Incidence and Risk Factors for Amniotic-Fluid
Embolism
Marian Knight, MBChB, DPhil, Derek Tuffnell, MBChB, Peter Brocklehurst, MBChB, MSc, Patsy Spark,
and Jennifer J. Kurinczuk, MBChB, MD, on behalf of the UK Obstetric Surveillance System
OBJECTIVE: To estimate the incidence of amniotic-fluid
embolism and to describe risk factors, management, and
outcomes.
METHODS: Through a population-based cohort study
and nested case-control analysis, using the UK Obstetric
Surveillance System, we identified 60 women in the
United Kingdom who had an amniotic-fluid embolism
between February 2005 and February 2009 and 1,227
women for the control group. We investigated the po-
tential factors underlying amniotic-fluid embolism using
an exploratory logistic regression analysis to estimate
odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: Sixty cases of amniotic-fluid embolism were
reported, an estimated incidence of 2.0 per 100,000
deliveries (95% CI 1.5–2.5). Amniotic-fluid embolism oc-
currence was significantly associated with induction of
labor (adjusted OR 3.86, 95% CI 2.04 –7.31) and multiple
pregnancy (adjusted OR 10.9, 95% CI 2.81– 42.7); an
increased risk also was noted in older, ethnic-minority
women (adjusted OR 9.85, 95% CI 3.57–27.2). Cesarean
delivery was associated with postnatal amniotic-fluid
embolism (adjusted OR 8.84, 95% CI 3.70 –21.1). Twelve
women died (case fatality 20%, 95% CI 11–32%); 5 of 37
From the National Perinatal Epidemiology Unit, University of Oxford, Oxford,
United Kingdom; and the Bradford Hospitals NHS Trust, Bradford, United
Kingdom.
Dr. Knight is funded by the National Coordinating Centre for Research Capacity
Development of the Department of Health. Dr. Kurinczuk was partially funded
by a National Public Health Career Scientist Award from the Department of
Health and NHS R&D (PHCS022).
The authors thank the UK Obstetric Surveillance System reporting clinicians
who reported cases and completed the data-collection forms.
This paper reports on an independent study which is funded by the Policy
Research Programme in the Department of Health. The views expressed are not
necessarily those of the Department.
Corresponding author: Marian Knight, National Perinatal Epidemiology Unit,
University of Oxford, Old Road Campus, Oxford, UK; e-mail: marian.
knight@npeu.ox.ac.uk.
Financial Disclosure
The authors did not report any potential conflicts of interest.
© 2010 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/10
910 VOL. 115, NO. 5, MAY 2010
BSc,
newborns of women with antenatal amniotic-fluid em-
bolism died (perinatal mortality 135 per 1,000 total births,
95% CI 45–288). Women who died were significantly
more likely to be from ethnic-minority groups (adjusted
OR 11.8, 95% CI 1.40 –99.5).
CONCLUSION: High-quality supportive care can result
in good maternal outcomes after amniotic-fluid embo-
lism. Clinicians should consider both the risks and ben-
efits of induction and cesarean delivery because more
restricted use may result in a decrease in the number of
women suffering a potentially fatal amniotic-fluid embo-
lism. The observed increased risk of fatality in ethnic-
minority women may be associated with differences in
underlying medical conditions or access to care, and
clinicians should that ensure appropriate services are
provided to minimize this risk.
(Obstet Gynecol 2010;115:910–7)
LEVEL OF EVIDENCE: II
A mniotic-fluid embolism is a leading cause of
maternal mortality, with recent rates appearing to
have increased in some countries1,2 although not in
others.3,4 There were no changes in diagnostic criteria
or methods of case ascertainment to account for the
observed rise in the number of deaths in the United
Kingdom and Australia, but the rarity of the disorder
makes it particularly difficult to investigate whether
the larger number of deaths reflects an increase in the
incidence of the condition, an increase in the case
fatality, or a chance finding. Two recent retrospective
analyses of incidence using large national hospital
databases in the United States and Canada,3,4 did not
find a temporal trend in the occurrence of fatal or
nonfatal cases.
Prospective surveillance of amniotic-fluid embo-
lism has been undertaken in the United Kingdom
through two routes. In a passive system, between
1997 and 2004, cases were reported on a voluntary
basis to the United Kingdom Amniotic Fluid Embo-
lism Register5; since 2005, cases have been reported
OBSTETRICS & GYNECOLOGY
actively on a national basis through the routine
monthly mailing of the UK Obstetric Surveillance
System.6 The aim of this study was to estimate the
current incidence of amniotic-fluid embolism in the
United Kingdom and to investigate whether there is
any evidence to suggest that disease incidence is
changing. In addition, we sought to describe risk
factors, current management, case fatality, and other
outcomes.
