Critical care in obstetrics: pregnancy-speciﬁc conditions Care in... · Critical care in obstetrics: pregnancy-speciﬁc conditions ... elevated in 85–100% and at least 93% of

Best Practice & Research Clinical Obstetrics and GynaecologyVol. 22, No. 5, pp. 825–846, 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 managementof six commonly encountered complications unique to pregnancy that require critical care man-agement: obstetric haemorrhage; pre-eclampsia/HELLP (haemolysis–elevated liver enzymes–lowplatelets) syndrome; acute fatty liver of pregnancy; peripartum cardiomyopathy; amniotic fluidembolism; 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, andthe leading cause of maternal death in developing countries, accounting for 25% ofmaternal 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.: þ1 734 764 1401; Fax: þ1 734 647 1006.

E-mail address: [email protected] (J. Williams).

1521-6934/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.

mailto:[email protected]

http://www.sciencedirect.com

826 J. Williams et al

>1000 mL.4 Risk of haemorrhage-related maternal death increases with maternal ageand is greater among African-Americans than among White Americans.5 Haemor-rhage-related obstetric death is usually preceded by haemorrhagic shock and rapidcardiovascular collapse.6 In one developing world setting, 88% of deaths occurredwithin 4 h of delivery.7

Aetiologies of obstetric haemorrhage

Life-threatening obstetric haemorrhage may develop in the antepartum or the post-partum period. Antepartum haemorrhage is most often attributable to placentalabruption or previa, whereas postpartum haemorrhage is most often associatedwith uterine atony.3 Other causes of postpartum haemorrhage include retainedplacenta, uterine inversion, placenta previa, placenta accreta, uterine rupture and gen-ital tract trauma.3,6 Risk factors for postpartum haemorrhage include: pre-existinganaemia; obesity; chorioamnionitis; fetal macrosomia; prior caesarean section; andmultiple gestation.6

Aetiologies of coagulopathy/disseminated intravascular coagulation

In the obstetric setting, disseminated intravascular coagulation (DIC) may developdue to the underlying shock process (abruption, amniotic fluid embolism)6 or dueto dilutional effects of massive blood loss and fluid replacement in the setting ofhypovolaemic shock.8 Bick defines DIC as ‘a systemic thrombohemorrhagic disor-der seen in association with well-defined clinical situations and laboratory evi-dence of (1) procoagulant activation, (2) fibrinolytic activation, (3) inhibitorconsumption and (4) biochemical evidence of end organ damage or failure’.9

Causes of DIC that are unique to pregnancy include retained fetus after in-uterofetal demise, placental abruption, severe pre-eclampsia/HELLP (haemolysis–ele-vated liver enzymes–low platelets) syndrome, and amniotic fluid embolism(AFE).9 DIC is always a secondary phenomenon, developing after procoagulantsubstances, such as collagen, tissue factor from tissue destruction, amniotic fluid,placental tissue, incompatible red blood cells or bacterial products, are releasedinto the maternal circulation.8,10,11 This phenomenon leads to increased produc-tion and breakdown of coagulation factors, including increased conversion of fi-brinogen to fibrin, platelet activation and consumption, activation of factors Vand VIII, protein C activation, endothelial cell activation and fibrinolysis.12 Subse-quent developments include increased intravascular fibrin deposition leading tothromboembolic complications.13 The consumption of platelets and coagulationfactors leads to massive, and often life-threatening, haemorrhage. In the obstetricsetting, increased circulating fibrin degradation products may decrease myometrialcontractility, leading to worsening haemorrhage from uterine atony.8 Althoughhaemorrhage is the immediate, life-threatening consequence of DIC, microvascu-lar thromboses may lead to end organ damage or failure, and longer rangemorbidities.9,10,13

Diagnosis of disseminated intravascular coagulation

There are no agreed upon clinical criteria diagnostic for DIC. Signs of DIC may includepersistent oozing from operative and venepuncture sites, ongoing postpartum hae-morrhage 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 unwiseand unnecessary to delay initiation of potentially life-saving therapies until laboratoryresults become available; however, many laboratory abnormalities can be seen andhelp with recognition of DIC. The prothrombin time and partial thromboplastintime are often elevated during DIC, but may be normal in up to 50% of cases.9 Fibrindegradation products and D-dimers are elevated in 85–100% and at least 93% of cases,respectively. However, both of these are commonly elevated in postpartum and/orpostoperative patients and are therefore not diagnostic.9 Variable degrees of throm-bocytopenia and hypofibrinogenaemia are also seen.8 A diagnostic scoring systemcombining clinical and laboratory manifestations of DIC has been proposed but isnot 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 capac-ity, and maintaining adequate tissue perfusion.6,14 Decreased cardiac output, hypoten-sion and vasoconstriction may result in decreased end organ perfusion of vital organsincluding kidneys, heart and brain.3,6,11 In order to restore oxygen carrying capacityand maintain adequate tissue perfusion, fluid resuscitation should begin with volumeexpansion with crystalloid at a volume approximately three times that of the estimatedblood loss.6,14 This should be followed immediately with replacement of packed redblood cells to restore oxygen carrying capacity, with the goal of maintaining haemoglo-bin at 7–10 g/dL.6,14 Lastly, clotting factors and platelets should be replaced in order toprevent or correct coagulopathy.8,14 This replacement should begin with fresh frozenplasma6, followed by cryoprecipitate and platelets. In cases in which coagulopathy doesnot respond to these measures, administration of recombinant activated factor VII canbe considered.6,13,15 In order to ‘fast-track’ availability of these blood products, someauthors have suggested availability of a ‘massive transfusion’ protocol for hospitalsproviding obstetric services.14 One published protocol recommends that blood banksshould provide massive transfusion packages containing red blood cells, fresh frozenplasma and platelets in a 6:4:1 ratio, which most closely approximates the compositionof whole blood.14

