Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 22, No. 5, pp. 825846, 2008

doi:10.1016/j.bpobgyn.2008.06.003
available online at http://www.sciencedirect.com

4
Critical care in obstetrics:
pregnancy-specific conditions
Jennifer Williams *

MD

Fellow, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology

Ellen Mozurkewich

MD, MS

Assistant Professor, Department of Obstetrics and Gynaecology

Julie Chilimigras

MPH

Clinical Research Coordinator, Department of Obstetrics and Gynaecology

Cosmas Van De Ven

MD

Professor, Director, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology

University of Michigan Hospital, F4835 Mott, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0264, USA

This chapter summarizes the clinical presentation, pathophysiology, evaluation and management
of six commonly encountered complications unique to pregnancy that require critical care management: obstetric haemorrhage; pre-eclampsia/HELLP (haemolysiselevated liver enzymeslow
platelets) syndrome; acute fatty liver of pregnancy; peripartum cardiomyopathy; amniotic fluid
embolism; and trauma.
Key words: obstetric haemorrhage; trauma; pre-eclampsia/HELLP syndrome; acute fatty liver;
peripartum cardiomyopathy; amniotic fluid embolism.

HAEMORRHAGE/DISSEMINATED INTRAVASCULAR COAGULATION

Haemorrhage is the second leading cause of pregnancy-related death in the USA1, and
the leading cause of maternal death in developing countries, accounting for 25% of
maternal deaths worldwide.2,3 Postpartum haemorrhage is defined as blood loss
>500 mL at delivery3, and severe postpartum haemorrhage is defined as blood loss
* Corresponding author. Tel.: 1 734 764 1401; Fax: 1 734 647 1006.
E-mail address: zelenock@umich.edu (J. Williams).
1521-6934/$ - see front matter 2008 Elsevier Ltd. All rights reserved.

826 J. Williams et al

>1000 mL.4 Risk of haemorrhage-related maternal death increases with maternal age
and is greater among African-Americans than among White Americans.5 Haemorrhage-related obstetric death is usually preceded by haemorrhagic shock and rapid
cardiovascular collapse.6 In one developing world setting, 88% of deaths occurred
within 4 h of delivery.7
Aetiologies of obstetric haemorrhage
Life-threatening obstetric haemorrhage may develop in the antepartum or the postpartum period. Antepartum haemorrhage is most often attributable to placental
abruption or previa, whereas postpartum haemorrhage is most often associated
with uterine atony.3 Other causes of postpartum haemorrhage include retained
placenta, uterine inversion, placenta previa, placenta accreta, uterine rupture and genital tract trauma.3,6 Risk factors for postpartum haemorrhage include: pre-existing
anaemia; obesity; chorioamnionitis; fetal macrosomia; prior caesarean section; and
multiple gestation.6
Aetiologies of coagulopathy/disseminated intravascular coagulation
In the obstetric setting, disseminated intravascular coagulation (DIC) may develop
due to the underlying shock process (abruption, amniotic fluid embolism)6 or due
to dilutional effects of massive blood loss and fluid replacement in the setting of
hypovolaemic shock.8 Bick defines DIC as a systemic thrombohemorrhagic disorder seen in association with well-defined clinical situations and laboratory evidence of (1) procoagulant activation, (2) fibrinolytic activation, (3) inhibitor
consumption and (4) biochemical evidence of end organ damage or failure.9
Causes of DIC that are unique to pregnancy include retained fetus after in-utero
fetal demise, placental abruption, severe pre-eclampsia/HELLP (haemolysiselevated liver enzymeslow platelets) syndrome, and amniotic fluid embolism
(AFE).9 DIC is always a secondary phenomenon, developing after procoagulant
substances, such as collagen, tissue factor from tissue destruction, amniotic fluid,
placental tissue, incompatible red blood cells or bacterial products, are released
into the maternal circulation.8,10,11 This phenomenon leads to increased production and breakdown of coagulation factors, including increased conversion of fibrinogen to fibrin, platelet activation and consumption, activation of factors V
and VIII, protein C activation, endothelial cell activation and fibrinolysis.12 Subsequent developments include increased intravascular fibrin deposition leading to
thromboembolic complications.13 The consumption of platelets and coagulation
factors leads to massive, and often life-threatening, haemorrhage. In the obstetric
setting, increased circulating fibrin degradation products may decrease myometrial
contractility, leading to worsening haemorrhage from uterine atony.8 Although
haemorrhage is the immediate, life-threatening consequence of DIC, microvascular thromboses may lead to end organ damage or failure, and longer range
morbidities.9,10,13
Diagnosis of disseminated intravascular coagulation
There are no agreed upon clinical criteria diagnostic for DIC. Signs of DIC may include
persistent oozing from operative and venepuncture sites, ongoing postpartum haemorrhage with decreased clotting, acral cyanosis, purpura and petichiae.9 Bleeding

Critical care in obstetrics: pregnancy-specific conditions

827

from unrelated sites is also typical.9 In the setting of massive haemorrhage, it is unwise
and unnecessary to delay initiation of potentially life-saving therapies until laboratory
results become available; however, many laboratory abnormalities can be seen and
help with recognition of DIC. The prothrombin time and partial thromboplastin
time are often elevated during DIC, but may be normal in up to 50% of cases.9 Fibrin
degradation products and D-dimers are elevated in 85100% and at least 93% of cases,
respectively. However, both of these are commonly elevated in postpartum and/or
postoperative patients and are therefore not diagnostic.9 Variable degrees of thrombocytopenia and hypofibrinogenaemia are also seen.8 A diagnostic scoring system
combining clinical and laboratory manifestations of DIC has been proposed but is
not in general use at this time.11
Management of obstetric haemorrhage
The goals of managing life-threatening obstetric haemorrhage, with or without DIC,
include controlling the source of blood loss, restoring adequate oxygen carrying capacity, and maintaining adequate tissue perfusion.6,14 Decreased cardiac output, hypotension and vasoconstriction may result in decreased end organ perfusion of vital organs
including kidneys, heart and brain.3,6,11 In order to restore oxygen carrying capacity
and maintain adequate tissue perfusion, fluid resuscitation should begin with volume
expansion with crystalloid at a volume approximately three times that of the estimated
blood loss.6,14 This should be followed immediately with replacement of packed red
blood cells to restore oxygen carrying capacity, with the goal of maintaining haemoglobin at 710 g/dL.6,14 Lastly, clotting factors and platelets should be replaced in order to
prevent or correct coagulopathy.8,14 This replacement should begin with fresh frozen
plasma6, followed by cryoprecipitate and platelets. In cases in which coagulopathy does
not respond to these measures, administration of recombinant activated factor VII can
be considered.6,13,15 In order to fast-track availability of these blood products, some
authors have suggested availability of a massive transfusion protocol for hospitals
providing obstetric services.14 One published protocol recommends that blood banks
should provide massive transfusion packages containing red blood cells, fresh frozen
plasma and platelets in a 6:4:1 ratio, which most closely approximates the composition
of whole blood.14
The source of bleeding may be controlled medically (with uterotonic drugs, such
as oxytocin, methergine, prostaglandin E2, prostaglandin F2a and misoprostol),
mechanically (with intra-uterine balloons or packs) or surgically. Surgical treatments
include conservative measures such as hypogastric artery ligation, uterine artery ligation and arterial embolization by interventional radiology. Hysterectomy is carried
out in the event of failure of these conservative measures. A recent Cochrane review
concluded that there is currently insufficient evidence from appropriately powered
randomized controlled trials to choose oxytocin/methergine over misoprostol as
the first-line therapy for atony.16 Likewise, there are no randomized controlled trials
comparing the effectiveness of mechanical and surgical measures to control severe
postpartum haemorrhage. However, one recent systematic review evaluated 46
observational studies comparing the modalities intended to control severe postpartum haemorrhage after uterotonic medications have failed. These modalities include
balloon tamponade, uterine compression sutures, internal iliac artery ligation or uterine devascularization, and arterial embolization.4 The reviewers found no significant
difference in success rates among these four procedures. Balloon tamponade was
successful in 84% of cases, uterine compression sutures were successful in 91.7%

828 J. Williams et al

of cases, internal iliac artery ligation or uterine devascularization was successful in

