inhibitor (C1INH) is a major inhibitor of C1 esterase,
coagulation factor XII activation and kallikrein.
C1INH activity levels in 106 AFE cases demonstrated
a significant decrease in the 21 fatal compared with
nonfatal cases [54], suggesting that C1INH may be
an important factor in the development of coagul-
opathy and may be an important future diagnostic
or prognostic biomarker.
Detection of squamous cells or other debris in
the pulmonary arterial bed of women is no longer
& depressant effects of circulating inflammatory
considered diagnostic of AFE [3 ]. There remains a
need for biomarkers to aid diagnosis and improve
our understanding of the pathogenesis of AFE. The
ideal biomarker would be noninvasive, cheap, easy
to run, sensitive, and specific. Many biomarkers
have been proposed to be of benefit in the
&
diagnosing AFE [40,42 ,50,51,54–70], as seen in
Table 3; however, further work is needed to deter-
mine whether these markers provide adequate
sensitivity and specificity for fatal and nonfatal
AFE. Blood samples and complete autopsy sup-
ported by histological and immune-histochemical
analysis are needed as soon as possible following
death in cases of fatal AFE, to reduce post-mortem
variations and allow for immunological marker
analysis.
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Amniotic fluid embolism Sultan et al.
CLINICAL PRESENTATION OF AMNIOTIC
FLUID EMBOLISM
Clinical signs and symptoms of AFE are outlined in
&
Table 4 [3 ]. The diagnosis of AFE is clinical and is a
diagnosis of exclusion. There is great variability in
the presentation of AFE from classical cardiopulmo-
nary collapse with coagulopathy to minor and sub-
clinical presentations. Subtle and nonspecific
symptoms such as restlessness, agitation, chest pain,
lightheadedness, feelings of distress, transient
hypoxia, and shortness of breath may be present
before cardiovascular collapse [71]. Kanayama and
&
Tamura [16 ] propose that two-thirds of AFE cases
present with atonic bleeding, and only one-third
with cardiopulmonary collapse.
AFE symptomatology evolution can be divided
&
classically into three phases [28 ]. The initial phase is
characterized by transient pulmonary and systemic
hypertension resulting in severe ventilation to
perfusion mismatch, hypoxemia, and potentially
development of right heart failure. The second
phase involves decreased left ventricular function
and development of acute pulmonary edema. The
third phase is characterized by heart failure, worsen-
ing acute lung injury/acute respiratory distress syn-
drome (ARDS), and coagulopathy.
Cardiovascular
Hypotension and cardiovascular collapse are
present in up to 80–90% of patients with classical
&
AFE [3 ]. When transesophageal echocardiogram
data are collected early following development of
cardiovascular instability, there is evidence of pul-
monary hypertension and pulmonary vasospasm
resulting in right ventricular failure [33,72,73]. Left
ventricular failure, ventricular arrhythmias, and/or
sudden cardiac arrest may occur because of ischemic
injury to the myocardium, or secondary to cardiac
&
mediators [3 ].
Respiratory
Acute pulmonary vasoconstriction results in
hypoxia, tachypnea, and respiratory distress/failure.
Milder presentations of AFE may lead to transient
&
hypoxia and dyspnea [1,3 ]. Development of acute
pulmonary edema and ARDS is likely to be multi-
factorial, secondary to localized pulmonary mast
cell degranulation resulting in capillary leak in
addition to left ventricular failure and volume over-
load [19]. Initial pulmonary hypertension may
result in severe ventilation to perfusion mismatch,
and significant dead space physiology.
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Obstetrics and gynecological anesthesia