MATERIALS AND METHODS
We carried out a prospective, population-based co-
hort and nested case-control study. We identified
cases through the monthly mailing of the UK Obstet-
ric Surveillance System6,7 between February 2005 and
February 2009. Clinicians were asked to report any
woman diagnosed with amniotic-fluid embolism with
symptoms and signs consistent with amniotic-fluid
embolism or any woman in whom amniotic-fluid
embolism was confirmed by biopsy or postmortem
examination (Box 1).
Box 1. Diagnostic Criteria for Amniotic-Fluid
Embolism
IN THE ABSENCE OF ANY OTHER CLEAR CAUSE
Either
Acute maternal collapse with one or more of the follow-
ing features:
• Acute fetal compromise
• Cardiac arrest
• Cardiac rhythm problems
• Coagulopathy
• Hypotension
• Maternal hemorrhage
• Premonitory symptoms, eg, restlessness, numbness,
agitation, tingling
• Seizure
• Shortness of breath
Excluding: women with maternal hemorrhage 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 postmor-
tem examination with the finding of fetal squames or
hair in the lungs
The UK Obstetric Surveillance System method-
ology has been described in detail elsewhere.6 In
brief, every month, the UK Obstetric Surveillance
System case-notification cards were sent to nominated
reporting clinicians in each hospital in the United
Kingdom with a consultant-led maternity unit, with a
tick box to indicate whether they had seen a woman
with amniotic-fluid embolism. They also were asked
VOL. 115, NO. 5, MAY 2010
to return cards indicating a “nil report” so that we
could monitor card-return rates and confirm the
denominator to calculate the incidence. Of note, any
women with amniotic-fluid embolism delivering in
other settings in the United Kingdom, including either
in a midwife-led unit or at home, would be transferred
to a consultant-led unit and therefore would be
captured by the UK Obstetric Surveillance System.
When a clinician reported a case, they were sent a
data-collection form asking for details of presentation,
management, and outcomes. All data were collected
anonymously.
Data were double entered into a customized data-
base. Two of the authors (D.T., M.K.) reviewed all cases
in which postpartum hemorrhage was reported as the
first symptom of amniotic-fluid embolism against the
diagnostic criteria (Box 1) to determine independently
whether amniotic-fluid embolism was the most likely
diagnosis.
The Centre for Maternal and Child Enquiries,
which has collected information on all maternal
deaths in the United Kingdom for more than 50 years,
provided information (year of birth and date of
diagnosis) about any maternal deaths from amniotic-
fluid embolism occurring during the study period.
These were compared with maternal deaths reported
through the UK Obstetric Surveillance System; no
additional cases were identified.
All analyses were carried out using STATA 10
software (StataCorp LP, College Station, TX). Inci-
dence with 95% confidence intervals (CIs) was calcu-
lated using the most recently available birth data
(2005 to 2007) as a proxy for February 2005 to
February 20098 –10; the total estimated number of
maternities (women delivering) was 3,049,100.
We investigated the potential factors underlying
amniotic-fluid embolism using an exploratory logistic
regression analysis to estimate odds ratios (ORs) and
95% CIs. We used national data where available to
conduct a univariable analysis and information from
1,227 women in the nested control group to conduct
an adjusted analysis because national data do not
have sufficient information on potential confounders.
The women in the control group were identified by
the UK Obstetric Surveillance System reporters as the
two women delivering in the same hospital immedi-
ately before other UK Obstetric Surveillance System
cases.11 A full regression model was developed by
including both explanatory and potential confound-
ing factors in a core model if there was a preexisting
hypothesis or evidence to suggest they were causally
related to amniotic-fluid embolism, for example, in-
duction of labor. Continuous variables were tested for
Knight et al Amniotic-Fluid Embolism in the UK 911
departure from linearity by the addition of quadratic
terms, and potential interactions were tested by the
addition of interaction terms between all variables in
the model and subsequent likelihood-ratio testing on
removal. P⬍.05 was considered evidence of a signif-
icant interaction or departure from linearity. The
association of amniotic-fluid embolism with cesarean
delivery was examined in a regression model includ-
ing only those women who had amniotic-fluid embo-
lism after delivery to exclude cases in which cesarean
delivery was likely to be a consequence rather than a
cause of the amniotic-fluid embolism. The analysis
had 80% power at the 5% level of statistical signifi-
cance to detect an OR for induction of labor of 2.6 or
greater.