The source of bleeding may be controlled medically (with uterotonic drugs, suchas oxytocin, methergine, prostaglandin E2, prostaglandin F2a and misoprostol),mechanically (with intra-uterine balloons or packs) or surgically. Surgical treatmentsinclude conservative measures such as hypogastric artery ligation, uterine artery liga-tion and arterial embolization by interventional radiology. Hysterectomy is carriedout in the event of failure of these conservative measures. A recent Cochrane reviewconcluded that there is currently insufficient evidence from appropriately poweredrandomized controlled trials to choose oxytocin/methergine over misoprostol asthe first-line therapy for atony.16 Likewise, there are no randomized controlled trialscomparing the effectiveness of mechanical and surgical measures to control severepostpartum haemorrhage. However, one recent systematic review evaluated 46observational studies comparing the modalities intended to control severe postpar-tum haemorrhage after uterotonic medications have failed. These modalities includeballoon tamponade, uterine compression sutures, internal iliac artery ligation or uter-ine devascularization, and arterial embolization.4 The reviewers found no significantdifference in success rates among these four procedures. Balloon tamponade wassuccessful in 84% of cases, uterine compression sutures were successful in 91.7%


of cases, internal iliac artery ligation or uterine devascularization was successful in84.6% of cases, and arterial embolization was successful in 90.7% of cases.4 Basedon these findings, the authors suggest that balloon tamponade, the least invasive ofthese procedures, should be considered as the first-line approach, particularly aftervaginal 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 ofchronic hypertension include idiopathic or essential hypertension, secondary hyper-tension from renal disease, Cushing’s syndrome or pheochromocytoma. Pre-eclampsiais not a hypertensive disorder but a pregnancy-specific syndrome, with high bloodpressure as one of the many possible symptoms.

Epidemiology

Pre-eclampsia is typically seen in the first pregnancy. The incidence of pre-eclampsiavaries between 5% and 8% depending on the population being studied.17 In mostWestern cultures, morbidity and mortality associated with pre-eclampsia are low;however, in countries with less access to health care, pre-eclampsia/eclampsia andtheir associated morbidity and mortality for both mother and fetus remain significantclinical problems.18

Pathophysiology

Recent discoveries have markedly improved our understanding of the pathophysiol-ogy of pre-eclampsia. It is hypothesized that an altered maternal immune responseto antigens expressed on the invading trophoblast results in a premature halting ofthe trophoblastic invasion into the maternal (spiral) arteries.19 The lack of this in-vasion causes these maternal vessels to remain narrow and vasoreactive, therebycreating an increase in resistance and poor perfusion of the placenta.20,21 In an at-tempt to improve perfusion, the placenta releases factors into the maternalcirculation.

Recent work22–24 has facilitated understanding of this process. The placentas ofpatients with pre-eclampsia produce angiogenic factors such as soluble fms-like tyro-sine kinase 1 (sFlt-1), which binds to placental growth factor (PlGF) and vascular en-dothelial growth factor (VEGF).22 PlGF is important in angiogenesis of the placentalvascular bed, and VEGF is essential in the stabilization of the maternal vascular endo-thelium. When sFlt-1 binds to PlGF and VEGF, these growth factors are no longerbio-available, resulting in decreased angiogenesis of the placenta, and destabilizationand dysfunction of the maternal vascular endothelium.25 The clinical manifestationsof pre-eclampsia, including hypertension, proteinuria, oedema, thrombocytopeniaand activation of the coagulation cascade, reflect altered maternal vascular endothe-lial function.26


Clinical management

Risk factors for pre-eclampsia include first pregnancy (85% of patients), multiplegestations and molar pregnancies.17 Patients with pre-existing maternal disordersinvolving 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 humoralfactors.

Pregnant patients who present with new-onset hypertension, defined as systolicpressure >140 mmHg or diastolic pressure >90 mmHg, should be assumed to havepre-eclampsia. Clinicians should solicit symptoms of headaches and epigastric or rightupper quadrant abdominal pain. Patients should have urine protein checked bydipstick. If positive, urine protein should be quantified by either a protein:creatinineratio or 12- or 24-h urine collection. The degree of oedema is of little clinical valueunless the patient presents with pulmonary oedema. Laboratory studies include com-plete blood count, platelet count, serum creatinine and uric acid, serum aspartatetransaminase (AST) and alanine aminotransferase (ALT). Fetal wellbeing should beassessed. The patient is classified as having mild pre-eclampsia, unless any of thecriteria listed in Table 1 are present.17,28

Patients with mild pre-eclampsia can be managed expectantly28 if premature, twice-weekly assessment of mother and fetus are indicated. When the gestational age is �37weeks or fetal lung maturity has been confirmed, delivery should be considered.

Patients with severe pre-eclampsia should be prepared for delivery.28 As describedabove, pre-eclampsia is a state of poor placental perfusion and altered maternal vas-cular endothelial function. Interventions are therefore focused on improving placentalperfusion through improving cardiac output and peripheral vasodilation. The patientshould be placed on her side (left or right) in a supine position. This will improvevenous return, preload and cardiac output. In the authors’ experience, most pre-eclamptic patients are intravascular volume depleted and require some degree ofvolume resuscitation, which will result in improved cardiac output, improved placentalperfusion and temporization of the disease process. If undelivered, continuous fetalmonitoring is performed.