84.6% of cases, and arterial embolization was successful in 90.7% of cases.4 Based
on these findings, the authors suggest that balloon tamponade, the least invasive of
these procedures, should be considered as the first-line approach, particularly after
vaginal delivery.4
PRE-ECLAMPSIA, ECLAMPSIA AND HELLP SYNDROME
Classification
Obstetric patients who have high blood pressure, whether pregnant or post partum,
can be classified into two categories: chronic hypertension or pre-eclampsia. Types of
chronic hypertension include idiopathic or essential hypertension, secondary hypertension from renal disease, Cushings syndrome or pheochromocytoma. Pre-eclampsia
is not a hypertensive disorder but a pregnancy-specific syndrome, with high blood
pressure as one of the many possible symptoms.
Epidemiology
Pre-eclampsia is typically seen in the first pregnancy. The incidence of pre-eclampsia
varies between 5% and 8% depending on the population being studied.17 In most
Western cultures, morbidity and mortality associated with pre-eclampsia are low;
however, in countries with less access to health care, pre-eclampsia/eclampsia and
their associated morbidity and mortality for both mother and fetus remain significant
clinical problems.18
Pathophysiology
Recent discoveries have markedly improved our understanding of the pathophysiology of pre-eclampsia. It is hypothesized that an altered maternal immune response
to antigens expressed on the invading trophoblast results in a premature halting of
the trophoblastic invasion into the maternal (spiral) arteries.19 The lack of this invasion causes these maternal vessels to remain narrow and vasoreactive, thereby
creating an increase in resistance and poor perfusion of the placenta.20,21 In an attempt to improve perfusion, the placenta releases factors into the maternal
circulation.
Recent work2224 has facilitated understanding of this process. The placentas of
patients with pre-eclampsia produce angiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1), which binds to placental growth factor (PlGF) and vascular endothelial growth factor (VEGF).22 PlGF is important in angiogenesis of the placental
vascular bed, and VEGF is essential in the stabilization of the maternal vascular endothelium. When sFlt-1 binds to PlGF and VEGF, these growth factors are no longer
bio-available, resulting in decreased angiogenesis of the placenta, and destabilization
and dysfunction of the maternal vascular endothelium.25 The clinical manifestations
of pre-eclampsia, including hypertension, proteinuria, oedema, thrombocytopenia
and activation of the coagulation cascade, reflect altered maternal vascular endothelial function.26

Critical care in obstetrics: pregnancy-specific conditions

829

Clinical management
Risk factors for pre-eclampsia include first pregnancy (85% of patients), multiple
gestations and molar pregnancies.17 Patients with pre-existing maternal disorders
involving the vascular endothelium, such as collagen vascular disease, diabetes mellitus,
obesity and antiphospholipid syndrome, are at increased risk for pre-eclampsia.27
These disorders render the endothelium more susceptible to placental humoral
factors.
Pregnant patients who present with new-onset hypertension, defined as systolic
pressure >140 mmHg or diastolic pressure >90 mmHg, should be assumed to have
pre-eclampsia. Clinicians should solicit symptoms of headaches and epigastric or right
upper quadrant abdominal pain. Patients should have urine protein checked by
dipstick. If positive, urine protein should be quantified by either a protein:creatinine
ratio or 12- or 24-h urine collection. The degree of oedema is of little clinical value
unless the patient presents with pulmonary oedema. Laboratory studies include complete blood count, platelet count, serum creatinine and uric acid, serum aspartate
transaminase (AST) and alanine aminotransferase (ALT). Fetal wellbeing should be
assessed. The patient is classified as having mild pre-eclampsia, unless any of the
criteria listed in Table 1 are present.17,28
Patients with mild pre-eclampsia can be managed expectantly28 if premature, twiceweekly assessment of mother and fetus are indicated. When the gestational age is 37
weeks or fetal lung maturity has been confirmed, delivery should be considered.
Patients with severe pre-eclampsia should be prepared for delivery.28 As described
above, pre-eclampsia is a state of poor placental perfusion and altered maternal vascular endothelial function. Interventions are therefore focused on improving placental
perfusion through improving cardiac output and peripheral vasodilation. The patient
should be placed on her side (left or right) in a supine position. This will improve
venous return, preload and cardiac output. In the authors experience, most preeclamptic patients are intravascular volume depleted and require some degree of
volume resuscitation, which will result in improved cardiac output, improved placental
perfusion and temporization of the disease process. If undelivered, continuous fetal
monitoring is performed.
Magnesium sulphate seizure prophylaxis should be initiated in the severe
pre-eclamptic, and there is great controversy regarding whether patients with
mild pre-eclampsia should also receive magnesium prophylaxis.29 The authors use
a loading dose of 46 g intravenously over 20 min, followed by a continuous intravenous drip at 2 g/h, which will maintain most patients in the therapeutic range of

Table 1. Criteria for severe pre-eclampsia.

Sustained systolic blood pressure >160 mmHg
Sustained diastolic blood pressure >110 mmHg
Pulmonary oedema
Proteinuria >5 g/24 h
Oliguria <500 mL/24 h
Persistent headaches or scotomata
Persistent right upper quadrant or epigastric pain
Thrombocytopenia <100 000/mm3
Intra-uterine growth restriction <10th percentile

830 J. Williams et al

>4 mEq/mL. Blood pressure can be controlled with the judicious use of hydralazine
or labetalol.32 The authors recommend target blood pressures of approximately
150 mmHg systolic and 100 mmHg diastolic. Rapid vasodilation should be avoided
by adequate intravascular resuscitation in order to prevent further decrease in perfusion of the placenta.
At gestational ages <34 weeks, the administration of betamethasone should be
considered and delivery delayed for 48 h if the maternal condition is stable.28 For
patients with extreme premature gestational ages (<32 weeks), expectant management can be considered, particularly for those who are classified as severe based
on isolated hypertension or proteinuria.30
Eclampsia
Patients who develop seizures or who present after having had a seizure should be
started on magnesium sulphate immediately (46 g intravenous loading dose, 2 g/h
continuous intravenous infusion).31 A thorough neurological examination should be
performed. The patient should be evaluated for other signs and symptoms suggestive
of eclampsia. If the diagnosis of eclampsia is likely and the neurological examination is
unremarkable, the patient is managed similarly as outlined for severe pre-eclampsia. If
neurological deficits are present or other signs or symptoms of pre-eclampsia are not
present, urgent central nervous system imaging and neurological consultation are
indicated.31
Pre-eclampsia is associated with an increased risk for both ischaemic and haemorrhagic stroke. Ischaemic stroke results from severe vasospasm, while haemorrhagic
stroke is associated with uncontrolled hypertension. Clinicians must distinguish
between eclampsia and primary intracranial pathologies which may also be associated
with hypertension and seizures, such as stroke or neoplasm.31 This distinction may be
difficult to make. Therefore, the authors recommend imaging studies in all patients
who present with a new onset of seizure(s), particularly if the diagnosis of eclampsia
is uncertain.
HELLP syndrome
Haemolysis should be demonstrated by either an elevation of lactate dehydrogenase of
>600 IU/L, bilirubin level of >1.2 mg/dL or a peripheral blood smear showing the
presence of schistocytes. Elevated liver enzymes are defined by either ALT or AST
>72 IU/L. Low platelets is defined as <100 000/mm3.28,32
If undelivered, patients with HELLP syndrome should be prepared for delivery and
managed as outlined for severe pre-eclampsia.
The use of (high-dose) steroids in order to stabilize platelet values and speed up
recovery has been suggested by some investigators.33 However, a recent randomized
controlled trial does not seem to support the use of steroids for this indication.34
Since pre-eclampsia, eclampsia and HELLP syndrome are caused by the placenta,
the ultimate treatment requires delivery of the baby and the placenta. The mode
of delivery is determined by the obstetric care provider. Many patients can be delivered safely vaginally and do not require a caesarean section. However, induction of
labour remote from term is associated with high rates of failed induction.3537 Importantly, one should only proceed with delivery after the maternal condition has been
stabilized.