To estimate the proportion of cases attributable to
specific causes, we calculated population-proportional
attributable risks using adjusted ORs and the propor-
tion of cases exposed.12 The UK Obstetric Surveil-
lance System general methodology (04/MRE02/45)
and this study (04/MRE02/46) were approved by the
London Multicentre Research Ethics Committee.
RESULTS
All 229 eligible U.K. hospitals contributed data to the
UK Obstetric Surveillance System during the study
period (100% participation). Data collection was com-
plete for 97% of cases (Fig. 1).
There were 60 confirmed cases in an estimated
3,049,100 maternities,8 –10 representing an estimated
incidence of 2.0 cases per 100,000 maternities (95%
Cases notified
N=93
Excluded: n=21; 23%
Duplicates: 4
Subsequently
reported by
clinicians as not
being cases: 17
No data received
n=3; 3%
Cases identified
Data collection
from additional
forms received
reporters
n=69
n=0
Did not meet
case definition
n=9
Amniotic fluid
embolism
n=60
Fig. 1. Case reporting and completeness of data collection.
Knight. Amniotic-Fluid Embolism in the UK. Obstet Gynecol
2010.
CI 1.5–2.5). There was no significant change in
incidence over the 4 years of the study, although the
study has low power to detect any difference owing to
small case numbers (data not shown). The nine
women whose cases were excluded all had primary
postpartum hemorrhage with no evidence of addi-
tional features, such as cardiac or respiratory compro-
mise or early coagulopathy, to suggest amniotic-fluid
embolism.
Characteristics of women with amniotic-fluid em-
bolism are shown in Table 1. Unadjusted analysis
suggested a linear increase in risk of amniotic-fluid
embolism with increasing age (OR 1.12 for every one
year increase in age, 95% CI 1.07–1.18). For ease of
presentation we have shown the data in binary groups
(OR 2.59, 95% CI 1.53– 4.41 in women aged 35 and
over compared with women aged under 35). There
was a nonsignificant association with maternal ethnic-
ity (OR 1.18, 95% CI 0.61–2.27 in ethnic minority
women compared with white women). The adjusted
analysis revealed a significant interaction between
ethnicity and age (P⬍.001), suggesting that the asso-
ciation with age varies between different ethnic
groups. We therefore have presented stratified results
that show the highest odds in ethnic-minority women
older than 35 years (OR 9.85, 95% CI 3.57–27.2)
(Table 2). In the U.K. population, the proportions of
different ethnicities in the ethnic-minority group were
Asian 47%, black 31%, mixed race 6%, Chinese 5%,
and other ethnic-minority groups 10%. We were
unable to identify any significantly raised risk associ-
ated with a particular minority ethnicity, but note that
this may be the result of small group sizes and limited
study power. After adjustment, no other sociodemo-
graphic factors significantly affected the risk of amni-
otic-fluid embolism.
The occurrence of amniotic-fluid embolism was
significantly associated with induction of labor and
multiple pregnancy (Table 2). Corresponding popu-
lation proportional attributable risks are 35% for
induction of labor, 13% for ethnic-minority women 35
years or older and 7% for multiple pregnancy.