Magnesium sulphate seizure prophylaxis should be initiated in the severepre-eclamptic, and there is great controversy regarding whether patients withmild pre-eclampsia should also receive magnesium prophylaxis.29 The authors usea loading dose of 4–6 g intravenously over 20 min, followed by a continuous intra-venous 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


>4 mEq/mL. Blood pressure can be controlled with the judicious use of hydralazineor labetalol.32 The authors recommend target blood pressures of approximately150 mmHg systolic and 100 mmHg diastolic. Rapid vasodilation should be avoidedby adequate intravascular resuscitation in order to prevent further decrease in per-fusion of the placenta.

At gestational ages <34 weeks, the administration of betamethasone should beconsidered and delivery delayed for 48 h if the maternal condition is stable.28 Forpatients with extreme premature gestational ages (<32 weeks), expectant manage-ment can be considered, particularly for those who are classified as severe basedon isolated hypertension or proteinuria.30

Eclampsia

Patients who develop seizures or who present after having had a seizure should bestarted on magnesium sulphate immediately (4–6 g intravenous loading dose, 2 g/hcontinuous intravenous infusion).31 A thorough neurological examination should beperformed. The patient should be evaluated for other signs and symptoms suggestiveof eclampsia. If the diagnosis of eclampsia is likely and the neurological examination isunremarkable, the patient is managed similarly as outlined for severe pre-eclampsia. Ifneurological deficits are present or other signs or symptoms of pre-eclampsia are notpresent, urgent central nervous system imaging and neurological consultation areindicated.31

Pre-eclampsia is associated with an increased risk for both ischaemic and haemor-rhagic stroke. Ischaemic stroke results from severe vasospasm, while haemorrhagicstroke is associated with uncontrolled hypertension. Clinicians must distinguishbetween eclampsia and primary intracranial pathologies which may also be associatedwith hypertension and seizures, such as stroke or neoplasm.31 This distinction may bedifficult to make. Therefore, the authors recommend imaging studies in all patientswho present with a new onset of seizure(s), particularly if the diagnosis of eclampsiais 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 thepresence 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 andmanaged as outlined for severe pre-eclampsia.

The use of (high-dose) steroids in order to stabilize platelet values and speed uprecovery has been suggested by some investigators.33 However, a recent randomizedcontrolled 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 modeof delivery is determined by the obstetric care provider. Many patients can be deliv-ered safely vaginally and do not require a caesarean section. However, induction oflabour remote from term is associated with high rates of failed induction.35–37 Impor-tantly, one should only proceed with delivery after the maternal condition has beenstabilized.


Chronic hypertension

The prevalence of chronic hypertension is low overall. However, as the number ofolder women having children increases, chronic hypertension will become more prev-alent in pregnant patient populations.

Once pre-eclampsia has been excluded, the patient is managed as having chronichypertension. A subgroup of these patients will have gestational hypertension, whichwill resolve within 6 weeks of delivery. It is critical to rule out other causes of hyper-tension including renal disease, primary hyperaldosteronism, collagen vascular diseaseand 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 significantmaternal and perinatal morbidity and mortality. The pathophysiology reflects poorplacental perfusion, release of placental humoral angiogenic factors and subsequentmaternal 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 prophylaxisinitiated and prepared for delivery. Complications of pre-eclampsia include seizures(eclampsia), HELLP syndrome, renal failure and DIC. Fortunately, with the deliveryof 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 700and one in 1300 deliveries.38–40 The disease is characterized by microvesicular fattyinfiltration of the liver with hepatic failure, and usually presents clinically in the thirdtrimester.41 Maternal and fetal/neonatal mortality estimates have ranged significantlyover time, with two recent reviews revealing maternal mortality of 0–12.5% and fetalmortality of 15–66%.39,41

Aetiology

While the aetiology of the disease is not currently understood, the pathology seen haslong been likened to that of Reye’s syndrome and other inherited fatty acid oxidationdisorders. As such, a link was made between mothers who developed acute fatty liverof pregnancy and those who have children with long-chain 3-ketoacyl-CoA dehydro-genate deficiency.42,43 One study evaluated 24 children with long-chain 3-ketoacyl-CoA dehydrogenate deficiency. Nineteen of them had a particular mutation(Glu474Gln), and of these, 79% of their mothers had developed acute fatty liver ofpregnancy or HELLP syndrome. Of the five children who did not carry this particularmutation, none of their mothers had developed liver disease during pregnancy.43 It isthought that the combination of genetic and acquired factors can compromise intra-mitochondrial fatty acid oxidation significantly, and acute fatty liver can develop. Theimplications of this genetic link raise important perinatal and neonatal issues whichwill be discussed later.


