International Journal of Obstetric Anesthesia (2013) 22, 329336

0959-289X/$ - see front matter Crown Copyright c

2013 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijoa.2013.08.004

REVIEW ARTICLE

www.obstetanesthesia.com

Amniotic uid embolism: a leading cause of maternal death yet

still a medical conundrum
N.J. McDonnell,a V. Percival,b M.J. Paechc
a

Department of Anaesthesia, St John of God Hospital, Subiaco, Western Australia, Australia

Department of Anaesthesia and Pain Medicine, King Edward Memorial Hospital for Women, Subiaco,
Western Australia, Australia
c
School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia,
Australia
b

ABSTRACT
Amniotic uid embolism is a rare and potentially catastrophic condition that is unique to pregnancy. The presentation may range
from relatively subtle clinical events to sudden maternal cardiac arrest. Despite an increased awareness of the condition, it remains
a leading cause of maternal mortality. The underlying mechanisms of amniotic uid embolism are poorly understood, but current
theories support an immune-based mechanism which is triggered by potentially small amounts of amniotic uid gaining access to
the maternal circulation. This can result in a wide spectrum of clinical ndings, with cardiovascular and haematological
disturbances being prominent. The management of a suspected episode of amniotic uid embolism is generally considered to be supportive, although in centres with specic expertise, echocardiography may assist in guiding management. Whilst outcomes after an
episode of amniotic uid embolism are still concerning, mortality would appear to have decreased in recent times, likely secondary to
an improved awareness of the condition, advances in acute care and the inclusion of less severe episodes in case registries.
Crown Copyright c 2013 Published by Elsevier Ltd. All rights reserved.

Keywords: Amniotic uid embolism; Maternal mortality; Maternal morbidity; Pregnancy; Cardiac arrest; Disseminated
intravascular coagulation

Introduction
Amniotic uid embolism (AFE) is a rare, unpredictable
and potentially catastrophic condition that is unique to
pregnancy. The clinical syndrome of AFE was rst described by Meyer in 1926,1 then again by Steiner and
Luschbough in 1941.2 It has since been shown to encompass a wide spectrum of presentations, from subtle clinical events to sudden and fatal maternal cardiac arrest.
It is characterised by the acute onset of combined cardio-respiratory compromise and coagulation disorders,
occurring in the pregnant or recently pregnant state.3
Currently, AFE is a leading cause of maternal mortality
in many developed countries46 and hence considerable
effort is being made to advance the understanding of
the condition, in the hope of improving the treatment
and outcomes as has been seen with the other causes
of maternal mortality. Despite this effort, there is still
a relatively incomplete understanding of many aspects
Accepted August 2013
Correspondence to: Nolan J McDonnell, Clinical Associate Professor,
Department of Anaesthesia, St John of God Hospital, Subiaco,
Western Australia 6008, Australia.
E-mail address: nolanvini@mac.co

of AFE. Because of the infrequency of the condition

and the lack of a reliable animal model, much of the
information about AFE is derived from case reports,
case series and registries. Consequently, there are significant variations in the reported incidence, risk factors
and outcomes, which are also contributed to by different
diagnostic criteria and potential false-positive cases.7
This review aims to examine the current understanding
of the underlying pathophysiology of AFE and to focus
on recent advances in knowledge related to the diagnosis, management and outcomes.

Incidence
The published incidence of AFE varies widely, likely because of a number of factors such as the methodology
used for case ascertainment7 (e.g. voluntary registries
versus population-linked data), non-specic diagnostic
criteria, uncertainty as to how the condition has been
diagnosed, and differences in reporting as a result of
varying levels of awareness (Table 1). Recent data suggest that the incidence ranges from 1:12 953 deliveries
in the USA8 to 1:52 600 deliveries in the UK,7 with

330

Amniotic uid embolism

Table 1 Incidence of amniotic uid embolism and case

fatality rates in published series

Knight7
Kramer21
Knight3
Oi44
Roberts72
Abenhaim8
Samuelsson73
Kramer74
Tunell36
Yang75
Gilbert76
Clark20
Burrows77
Hogberg78
Morgan64

Year
published

Incidence
(per 100 000
maternities)

Case fatality
rate (%)

2012
2012
2010
2010
2010
2008
2007
2006
2005
2000
1999
1996
1995
1985
1979

1.9-6.1
2.5
2.0
Not reported
3.3
7.7
1.9
6.1
Not reported
Not reported
4.8
Not reported
3.4
Not reported
Not reported

1143
27
20
48
35
21.6
44
13
29.5
89
26.4
61
22
67
86

Australia reporting a gure within this range of 1:16

393.7 Knight et al. noted the variation in the incidence
of AFE between countries based on the methodology
used for case ascertainment.7 The lowest rates of AFE
were obtained with prospective case identication, suggesting there may be a signicant number of false-positive cases reported. They recommended that future
comparisons of incidence data between countries be
based on use of similar methodology and case
denitions.