Twenty-six women had amniotic-fluid embolism
after delivery; 19 (73%) of these occurred after cesar-
ean delivery. The adjusted OR for delivery by cesar-
ean in women who had amniotic-fluid embolism after
delivery was 8.84 (95% CI 3.70 –21.1). Ten of the 19
women who had amniotic-fluid embolism after cesar-
ean delivery were not in labor at the time of the
cesarean. Five of these had elective cesarean opera-
tions (one at maternal request and four after previous
cesarean deliveries), and four had emergency cesar-
ean deliveries (three for fetal distress and one for

912 Knight et al Amniotic-Fluid Embolism in the UK OBSTETRICS & GYNECOLOGY

Table 1. Characteristics of Women With Amniotic-Fluid Embolism
Fatal Cases* Non-Fatal Cases* Total Cases*
Characteristic (nⴝ12) (nⴝ48) (nⴝ60)

Sociodemographic characteristics
Age 35 y or older 8 (67) 17 (35) 25 (42)
Ethnic minority group 5 (45) 7 (15) 12 (20)
Professional or managerial occupation 4 (33) 19 (45) 23 (38)
BMI 30 or higher 4 (40) 11 (26) 15 (25)
Current smoking 1 (8) 13 (27) 14 (23)
History of atopic disease 1 (8) 15 (31) 16 (27)
Coexisting medical problems 3 (25) 18 (38) 21 (35)
Pregnancy characteristics
Primiparity 3 (25) 19 (40) 22 (37)
Twin pregnancy 2 (17) 3 (6) 5 (8)
Induction of labor using any method 6 (50) 22 (46) 28 (47)
Induction of labor with vaginal prostaglandin 5 (42) 19 (40) 24 (40)
Oxytocin in labor† 1 (11) 12 (38) 13 (22)
Hyperstimulation 0 (0) 5 (16) 5 (8)
Cesarean delivery 9 (75) 39 (81) 48 (80)
Preterm delivery 4 (33) 5 (11) 9 (15)
AFE presenting before or at delivery 7 (58) 26 (54) 33 (55)
Management
Obstetrician present at time of event or arrived 11 (92) 42 (89) 53 (90)
within 15 min
Anesthetist present at time of event or arrived 10 (83) 38 (83) 48 (83)
within 15 min
Neither obstetrician nor anesthetist present at 7 (58) 19 (41) 26 (43)
time of event
BMI, body mass index; AFE, amniotic-fluid embolism.
Data are n (%).
* Percentages of those with data.
†
Defined as any use of oxytocin to enhance uterine contractions, whether as part of an induction process or to augment spontaneous
labor.

suspected placenta previa); for one woman, the
reason for cesarean delivery is unknown. The pop-
ulation-proportional attributable risk associated
with cesarean delivery (before amniotic-fluid em-
bolism) was 62%.
Information on time of event was missing for one
woman. Thirty-three women (56%) had symptoms or
signs of embolism at or before delivery; the remain-
der had symptoms or signs after delivery. The amni-
otic-fluid embolism occurred at a median gestation of
39 weeks (range 28 – 42) (Fig. 2) and presented clini-
cally within a 6-hour range around delivery (range 2
hours, 18 minutes before delivery to 4 hours after
delivery). Symptoms and signs at presentation are
shown in Table 3. All the women had at least one, and
16 (27%) women had at least four of the five cardinal
features of shortness of breath, hypotension, maternal
hemorrhage, coagulopathy, and premonitory symp-
toms. Fetal distress occurred before maternal collapse
in 19 cases (32%); in six (32%) of these cases, the
woman was delivered urgently as a consequence of
fetal distress and collapsed after delivery.
The majority of women (55, 92%) had ruptured
membranes at or before the time of presentation
with amniotic-fluid embolism. In those women who
had amniotic-fluid embolism before delivery, the
amniotic-fluid embolism presented a median of 45
minutes after membrane rupture (range 0 minutes
to 6 days after); in four women the amniotic-fluid
embolism presented at the time of membrane rup-
ture, and a further three women presented within 10
minutes of membrane rupture. An obstetrician was
present at the time of presentation in 28 cases (47%)
and an anesthetist in 27 (45%); neither was present in
26 cases (43%) (Table 1).