Clinical presentation/diagnosis

As stated, the clinical presentation is usually in the third trimester, with an averagegestational age of 35 weeks.39,41 Nausea and vomiting are the most common present-ing symptoms, but malaise, epigastric or right upper quadrant pain, headache andfatigue are also seen. In two retrospective reviews, jaundice was seen at presentationin 37%41 and 100%39 of patients. Laboratory abnormalities overlap with abnormalitiesseen in HELLP syndrome (thrombocytopenia, elevated transaminases, hyperuricaemiaand elevated creatinine), although the thrombocytopenia and elevations in transami-nases may be mild to moderate (average platelets 151 000 and average AST/ALT523/423 at presentation).41 Other abnormalities such as hyperbilirubinaemia, hypogly-caemia and hyperammonaemia can help to delineate the diagnosis. If the patientdevelops DIC, a deficiency of antithrombin III can be particularly prominent.44 Whileacute fatty liver is usually a clinical diagnosis, liver biopsy and imaging studies are some-times performed in order to rule out other aetiologies for the presentation.

Clinical course/management

Prompt recognition, aggressive maternal stabilization and rapid delivery characterizethe necessary treatment of this disease in order to minimize maternal and fetal mor-bidity and mortality. Hypoglycaemia and coagulopathy are seen in 40–50% ofpatients39, and therefore, glucose infusion and aggressive resuscitation with bloodproducts are common. Renal failure, encephalopathy and pancreatitis may also developand need to be treated supportively. Most commonly, there is eventual resolution ofthe disease and recovery of organ systems involved, but this may require prolongedhospitalization (average stay in intensive care of 10.4 days39, average hospitalizationof 15.1 days41). Liver transplantation is infrequent.41

An important management issue is counselling with respect to subsequentpregnancy. Recurrence was first reported in 199142, and subsequently, a link has beenestablished between development of acute fatty liver of pregnancy and mutation ingenes related to fatty acid oxidation, most commonly in the gene for long-chain3-ketoacyl-CoA dehydrogenase.43 As such, neonates born to mothers with acute fattyliver of pregnancy should be tested immediately for long-chain 3-ketoacyl-CoA dehy-drogenase deficiency as well as other disorders of fatty acid oxidation. This is beingdone as part of the newborn metabolic screen in many regions.45 Counselling thepatient regarding future pregnancy should include the option of testing for knownmutations in the long-chain 3-ketoacyl-CoA dehydrogenase gene, as the presence ofsuch a mutation increases the possibility of recurrence of acute fatty liver in subsequentpregnancies. Additionally, if such a mutation is found, there are important implications interms of having an affected fetus (the disease state is inherited in an autosomal-recessivefashion). Ongoing research will aid understanding of the maternal–fetal interaction seenin 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 associatedwith pregnancy. The National Institutes of Health have identified peripartum cardiomy-opathy as a distinct clinical entity, occurring more often than idiopathic heart failure innon-pregnant women of the same age.46


Four criteria have been developed to characterize peripartum cardiomyopathy: (1)development of heart failure within the last 4 weeks of pregnancy or within 5 monthsof delivery; (2) no pre-existing heart disease; (3) no other identifiable cause of heartfailure; and (4) left ventricular systolic dysfunction.

The first two criteria are linked; the time constraints serve to minimize the possibilityof pre-existing heart disease because the haemodynamic stresses of pregnancy in pa-tients with pre-existing disease would likely lead to symptoms prior to the last 4 weeksof pregnancy. One study has questioned this component of the definition. This study in-cluded 100 women meeting the traditional definition of cardiomyopathy and 23 who dif-fered in that they presented earlier than the last gestational month (but met the othercriteria). This study found that there were no significant differences in the characteris-tics or clinical course between these two groups.47 From this, it was postulated thatthere may be a spectrum of disease which usually includes women characterized bythe temporal characteristics described traditionally, but that also includes womenwith 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 clinicalentity. Finally, although peripartum cardiomyopathy is a dilated form of cardiomyopa-thy, the definition also requires that systolic function be demonstrably impaired, inorder to distinguish pathology from pregnancy itself which can lead to a dilated (butfunctional) left ventricle.

Epidemiology

The reported incidence of peripartum cardiomyopathy has varied greatly over timeand worldwide. A recent review in a multi-ethnic community in the USA describedan overall incidence of one in 4025 deliveries. The incidence was determined in Cau-casians, African-Americans, Hispanics and Asians, and was highest in African-Ameri-cans (one in 1421) and lowest in Hispanics (one in 9861).48 The higher incidence inparticular geographic/ethnic groups has been reported many times previously; thehighest 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 withbeta-adrenergic medications.

Aetiology

The aetiology of peripartum cardiomyopathy is unknown; however, leading theoriesinclude damage caused by the release of inflammatory cytokines50, viral or idiopathicmyocarditis51,52, abnormal immune response to fetal antigen, and maladaptiveresponse to haemodynamic factors associated with pregnancy. Levels of inflammatorycytokines, such as tumour necrosis factor-alpha, interleukin-6 and Fas/APO-1 (anapoptosis-signalling surface receptor), have been shown to be significantly elevatedin women with peripartum cardiomyopathy compared with healthy women.50 Thepossibility of postviral myocarditis or that seen as a result of an auto-immune aetiologyhas been explored and remains controversial.52,53

Clinical presentation/diagnosis

Peripartum cardiomyopathy usually presents post partum.54 The diagnosis can be dif-ficult due to the fact that many of the symptoms (such as dyspnoea, swelling and


fatigue) are common in the first postpartum month following a normal pregnancy. Pa-tients most commonly present with dyspnoea, cough and orthopnoea.55 Other symp-toms include fatigue, non-specific chest discomfort and abdominal pain. Rarely,a patient can present with systemic emboli as a result of the dilated, dysfunctionalleft ventricle, or with an acute myocardial farction due to inadequate perfusion ofthe coronary arteries.