Critical care in obstetrics: pregnancy-specific conditions

831

Chronic hypertension
The prevalence of chronic hypertension is low overall. However, as the number of
older women having children increases, chronic hypertension will become more prevalent in pregnant patient populations.
Once pre-eclampsia has been excluded, the patient is managed as having chronic
hypertension. A subgroup of these patients will have gestational hypertension, which
will resolve within 6 weeks of delivery. It is critical to rule out other causes of hypertension including renal disease, primary hyperaldosteronism, collagen vascular disease
and pheochromocytoma. The underlying disorder should be managed as appropriate;
the authors recommend a continued blood pressure target of 140/90 mmHg.
Summary
Pre-eclampsia is a common complication of pregnancy associated with significant
maternal and perinatal morbidity and mortality. The pathophysiology reflects poor
placental perfusion, release of placental humoral angiogenic factors and subsequent
maternal vascular endothelial dysfunction. Patients are classified as mild or severe.
Mild pre-eclampsia may be managed expectantly, particularly if <37 weeks of gestation.
Patients with severe pre-eclampsia should be stabilized, magnesium seizure prophylaxis
initiated and prepared for delivery. Complications of pre-eclampsia include seizures
(eclampsia), HELLP syndrome, renal failure and DIC. Fortunately, with the delivery
of the placenta, these complications tend to be self-limiting.
ACUTE FATTY LIVER OF PREGNANCY
Acute fatty liver of pregnancy is a rare disorder with an incidence between one in 700
and one in 1300 deliveries.3840 The disease is characterized by microvesicular fatty
infiltration of the liver with hepatic failure, and usually presents clinically in the third
trimester.41 Maternal and fetal/neonatal mortality estimates have ranged significantly
over time, with two recent reviews revealing maternal mortality of 012.5% and fetal
mortality of 1566%.39,41
Aetiology
While the aetiology of the disease is not currently understood, the pathology seen has
long been likened to that of Reyes syndrome and other inherited fatty acid oxidation
disorders. As such, a link was made between mothers who developed acute fatty liver
of pregnancy and those who have children with long-chain 3-ketoacyl-CoA dehydrogenate deficiency.42,43 One study evaluated 24 children with long-chain 3-ketoacylCoA dehydrogenate deficiency. Nineteen of them had a particular mutation
(Glu474Gln), and of these, 79% of their mothers had developed acute fatty liver of
pregnancy or HELLP syndrome. Of the five children who did not carry this particular
mutation, none of their mothers had developed liver disease during pregnancy.43 It is
thought that the combination of genetic and acquired factors can compromise intramitochondrial fatty acid oxidation significantly, and acute fatty liver can develop. The
implications of this genetic link raise important perinatal and neonatal issues which
will be discussed later.

832 J. Williams et al

Clinical presentation/diagnosis
As stated, the clinical presentation is usually in the third trimester, with an average
gestational age of 35 weeks.39,41 Nausea and vomiting are the most common presenting symptoms, but malaise, epigastric or right upper quadrant pain, headache and
fatigue are also seen. In two retrospective reviews, jaundice was seen at presentation
in 37%41 and 100%39 of patients. Laboratory abnormalities overlap with abnormalities
seen in HELLP syndrome (thrombocytopenia, elevated transaminases, hyperuricaemia
and elevated creatinine), although the thrombocytopenia and elevations in transaminases may be mild to moderate (average platelets 151 000 and average AST/ALT
523/423 at presentation).41 Other abnormalities such as hyperbilirubinaemia, hypoglycaemia and hyperammonaemia can help to delineate the diagnosis. If the patient
develops DIC, a deficiency of antithrombin III can be particularly prominent.44 While
acute fatty liver is usually a clinical diagnosis, liver biopsy and imaging studies are sometimes performed in order to rule out other aetiologies for the presentation.
Clinical course/management
Prompt recognition, aggressive maternal stabilization and rapid delivery characterize
the necessary treatment of this disease in order to minimize maternal and fetal morbidity and mortality. Hypoglycaemia and coagulopathy are seen in 4050% of
patients39, and therefore, glucose infusion and aggressive resuscitation with blood
products are common. Renal failure, encephalopathy and pancreatitis may also develop
and need to be treated supportively. Most commonly, there is eventual resolution of
the disease and recovery of organ systems involved, but this may require prolonged
hospitalization (average stay in intensive care of 10.4 days39, average hospitalization
of 15.1 days41). Liver transplantation is infrequent.41
An important management issue is counselling with respect to subsequent
pregnancy. Recurrence was first reported in 199142, and subsequently, a link has been
established between development of acute fatty liver of pregnancy and mutation in
genes related to fatty acid oxidation, most commonly in the gene for long-chain
3-ketoacyl-CoA dehydrogenase.43 As such, neonates born to mothers with acute fatty
liver of pregnancy should be tested immediately for long-chain 3-ketoacyl-CoA dehydrogenase deficiency as well as other disorders of fatty acid oxidation. This is being
done as part of the newborn metabolic screen in many regions.45 Counselling the
patient regarding future pregnancy should include the option of testing for known
mutations in the long-chain 3-ketoacyl-CoA dehydrogenase gene, as the presence of
such a mutation increases the possibility of recurrence of acute fatty liver in subsequent
pregnancies. Additionally, if such a mutation is found, there are important implications in
terms of having an affected fetus (the disease state is inherited in an autosomal-recessive
fashion). Ongoing research will aid understanding of the maternalfetal interaction seen
in this disease, and this will facilitate improved counselling for these patients.
PERIPARTUM CARDIOMYOPATHY
Peripartum cardiomyopathy is a well-known but rare cause of heart failure associated
with pregnancy. The National Institutes of Health have identified peripartum cardiomyopathy as a distinct clinical entity, occurring more often than idiopathic heart failure in
non-pregnant women of the same age.46

Critical care in obstetrics: pregnancy-specific conditions

833

Four criteria have been developed to characterize peripartum cardiomyopathy: (1)

development of heart failure within the last 4 weeks of pregnancy or within 5 months
of delivery; (2) no pre-existing heart disease; (3) no other identifiable cause of heart
failure; and (4) left ventricular systolic dysfunction.
The first two criteria are linked; the time constraints serve to minimize the possibility
of pre-existing heart disease because the haemodynamic stresses of pregnancy in patients with pre-existing disease would likely lead to symptoms prior to the last 4 weeks
of pregnancy. One study has questioned this component of the definition. This study included 100 women meeting the traditional definition of cardiomyopathy and 23 who differed in that they presented earlier than the last gestational month (but met the other
criteria). This study found that there were no significant differences in the characteristics or clinical course between these two groups.47 From this, it was postulated that
there may be a spectrum of disease which usually includes women characterized by
the temporal characteristics described traditionally, but that also includes women
with earlier presentation. Further research will be needed to clarify this issue.
Having no other identifiable cause of heart failure is the third part of the definition,
and is important in that it distinguishes peripartum cardiomyopathy as its own clinical
entity. Finally, although peripartum cardiomyopathy is a dilated form of cardiomyopathy, the definition also requires that systolic function be demonstrably impaired, in
order to distinguish pathology from pregnancy itself which can lead to a dilated (but
functional) left ventricle.
Epidemiology
The reported incidence of peripartum cardiomyopathy has varied greatly over time
and worldwide. A recent review in a multi-ethnic community in the USA described
an overall incidence of one in 4025 deliveries. The incidence was determined in Caucasians, African-Americans, Hispanics and Asians, and was highest in African-Americans (one in 1421) and lowest in Hispanics (one in 9861).48 The higher incidence in
particular geographic/ethnic groups has been reported many times previously; the
highest rates reported are one in 400 in Haiti.49 The risk factors are: age >30 years;
multiparity; pre-eclampsia or hypertension; and long-term tocolytic therapy with
beta-adrenergic medications.
Aetiology
The aetiology of peripartum cardiomyopathy is unknown; however, leading theories
include damage caused by the release of inflammatory cytokines50, viral or idiopathic
myocarditis51,52, abnormal immune response to fetal antigen, and maladaptive
response to haemodynamic factors associated with pregnancy. Levels of inflammatory
cytokines, such as tumour necrosis factor-alpha, interleukin-6 and Fas/APO-1 (an
apoptosis-signalling surface receptor), have been shown to be significantly elevated
in women with peripartum cardiomyopathy compared with healthy women.50 The
possibility of postviral myocarditis or that seen as a result of an auto-immune aetiology
has been explored and remains controversial.52,53
Clinical presentation/diagnosis
Peripartum cardiomyopathy usually presents post partum.54 The diagnosis can be difficult due to the fact that many of the symptoms (such as dyspnoea, swelling and