Table 3. Biomarkers with potential to aid diagnosis of amniotic fluid embolism

Biomarker Relationship AF : MS

Activin A [55,71] " with gestational age 5:1

Brain natriuretic peptide [56,57] " with pulmonary insult 50 : 1
CA125 [58] 100 : 1
C1 esterase inhibitor [54] # activity in fatal AFE compared with nonfatal AFE
Carcinoembyonic antigen (CEA) [59] 200 : 1
Chromogranin A (CgA) [60] Fluctuates during pregnancy 2.5 : 1
Endothelin [61] Elevate in animal models with injection of meconium
Fetal cell identification in mat circulation [62] 50% with AFE had fetal products detected; not
pathognomonic
Insulin-like growth factor binding protein 1 (IGFBP-1) [63] 150 : 1
IL-6, IL-8, sTNFp55 [64] May be useful diagnosing AFE in presence of SIRS
Procollagen type I N-terminal propeptide (PINP) [65] 450 : 1
Pro-early placenta insulin-like peptide (pro-EPIL) [66] " in pathologic conditions 10 : 1
Pro-opiomelanocortin (POMC) [67] " at feto-maternal interface 10 : 1
Prostate-specific antigen (PSA) [68] " from 11 to 21 weeks gestational age,
#after delivery
Sialosyl Tn (STN) [40] Direct diagnostic method confirming AF derived mucin
in maternal circulation. Possibly prognostic in
maternal mortality
Squamous cell carcinoma (SCC) antigen [58] Released from fetal epidermis 410 : 1
Tissue polypeptide-specific (TPS) antigen [68] 10 : 1 to 20 : 1
TKH-2 [50,51] Sensitive at detecting meconium and AF derived mucin
in lung secretions in >90% women with AFE
Zinc Coproporphyrin 1 (ZnCP-1) [69,70] " in AFE
Noninvasive and sensitive

&
Adapted with permission from [42 ]. AF, amniotic fluid; AFE, amniotic fluid embolism; CA125, cancer antigen 125, carcinoma antigen 125; IL, interleukin; MS,
maternal serum; SIRS, systemic inflammatory response syndrome; sTNFp55, tumor necrosis factor-alpha-soluble-receptor p55; TKH-2, monoclonal antibody
directed toward the sialosyl-Tn structure.

Hematological activation [21]. In some patients, atonic bleeding

One of the hallmark features of AFE is intractable
hemorrhage and the development of coagulopathy.
The hematological derangements are likely to
be secondary to mediators within the amniotic
fluid that reach the maternal circulation, or are
the result of systemic inflammatory cascade
and coagulopathy may develop before cardiovascu-
&
lar collapse [16 ]. There is uncertainty if this
coagulopathy is consumptive or because of over-
whelming fibrinolysis. Amniotic fluid contains
procoagulant thromboplastin, urokinase-like plas-
min activator, thrombin–antithrombin complexes,

Table 4. Clinical signs and symptoms of amniotic fluid embolism

Cardiovascular Respiratory Hematologic Neurologic Obstetric

Hypotension Respiratory arrest Coagulopathy Altered mental status Fetal distress

Cardiogenic shock Hypoxemia DIC Seizure Uterine atony
Right heart failure Tachypnea/dyspnea Hemorrhage
Left heart failure Pulmonary edema/ARDS
Dysrhythmias V:Q mismatch
Tachycardia
Cardiac arrest

&
Adapted with permission from [3 ]. ARDS, acute respiratory distress syndrome; DIC, disseminated intravascular coagulation; V:Q, ventilation:perfusion.