The physical examination will show signs typical of heart failure: hypoxia; jugularvenous distention; S3 gallop; rales; and hepatomegaly. The chest x-ray will showcardiomegaly with pulmonary congestion and/or pleural effusions. The electrocardio-gram 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 infarc-tion, although these elevations can occasionally be seen in peripartum cardiomyopathyas well.56 Ultimately, an echocardiogram is imperative for the diagnosis of peripartumcardiomyopathy; it will show a dilated left atrium and ventricle, left ventricular systolicdysfunction, 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 recentpregnancy with associated third spacing of excess intravascular volume. Breathing isaddressed via continuous pulse oximetry and placement of the patient on supplemen-tal oxygen. The circulation should be assessed with cardiac and blood pressure mon-itoring. Appropriate venous and/or arterial access should be obtained rapidly so thatmedications 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 ab-normalities. In this case, it is critically important to stabilize maternal status; this mayresult in resolution of fetal heart rate tracing abnormalities and will prevent haste inperforming 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 goalsof improving haemodynamics, minimizing patient symptoms, and optimizing long-term outcomes. Choice of medications requires consideration regarding whetherthe patient is still pregnant or breast feeding. Preload reduction is accomplishedwith nitrates, most of which are safe during pregnancy and breast feeding. Diureticsare also important, although caution is warranted in pregnant patients in order toavoid rapid changes in intravascular volume that can lead to decreasing the bloodsupply to the uterus. Afterload reduction can be achieved in the pregnant patientwith vasodilators such as hydralazine. For the postpartum patient, angiotensin-con-verting-enzyme inhibitors are the preferred agents. To increase inotropy, beta-blockers are used and have been shown to improve survival in patients with dilatedcardiomyopathy; however, it is important to note that these must not be initiated inthe acute decompensated phase as they can decrease perfusion in this setting. Dopa-mine, dobutamine and digoxin are not contra-indicated in pregnancy, and are particu-larly useful in the case of acute decompensated heart failure with hypotension.57

Anticoagulation is an important adjunct to therapy due to the hypercoagulable stateof pregnancy, as well as the stasis of blood seen with severe left ventricle dysfunc-tion.58 Therapy is suggested with an ejection fraction <30%, and an agent otherthan coumadin (heparin, low-molecular-weight heparin) should be used when the


patient is pregnant. Aggressive medical management of ventricular arrhythmias is rec-ommended, and 2–3% of patients will require implantable defibrillators/pacemakers.47

Treatment with immunosuppressive agents and intravenous immunoglobulin remaincontroversial at present. Left ventricular assist devices and heart transplant arereserved for the postpartum patient in whom other therapy is unsuccessful. Accordingto 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 withcontemporary management than has been reported previously. Of these, one study fol-lowed 123 women and reported a mortality rate of 9% at a mean follow-up of 24months.47 Another reported zero deaths in 55 women at a mean follow-up of 43months.59 However, a study of a cohort of 29 African women reported eight deathsby 6 months following the diagnosis.50 These results suggest that although mortality rateshave improved, mortality remains extremely high in a significant population of women.

With appropriate medical support, most patients will improve following theirpresentation. 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 improveand will go on to need further treatment (left ventricular assist devices, heart trans-plant). Several factors have been identified which are associated with these poorerprognoses: ejection fraction <30% at diagnosis50; left ventricular end diastolic dimen-sion >6 cm60; elevated cardiac troponin T56; and elevated sFas/APO-1.50

Counselling women regarding the risks associated with subsequent pregnancy isdifficult; however, studies have suggested that dividing women into two risk categories(recovered versus non-recovered left ventricle function) is most appropriate.61,62 Ina study of 28 women with recovered left ventricle function who became pregnant,there were no deaths, but six women developed heart failure symptoms and sixwomen had a reduction in ejection fraction >20%. In the same study, 16 womenhad persistent left ventricle dysfunction and subsequently became pregnant. Of these,four women underwent therapeutic abortion and 12 women continued their pregnan-cies. Among those continuing their pregnancy, three died, six developed heart failuresymptoms and four had a reduction in their ejection fraction >20% (groups not mu-tually exclusive). With regard to neonatal outcomes, preterm delivery (between 30and 36 weeks) was seen in 13% (three patients) of pregnancies in women with recov-ered left ventricle function and 50% (six patients) of pregnancies in women with per-sistent left ventricle dysfunction. There were no neonatal deaths.61 In summary, whilesome women will tolerate subsequent pregnancies, many will experience a decline intheir left ventricular function. Furthermore, the subset of women with persistent leftventricular 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 typicallypresents with an acute onset of severe hypoxia, mental status changes, cardiovascularcollapse and DIC. Mortality risk for the mother and baby is high, and survivors mayhave long-term clinical sequelae.