Pathogenesis
Whilst the underlying mechanisms of AFE are poorly
understood, it is relatively well accepted that the aetiology relates to the transfer of amniotic uid into the
maternal circulation, whereby an idiosyncratic reaction
is triggered. For amniotic uid to gain access to the
maternal circulation there must be a breech of the physical barriers within the utero-placental unit, for example
the endocervical veins,9,10 uterine trauma sites11 or the
site of placental attachment.11 There must also be a pressure gradient favouring transfer into the maternal circulation.12,13 These theories are supported by a number of
identied risk factors for AFE that involve breeches of
these barriers (e.g. placenta praevia and placental
abruption) or that are associated with increases in intrauterine pressure (e.g. uterine contractions, augmentation
of labour).3,7,8
Once amniotic uid is present in the maternal circulation the process by which an AFE reaction is triggered
remains unclear. Two main theories have evolved to explain the clinical consequences. The rst and more traditional view is that the amniotic uid and cellular
components (squames, vernix, mucin, lanugo) create
an obstruction to the pulmonary circulation, leading

to decreased cardiac output with consequent maternal

collapse hence the term embolism.14 However, this
theory fails to support all of the clinical manifestations
of AFE and whilst a physical obstruction to pulmonary
blood ow may be a component of a reaction, especially
with meconium-stained amniotic uid, it does not appear to be the primary mechanism.14
The second theory is that the reaction is immunemediated, this being supported by a number of factors.
Amniotic uid has been shown to be present in the
maternal circulation without any clinical consequences1517 and in attempts to develop animal models
of AFE, the injection of amniotic uid has not reliably
triggered a reaction.18,19 Amniotic uid contains many
vasoactive and procoagulant substances, such as platelet-activating factor, cytokines, bradykinin, thromboxane, leukotrienes and arachadonic acid,14 so it may
require only small amounts of such substances to enter
the maternal circulation to produce the events of an
AFE. In addition, AFE reactions have been shown to
be more common in women carrying a male fetus and
in cases of rhesus iso-immunisation.20 Clark suggests
that differences in the nature or severity of the presentation of AFE may be a result of variations in antigen
exposure and individual response.20 Because of the similarities of some cases of AFE to anaphylaxis, Clark suggested that a more appropriate name for the condition is
anaphylactoid syndrome of pregnancy.20

Risk factors
A large number of risk factors for AFE have been identied. These include maternal age over 35 years, multiple
pregnancy, caesarean birth, assisted delivery, placenta
praevia, placental abruption, eclampsia, fetal distress,
polyhydramnios, uterine rupture and ethnic minority.3,8,21 Labour induction has received recent particular
attention as a possible risk factor. Data from the UK
Obstetric Surveillance System (UKOSS) suggested that
induction of labour greatly increased the risk of AFE
(OR 3.86, 95% CI 2.047.31).3 This nding supported
a Canadian study that also showed an increased risk
(OR 1.8, 95% CI 1.32.7).21 However, a large USA population study of 3 million births and 227 cases of AFE
did not nd a signicant association (adjusted OR 1.5,
95% CI 0.22.3).8 The plethora of associations means
that identication of risk factors for AFE has an exceptionally low positive predictive value and is of no benet
in the acute setting. Further, as many risk factors are not
potentially modiable, identication may not prove useful in reducing the incidence of AFE.

Pathophysiology and clinical manifestations

Amniotic uid embolism can present with a wide range
of symptoms and signs, from cardiac arrest through to

N.J. McDonnell et al.

331

relatively minor or possibly sub-clinical events. In

Clarks initial analysis of clinical features, hypotension
and fetal distress were universal ndings, with cardiac
arrest, pulmonary oedema and coagulation disturbances
also common (Table 2).20 With improving awareness
and recognition of the condition, it is evident that the
presenting features may not be dramatic, with Knight
et al. reporting that the most common manifestations
are premonitory symptoms (30%), shortness of breath
(20%) and acute fetal compromise (20%).3 However, as
the condition progresses or when it is more severe, other
features typical of AFE may be apparent, particularly
maternal haemorrhage, hypotension, marked dyspnoea,
severe coagulopathy and acute fetal compromise.3
AFE can occur at any time during pregnancy or in
the immediate postpartum period, with reports of cases
also at the time of amniocentesis,22,23 at induction of labour for miscarriage24 and termination of pregnancy.25
Knight et al. noted that in their UK study population
of 60 cases, AFE generally occurred between two hours
before delivery and four hours after delivery.3 In 56% of
cases AFE presented at or before delivery and when it
occurred after delivery, 73% of cases were at caesarean
delivery, making this a signicant risk factor (adjusted
OR 8.84, 95% CI 3.7021.1).
Cardiovascular changes associated with AFE may be
complex and the detail is open to debate. The increasing
availability of echocardiography, which allows earlier
and more rapid assessment of underlying cardiovascular
changes than pulmonary artery catheterisation, has generated new insights into circulatory abnormalities.26,27
Currently, it is thought that there is likely to be a biphasic response.28 In the initial phase of an AFE reaction
there may be severe pulmonary hypertension associated
with acute right ventricular failure, which can lead to severe impairment of left ventricular lling due to deviation of the inter-ventricular septum into the left atrium
and ventricle.26 These ndings are likely to explain the
Table 2