834 J. Williams et al

fatigue) are common in the first postpartum month following a normal pregnancy. Patients most commonly present with dyspnoea, cough and orthopnoea.55 Other symptoms include fatigue, non-specific chest discomfort and abdominal pain. Rarely,
a patient can present with systemic emboli as a result of the dilated, dysfunctional
left ventricle, or with an acute myocardial farction due to inadequate perfusion of
the coronary arteries.
The physical examination will show signs typical of heart failure: hypoxia; jugular
venous distention; S3 gallop; rales; and hepatomegaly. The chest x-ray will show
cardiomegaly with pulmonary congestion and/or pleural effusions. The electrocardiogram can be normal, but may show left ventricular hypertrophy and/or dysrhythmias.
In the initial evaluation, serum troponins may be useful to rule out myocardial infarction, although these elevations can occasionally be seen in peripartum cardiomyopathy
as well.56 Ultimately, an echocardiogram is imperative for the diagnosis of peripartum
cardiomyopathy; it will show a dilated left atrium and ventricle, left ventricular systolic
dysfunction, and a diminished ejection fraction.
Management
In the acute setting, management begins with the ABCs (airway, breathing, circulation).
Assessment of the airway is critical, as it can be suboptimal due to pregnancy or recent
pregnancy with associated third spacing of excess intravascular volume. Breathing is
addressed via continuous pulse oximetry and placement of the patient on supplemental oxygen. The circulation should be assessed with cardiac and blood pressure monitoring. Appropriate venous and/or arterial access should be obtained rapidly so that
medications can be administered expeditiously and monitoring can be streamlined.
In antepartum patients, fetal heart rate monitoring should be obtained immediately.
With impaired breathing and/or circulation, it is common to see heart rate tracing abnormalities. In this case, it is critically important to stabilize maternal status; this may
result in resolution of fetal heart rate tracing abnormalities and will prevent haste in
performing a caesarean delivery that may be poorly tolerated by the mother.
Maternal medical stabilization should then have three objectives: reduce preload;
reduce afterload; and increase inotropy.57 This is done in order to achieve the goals
of improving haemodynamics, minimizing patient symptoms, and optimizing longterm outcomes. Choice of medications requires consideration regarding whether
the patient is still pregnant or breast feeding. Preload reduction is accomplished
with nitrates, most of which are safe during pregnancy and breast feeding. Diuretics
are also important, although caution is warranted in pregnant patients in order to
avoid rapid changes in intravascular volume that can lead to decreasing the blood
supply to the uterus. Afterload reduction can be achieved in the pregnant patient
with vasodilators such as hydralazine. For the postpartum patient, angiotensin-converting-enzyme inhibitors are the preferred agents. To increase inotropy, betablockers are used and have been shown to improve survival in patients with dilated
cardiomyopathy; however, it is important to note that these must not be initiated in
the acute decompensated phase as they can decrease perfusion in this setting. Dopamine, dobutamine and digoxin are not contra-indicated in pregnancy, and are particularly useful in the case of acute decompensated heart failure with hypotension.57
Anticoagulation is an important adjunct to therapy due to the hypercoagulable state
of pregnancy, as well as the stasis of blood seen with severe left ventricle dysfunction.58 Therapy is suggested with an ejection fraction <30%, and an agent other
than coumadin (heparin, low-molecular-weight heparin) should be used when the

Critical care in obstetrics: pregnancy-specific conditions

835

patient is pregnant. Aggressive medical management of ventricular arrhythmias is recommended, and 23% of patients will require implantable defibrillators/pacemakers.47
Treatment with immunosuppressive agents and intravenous immunoglobulin remain
controversial at present. Left ventricular assist devices and heart transplant are
reserved for the postpartum patient in whom other therapy is unsuccessful. According
to one study, heart transplantation was necessary in 4% of patients.47
Prognosis/future pregnancy
The prognosis of women with peripartum cardiomyopathy has varied greatly over time.
Several current studies suggest that mortality and morbidity are significantly better with
contemporary management than has been reported previously. Of these, one study followed 123 women and reported a mortality rate of 9% at a mean follow-up of 24
months.47 Another reported zero deaths in 55 women at a mean follow-up of 43
months.59 However, a study of a cohort of 29 African women reported eight deaths
by 6 months following the diagnosis.50 These results suggest that although mortality rates
have improved, mortality remains extremely high in a significant population of women.
With appropriate medical support, most patients will improve following their
presentation. In one study, ejection fraction improved from 29% to 46% by 2 years,
with most of the recovery occurring in the first 6 months. In the same study, 54%
recovered fully (ejection fraction >50%).47 However, many patients will not improve
and will go on to need further treatment (left ventricular assist devices, heart transplant). Several factors have been identified which are associated with these poorer
prognoses: ejection fraction <30% at diagnosis50; left ventricular end diastolic dimension >6 cm60; elevated cardiac troponin T56; and elevated sFas/APO-1.50
Counselling women regarding the risks associated with subsequent pregnancy is
difficult; however, studies have suggested that dividing women into two risk categories
(recovered versus non-recovered left ventricle function) is most appropriate.61,62 In
a study of 28 women with recovered left ventricle function who became pregnant,
there were no deaths, but six women developed heart failure symptoms and six
women had a reduction in ejection fraction >20%. In the same study, 16 women
had persistent left ventricle dysfunction and subsequently became pregnant. Of these,
four women underwent therapeutic abortion and 12 women continued their pregnancies. Among those continuing their pregnancy, three died, six developed heart failure
symptoms and four had a reduction in their ejection fraction >20% (groups not mutually exclusive). With regard to neonatal outcomes, preterm delivery (between 30
and 36 weeks) was seen in 13% (three patients) of pregnancies in women with recovered left ventricle function and 50% (six patients) of pregnancies in women with persistent left ventricle dysfunction. There were no neonatal deaths.61 In summary, while
some women will tolerate subsequent pregnancies, many will experience a decline in
their left ventricular function. Furthermore, the subset of women with persistent left
ventricular dysfunction has a significant risk of preterm birth and maternal death.
AMNIOTIC FLUID EMBOLISM
AFE is a rare, but often devastating, obstetric emergency. The patient typically
presents with an acute onset of severe hypoxia, mental status changes, cardiovascular
collapse and DIC. Mortality risk for the mother and baby is high, and survivors may
have long-term clinical sequelae.

836 J. Williams et al

Epidemiology
There is a wide variation in the incidence of AFE, ranging from one in 8000 to one in
80 000. The incidence is reported as one in 20 00030 000 in the USA, one in 27 000 in
South-east Asia, and one in 80 000 in the UK. The clinical presentation is highly
variable and milder cases may not be reported. The diagnosis of AFE is often made
by exclusion, as there is no definitive diagnostic test.63
Although earlier publications reported maternal mortality as high as 86% in 197964
and 61% in 199565, more recent data from 1999 suggest a lower mortality rate of
26%.66 The UK AFE registry reported case fatality of 37% in 2005.67 Morbidity is also
significant, but numbers vary largely between reports. In a retrospective review of 46
women, Clark et al reported that only 15% of the survivors were neurologically intact.65
The UK registry reports an incidence of poor long-term neurological outcome of 7%.67
AFE most commonly occurs intra partum or immediately post partum. When AFE
occurs prior to delivery, perinatal morbidity and mortality are also high. Clark et al
reported a perinatal survival rate of 79% with 50% neurological morbidity.65 In the
UK registry, 78% of infants survived, with 29% of these showing evidence of hypoxic
ischaemic encephalopathy.67
These data suggest that with improved diagnosis and medical intensive care, the
maternal mortality rate has improved markedly but remains high at approximately
2535%, with an estimated risk of 1020% for long-term sequelae.67 Approximately
80% of infants will survive, with an estimated 30% risk for long-term morbidity.67
Pathophysiology
Traditionally, AFE has been believed to be caused by the entry of amniotic fluid and its
contents into the maternal venous blood stream. This sets off a chain of events in
which the amniotic fluid travels to the pulmonary vasculature and causes a massive,
pulmonary embolism-like clinical presentation, including acute pulmonary vasospasm
with severe hypoxia, pulmonary hypertension, right heart failure, cardiovascular
collapse, mental status changes and often death. If the patient survives the initial event,
she will often develop DIC and left ventricular heart failure. However, this classic theory remains controversial. The question remains whether it is the actual amniotic fluid,
certain components within the amniotic fluid or an altered, immunopathological
response to these components that sets off this chain of events.
Early autopsy studies in which amniotic fluid was described in the pulmonary
vasculature provided evidence to support this theory.68 Later, Resnik et al identified
mucin and fetal squamous cells in the pulmonary artery catheter aspirate of a patient
who was diagnosed with AFE.69 James et al70 described gross enlargement of the right
ventricle and pulmonary artery by transoesophageal echocardiography prior to the
death of a 36-year-old patient with suspected AFE. Autopsy demonstrated extensive
microvascular plugging of the pulmonary capillaries. However, the presence of fetal
cells in the maternal circulation has also been described in patients without AFE.
Amniotic fluid is comprised of fetal urine and contains many cellular components,
fetal hair, vernix and a variety of prostaglandins and leukotrienes. It may not be the
actual presence of the amniotic fluid or its components, but the maternal (immune)
response to these chemical mediators which ultimately determines whether the
patient develops AFE. Clark described this as an anaphylactoid reaction to amniotic
fluid.71 Several publications posit a role for a number of vasoactive and inflammatory
mediators including endothelin, histamine, serotonin, bradykinin, prostaglandins and