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and plasminogen activator inhibitor-1. Both
consumptive coagulopathy (with decreased levels
of fibrinogen, elevated prothrombin and partial
thromboplastin time, decreased platelet concen-
trations, and a precipitous decline in hemoglobin)
as well as hyperfibrinolysis have been demonstrated
in AFE [74,75].
Neurologic
Altered mental state, agitation, seizures, and the
development of encephalopathy are believed to be
secondary to hypoxic insult because of cardiopul-
monary collapse and ventilation to perfusion mis-
match. In AFE survivors, up to 80% may suffer from
permanent neurologic sequelae including hypoxic
brain injury and seizures [76].
Fetal
If a fetus is still in utero during the initial onset of an
AFE, fetal heart rate abnormalities are almost uni-
& partial thromboplastin time, INR, fibrinogen)
versal [3 ]. Acute, prolonged decelerations or late
decelerations may indicate fetal hypoxia and
decreased uterine blood flow secondary to maternal
& in conjunction with other coagulation tests. Labora-
shunting of blood to the central circulation [3 ].
TREATMENT AND MANAGEMENT OF
AMNIOTIC FLUID EMBOLISM
Clinical management of AFE should focus on
aggressive cardiovascular support, treatment of
hypoxia, management of hemorrhage and coagul-
opathy, and delivery of the fetus. In the setting of
maternal cardiac arrest, basic and advanced life
support should be undertaken as outlined by the
recently published scientific statement from the
American Heart Association and consensus state-
ment from the Society for Obstetric Anesthesia and
&
Perinatology [77 ,78]. Key interventions in the
setting of maternal cardiac arrest include manual
left uterine displacement (if the uterus is palpated
at or above the umbilicus) and perimortem cesar-
ean delivery (considered if return to spontaneous
circulation has not been achieved within approxi-
mately 4 min of resuscitative efforts) [77 ,78].
&
These interventions should be implemented to
help relieve aortocaval compression and optimize
cardiopulmonary resuscitation. AFE is a diagnosis
of exclusion, and all other causes of maternal
&
collapse must be considered [77 ,78]. Early and
effective basic and advanced life support is
essential to optimize maternal outcome [77 ,78].
&
Following initial resuscitative measures, most
patients will require continued monitoring and
support in an ICU.
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Amniotic fluid embolism Sultan et al.
Monitoring
Standard monitors (EKG, pulse oximetry, and non-
invasive blood pressure) should be immediately
applied following demonstration of clinical signs
of AFE. Large bore intravenous access above the
diaphragm should be obtained; interosseous or
ultrasound guidance should be considered for diffi-
cult vascular access. An arterial line should be sited
in hemodynamically unstable women. A central
line and pulmonary artery catheter may provide
hemodynamic information and facilitate drug
administration, but placement should not delay
treatment. Transthoracic or transesophageal echo-
cardiography may allow for immediate evaluation
of right and left ventricular function and help guide
resuscitation [33].
Laboratory investigations
Complete blood count, electrolytes, arterial blood
gas, and coagulation studies (prothrombin time,
should be collected. If available, a thromboelasto-
gram may help to guide blood component therapy
tory tests should be repeated frequently in the initial
phase of AFE presentation as coagulopathy may
develop in the first few hours.
Respiratory and cardiovascular support
Oxygen (100% face mask or bag mask) should be
applied to treat hypoxia and prevent further
hypoxic injury. The goal should be to keep oxygen
saturation greater than 90% [21]. Intubation and
advance airway support are often required. As ARDS
and pulmonary edema are often present, ventilation
strategies of low tidal volume, high respiratory rate,
and high PEEP may be beneficial. Initial severe
pulmonary vasoconstriction and ventilation to per-
fusion mismatch have been successfully treated
with inhaled nitric oxide and aerosolized prostacy-
clin in published case reports [72].
Treatment of maternal hemodynamic instabil-
ity and hypotension should be goal-directed with
volume resuscitation, vasopressors, and inotropic
support to optimize preload, contractility, and after-
load as appropriate. Fluid resuscitation should be
undertaken with the knowledge that patients often
develop significant pulmonary edema and fluid
overload. There is no vasopressor or inotrope of
choice; selection depends on hemodynamic
parameters, preferably with guidance from trans-
thoracic or transesophageal echocardiography and
invasive monitors. Hemodynamic goals in the
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Obstetrics and gynecological anesthesia
initial resuscitation period mirror those of other
shock states including a systolic blood pressure more
than 90 mmHg, PaO2 more than 60 mmHg, and
urinary output more than 0.5 ml/kg/h [21].
Treatment of coagulopathy
Blood loss secondary to AFE can be persistent and
severe, generally presenting as uncontrollable ute-
rine hemorrhage. Massive transfusion protocol, if
available, should be initiated in the setting of
uncontrolled hemorrhage to ensure timely red