Twenty-eight women (85%) who presented with
amniotic-fluid embolism at or before delivery were
delivered by cesarean. A range of management strat-
egies were used after amniotic-fluid embolism in
addition to supportive therapies (Table 4). Supportive
therapies alone, defined as fluids and blood products
only, were used in 35 women (58%); 15 women (25%)
had hysterectomy to control hemorrhage, and 15
women (25%), including one who also had a hyster-

VOL. 115, NO. 5, MAY 2010 Knight et al Amniotic-Fluid Embolism in the UK 913
Table 2. Maternal Risk Factors for Amniotic-Fluid Embolism
Number of UKOSS
Women* UKOSS National Case-Control
Cases* Controls* (National Case-Control Comparison Data [Adjusted
Risk Factor (nⴝ60) (nⴝ1,227) Data) Data Data OR (95% CI)]†

Sociodemographic factors
Ethnicity
White
Younger than 35 y 29 (51) 751 (63) N/A 1‡ N/A 1‡
35 y or older 16 (28) 223 (19) N/A 1.86 (0.99–3.48) N/A 1.54 (0.72–3.28)
Nonwhite
Younger than 35 y 5 (9) 182 (15) N/A 0.71 (0.27–1.86) N/A 0.60 (0.17–2.13)
35 y or older 7 (12) 38 (3) N/A 4.77 (1.96–11.6) N/A 9.85 (3.57–27.2)
Socioeconomic group
Managerial and 31 (57) 334 (30) N/A 1.70 (0.98–2.96) N/A 1.55 (0.79–3.04)
professional
occupations
Other occupations 23 (43) 766 (70) N/A 1‡ N/A 1‡
Smoking status
Never/ex smoker 45 (76) 940 (78) N/A 1‡ N/A 1‡
Current smoker 14 (24) 258 (22) N/A 1.13 (0.61–2.10) N/A 1.28 (0.57–2.90)
Booking body mass index
Lower than 30 37 (71) 886 (83) N/A 1‡ N/A 1‡
30 or higher 15 (29) 186 (17) N/A 1.93 (1.04–3.59) N/A 1.65 (0.82–3.33)
Factors related to pregnancy
and reproduction
Parity
0 22 (37) 525 (43) N/A 1‡ N/A 1‡
1 or more 38 (63) 696 (57) N/A 1.30 (0.76–2.23) N/A 1.03 (0.53–2.00)
Multiple pregnancy
No 55 (92) 1,211 (99) 652,915 (98)§ 1‡ 1‡ 1‡
Yes 5 (8) 13 (1) 10,137 (2)§ 8.47 (2.92–24.6) 5.86 (1.83–14.5) 10.9 (2.81–42.7)
Induction of labor (medical
and surgical
methods)
No 32 (53) 953 (78) 378,434 (80)㛳 1‡ 1‡ 1‡
Yes 28 (47) 269 (22) 96,389 (20)㛳 3.10 (1.83–5.24) 3.44 (1.99–5.89) 3.86 (2.04–7.31)
Delivery by cesarean
No 12 (20) 925 (76) 452,709 (76)㛳 1‡ 1‡ Not included¶
Yes 48 (80) 299 (24) 145,322 (24)㛳 12.4 (6.49–23.6) 12.5 (6.52–25.8) Not included¶
Placenta praevia
No 58 (98) 1,215 (100) N/A 1‡ N/A Not included
Yes 1 (2) 2 (0.2) N/A 10.5 (0.94–117.2) N/A Not included
UKOSS, UK Obstetric Surveillance System; OR, odds ratio; CI, confidence interval; N/A, national data not available.
Data are n (%) or unadjusted odds ratio (95% CI) unless otherwise specified.
* Percentages of those with complete data.
†
Adjusted for all the other factors indicated in the table.
‡
Baseline comparison group.
§
Data for maternities in England and Wales 2006, Office for National Birth Statistics 2006.
㛳
Data for maternities in England 2006 –7, source Hospital Episode Statistics 2006 –2007.
¶
See text for adjusted OR in women who had amniotic-fluid embolism after delivery.

ectomy, were treated with factor VIIa. In total, five
women (8%) had a combination of different treatment
strategies in addition to supportive therapies. Women
were transfused a median of 6.5 units of blood (range
0 – 62 units).
Twelve women died (case fatality rate 20%, 95%
CI 11–32%) (Table 1). All the women died within 1
day of the amniotic-fluid embolism at a median of 1
hour, 40 minutes after the acute event (range 0
minutes to 23 hours, 18 minutes). Women who died
were significantly more likely to be from an ethnic-
minority group than were those who survived (OR
4.64, 95% CI 1.11–19.5); this association persisted
after adjustment for differences in age, socioeconomic
status, body mass index, and parity (adjusted OR
11.8, 95% CI 1.40 –99.5). There were no other signif-

914 Knight et al Amniotic-Fluid Embolism in the UK OBSTETRICS & GYNECOLOGY

 16 Table 4. Management Techniques Used
Event after delivery
14 Survivors Deaths
Event before or at delivery
Technique Used (nⴝ48)* (nⴝ12)* P†
12
Hysterectomy 12 (25) 3 (25) 1.00
10 Exchange transfusion 3 (6) 0 (0) 1.00
Women (n)

Plasma exchange 4 (8) 0 (0) .57

8
Factor VIIa 14 (29) 1 (8) .26
6 Supportive therapies 26 (54) 9 (75) .33
only
4
Data are n (%).
* Some women had multiple techniques, therefore totals are
2
greater than 100%.