Critical care in obstetrics: pregnancy-specific conditions

837

leukotrienes.7274 These mediators may play a causative role in the pathogenesis of

AFE, or may only reflect components of the systemic maternal response.
Well over 50% of patients with AFE will develop DIC, which may be the presenting
or only symptom. The degree of consumptive coagulopathy appears to be disproportionate to the observed blood loss. It has been postulated that amniotic fluid activates
factor X.90 Uszynski et al described the role of tissue factor and tissue factor pathway
inhibitor in amniotic fluid and blood plasma as a possible mechanism.75
Clinical presentation
AFE must be considered when a labouring or immediately postpartum patient presents with either one or a combination of the following primary symptoms: dyspnoea;
coughing; severe hypoxia; profound hypotension; seizures; or mental status changes.
Secondary symptoms may include fetal bradycardia and DIC.
The typical patient initially presents with coughing and complaints of shortness of
breath, and then rapidly becomes hypoxic. If the patient is still pregnant, fetal bradycardia will develop. Pulmonary vasoconstriction leads to severe hypoxia, and is
followed by the development of profound hypotension and systemic vascular collapse.
Mental status changes may be seen at this point. The second phase of the disease then
evolves and is characterized by the development of left ventricular heart failure. This is
due to poor diastolic filling as well as decreased cardiac contractility. The compromised filling is related to compression of the ventricle caused by increased volumes
seen by the right heart, which are secondary to the impedence of flow caused by pulmonary vasoconstriction. The decreased contractility is felt to be secondary to a direct
toxic effect on the myocytes. This combination leads to cardiac dysfunction which
must be treated aggressively and monitored carefully. This second phase is also
commonly characterized by DIC, and seizure activity also been reported.
Importantly, patients with AFE may present with some but not all of these clinical
findings, and the sequence of events may vary considerably. Ultimately, the diagnosis is
based on the interpretation of the clinical presentation as well as the exclusion of
other differential diagnoses, including pulmonary embolus, acute myocardial infarction,
cerebral vascular accident, sepsis, placental abruption and uncompensated maternal
blood loss (with or without consumptive coagulopathy). When the diagnosis remains
unclear, some experimental assays (serum tryptase, serum sialyl Tn antigen levels and
zinc coproporphyrin) have been proposed to be more specific and may be available in
some centres.
Clinical management
The initial treatment begins with basic and advanced cardiac life support protocols.
The need for an intensive care facility and personnel should be recognized and organized immediately. The patient should be intubated and mechanical ventilation initiated. High oxygen concentrations will be required in order to manage severe
hypoxia. Adequate intravenous access needs to be established with large-bore catheters. Aggressive measures to maintain perfusion will be necessary (using crystalloid,
blood products and vasopressors). Intra-arterial monitoring (with an arterial line
and pulmonary artery catheter) are important tools to aid in this resuscitation.
If the patient is still pregnant, the care team needs to assess whether the maternal condition is stable enough to proceed with an emergency delivery; if not, a decision may

838 J. Williams et al

be made not to intervene on behalf of the fetus. Concise communication between all
participating care teams is critical.
After the initial stabilization and notification of care teams, communication with the
blood bank is critical and the following serum studies should be obtained immediately:
type and crossmatch; complete blood count with platelet count; coagulation profile
(pro-time, partial thromboplasin time, fibrinogen, D-dimer, fibrin split products); and
an arterial blood gas. Additionally, a chest x-ray, 12-lead electrocardiogram and cardiac
echo (surface or transoesophageal) are needed.
When coagulopathy develops, significant resuscitation with blood products (packed
red blood cells and fresh frozen plasma) will be required. Cryoprecipitate may be used
when fibrinogen levels are low and administration of less volume is desired. Patients
with DIC in the setting of AFE seem to require an unusually high amount of fresh frozen
plasma in order to correct the coagulopathy. The administration of these blood products
in this setting of impaired cardiac function requires particular attention to fluid balance,
and tools to evaluate right and left cardiac dysfunction (pulmonary artery catheter, SwanGanz catheter) are advocated. When echocardiography is performed, it will reveal high
pulmonary pressures and marked right ventricular dilation. As stated previously, the dilated right ventricle may prevent adequate diastolic filling of the left ventricle and worsen
cardiac output. In this situation, nitric oxide has been reported to be beneficial.76
After the acute coagulopathy is resolved, the use of prophylactic heparin (unfractionated or fractionated) should be considered in patients with AFE, as there is an
increased risk for development of thrombotic complications.9 Supportive care is
continued in intensive care until resolution of the disease process occurs.
Risk factors for AFE
A tumultuous labour pattern, particularly when oxytocin is used, has been postulated
as having a causative relationship on the occurrence of AFE, although Morgan64 and
Clark and Butt77 could not confirm any maternal risk factor related to AFE. The American College of Obstetrics and Gynecology (ACOG) and many textbooks reflect the
opinion that oxytocin use is not associated with AFE.78 In the current setting of the
increased use of prostaglandins, some feel that we may need to re-evaluate the association between uterine stimulation and AFE.79 One retrospective cohort study of risk
factors for AFE found that medical induction of labour nearly doubled the risk of AFE,
although the absolute risk (10 in 100 000) was still quite small.80 They also identified
other risk factors including uterine rupture, placenta previa and abruptio placentae.80
There are published case reports of AFE after abdominal and surgical trauma, first- and
second-trimester abortion, amniocentesis and removal of a cervical cerclage.81
Summary
AFE is a rare but potentially catastrophic syndrome with an estimated incidence of one
in 25 000 to one in 30 000. Mortality is high (3040%) in those patients who exhibit the
classic presentation of acute severe hypoxia, cardiovascular collapse, mental status
changes, and DIC.66,67 Long-term neurological sequelae may persist in 1020% of patients. If AFE occurs while the mother is still pregnant, immediate delivery of the fetus
may result in good survival; otherwise, perinatal mortality and morbidity are high.
The pathophysiology of AFE remains controversial. There is clear evidence that
amniotic fluid and its components enter the maternal venous circulation.6870 This
may result in mechanical obstruction in the pulmonary capillaries and/or incite

Critical care in obstetrics: pregnancy-specific conditions

839

a systemic response by the mother which is similar to anaphylaxis or sepsis. The notion that labour induction or augmentation is not associated with AFE may need to be
re-addressed. It may be that it is not the uterine tone or force that makes it more
likely to push amniotic fluid into the maternal circulation, but that the production
of different mediators inciting AFE are associated with labour induction and
augmentation.
Every obstetric care provider should be familiar with this clinical syndrome and
consider the diagnosis early in its presentation. Early diagnosis and initiation of treatment are paramount. Treatment includes cardiovascular and respiratory resuscitation
(with intubation/ventilation, crystalloids, vasopressors) in order to optimize cardiac
output, and correction of coagulopathy.
TRAUMA IN PREGNANCY
Trauma during pregnancy is the leading non-obstetric cause of maternal mortality and
is responsible for at least one million maternal deaths worldwide each year.82 Approximately 67% of pregnancies will be complicated by maternal trauma.8385 Motor
vehicle accidents are the most common cause of maternal trauma (55%)83,85,86,
followed by falls and assaults, both of which account for 22%.86,87 Traumatic injuries
can be further classified as blunt (most frequently resulting from falls, motor vehicle
accidents or partner violence) or penetrating (prevalent in high-crime settings).
Motor vehicle accidents
Motor vehicle accidents account for the largest number of trauma-related fetal
deaths, accounting for 4000 fetal losses annually in the USA.82,86 Motor vehicle accidents fall under the general category of blunt injury.82 The risk that a motor vehicle
accident will result in an obstetric complication is proportional to the speed at which
the motor vehicle accident occurred and the severity of the injury.82 Although the risk
of fetal loss is greatest after severe maternal trauma, even minor blunt abdominal
trauma increases the risk for fetal loss compared with controls not experiencing
trauma.83
Approximately 70% of fetal losses resulting from maternal trauma are caused by
placental abruption.83 Placental abruption complicates up to 40% of cases of severe
maternal trauma and 15% of cases of minor maternal trauma.88 During blunt trauma,
the myometrial tissue is able to respond to accelerationdeceleration forces by changing its shape. However, the placenta is relatively inelastic, and this mismatch between
the myometrium and the placenta creates a shearing force which leads to placental
abruption.82,88
Partner abuse
Intimate partner violence is the most common cause of trauma-related maternal death
during pregnancy, and maternal deaths due to homicide exceed those due to any
obstetric cause.89 Between 6% and 22% of gravid women experience intimate partner
violence during pregnancy and are at increased risk for violent assault compared with
non-pregnant women.89 Kicks and punches to the abdomen are frequent types of
intimate partner violence, and women who experience such violence are at increased