Signs and symptoms of amniotic uid embolism

Frequency

Hypotension
Fetal distress
Pulmonary oedema or ARDS
Cardiopulmonary arrest
Cyanosis
Coagulopathy
Dyspnoea
Seizure
Uterine atony
Bronchospasm
Transient hypertension
Cough
Headache
Chest pain

100%
100%
93%
87%
83%
83%
49%
48%
23%
15%
11%
7%
7%
2%

Adapted from Clark SL.20; ARDS: adult respiratory distress

syndrome.

sudden cardiovascular collapse seen in some AFE reactions. If the patient survives this initial insult, the second
phase is thought to involve continuing left ventricular
failure, without severe pulmonary hypertension. Clark
et al. found only mildly increased pulmonary artery
pressures and increased central venous and pulmonary
capillary wedge pressures.29,30 The mechanism of the
on-going left ventricular failure is unclear, but has been
postulated to be a result of myocardial ischaemia30 or
the presence of substances that depress myocardial
function.28
A number of vasoactive mediators are present in
amniotic uid and may explain the potential for pulmonary hypertension. Hankins et al. were able to demonstrate that the injection of homologous amniotic uid
into the maternal circulation of goats caused marked increases in both the pulmonary and systemic vascular
resistances.31 This response was more intense in the
presence of meconium. This may explain why in Clark
et al.s initial case series, worse maternal outcomes were
seen in women with meconium-stained amniotic uid.20
Endothelin has also been implicated in the pathophysiology,32 because amniotic uid contains high concentrations, which may be sufcient to generate the
vasoconstriction seen during AFE.32,33 Other humoral
factors such as proteolytic enzymes, histamine, serotonin, prostaglandins and leukotrienes may also have a
role.34,35
Coagulation disorders in AFE occur in the majority of
cases, occurring in over 80% of cases and are sometimes
the presenting feature.3,36 The coagulopathy seen with
AFE is postulated to occur as a result of both procoagulant and anticoagulant factors and is likely to be multifactorial.14,34 Amniotic uid contains a number of factors
that inuence coagulation, including activated clotting
factors II, VII and X and tissue factor.33,37 It is not clear
whether the coagulopathy is due primarily to a consumptive process or massive brinolysis. The procoagulant
thromboplastin is found in amniotic uid and might contribute to a consumptive coagulopathy.38 Signicant
early-onset hyperbrinolysis has recently been demonstrated in a case of AFE39 and may be secondary to increased levels of urokinase-like plasmin activator,
thrombin-antithrombin complexes and plasminogen activator inhibitor-1 found in amniotic uid.33,40
Respiratory symptoms are a feature of AFE and can
range from mild dyspnoea to respiratory arrest. Intrapulmonary shunting is seen acutely in many women,
leading to low arterial oxygenation despite oxygen therapy. In severe reactions pulmonary oedema may be a
consequence of left ventricular failure or potentially
from capillary damage.20

Diagnosis
Historically, the diagnosis of AFE was usually made at
autopsy when fetal squames were found within the

332

Amniotic uid embolism

pulmonary vasculature. With the improved survival

rate, most cases are now diagnosed on clinical grounds.
In addition, the relevance of detection of fetal squamous
material in the pulmonary vasculature, as an indicator
of AFE, is uncertain.1517 AFE is considered to be a
diagnosis of exclusion, with the entry criteria used by
some of the AFE registries summarising the key diagnostic features. Whilst there are minor differences between registries, they tend to have the following four
inclusion criteria: (1) acute hypotension or cardiac arrest; (2) acute hypoxia; (3) coagulopathy or severe clinical haemorrhage in the absence of other explanations;
and (4) an event during labour, caesarean delivery, uterine surgery or within a dened postpartum period and
with no other explanation for the ndings (Fig. 1).3
Alternative explanations for maternal compromise that
may need to be ruled out are broad and are both
obstetric and non-obstetric (Fig. 2).33,34 A range of
investigations, such as haematological studies, electrocardiograms, chest X-rays, CT scans and echocardiographs may be required.
There is no recognised or readily available diagnostic
test for AFE. With the potential immunological involvement, there has been interest in the measurement of
markers such as complement, tryptase and amniotic
uid.41 The sensitivity and specicity of the tests is poor,
so they should currently be considered as investigational
tools rather than clinical tests to conrm or exclude
AFE.41 Activation of the complement system is demonstrated by decreased complement levels during AFE episodes42 and this has been suggested as a possible trigger
of events.43 Decreased levels of C3, C3a and C4 have
been found.4346 Complement activation also occurs
during normal labour and delivery, although the decrease does not appear to be as large as during an
AFE episode.45,47 Elevated serum tryptase levels have
been reported in a small number of cases but this
does not appear to be a common nding, so tryptase

levels are likely to be more useful in ruling out

anaphylaxis.41
Additional diagnostic tests described include zinc
coproporphyrin (Zn-CPI) (a component of meconium)
and sialyl Tn (STN), a fetal antigen present in both
meconium and amniotic uid.14 Levels of Zn-CPI may
be elevated in women with AFE48 and this test may indicate the passage of meconium into the maternal circulation. Serum STN levels have been examined in a number
of studies and show high sensitivity and specicity for
AFE.45,49,50 In addition, higher levels of STN have been
found in non-survivors of AFE, raising the possibility of
utility in predicting the severity or mortality from
AFE.44