†
Fisher’s exact test.
0
27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
Gestation at event/delivery (weeks)
There was one stillbirth and four neonatal deaths
Fig. 2. Gestational age at amniotic fluid embolism (antena-
tal cases) or delivery (postnatal cases).
(all due to asphyxia before birth) among the 37
Knight. Amniotic-Fluid Embolism in the UK. Obstet Gynecol
neonates for whom outcomes are known and who
2010. were born to mothers who had amniotic-fluid embo-
lism at or before delivery, giving a perinatal mortality
icant differences between fatal and nonfatal cases, rate of 135 per 1,000 total births (95% CI 45–288).
although this analysis has limited power to detect Neither mother nor neonate survived in three cases.
differences. Eight women who survived had other None of the neonates born to mothers who had
severe morbidities: four had cerebral neurologic in- amniotic-fluid embolism after delivery died.
jury, two suffered a thrombotic event, one had septi-
DISCUSSION
cemia, and one had renal failure. Forty-five of the 48
women who survived (94%) were admitted to inten- The incidence of amniotic-fluid embolism as esti-
sive care. Only 3 of the 12 women who died (25%) mated by this 4-year prospective national study is 2.0
were admitted to intensive care; the remainder died per 100,000 maternities (95% CI 1.5–2.5), which is
before admission. The median length of stay in inten- significantly lower than the rate documented in retro-
sive care was 3 days (range 1–39 days). spective reviews of population-based hospital dis-
charge databases in Canada (6.1 cases per 100,000
deliveries, 95% CI 5.3–7.14) and the United States (7.7
Table 3. Features of Amniotic-Fluid Embolism at
cases per 100,000 births, 95% CI 6.7– 8.73). As we
Presentation
demonstrated, amniotic-fluid embolism is difficult to
Women Women Exhibiting diagnose; of 86 nonduplicate cases reported, further
Exhibiting Feature as the First examination of the records revealed a more likely
Feature*† Symptom or Sign
(nⴝ60) of AFE*† (nⴝ60) diagnosis in 26 (30%). Hospital discharge databases
do not allow for examination of sufficiently detailed
Maternal hemorrhage 39 (65) 1 (2) clinical information to either confirm or refute the
Hypotension 38 (63) 5 (8) diagnosis of amniotic-fluid embolism and, therefore,
Shortness of breath 37 (62) 12 (20)
Coagulopathy 37 (62) 0 (0) are likely to be subject to a degree of overreporting.
Premonitory symptoms 28 (47) 18 (30) Neither of the previous studies undertook validation
(eg, restlessness, of the diagnosis by examining medical charts. The
agitation, numbness, authors of the Canadian report cite their observed
tingling) associations of amniotic-fluid embolism with compli-
Acute fetal compromise 26 (43) 12 (20)
Cardiac arrest 24 (40) 5 (8) cations including eclampsia, placenta previa, and
Cardiac rhythm 16 (27) 3 (5) abruption as evidence of overreporting; similar asso-
problems ciations were observed in the U.S. study.
Seizures 9 (15) 4 (7) Although a possibility, we believe that our lower
AFE, amniotic-fluid embolism. incidence estimate is unlikely to be due to underre-
Data are n (%). porting of cases because the UK Obstetric Surveil-
* Percentages of those with complete data.
†
Some women had multiple features, therefore totals are greater lance System is an active, prospective surveillance
than 100%. system in which we require negative reports, ie,

VOL. 115, NO. 5, MAY 2010 Knight et al Amniotic-Fluid Embolism in the UK 915
participating hospitals return a report card every
month, regardless of whether there are cases to report.
We thus can be confident that reports of “no cases”
from an individual hospital are true negative reports.
Furthermore, all of the fatal cases reported to the
Centre for Maternal and Child Enquiries in the study
period had been reported to the UK Obstetric Sur-
veillance System. If the true incidence in the U.K.
population were the same as that estimated in Canada
(6.1 per 100,000), there would have been 186 cases in
total, implying that we had missed 126 nonfatal cases
and that the case fatality rate was only 6% (12 of 186);
levels of both missing cases and fatalities that seem
highly improbable.
A third explanation for the threefold difference in
incidence estimates is that this reflects a true differ-
ence in incidence in the United Kingdom compared
with North America. Given that the population-pro-
portional attributable risk associated with cesarean
delivery is 62% and that the cesarean-delivery rate in
the United States is 50% higher than in the United
Kingdom, one might indeed anticipate a higher rate
of amniotic-fluid embolism in the United States than
in the United Kingdom.