840 J. Williams et al

risk for miscarriage, preterm labour, premature rupture of membranes and low birth
weight.89
Falls
Pregnancy may result in decreased postural stability and balance, leading to increased
falls compared with the non-pregnant state.90,91 The risk that a fall will result in fetal
loss is low compared with other types of maternal trauma.92 In a recent prospective
cohort study of minor trauma during the third trimester of pregnancy, there were no
placental abruptions experienced among 153 women who presented for evaluation of
falls.93
Penetrating trauma
Gunshot wounds are the most frequent cause of maternal penetrating trauma,
followed by knife wounds.88 Pregnant women are at decreased risk of death from
penetrating abdominal trauma compared with non-pregnant women, owing to the
protective effect of the gravid uterus.82,88 Conversely, penetrating injury to the maternal upper abdomen is associated with increased risk of bowel injury compared with
the non-gravid state due to the upward displacement of the bowel by the uterus.88
However, penetrating abdominal trauma is associated with a very high risk of fetal
death, ranging from 40% to 70%.82,88 In general, gunshot wounds are associated
with a higher risk of fetal mortality than knife wounds.88
Direct fetal injuries
Direct fetal injury is less common than indirect injury but can occur, particularly when
the fetal head is engaged in the pelvis.82 These injuries, which complicate <1% of pregnancies affected by trauma, can result in fetal skull fractures, intracranial haemorrhage
and cerebral oedema, all of which can lead to adverse neurological outcome.82,94
Advances in fetal imaging may lead to detection of more cases of direct injury.
Evaluation and management
Immediate response to suspected maternal trauma should include positioning the
mother in the left lateral tilt position in order to displace the uterus from the inferior
vena cava.86 Laboratory evaluation should include a complete blood count and platelet
count, evaluation of coagulation and a Kleihauer-Betke (KB) test.88 The KB test, which
detects the presence of fetal red blood cells in the maternal circulation, may be used to
quantify the extent of maternalfetal haemorrhage. ACOG advocates use of the KB
test in order to identify those Rhesus-negative women who experience fetalmaternal
haemorrhage >30 mL and who will require additional vials of RhoGam.86,94 In >90%
of trauma cases, the fetomaternal haemorrhage will be <30 mL, and one vial of
Rhesus immunoglobulin will be sufficient to prevent sensitization in Rhesus-negative
women. KB testing may also be used as a screen for preterm labour in Rhesus-positive
women. In one series of 71 pregnant women experiencing trauma, the KB test had 100%
sensitivity for predicting preterm labour, correctly identifying all of the 25 women who
developed preterm labour with a 4% false-positive rate.95 Based on these findings, the
authors advocate KB testing in all pregnant trauma patients, regardless of Rhesus

Critical care in obstetrics: pregnancy-specific conditions

841

status.95 However, these findings have not been duplicated by other authors and definitive recommendations await further studies.
Several authors recommend maternal/fetal assessment via the FAST (Focused
Assessment with Sonography in Trauma) examination.86,88 The FAST examination
consists of fetal position, fetal heart rate, gestational age assessment, biophysical
profile, middle cerebral artery Doppler study, and evaluation of the placenta for abruption.88 Ultrasound assessment for maternal intraperitoneal haemorrhage can be
performed at the same time.86 This evaluation has sensitivity of 8083% and specificity
of 98100% for intraperitoneal haemorrhage.86
Fetal monitoring
The fetal heart rate has been called the fifth vital sign because of its role as a very
early manifestation of maternal hypotension or hypovolaemia.88 Similarly, uterine activity may be a more sensitive indicator of placental abruption than ultrasound.94 As
placental abruption has been observed up to 48 h after maternal trauma, a minimum
of 4 h of fetal monitoring after trauma is advised, with 24 h of monitoring undertaken if
frequent uterine activity is detected on initial screening.88,94
Diagnostic imaging
Imaging with ultrasound is safe in all trimesters of pregnancy, and there are no known
harmful effects of magnetic resonance imaging (MRI) during pregnancy.85 Some authors
advise restricting MRI scanning to the second and third trimesters of pregnancy, owing
to the relative scarcity of safety data concerning use in the first trimester.87 Computed
tomography (CT) may be used during pregnancy when clearly indicated. Fetal exposure from CT scans not involving the abdomen or pelvis is low, and these scans
may be performed safely in any trimester of pregnancy.85 CT scans of the abdomen
and pelvis result in a maximum fetal dose of approximately 12 rad, well below the
threshold dose of 1020 rad for fetal loss or malformation; however, concerns regarding a small increased risk of childhood cancers in exposed infants have been raised.88,94
In cases of penetrating trauma, management options include surgical exploration or
conservative management, which consists of peritoneal lavage, ultrasound, contrastenhanced CT scanning, local wound exploration and observation.88
Prevention
Physician counselling for seatbelt use during prenatal care has been shown to increase seatbelt usage significantly.96 In primate (baboon) studies employing experimental crash injuries, Pearlman demonstrated that compared with two-point
restraints, three-point restraints reduced fetal mortality from 100% to 40%.83
Based on these and other data, ACOG advocates prenatal education on proper
placement of three-point restraints. Although concerns have been raised regarding
the safety of airbag use, ACOG and the National Highway Traffic Safety Administration (NHTSA) do not recommend disabling airbags during pregnancy.88,94 However, NHTSA does recommend disabling airbags if the womans sternum or uterine
fundus cannot be positioned at least 10 inches behind the centre of the airbag
cover.88

842 J. Williams et al

Practice points
 approximately 70% of fetal losses complicating maternal trauma result from
placental abruption. A minimum of 4 h of fetal monitoring following maternal
trauma is advised
 providers of prenatal care should educate prenatal women on the proper use
of three-point restraints
 in the setting of massive haemorrhage, do not await laboratory confirmation of
DIC before initiating resuscitation with blood products
 balloon tamponade is the easiest and least invasive therapy for postpartum haemorrhage when uterotonic medications have failed
 an echocardiogram is the most useful diagnostic study for peripartum
cardiomyopathy
 AFE is a clinical diagnosis. Upon suspicion, presumptive treatment should be
immediate and aggressive
 patients with persistent left ventricular dysfunction after peripartum cardiomyopathy should be strongly counselled against future pregnancies
 infants born to mothers with acute fatty liver of pregnancy should be tested for
disorders of fatty acid metabolism
 serum glucose and ammonia are the most useful tests to help distinguish acute
fatty liver of pregnancy from HELLP syndrome
 patients with mild pre-eclampsia may be managed expectantly, particularly
when remote from term. Patients with severe pre-eclampsia should be prepared for delivery

Research agenda
 development and validation of a diagnostic scoring system for DIC
 review of outcomes and cost-effectiveness of current monitoring and evaluation of recommendations for fetalplacental surveillance after minor maternal
trauma
 more randomized controlled trials are needed to determine whether oxytocin
plus methergine or misoprostol is the more appropriate first-line strategy for
postpartum haemorrhage caused by uterine atony
 prior clinical trials have failed to find the benefit of a variety of treatments to
prevent recurrent pre-eclampsia. Clinical trials to determine whether use of
anticoagulants will prevent recurrent pre-eclampsia in patients with inherited
thrombophilias are needed

REFERENCES
1. Jeani Chang MPH, Laurie D, Elam-Evans PD et al. Pregnancy-related mortality surveillance United
States, 19911999. MMWR Morbid Mortal Weekly Rep 2003; 52(SS02): 18.