Management
The management of a suspected case of AFE is determined by the severity of the presentation and the
associated cardio-respiratory, neurological and haematological dysfunction. Multidisciplinary support, with
input from obstetric, anaesthesia, intensive care, haematology and neonatal teams, should be sought. In general,
management is supportive and for collapsed patients
follows the principles of basic and advanced life support
in pregnancy.51 This includes early intubation of the
maternal airway, prevention of aortocaval compression
(lateral tilt or manual uterine displacement) and the
early consideration of a perimortem caesarean delivery,
depending on the estimated gestational age of the undelivered fetus.52,53
More advanced measures may be required or indicated but depend on the resources available at the treatment facility. The degree of respiratory support required
varies from simple measures, such as supplemental oxygen, through to tracheal intubation, mechanical ventilation and advanced ventilation techniques. The clinical
picture can be consistent with an adult respiratory dis-

In the absence of any other clear cause the diagnosis of AFE is made by:
Either
Acute maternal collapse with one or more of the following features:

Acute fetal compromise

Cardiac arrest

Cardiac rhythm problems

Coagulopathy

Hypotension

Maternal haemorrhage

Premonitory symptoms, e.g., restlessness, numbness, agitation, tingling

Seizure

Shortness of breath
Excluding women with maternal haemorrhage as the first presenting feature in whom there was
no evidence of early coagulopathy or cardio-respiratory compromise
Or
Women in whom the diagnosis was made at post-mortem examination with the finding of fetal
squames or hair in the lungs

Fig. 1

Diagnostic criteria for amniotic uid embolism.

N.J. McDonnell et al.

Fig. 2

333

Obstetric causes:

Eclampsia

Uterine rupture

Placental abruption

Acute haemorrhage

Peripartum cardiomyopathy

vasodilators to assist in the acute management of severe

pulmonary hypertension is also described.26,63

Non-Obstetric causes:
Emboli (air, fat, thrombus)
Cardiac (myocardial infarction, cardiomyopathy)
Anaphylaxis
Sepsis
Local anaesthetic toxicity
High spinal anaesthesia
Transfusion reaction
Aspiration

In keeping with the variation seen in the incidence and

severity of AFE, the mortality associated also varies
considerably. Thirty years ago AFE was associated with
a very high mortality rate, with a reported case fatality
of 86%.64 Such mortality, and the unpredictable nature
of the condition, has almost certainly contributed to
the fear with which the condition is associated. In recent
times the case fatality rate appears to have decreased signicantly, with the lowest incidence since 1999 being
11%7 and most series reporting a much lower mortality
than that originally reported (Table 1). Risk factors for
a fatal outcome from AFE have not been extensively
studied. Cardiac arrest, whilst a potential indicator of
severity, is associated with reasonable survival rates of
between 3039%.20,36 A Japanese study identied a
number of potential risk factors for mortality, including
term gestation, multiparity, vaginal delivery, cardiac arrest, dyspnoea, loss of consciousness and higher maternal STN levels.44
Despite this encouraging news in regards to fatality
risk, AFE remains a signicant contributor to maternal
mortality in developed countries and is currently the
leading cause of direct maternal death in both Australia5
and New Zealand65 and consistently in the top ve
causes of direct maternal death in the USA6 and UK.4
The decreased case fatality rate associated with AFE
in recent times is not fully explained but is likely to be
secondary to a combination of factors. Awareness of
the condition has increased signicantly amongst obstetric care providers so it is likely that women experiencing
less severe episodes of AFE that may not have been
diagnosed previously are now being included in registries. In addition, advances in resuscitation and intensive
care may mean that women who previously may not
have survived the event now have an improved chance
of survival. Of particular relevance to the obstetric
anaesthetist, multidisciplinary obstetric resuscitation
simulation training has been associated with improved
management of uncommon obstetric emergencies.6668
This is likely to have contributed to reductions in maternal morbidity and mortality, although evidence of clinical benet is difcult to ascertain.
The morbidity associated with AFE in those women
who survive may be considerable although advances in
care appear to have improved outcomes. In Clarks initial registry data, 61% of women had a persisting neurological impairment.20 However, recent data from the
UK document an incidence of cerebral injury in only
6% and in Australia the incidence of cerebral infarction
was 20%.7 An indicator of signicant morbidity is the
extent of supportive therapy required and in the UK