Induction of labor was associated with a popula-
tion-attributable risk of 35% in our study, suggesting
that, assuming causality, if induction of labor were no
longer performed, 35% of cases of amniotic-fluid
embolism could be prevented. The practice of induc-
ing labor, with its many potential benefits, clearly will
continue, and amniotic-fluid embolism remains a
very rare complication; nevertheless, clinicians
should be aware of both the risks and benefits of
induction because more restricted use may result in a
decrease in the number of women suffering a poten-
tially fatal amniotic-fluid embolism.
Both Canadian and U.S. studies show an in-
creased rate of cesarean delivery among women with
amniotic-fluid embolism, which the authors of the
U.S. study interpret as causal. However, as the inves-
tigators discuss, one of the limitations of administra-
tive databases is that they do not indicate whether the
amniotic-fluid embolism occurred before, during, or
after delivery. Our prospectively collected data in-
clude timing of all the events, and we found that 56%
of women had amniotic-fluid embolism at or before
delivery, with 44% after delivery. More than 80% of
women who had amniotic-fluid embolism at or before
delivery subsequently were delivered by cesarean;
clearly, in these cases, the cesarean delivery was a
consequence and not a cause of amniotic-fluid embo-
lism. However, we also found more than an eightfold
increase in the odds of amniotic-fluid embolism asso-
916 Knight et al Amniotic-Fluid Embolism in the UK
ciated with cesarean delivery in the group who had
amniotic-fluid embolism after delivery, suggesting
that there indeed may be a causal relationship. The
clinical message from this study thus echoes other
studies in noting that cesarean delivery is not risk-
free7 and that all risks and benefits should be assessed
before a decision for cesarean delivery is made.
Older maternal age was also an important factor
in all the studies, although, in our population, having
adjusted for confounders, the increase in risk with age
was limited to ethnic-minority women. The small
number of older ethnic-minority women with amni-
otic-fluid embolism means that we do not have suffi-
cient power to investigate this association further, but
continued surveillance through the UK Obstetric
Surveillance System may allow us to address this in
the future. In the meantime, clinicians should be
aware of the increased risk when caring for older
pregnant women who are ethnic-minorities.
All the women in our study experienced at least
one of the cardinal features of shortness of breath,
hypotension, hemorrhage, coagulopathy, and pre-
monitory symptoms at the time of amniotic-fluid
embolism, and all cases were consistent with the
reporting criteria used in a U.S. amniotic-fluid embo-
lism registry.13 Premonitory symptoms such as numb-
ness, tingling, and agitation were the most common
initial presenting feature, although acute fetal com-
promise was the first feature noted in 36% of antenatal
cases. Fetal compromise was noted first as a fetal heart
rate abnormality in the majority of cases; clinicians
should consider amniotic-fluid embolism as part of
the differential diagnosis of a sudden, unexplained
deterioration in the fetal heart rate even in the ab-
sence of maternal symptoms or signs.
The mainstay of the management of amniotic-
fluid embolism remains supportive therapy, and this
study shows that high-quality supportive care can
result in a good maternal outcome in the majority of
cases. The results also highlight the use of a number of
therapies for amniotic-fluid embolism previously de-
scribed only in case reports. Coagulopathy is a com-
mon feature of amniotic-fluid embolism (occurring in
more than 60% of our cases), and, therefore, use of
recombinant factor VIIa, a procoagulant leading to
increased thrombin formation, has been proposed,
with individual reports of its success.14 –16 In our study,
14 women were treated with factor VIIa for coagu-
lopathy; 13 survived.
Seven women were treated with exchange trans-
fusion or plasma exchange, a therapy first described
more than 20 years ago.17 Authors have suggested
variously that clinical improvement is related to the
OBSTETRICS & GYNECOLOGY
removal of red cell debris and hemoglobin from the
circulation17 or that the process removes amniotic
fluid and cytokines from the circulation and corrects
metabolic acidosis.18 Thus, these therapies should be
regarded as an extension of supportive care and not as
a substitute. All seven women treated with these
therapies survived, although the small numbers in-
volved means that we should not assume that this
form of therapy is more effective than any other;
survival to the point where these techniques are
possible may put the women in a more favorable
prognosis group.