blood cells (RBC) and blood products adminis-
tration [79]. Transfusion should be performed with
O negative RBC without delay in case of massive
hemorrhage. Prevention and treatment of coagul-
opathy requires early and ongoing administration of
fresh frozen plasma (FFP), platelets, and cryopreci-
pitate. Administration of blood products and drugs
in the setting of massive hemorrhage should
initially be empiric, then guided by frequent labora-
tory coagulation profile analysis and optimized by
point-of-care viscoelastic tests.
The optimal RBC to FFP ratio is not known,
but given the associated coagulopathy with AFE, a
&
1 : 1–1.5 ratio may be preferable [16 ,79]. Amniotic
&
fluid can induce thrombocytopenia [3 ], and
platelet transfusions should be given empirically.
Fibrinogen is critical for hemostasis and is the first
coagulation factor to decrease in obstetric hemor-
rhage. Fibrinogen levels can be used as a predictor
of severity of obstetric hemorrhage; low levels
&
have been found in the setting of AFE [16 ,80].
Although outcome studies in this setting are
lacking, fibrinogen replacement is likely to be
important in the management of massive hemor-
rhage during AFE [80]. FFP does not contain
adequate levels of fibrinogen; therefore, cryopre-
cipitate and/or human plasma-derived fibrinogen
concentrates should be administered. The use of
antifibrinolytic agents such as tranexamic acid
during hemorrhage secondary to AFE has been
described [75], and there is evidence for efficacy
of antifibrinolytics in non-AFE obstetric and
trauma hemorrhage [81]. A recent review of the
use of recombinant factor VIIa in women with AFE
demonstrated poorer outcomes and increased
mortality, and therefore is currently not recom-
mended for routine use [82]. Uterine atony in the
setting of AFE should be treated with standard
pharmacologic interventions including oxytocin,
carboprost tromethamine, methylergonovine, and
misoprostol, and surgical interventions including
Bakri balloon tamponade, uterine artery ligation/
embolization, B-Lynch suture, or hysterectomy as
required [83].
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NOVEL TREATMENT STRATEGIES
Antithrombin concentrates have previously been
described in the treatment of coagulopathy in
obstetric patients, and may lead to improved
outcomes in patients with AFE that develop coagul-
opathy [34]. Heparin has also been suggested for
treatment of the consumptive phase of dissemi-
nated intravascular coagulation; however, because
of the almost universal risk of massive hemorrhage
in the setting of AFE, heparin is currently not a
recommended treatment [16 ].
&
In patients suffering from cardiopulmonary
collapse secondary to AFE that is refractory to
advance life support medications and interventions,
invasive hemodynamic support may be beneficial.
Extracorporeal membrane oxygenation [84–86],
cardiopulmonary bypass [73], intra-aortic balloon
pump [86], pulmonary artery thromboembolec-
tomy [87], hemofiltration [88], and plasma
exchange transfusions [89] have all been described
in various case reports, and although unproven and
experimental, may be considered when institution-
ally available in patients unresponsive to initial
resuscitative interventions. The utility of plasma
exchange may be related to removal of chemical
mediators and cytokines responsible for the anaphy-
lactoid response [90]. High-dose corticosteroid
treatment for presumed inflammatory-mediated
anaphylactoid response has also been proposed
[73]. Another novel treatment described is the use
of synthetic C1 esterase inhibitors (C1NH) [17].
C1NHs inhibit both C1 esterase, Factor XIIa, and
complement activation; low levels of C1NH
may play a role in development of AFE. Kanayama
&
and Tamura [16 ] found that women with AFE had
decreased serum levels of C1NH, which responded
to treatment with FFP which contains C1NH.
CONCLUSION
AFE remains a poorly understood condition that
presents rarely but with often devastating con-
sequences. Why some mothers have such an exag-
gerated response to fetal and amniotic material in
their circulation compared with others is unclear,
and requires further immunological research.
Improvements in diagnosis by standardized case
reporting coupled with development of serum
biomarkers as well as histological and immune-
histochemical analysis at autopsy are critical to
improving our understanding of the pathogenesis
and advanced treatment options of AFE. Biomarkers
discussed in this review although encouraging, are
still considered to be research tools by many. AFE
treatment is currently largely supportive with
Volume 29  Number 3  June 2016

emphasis on high quality basic and advanced life
support as well as hemorrhage and coagulopathy
management to try to optimize patient outcome
and minimize morbidity and mortality. Novel treat-
ment options outlined in this review can be con-
sidered on a case-by-case basis. Simulation and a
multidisciplinary team-based approach to AFE man-
agement are recommended.
Acknowledgements
None.
Financial support and sponsorship
P.S. has received NIHR (UK) funding (Award reference:
RCF146/PS/2014).
Conflicts of interest
All authors helped write the article and approve the final
manuscript. None of the authors have any conflicts of
interest to declare.
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