Differential diagnosis for amniotic uid embolism.

tress syndrome (ARDS) picture and hence lung protection strategies may be benecial.54,55 Similarly, the degree of circulatory support required can vary widely.
The management of hypotension often involves the optimisation of preload with uid administration, and vasopressor and inotropic drugs. As the underlying
pathophysiology may vary from case to case, advanced
haemodynamic monitoring (echocardiography or possibly pulmonary artery catheterisation) should be employed where available to further guide uid and
inotropic therapy. Both respiratory and haemodynamic
compromise are likely to be worsened in the presence of
a gravid uterus. Patients who are difcult to ventilate or
who are receiving maximal haemodynamic support in
the intensive care unit may benet from urgent delivery.
Coagulation abnormalities and maternal haemorrhage should be anticipated from the outset. Blood
and blood product transfusion with fresh frozen plasma,
cryoprecipitate and platelets is often required. The
increasing use of point-of-care coagulation testing with
thromboelastometry or thromboelastography may aid
the precise targeting of coagulation disturbances. Recombinant factor VIIa has been used in a number of
cases of AFE, but poorer maternal outcome due to massive intravascular thrombosis has been reported56 so this
is not recommended as a routine. Hyperbrinolysis may
be a signicant contributor to the coagulopathy but is
difcult to detect with traditional coagulation testing.39
Both tranexamic acid and aprotinin have been used in
cases of AFE.39,57
In addition to these strategies, a number of case reports describe other management approaches, although
these are highly dependent on the local resources and
expertise available. Examples include the use of pelvic
embolisation for the management of haemorrhage,58
cardio-respiratory support in the form of cardiopulmonary bypass,59 pulmonary artery thromboembolectomy,60
extracorporeal membrane oxygenation and intra-aortic
balloon counterpulsation,61 haemoltration62 and exchange transfusions.22 The use of selective pulmonary

Outcomes

334
Obstetric Surveillance System data, 25% of women who
survived required a hysterectomy3 and more than 50%
required a blood transfusion.21
Neonatal outcome is dependent on a number of factors,
mostly linked with maternal status. Fetal distress is a common presenting feature of AFE, and if the condition manifests with the fetus in utero the neonatal outcomes may be
poor. A number of complications may occur, including
stillbirth, early neonatal death, hypoxic ischaemic encephalopathy and seizures. Mortality rates approaching 40%
are reported7,69 and Clark found that neonatal neurological morbidity was close to 50%.20 In keeping with improved maternal outcomes, this may no longer be
accurate and the impact of perimortem caesarean delivery
is unclear.36 It is worth reinforcing the point that appropriate resuscitation of the mother, with prompt restoration of
maternal cardiac output and hence utero-placental blood
ow, is likely to optimise outcomes for the neonate.

Future pregnancies
With an increasing number of women surviving an episode of AFE and going on to another pregnancy, the
question of whether these women are at an increased
risk of a repeat AFE is highly relevant. There are a number of case reports of successful pregnancies after AFE
and to date no conrmed cases of a woman suffering another AFE in a subsequent pregnancy.14,70 While numbers are comparatively small, it has been suggested
that the risk of recurrence is likely to be very low, because AFE appears to be related to the specic antigenic
makeup of the index pregnancy, with subsequent pregnancies likely to be antigenically dissimilar.71

Conclusions
AFE continues to be a feared condition in obstetric
anaesthesia, due in part to the unpredictable nature of
the condition, the potential severity of the presentation
and the associated maternal and neonatal morbidity
and mortality. Despite an increased awareness and signicant research into the condition, our understanding
of the underlying mechanisms remains incomplete. Differences in the reporting of the condition make conclusions in relation to the incidence, risk factors and
outcomes difcult to compare between groups and
standardised methods are required. The management
of a suspected episode of AFE remains essentially supportive. Assessment of signicant cardiovascular compromise with echocardiography may allow more
accurate tailoring of haemodynamic therapy, whilst
transfusion requirements may be substantial and
should be anticipated. Currently, no widely available
diagnostic test is available although a number of
promising biochemical markers are being investigated.

Amniotic uid embolism

Disclosure
Nolan McDonnell is the lead investigator for the Amniotic Fluid Embolism Project for the Australasian Maternity Outcomes Surveillance System (AMOSS).