Epidemiology

There is a wide variation in the incidence of AFE, ranging from one in 8000 to one in80 000. The incidence is reported as one in 20 000–30 000 in the USA, one in 27 000 inSouth-east Asia, and one in 80 000 in the UK. The clinical presentation is highlyvariable and milder cases may not be reported. The diagnosis of AFE is often madeby 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 of26%.66 The UK AFE registry reported case fatality of 37% in 2005.67 Morbidity is alsosignificant, but numbers vary largely between reports. In a retrospective review of 46women, 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 AFEoccurs prior to delivery, perinatal morbidity and mortality are also high. Clark et alreported a perinatal survival rate of 79% with 50% neurological morbidity.65 In theUK registry, 78% of infants survived, with 29% of these showing evidence of hypoxicischaemic encephalopathy.67

These data suggest that with improved diagnosis and medical intensive care, thematernal mortality rate has improved markedly but remains high at approximately25–35%, with an estimated risk of 10–20% for long-term sequelae.67 Approximately80% 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 itscontents into the maternal venous blood stream. This sets off a chain of events inwhich the amniotic fluid travels to the pulmonary vasculature and causes a ‘massive,pulmonary embolism-like’ clinical presentation, including acute pulmonary vasospasmwith severe hypoxia, pulmonary hypertension, right heart failure, cardiovascularcollapse, 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 the-ory remains controversial. The question remains whether it is the actual amniotic fluid,certain components within the amniotic fluid or an altered, immunopathologicalresponse to these components that sets off this chain of events.

Early autopsy studies in which amniotic fluid was described in the pulmonaryvasculature provided evidence to support this theory.68 Later, Resnik et al identifiedmucin and fetal squamous cells in the pulmonary artery catheter aspirate of a patientwho was diagnosed with AFE.69 James et al70 described gross enlargement of the rightventricle and pulmonary artery by transoesophageal echocardiography prior to thedeath of a 36-year-old patient with suspected AFE. Autopsy demonstrated extensivemicrovascular plugging of the pulmonary capillaries. However, the presence of fetalcells 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 theactual presence of the amniotic fluid or its components, but the maternal (immune)response to these chemical mediators which ultimately determines whether thepatient develops AFE. Clark described this as an ‘anaphylactoid’ reaction to amnioticfluid.71 Several publications posit a role for a number of vasoactive and inflammatorymediators including endothelin, histamine, serotonin, bradykinin, prostaglandins and


leukotrienes.72–74 These mediators may play a causative role in the pathogenesis ofAFE, or may only reflect components of the systemic maternal response.

Well over 50% of patients with AFE will develop DIC, which may be the presentingor only symptom. The degree of consumptive coagulopathy appears to be dispropor-tionate to the observed blood loss. It has been postulated that amniotic fluid activatesfactor X.90 Uszynski et al described the role of tissue factor and tissue factor pathwayinhibitor in amniotic fluid and blood plasma as a possible mechanism.75

Clinical presentation

AFE must be considered when a labouring or immediately postpartum patient pres-ents 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 ofbreath, and then rapidly becomes hypoxic. If the patient is still pregnant, fetal brady-cardia will develop. Pulmonary vasoconstriction leads to severe hypoxia, and isfollowed 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 thenevolves and is characterized by the development of left ventricular heart failure. This isdue to poor diastolic filling as well as decreased cardiac contractility. The compro-mised filling is related to compression of the ventricle caused by increased volumesseen by the right heart, which are secondary to the impedence of flow caused by pul-monary vasoconstriction. The decreased contractility is felt to be secondary to a directtoxic effect on the myocytes. This combination leads to cardiac dysfunction whichmust be treated aggressively and monitored carefully. This ‘second phase’ is alsocommonly characterized by DIC, and seizure activity also been reported.

Importantly, patients with AFE may present with some but not all of these clinicalfindings, and the sequence of events may vary considerably. Ultimately, the diagnosis isbased on the interpretation of the clinical presentation as well as the exclusion ofother differential diagnoses, including pulmonary embolus, acute myocardial infarction,cerebral vascular accident, sepsis, placental abruption and uncompensated maternalblood loss (with or without consumptive coagulopathy). When the diagnosis remainsunclear, some experimental assays (serum tryptase, serum sialyl Tn antigen levels andzinc coproporphyrin) have been proposed to be more specific and may be available insome 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 orga-nized immediately. The patient should be intubated and mechanical ventilation initi-ated. High oxygen concentrations will be required in order to manage severehypoxia. Adequate intravenous access needs to be established with large-bore cathe-ters. Aggressive measures to maintain perfusion will be necessary (using crystalloid,blood products and vasopressors). Intra-arterial monitoring (with an arterial lineand 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 con-dition is stable enough to proceed with an emergency delivery; if not, a decision may


be made not to intervene on behalf of the fetus. Concise communication between allparticipating care teams is critical.

After the initial stabilization and notification of care teams, communication with theblood 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); andan arterial blood gas. Additionally, a chest x-ray, 12-lead electrocardiogram and cardiacecho (surface or transoesophageal) are needed.

When coagulopathy develops, significant resuscitation with blood products (packedred blood cells and fresh frozen plasma) will be required. Cryoprecipitate may be usedwhen fibrinogen levels are low and administration of less volume is desired. Patientswith DIC in the setting of AFE seem to require an unusually high amount of fresh frozenplasma in order to correct the coagulopathy. The administration of these blood productsin this setting of impaired cardiac function requires particular attention to fluid balance,and tools to evaluate right and left cardiac dysfunction (pulmonary artery catheter, Swan-Ganz catheter) are advocated. When echocardiography is performed, it will reveal highpulmonary pressures and marked right ventricular dilation. As stated previously, the di-lated right ventricle may prevent adequate diastolic filling of the left ventricle and worsencardiac output. In this situation, nitric oxide has been reported to be beneficial.76