Critical care in obstetrics: pregnancy-specific conditions

843

2. Khan KS, Wojdyla D, Say L et al. WHO analysis of causes of maternal death: a systematic review. Lancet
2006; 367: 10661074.
3. Tsu VD, Langer A & Aldrich T. Postpartum hemorrhage in developing countries: is the public health
community using the right tools? Int J Gynaecol Obstet 2004; 85(Suppl 1): S42S51.
*4. Doumouchtsis SK, Papageorghiou AT & Arulkumaran S. Systematic review of conservative management of
postpartum hemorrhage: what to do when medical treatment fails. Obstet Gynecol Surv 2007; 62: 540547.
5. Chichakli LO, Atrash HK, Mackay AP et al. Pregnancy-related mortality in the United States due to
hemorrhage: 19791992. Obstet Gynecol 1999; 94: 721725.
6. Cohen WR. Hemorrhagic shock in obstetrics. J Perinat Med 2006; 34: 263271.
7. Chong Y-S, Su L-L & Arulkumaran S. Current strategies for the prevention of postpartum haemorrhage
in the third stage of labour. Curr Opin Obstet Gynecol 2004; 16: 143150.
8. Letsky EA. Disseminated intravascular coagulation. Best Pract Res Clin Obstet Gynaecol 2001; 15: 623
644.
9. Bick RL. Disseminated intravascular coagulation: a review of etiology, pathophysiology, diagnosis, and
management: guidelines for care. Clin Appl Thromb Hemost 2002; 8: 131.
10. Djelmis J, Ivanisevic M, Kurjak A et al. Hemostatic problems before, during and after delivery. J Perinat
Med 2001; 29: 241246.
11. Kobayashi T, Terao T, Maki M et al. Diagnosis and management of acute obstetrical DIC. Semin Thrombosis Hemostasis 2001; 27: 161167.
12. DeLoughery TG. Critical care clotting catastrophies. Crit Care Clin 2005; 21: 531562.
13. Pepas LP, Arif-Adib M & Kadir RA. Factor VIIa in puerperal hemorrhage with disseminated intravascular
coagulation. Obstet Gynecol 2006; 108: 757761.
14. Burtelow M, Riley E, Druzin M et al. How we treat: management of life-threatening primary postpartum
hemorrhage with a standardized massive transfusion protocol. Transfusion 2007; 47: 15641572.
15. Lim Y, Loo CC, Chia V et al. Recombinant factor VIIa after amniotic fluid embolism and disseminated
intravascular coagulopathy. Int J Gynaecol Obstet 2004; 87: 178179.
*16. Mousa HA & Alfirevic Z. Treatment for primary postpartum haemorrhage. Cochrane Database Syst Rev
2007; 1: CD003249.
*17. ACOG Practice Bulletin. Diagnosis and Management of Preeclampsia and Eclampsia. Clinical Management
Guidelines for Obstetrician-Gynecologists. Washington D.C.: American College of Obstetricians and
Gynecologists, 2002 Number 33.
18. Villar J, Say L, Gulmezoglu M et al. Eclampsia and pre-eclampsia: a world health problem for 2000 years.
In Critchley H, Maclean A, Poston L & Walker J (eds.). Pre-eclampsia. London: Royal College of Obstetricians and Gynaecologists, 2003, pp. 210225.
19. Hanna J, Goldman-Wohl D, Hamani Y et al. Decidual NK cells regulate key developmental processes at
the human fetal-maternal interface. Nat Med 2006; 12: 10651074.
20. Lyall F. Mechanisms regulating cytotrophoblast invasion in normal pregnancy and pre-eclampsia. Aust N
Z J Obstet Gynaecol 2006; 46: 266273.
21. Brosens JJ, Pijnenborg R & Brosens IA. The myometrial junctional zone spiral arteries in normal and
abnormal pregnancies: a review of the literature. Am J Obstet Gynecol 2002; 187: 14161423.
22. Karumanchi SA & Epstein FH. Placental ischemia and soluble fms-like tyrosine kinase 1: cause or consequence of preeclampsia? Kidney Int 2007; 71: 959961.
23. Lopez-Novoa JM. Soluble endoglin is an accurate predictor and a pathogenic molecule in pre-eclampsia.
Nephrol Dial Transplant 2007; 22: 712714.
24. Levine RJ, Maynard SE, Qian C et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J
Med 2004; 350: 672683.
25. Widmer M, Villar J, Benigni A et al. Mapping the theories of preeclampsia and the role of angiogenic
factors: a systematic review. Obstet Gynecol 2007; 109: 168180.
26. Baumwell S & Karumanchi SA. Pre-eclampsia: clinical manifestations and molecular mechanisms. Nephron 2007; 106: c72c81.
27. Poston L. Endothelial dysfunction in pre-eclampsia. Pharmacol Rep 2006; 58(Suppl): 6974.
28. von Dadelszen P, Menzies J, Gilgoff S et al. Evidence-based management for preeclampsia. Front Biosci
2007; 12: 28762889.
*29. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: evidence from randomized trials. Clin Obstet
Gynecol 2005; 48: 478488.

844 J. Williams et al
*30. Sibai BM, Mercer BM, Schiff E et al. Aggressive versus expectant management of severe preeclampsia at
28 to 32 weeks gestation: a randomized controlled trial. Am J Obstet Gynecol 1994; 171: 818822.
31. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol 2005; 105: 402410.
32. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver
enzymes, and low platelet count. Obstet Gynecol 2004; 103: 981991.
33. Martin Jr. JN, Rose CH & Briery CM. Understanding and managing HELLP syndrome: the integral role of
aggressive glucocorticoids for mother and child. Am J Obstet Gynecol 2006; 195: 914934.
34. Fonseca JE, Mendez F, Catano C et al. Dexamethasone treatment does not improve the outcome of
women with HELLP syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am J Obstet
Gynecol 2005; 193: 15911598.
35. Nassar AH, Adra AM, Chakhtoura N et al. Severe preeclampsia remote from term: labor induction or
elective cesarean delivery? Am J Obstet Gynecol 1998; 179: 12101213.
36. Park KH, Cho YK, Lee CM et al. Effect of preeclampsia, magnesium sulfate prophylaxis, and maternal
weight on labor induction: a retrospective analysis. Gynecol Obstet Invest 2006; 61: 4044.
37. Xenakis EM, Piper JM, Field N et al. Preeclampsia: is induction of labor more successful? Obstet Gynecol
1997; 89: 600603.
38. Castro MA, Fassett MJ, Reynolds TB et al. Reversible peripartum liver failure: a new perspective on the
diagnosis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases. Am J
Obstet Gynecol 1999; 181: 389395.
39. Mjahed K, Charra B, Hamoudi D et al. Acute fatty liver of pregnancy. Arch Gynecol Obstet 2006; 274:
349353.
40. Pockros PJ, Peters RL & Reynolds TB. Idiopathic fatty liver of pregnancy: findings in ten cases. Medicine
(Baltimore) 1984; 63: 111.
41. Fesenmeier MF, Coppage KH, Lambers DS et al. Acute fatty liver of pregnancy in 3 tertiary care centers. Am J Obstet Gynecol 2005; 192: 14161419.
42. Schoeman MN, Batey RG & Wilcken B. Recurrent acute fatty liver of pregnancy associated with a fattyacid oxidation defect in the offspring. Gastroenterology 1991; 100: 544548.
43. Ibdah JA, Bennett MJ, Rinaldo P et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in
pregnant women. N Engl J Med 1999; 340: 17231731.
44. Castro MA, Goodwin TM, Shaw KJ et al. Disseminated intravascular coagulation and antithrombin III
depression in acute fatty liver of pregnancy. Am J Obstet Gynecol 1996; 174: 211216.
45. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J
Gastroenterol 2006; 12: 73977404.
46. Pearson GD, Veille JC, Rahimtoola S et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood
Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and
review. JAMA 2000; 283: 11831188.
*47. Elkayam U, Akhter MW, Singh H et al. Pregnancy-associated cardiomyopathy: clinical characteristics and
a comparison between early and late presentation. Circulation 2005; 111: 20502055.
48. Brar SS, Khan SS, Sandhu GK et al. Incidence, mortality, and racial differences in peripartum cardiomyopathy. Am J Cardiol 2007; 100: 302304.
49. Fett JD, Carraway RD, Dowell DL et al. Peripartum cardiomyopathy in the Hospital Albert Schweitzer
District of Haiti. Am J Obstet Gynecol 2002; 186: 10051010.
50. Sliwa K, Skudicky D, Bergemann A et al. Peripartum cardiomyopathy: analysis of clinical outcome, left ventricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000; 35: 701705.
51. OConnell JB, Costanzo-Nordin MR, Subramanian R et al. Peripartum cardiomyopathy: clinical, hemodynamic, histologic and prognostic characteristics. J Am Coll Cardiol 1986; 8: 5256.
52. Bultmann BD, Klingel K, Nabauer M et al. High prevalence of viral genomes and inflammation in peripartum cardiomyopathy. Am J Obstet Gynecol 2005; 193: 363365.
53. Cenac A, Beaufils H, Soumana I et al. Absence of humoral autoimmunity in peripartum cardiomyopathy.
A comparative study in Niger. Int J Cardiol 1990; 26: 4952.
54. Demakis JG & Rahimtoola SH. Peripartum cardiomyopathy. Circulation 1971; 44: 964968.
55. Demakis JG, Rahimtoola SH, Sutton GC et al. Natural course of peripartum cardiomyopathy. Circulation
1971; 44: 10531061.
56. Hu CL, Li YB, Zou YG et al. Troponin T measurement can predict persistent left ventricular dysfunction
in peripartum cardiomyopathy. Heart 2007; 93: 488490.