References
1. Meyer JR. Embolia pulmonar amnio caseosa. Bra Med
1926;2:3013.
2. Steiner PE, Lushbaugh CC. Landmark article, Oct. 1941: Maternal pulmonary embolism by amniotic uid as a cause of obstetric
shock and unexpected deaths in obstetrics. By Paul E. Steiner and
C. C. Lushbaugh. JAMA 1986;255:2187203.
3. Knight M, Tuffnell D, Brocklehurst P, Spark P, Kurinczuk JJ;
UK Obstetric Surveillance System. Incidence and risk factors for
amniotic-uid embolism. Obstet. Gynecol. 2010;115:9107.
4. Cantwell R, Clutton-Brock T, Cooper G, et al. Centre for
Maternal and Child Enquiries (CMACE): Reviewing maternal
deaths to make motherhood safer: 20062008. The Eighth Report
of the Condential Enquiries into Maternal Deaths in the United
Kingdom. BJOG 2011;118(Suppl 1):1203.
5. Sullivan, EA, Hall, B, King, JF. Maternal deaths in Australia
20032005. AIHW National Perinatal Statistics Unit 2007;
Maternal deaths series no. 3. Cat. no. PER 42.
6. Lang CT, King JC. Maternal mortality in the United States. Best
Pract Res Clin Obstet Gynaecol 2008;22:51731.
7. Knight M, Berg C, Brocklehurst P, et al. Amniotic uid embolism
incidence, risk factors and outcomes: a review and recommendations. BMC Pregnancy Childbirth 2012;12:7.
8. Abenhaim HA, Azoulay L, Kramer MS, Leduc L. Incidence and
risk factors of amniotic uid embolisms: a population-based study
on 3 million births in the United States. Am J Obstet Gynecol
2008;199:49. e4148.
9. Cheung AN, Luk SC. The importance of extensive sampling and
examination of cervix in suspected cases of amniotic uid
embolism. Arch Gynecol Obstet 1994;255:1015.
10. Bastien JL, Graves JR, Bailey S. Atypical presentation of amniotic
uid embolism. Anesth Analg 1998;87:1246.
11. Thomson AJ, Greer IA. Non-haemorrhagic obstetric shock.
Baillieres Best Pract Res Clin Obstet Gynaecol 2000;14:1941.
12. Masson RG, Ruggieri J, Siddiqui MM. Amniotic uid embolism:
denitive diagnosis in a survivor. Am Rev Respir Dis
1979;120:18792.
13. Talbert LM, Adcock DF, Weiss AE, Easterling WE Jr, Odom
MH. Studies on the pathogenesis of clotting defects during saltinduced abortions. Am J Obstet Gynecol 1973;115:65662.
14. Conde-Agudelo A, Romero R. Amniotic uid embolism: an
evidence-based review. Am J Obstet Gynecol 2009;201:445. e113.
15. Kuhlman K, Hidvegi D, Tamura RK, Depp R. Is amniotic uid
material in the central circulation of peripartum patients pathologic? Am J Perinatol 1985;2:2959.
16. Lee W, Ginsburg KA, Cotton DB, Kaufman RH. Squamous and
trophoblastic cells in the maternal pulmonary circulation identied
by invasive hemodynamic monitoring during the peripartum
period. Am J Obstet Gynecol 1986;155:9991001.
17. Clark SL, Pavlova Z, Greenspoon J, Horenstein J, Phelan JP.
Squamous cells in the maternal pulmonary circulation. Am J
Obstet Gynecol 1986;154:1046.
18. Spence M, Mason KG. Experimental amniotic uid embolism in
rabbits. Am J Obstet Gynecol 1974;119:10738.
19. Stolte L, van Kessel H, Seelen J, Eskes T, Wagatsuma T. Failure
to produce the syndrome of amniotic uid embolism by infusion of
amniotic uid and meconium into monkeys. Am J Obstet Gynecol
1967;98:6947.

N.J. McDonnell et al.