One fifth of women with amniotic-fluid embolism
and 1 in 10 of their newborns died. Maternal fatality
was comparable with that in the Canadian and U.S.
studies (13% [95% CI 9 –19%] and 22% [95% CI
16 –28%], respectively). This confirms the view that
maternal fatality in large, unselected populations is
lower than previously suggested. We found that
women who died were significantly more likely to
come from ethnic-minority groups than were survi-
vors, an association that could not be explained by
differences in age, socioeconomic status, body mass
index, or parity. In previous UK Obstetric Surveil-
lance System studies,11 we found that the incidence of
severe maternal morbidity is higher among ethnic-
minority women, and we postulate that this may be
due to differences in underlying medical conditions or
access to care. It is possible that these factors also may
play a role in the increased risk of fatality from
amniotic-fluid embolism for these women.
REFERENCES
1. Lewis GE, editor. The Confidential Enquiry into Maternal and
Child Health (CEMACH). Saving mothers lives: reviewing
maternal deaths to make motherhood safer 2003–2005. Lon-
don (UK): CEMACH; 2007.
2. Sullivan E, Hall B, King J. Maternal deaths in Australia
2003–2005. Canberra (Australia): Australian Institute of
Health and Welfare; 2008.
3. Abenhaim HA, Azoulay L, Kramer MS, Leduc L. Incidence
and risk factors of amniotic fluid embolisms: a population-
VOL. 115, NO. 5, MAY 2010
based study on 3 million births in the United States. Am J
Obstet Gynecol 2008;199:49.e1– 8.
4. Kramer MS, Rouleau J, Baskett TF, Joseph KS. Amniotic-fluid
embolism and medical induction of labour: a retrospective,
population-based cohort study. Lancet 2006;368:1444 – 8.
5. Tuffnell DJ. United Kingdom Amniotic Fluid Embolism Reg-
ister. BJOG 2005;112:1625–9.
6. Knight M, Kurinczuk JJ, Tuffnell D, Brocklehurst P. The UK
Obstetric Surveillance System for rare disorders of pregnancy.
BJOG 2005;112:263–5.
7. Knight M, Kurinczuk JJ, Spark P, Brocklehurst P. Cesarean
delivery and peripartum hysterectomy. Obstet Gynecol 2008;
111:97–105.
8. Office for National Statistics. Key population and vital statistics
(2005). Newport (UK): Office for National Statistics; 2007.
9. Office for National Statistics. Key population and vital statistics
(2006). Newport (UK): Office for National Statistics; 2008.
10. Office for National Statistics. Key Population and Vital Statis-
tics (2007). Newport (UK): Office for National Statistics; 2009.
11. Knight M, Kurinczuk JJ, Spark P, Brocklehurst P, UKOSS.
Inequalities in maternal health: national cohort study of ethnic
variation in severe maternal morbidities. BMJ 2009;338:b542.
12. Rockhill B, Newman B, Weinberg C. Use and misuse of
population attributable fractions. Am J Public Health 1998;88:
15–9.
13. Clark SL, Hankins GD, Dudley DA, Dildy GA, Porter TF.
Amniotic fluid embolism: analysis of the national registry.
Am J Obstet Gynecol 1995;172:1158 – 67.
14. Kahyaoglu I, Kahyaoglu S, Mollamahmutoglu L. Factor VIIa
treatment of DIC as a clinical manifestation of amniotic fluid
embolism in a patient with fetal demise. Arch Gynecol Obstet
2009;280:127–9.
15. Lim Y, Loo CC, Chia V, Fun W. Recombinant factor VIIa
after amniotic fluid embolism and disseminated intravascular
coagulopathy. Int J Gynaecol Obstet 2004;87:178 –9.
16. Prosper SC, Goudge CS, Lupo VR. Recombinant factor VIIa
to successfully manage disseminated intravascular coagulation
from amniotic fluid embolism. Obstet Gynecol 2007;109:
524 –5.
17. Dodgson J, Martin J, Boswell J, Goodall HB, Smith R. Proba-
ble amniotic fluid embolism precipitated by amniocentesis and
treated by exchange transfusion. Br Med J (Clin Res Ed)
1987;294:1322–3.
18. Kaneko Y, Ogihara T, Tajima H, Mochimaru F. Continuous
hemodiafiltration for disseminated intravascular coagulation
and shock due to amniotic fluid embolism: report of a dramatic
response. Intern Med 2001;40:945–7.
Knight et al Amniotic-Fluid Embolism in the UK 917