After the acute coagulopathy is resolved, the use of prophylactic heparin (unfractio-nated or fractionated) should be considered in patients with AFE, as there is anincreased risk for development of thrombotic complications.9 Supportive care iscontinued 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 postulatedas having a causative relationship on the occurrence of AFE, although Morgan64 andClark and Butt77 could not confirm any maternal risk factor related to AFE. The Amer-ican College of Obstetrics and Gynecology (ACOG) and many textbooks reflect theopinion that oxytocin use is not associated with AFE.78 In the current setting of theincreased use of prostaglandins, some feel that we may need to re-evaluate the asso-ciation between uterine stimulation and AFE.79 One retrospective cohort study of riskfactors 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 identifiedother risk factors including uterine rupture, placenta previa and abruptio placentae.80

There are published case reports of AFE after abdominal and surgical trauma, first- andsecond-trimester abortion, amniocentesis and removal of a cervical cerclage.81

Summary

AFE is a rare but potentially catastrophic syndrome with an estimated incidence of onein 25 000 to one in 30 000. Mortality is high (30–40%) in those patients who exhibit theclassic presentation of acute severe hypoxia, cardiovascular collapse, mental statuschanges, and DIC.66,67 Long-term neurological sequelae may persist in 10–20% of pa-tients. If AFE occurs while the mother is still pregnant, immediate delivery of the fetusmay result in good survival; otherwise, perinatal mortality and morbidity are high.

The pathophysiology of AFE remains controversial. There is clear evidence thatamniotic fluid and its components enter the maternal venous circulation.68–70 Thismay result in mechanical obstruction in the pulmonary capillaries and/or incite


a systemic response by the mother which is similar to anaphylaxis or sepsis. The no-tion that labour induction or augmentation is not associated with AFE may need to bere-addressed. It may be that it is not the uterine tone or force that makes it morelikely to ‘push’ amniotic fluid into the maternal circulation, but that the productionof different mediators inciting AFE are associated with labour induction andaugmentation.

Every obstetric care provider should be familiar with this clinical syndrome andconsider the diagnosis early in its presentation. Early diagnosis and initiation of treat-ment are paramount. Treatment includes cardiovascular and respiratory resuscitation(with intubation/ventilation, crystalloids, vasopressors) in order to optimize cardiacoutput, and correction of coagulopathy.

TRAUMA IN PREGNANCY

Trauma during pregnancy is the leading non-obstetric cause of maternal mortality andis responsible for at least one million maternal deaths worldwide each year.82 Approx-imately 6–7% of pregnancies will be complicated by maternal trauma.83–85 Motorvehicle 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 injuriescan be further classified as blunt (most frequently resulting from falls, motor vehicleaccidents or partner violence) or penetrating (prevalent in high-crime settings).

Motor vehicle accidents

Motor vehicle accidents account for the largest number of trauma-related fetaldeaths, accounting for 4000 fetal losses annually in the USA.82,86 Motor vehicle acci-dents fall under the general category of blunt injury.82 The risk that a motor vehicleaccident will result in an obstetric complication is proportional to the speed at whichthe motor vehicle accident occurred and the severity of the injury.82 Although the riskof fetal loss is greatest after severe maternal trauma, even minor blunt abdominaltrauma increases the risk for fetal loss compared with controls not experiencingtrauma.83

Approximately 70% of fetal losses resulting from maternal trauma are caused byplacental abruption.83 Placental abruption complicates up to 40% of cases of severematernal trauma and 1–5% of cases of minor maternal trauma.88 During blunt trauma,the myometrial tissue is able to respond to acceleration–deceleration forces by chang-ing its shape. However, the placenta is relatively inelastic, and this mismatch betweenthe myometrium and the placenta creates a shearing force which leads to placentalabruption.82,88

Partner abuse

Intimate partner violence is the most common cause of trauma-related maternal deathduring pregnancy, and maternal deaths due to homicide exceed those due to anyobstetric cause.89 Between 6% and 22% of gravid women experience intimate partnerviolence during pregnancy and are at increased risk for violent assault compared withnon-pregnant women.89 Kicks and punches to the abdomen are frequent types ofintimate partner violence, and women who experience such violence are at increased


risk for miscarriage, preterm labour, premature rupture of membranes and low birthweight.89

Falls

Pregnancy may result in decreased postural stability and balance, leading to increasedfalls compared with the non-pregnant state.90,91 The risk that a fall will result in fetalloss is low compared with other types of maternal trauma.92 In a recent prospectivecohort study of minor trauma during the third trimester of pregnancy, there were noplacental abruptions experienced among 153 women who presented for evaluation offalls.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 frompenetrating abdominal trauma compared with non-pregnant women, owing to theprotective effect of the gravid uterus.82,88 Conversely, penetrating injury to the mater-nal upper abdomen is associated with increased risk of bowel injury compared withthe 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 fetaldeath, ranging from 40% to 70%.82,88 In general, gunshot wounds are associatedwith 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 whenthe fetal head is engaged in the pelvis.82 These injuries, which complicate <1% of preg-nancies affected by trauma, can result in fetal skull fractures, intracranial haemorrhageand 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 themother in the left lateral tilt position in order to displace the uterus from the inferiorvena cava.86 Laboratory evaluation should include a complete blood count and plateletcount, evaluation of coagulation and a Kleihauer-Betke (KB) test.88 The KB test, whichdetects the presence of fetal red blood cells in the maternal circulation, may be used toquantify the extent of maternal–fetal haemorrhage. ACOG advocates use of the KBtest in order to identify those Rhesus-negative women who experience fetal–maternalhaemorrhage >30 mL and who will require additional vials of RhoGam.86,94 In >90%of trauma cases, the feto–maternal haemorrhage will be <30 mL, and one vial ofRhesus immunoglobulin will be sufficient to prevent sensitization in Rhesus-negativewomen. KB testing may also be used as a screen for preterm labour in Rhesus-positivewomen. 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 whodeveloped preterm labour with a 4% false-positive rate.95 Based on these findings, theauthors advocate KB testing in all pregnant trauma patients, regardless of Rhesus


status.95 However, these findings have not been duplicated by other authors and de-finitive recommendations await further studies.