20. Clark SL, Hankins GD, Dudley DA, Dildy GA, Porter TF.
Amniotic uid embolism: analysis of the national registry. Am J
Obstet Gynecol 1995;172:115867.
21. Kramer MS, Rouleau J, Liu S, Bartholomew S, Joseph KS.
Amniotic uid embolism: incidence, risk factors, and impact on
perinatal outcome. BJOG 2012;119:8749.
22. Dodgson J, Martin J, Boswell J, Goodall HB, Smith R. Probable
amniotic uid embolism precipitated by amniocentesis and treated
by exchange transfusion. Br Med J (Clin Res Ed)
1987;294:13223.
23. Hasaart TH, Essed GG. Amniotic uid embolism after transabdominal amniocentesis. Eur J Obstet Gynecol Reprod Biol
1983;16:2530.
24. Wallace F, Clayton R, Davies S, Saleh S. Successful resuscitation
following amniotic uid embolism in a patient undergoing
induction of labour for late miscarriage. Int J Obstet Anesth
2012;21:2023.
25. Ray BK, Vallejo MC, Creinin MD, et al. Amniotic uid embolism
with second trimester pregnancy termination: a case report. Can J
Anesth 2004;51:13944.
26. McDonnell NJ, Chan BO, Frengley RW. Rapid reversal of critical
haemodynamic compromise with nitric oxide in a parturient with
amniotic uid embolism. Int J Obstet Anesth 2007;16:26973.
27. James CF, Feinglass NG, Menke DM, Grinton SF, Papadimos
TJ. Massive amniotic uid embolism: diagnosis aided by emergency transesophageal echocardiography. Int J Obstet Anesth
2004;13:27983.
28. Clark SL. New concepts of amniotic uid embolism: a review.
Obstet Gynecol Surv 1990;45:3608.
29. Clark SL, Cotton DB, Gonik B, Greenspoon J, Phelan JP. Central
hemodynamic alterations in amniotic uid embolism. Am J Obstet
Gynecol 1988;158:11246.
30. Clark SL, Montz FJ, Phelan JP. Hemodynamic alterations
associated with amniotic uid embolism: a reappraisal. Am J
Obstet Gynecol 1985;151:61721.
31. Hankins GD, Snyder RR, Clark SL, Schwartz L, Patterson WR,
Butzin CA. Acute hemodynamic and respiratory effects of
amniotic uid embolism in the pregnant goat model. Am J Obstet
Gynecol 1993;168:111329.
32. el Maradny E, Kanayama N, Halim A, Maehara K, Terao T.
Endothelin has a role in early pathogenesis of amniotic uid
embolism. Gynecol Obstet Invest 1995;40:148.
33. Davies S. Amniotic uid embolus: A review of the literature. Can J
Anesth 2000;48:8898.
34. Gist RS, Stafford IP, Leibowitz AB, Beilin Y. Amniotic uid
embolism. Anesth Analg 2009;108:1599602.
35. Walsh SW, Wang Y. Secretion of lipid peroxides by the human
placenta. Am J Obstet Gynecol 1993;169:14626.
36. Tuffnell DJ. United Kingdom amniotic uid embolism register.
BJOG 2005;112:16259.
37. Lockwood CJ, Bach R, Guha A, Zhou XD, Miller WA, Nemerson
Y. Amniotic uid contains tissue factor, a potent initiator of
coagulation. Am J Obstet Gynecol 1991;165:133541.
38. Harnett MJ, Hepner DL, Datta S, Kodali BS. Effect of amniotic
uid on coagulation and platelet function in pregnancy: an
evaluation
using
thromboelastography.
Anaesthesia
2005;60:106872.
39. Collins NF, Bloor M, McDonnell NJ. Hyperbrinolysis diagnosed
by rotational thromboelastometry in a case of suspected amniotic
uid embolism. Int J Obstet Anesth 2013;22:716.
40. Estelles A, Gilabert J, Andres C, Espana F, Aznar J. Plasminogen
activator inhibitors type 1 and type 2 and plasminogen activators in
amniotic uid during pregnancy. Thromb Haemost 1990;64:2815.
41. Benson MD. Current concepts of immunology and diagnosis in
amniotic uid embolism. Clin Dev Immunol 2012;2012:946576.
42. Hammerschmidt DE, Ogburn PL, Williams JE. Amniotic uid
activates complement. A role in amniotic uid embolism syndrome? J Lab Clin Med 1984;104:9017.

335
43. Benson MD. A hypothesis regarding complement activation and
amniotic uid embolism. Med Hypotheses 2007;68:101925.
44. Oi H, Naruse K, Noguchi T, et al. Fatal factors of clinical
manifestations and laboratory testing in patients with amniotic
uid embolism. Gynecol Obstet Invest 2010;70:13844.
45. Benson MD, Kobayashi H, Silver RK, Oi H, Greenberger PA,
Terao T. Immunologic studies in presumed amniotic uid embolism. Obstet Gynecol 2001;97:5104.
46. Fineschi V, Riezzo I, Cantatore S, Pomara C, Turillazzi E, Neri
M. Complement C3a expression and tryptase degranulation as
promising histopathological tests for diagnosing fatal amniotic
uid embolism. Virchows Arch 2009;454:28390.
47. Benson MD, Kobayashi H, Sehgal LR, Oi H, Haney EI.
Complement, fetal antigen, and shaking rigors in parturients. J
Matern Fetal Neonatal Med 2006;19:314.
48. Kanayama N, Yamazaki T, Naruse H, Sumimoto K, Horiuchi K,
Terao T. Determining zinc coproporphyrin in maternal plasmaa
new method for diagnosing amniotic uid embolism. Clin Chem
1992;38:5269.
49. Kobayashi H, Ohi H, Terao T. A simple, noninvasive, sensitive
method for diagnosis of amniotic uid embolism by monoclonal
antibody TKH-2 that recognizes NeuAc alpha 26GalNAc. Am J
Obstet Gynecol 1993;168:84853.
50. Oi H, Kobayashi H, Hirashima Y, Yamazaki T, Kobayashi T,
Terao T. Serological and immunohistochemical diagnosis of
amniotic uid embolism. Semin Thromb Hemost 1998;24:47984.
51. Morrison LJ, Deakin CD, Morley PT, et al. Part 8: Advanced life
support: 2010 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment
recommendations. Circulation 2010;122:S345421.
52. Warraich Q, Esen U. Perimortem caesarean section. J Obstet
Gynaecol 2009;29:6903.
53. Katz V, Balderston K, DeFreest M. Perimortem cesarean delivery:
were our assumptions correct? Am J Obstet Gynecol
2005;192:191620.
54. Imanaka H, Takahara B, Yamaguchi H, et al. Chest computed
tomography of a patient revealing severe hypoxia due to amniotic
uid embolism: a case report. J Med Case Rep 2010;4:55.
55. Munnur U, Bandi V, Guntupalli KK. Management principles of
the critically ill obstetric patient. Clin Chest Med 2011;32:5360.
56. Knight M, Fitzpatrick K, Kurinczuk JJ, Tuffnell D. Use of
recombinant factor VIIa in patients with amniotic uid embolism.
Anesthesiology 2012;117:423.
57. Stroup J, Haraway D, Beal JM. Aprotinin in the management of
coagulopathy associated with amniotic uid embolus. Pharmacotherapy 2006;26:68993.
58. Goldszmidt E, Davies S. Two cases of hemorrhage secondary to
amniotic uid embolus managed with uterine artery embolization.
Can J Anesth 2003;50:91721.
59. Rufforny-Doudenko I, Sipp C, Shehata BM. Pathologic quiz case.
A 30-year-old woman with severe disseminated intravascular
coagulation during delivery. Arch Pathol Lab Med
2002;126:86970.
60. Esposito RA, Grossi EA, Coppa G, et al. Successful treatment of
postpartum shock caused by amniotic uid embolism with
cardiopulmonary bypass and pulmonary artery thromboembolectomy. Am J Obstet Gynecol 1990;163:5724.
61. Hsieh YY, Chang CC, Li PC, Tsai HD, Tsai CH. Successful
application of extracorporeal membrane oxygenation and intraaortic balloon counterpulsation as lifesaving therapy for a patient
with amniotic uid embolism. Am J Obstet Gynecol 2000;183:4967.
62. Weksler N, Ovadia L, Stav A, Ribac L, Iuchtman M. Continuous
arteriovenous hemoltration in the treatment of amniotic uid
embolism. Int J Obstet Anesth 1994;3:926.
63. Van Heerden PV, Webb SA, Hee G, Corkeron M, Thompson
WR. Inhaled aerosolized prostacyclin as a selective pulmonary
vasodilator for the treatment of severe hypoxaemia. Anaesth
Intensive Care 1996;24:8790.