Critical care in obstetrics: pregnancy-specific conditions

845

*57. Egan DJ, Bisanzo MC & Hutson HR. Emergency department evaluation and management of peripartum
cardiomyopathy. J Emerg Med 2007.
58. Fuster V, Stein B, Halperin JL et al. Antithrombotic therapy in cardiac disease: an approach based on
pathogenesis and risk stratification. Am J Cardiol 1990; 65: 38C44C.
59. Amos AM, Jaber WA & Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary. Am Heart J 2006; 152: 509513.
60. Chapa JB, Heiberger HB, Weinert L et al. Prognostic value of echocardiography in peripartum cardiomyopathy. Obstet Gynecol 2005; 105: 13031308.
*61. Elkayam U, Tummala PP, Rao K et al. Maternal and fetal outcomes of subsequent pregnancies in women
with peripartum cardiomyopathy. N Engl J Med 2001; 344: 15671571.
62. Sliwa K, Forster O, Zhanje F et al. Outcome of subsequent pregnancy in patients with documented
peripartum cardiomyopathy. Am J Cardiol 2004; 93: 14411443. A10.
63. Porat S, Leibowitz D, Milwidsky A et al. Transient intracardiac thrombi in amniotic fluid embolism. Br J
Obstet Gynaecol 2004; 111: 506510.
64. Morgan M. Amniotic fluid embolism. Anaesthesia 1979; 34: 2032.
65. Clark SL, Hankins GD, Dudley DA et al. Amniotic fluid embolism: analysis of the national registry. Am J
Obstet Gynecol 1995; 172: 11581167. discussion 6769.
66. Gilbert WM & Danielsen B. Amniotic fluid embolism: decreased mortality in a population-based study.
Obstet Gynecol 1999; 93: 973977.
*67. Tuffnell DJ. United Kingdom amniotic fluid embolism register. Br J Obstet Gynaecol 2005; 112: 1625
1629.
68. Steiner PE & Lushbaugh CC. Landmark article, Oct. 1941: Maternal pulmonary embolism by amniotic
fluid as a cause of obstetric shock and unexpected deaths in obstetrics. JAMA 1986; 255: 21872203.
69. Resnik R, Swartz WH, Plumer MH et al. Amniotic fluid embolism with survival. Obstet Gynecol 1976; 47:
295298.
70. James CF, Feinglass NG, Menke DM et al. Massive amniotic fluid embolism: diagnosis aided by emergency transesophageal echocardiography. Int J Obstet Anesth 2004; 13: 279283.
71. Clark SL. New concepts of amniotic fluid embolism: a review. Obstet Gynecol Surv 1990; 45: 360368.
72. Oi H, Kobayashi H, Hirashima Y et al. Serological and immunohistochemical diagnosis of amniotic fluid
embolism. Semin Thrombosis Hemostasis 1998; 24: 479484.
73. Benson MD, Kobayashi H, Silver RK et al. Immunologic studies in presumed amniotic fluid embolism.
Obstet Gynecol 2001; 97: 510514.
74. Robillard J, Gauvin F, Molinaro G et al. The syndrome of amniotic fluid embolism: a potential contribution of bradykinin. Am J Obstet Gynecol 2005; 193: 15081512.
75. Uszynski M, Zekanowska E, Uszynski W et al. Tissue factor (TF) and tissue factor pathway inhibitor
(TFPI) in amniotic fluid and blood plasma: implications for the mechanism of amniotic fluid embolism.
Eur J Obstet Gynecol Reprod Biol 2001; 95: 163166.
76. McDonnell NJ, Chan BO & Frengley RW. Rapid reversal of critical haemodynamic compromise with
nitric oxide in a parturient with amniotic fluid embolism. Int J Obstet Anesth 2007; 16: 269273.
77. Clarke J & Butt M. Maternal collapse. Curr Opin Obstet Gynecol 2005; 17: 157160.
78. ACOG Practice Bulletin. Induction of Labor. Clinical Management Guidelines for Obstetrician-Gynecologists.
Washington D.C.: American College of Obstetricians and Gynecologists, 1999. Number 10.
79. Wagner M. From caution to certainty: hazards in the formation of evidence-based practice a case
study on evidence for an association between the use of uterine stimulant drugs and amniotic fluid embolism. Paediatr Perinat Epidemiol 2005; 19: 173176.
80. Kramer MS, Rouleau J, Baskett TF et al. Amniotic-fluid embolism and medical induction of labour: a retrospective, population-based cohort study. Lancet 2006; 368: 14441448.
81. Pluymakers C, De Weerdt A, Jacquemyn Y et al. Amniotic fluid embolism after surgical trauma: two
case reports and review of the literature. Resuscitation 2007; 72: 324332.
82. El Kady D. Perinatal outcomes of traumatic injuries during pregnancy. Clin Obstet Gynecol 2007; 50:
582591.
83. Pearlman MD. Motor vehicle crashes, pregnancy loss and preterm labor. Int J Gynaecol Obstet 1997; 57:
127132.
84. Green W, Robinson LM, Rizzo AG et al. Pregnancy is not a sufficient indicator for trauma team activation. J Trauma Inj Infect Crit Care 2007; 63: 550555.

846 J. Williams et al
85. Patel SJ, Reede DL, Katz DS et al. Imaging the pregnant patient for nonobstetric conditions: algorithms
and radiation dose considerations. RadioGraphics 2007; 27: 17051722.
86. Cusick SS & Tibbles CD. Trauma in pregnancy. Emerg Med Clin N Am 2007; 25: 861872.
87. Barraco R, Chiu W, Clancy T et al. Practice Management Guidelines for the Diagnosis and Management
of Injury in the Pregnant Patient: The EAST Practice Management Guidelines Work Group. Available
from: http://www.east.org/tpg/pregnancy.pdf; 2005. Last accessed 14 January 2007.
88. Muench MV & Canterino JC. Trauma in pregnancy. Obstet Gynecol Clin N Am 2007; 34: 555583.
89. Gunter JJ. Intimate partner violence. Obstet Gynecol Clin N Am 2007; 34: 367388, ix.
90. Butler EE, Colon I, Druzin ML et al. Postural equilibrium during pregnancy: decreased stability with an
increased reliance on visual cues. Am J Obstet Gynecol 2006; 195: 11041108.
91. Dunning K, LeMasters G, Levin L et al. Falls in workers during pregnancy: risk factors, job hazards, and
high risk occupations. Am J Ind Med 2003; 44: 664672.
92. Weiss HB, Songer TJ & Fabio A. Fetal deaths related to maternal injury. JAMA 2001; 286: 18631868.
93. Cahill AG, Bastek JA, Stamilio DM et al. Minor trauma in pregnancy is the evaluation unwarranted? Am
J Obstet Gynecol 2008; 198: 208e15.
*94. ACOG Educational Bulletin. Obstetric aspects of trauma management. Washington D.C: American College of Obstetricians and Gynecologists, 1998. Number 251.
95. Muench MV, Baschat AA, Reddy UM et al. Kleihauer-betke testing is important in all cases of maternal
trauma. J Trauma-Inj Infect Crit Care 2004; 57: 10941098.
96. Pearlman MD & Phillips ME. Safety belt use during pregnancy. Obstet Gynecol 1996; 88: 10261029.