336
64. Morgan M. Amniotic uid embolism. Anaesthesia 1979;34:2032.
65. PMMRC. Sixth Annual Report of the Perinatal and Maternal
Mortality Review Committee. Reporting mortality 2010. Wellington: Health Quality & Safety Commission; 2012.
66. Fransen AF, van de Ven J, Merien AE, et al. Effect of obstetric
team training on team performance and medical technical skills: a
randomised controlled trial. BJOG 2012;119:138793.
67. Bolden N, Lee S, Gebre E. Making the case for obstetric response
teams and simulation in labor and delivery: management of
catastrophic amniotic uid embolism during labor. J Clin Anesth
2012;24:5178.
68. Vadnais MA, Dodge LE, Awtrey CS, Ricciotti HA, Golen TH,
Hacker MR. Assessment of long-term knowledge retention
following single-day simulation training for uncommon but
critical obstetrical events. J Matern Fetal Neonatal Med
2012;25:16405.
69. Stolk KH, Zwart JJ, Schutte J, VAN Roosmalen J. Severe
maternal morbidity and mortality from amniotic uid embolism in
the Netherlands. Acta Obstet Gynecol Scand 2012;91:9915.
70. Abecassis P, Benhamou D. Is amniotic uid embolism likely to
recur in a subsequent pregnancy? Int J Obstet Anesth 2006;15:90.
71. Clark SL. Amniotic uid embolism. Clin Obstet Gynecol
2010;53:3228.

Amniotic uid embolism

72. Roberts CL, Algert CS, Knight M, Morris JM. Amniotic uid
embolism in an Australian population-based cohort. BJOG
2010;117:141721.
73. Samuelsson E, Hellgren M, Hogberg U. Pregnancy-related deaths
due to pulmonary embolism in Sweden. Acta Obstet Gynecol
Scand 2007;86:43543.
74. Kramer MS, Rouleau J, Baskett TF, Joseph KS; Maternal Health
Study Group of the Canadian Perinatal Surveillance System.
Amniotic-uid embolism and medical induction of labour: a
retrospective,
population-based
cohort
study.
Lancet
2006;368:14448.
75. Yang W, Zhou N, Zhou Y. The clinical analysis of 38 cases with
amniotic uid embolism. Zhonghua Fu Chan Ke Za Zhi
2000;35:758.
76. Gilbert WM, Danielsen B. Amniotic uid embolism: decreased
mortality in a population-based study. Obstet Gynecol
1999;93:9736.
77. Burrows A, Khoo SK. The amniotic uid embolism syndrome:
10 years experience at a major teaching hospital. Aust N Z J
Obstet Gynecol 1995;35:24550.
78. Hogberg U, Joelsson I. Amniotic uid embolism in Sweden, 1951
1980. Gynecol Obstet Invest 1985;20:1307.