Several authors recommend maternal/fetal assessment via the FAST (FocusedAssessment with Sonography in Trauma) examination.86,88 The FAST examinationconsists of fetal position, fetal heart rate, gestational age assessment, biophysicalprofile, middle cerebral artery Doppler study, and evaluation of the placenta for abrup-tion.88 Ultrasound assessment for maternal intraperitoneal haemorrhage can beperformed at the same time.86 This evaluation has sensitivity of 80–83% and specificityof 98–100% for intraperitoneal haemorrhage.86

Fetal monitoring

The fetal heart rate has been called the ‘fifth vital sign’ because of its role as a veryearly manifestation of maternal hypotension or hypovolaemia.88 Similarly, uterine activ-ity may be a more sensitive indicator of placental abruption than ultrasound.94 Asplacental abruption has been observed up to 48 h after maternal trauma, a minimumof 4 h of fetal monitoring after trauma is advised, with 24 h of monitoring undertaken iffrequent 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 knownharmful effects of magnetic resonance imaging (MRI) during pregnancy.85 Some authorsadvise restricting MRI scanning to the second and third trimesters of pregnancy, owingto the relative scarcity of safety data concerning use in the first trimester.87 Computedtomography (CT) may be used during pregnancy when clearly indicated. Fetal expo-sure from CT scans not involving the abdomen or pelvis is low, and these scansmay be performed safely in any trimester of pregnancy.85 CT scans of the abdomenand pelvis result in a maximum fetal dose of approximately 1–2 rad, well below thethreshold dose of 10–20 rad for fetal loss or malformation; however, concerns regard-ing 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 orconservative management, which consists of peritoneal lavage, ultrasound, contrast-enhanced CT scanning, local wound exploration and observation.88

Prevention

Physician counselling for seatbelt use during prenatal care has been shown to in-crease seatbelt usage significantly.96 In primate (baboon) studies employing experi-mental crash injuries, Pearlman demonstrated that compared with two-pointrestraints, three-point restraints reduced fetal mortality from 100% to 40%.83

Based on these and other data, ACOG advocates prenatal education on properplacement of three-point restraints. Although concerns have been raised regardingthe safety of airbag use, ACOG and the National Highway Traffic Safety Adminis-tration (NHTSA) do not recommend disabling airbags during pregnancy.88,94 How-ever, NHTSA does recommend disabling airbags if the woman’s sternum or uterinefundus cannot be positioned at least 10 inches behind the centre of the airbagcover.88

Practice points

� approximately 70% of fetal losses complicating maternal trauma result fromplacental abruption. A minimum of 4 h of fetal monitoring following maternaltrauma 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 hae-

morrhage 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 cardiomy-

opathy 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 pre-pared for delivery

Research agenda

� development and validation of a diagnostic scoring system for DIC� review of outcomes and cost-effectiveness of current monitoring and evalua-

tion of recommendations for fetal–placental surveillance after minor maternaltrauma� more randomized controlled trials are needed to determine whether oxytocin

plus methergine or misoprostol is the more appropriate first-line strategy forpostpartum 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 ofanticoagulants will prevent recurrent pre-eclampsia in patients with inheritedthrombophilias are needed


REFERENCES

1. Jeani Chang MPH, Laurie D, Elam-Evans PD et al. Pregnancy-related mortality surveillance – United

States, 1991–1999. MMWR Morbid Mortal Weekly Rep 2003; 52(SS02): 1–8.


2. Khan KS, Wojdyla D, Say L et al. WHO analysis of causes of maternal death: a systematic review. Lancet

2006; 367: 1066–1074.

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): S42–S51.

*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: 540–547.

5. Chichakli LO, Atrash HK, Mackay AP et al. Pregnancy-related mortality in the United States due to

hemorrhage: 1979–1992. Obstet Gynecol 1999; 94: 721–725.

6. Cohen WR. Hemorrhagic shock in obstetrics. J Perinat Med 2006; 34: 263–271.

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: 143–150.

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: 1–31.

10. Djelmis J, Ivanisevic M, Kurjak A et al. Hemostatic problems before, during and after delivery. J Perinat

Med 2001; 29: 241–246.

11. Kobayashi T, Terao T, Maki M et al. Diagnosis and management of acute obstetrical DIC. Semin Throm-

bosis Hemostasis 2001; 27: 161–167.

12. DeLoughery TG. Critical care clotting catastrophies. Crit Care Clin 2005; 21: 531–562.

13. Pepas LP, Arif-Adib M & Kadir RA. Factor VIIa in puerperal hemorrhage with disseminated intravascular

coagulation. Obstet Gynecol 2006; 108: 757–761.

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: 1564–1572.

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: 178–179.

*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 Obste-

tricians and Gynaecologists, 2003, pp. 210–225.

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: 1065–1074.

20. Lyall F. Mechanisms regulating cytotrophoblast invasion in normal pregnancy and pre-eclampsia. Aust N

Z J Obstet Gynaecol 2006; 46: 266–273.

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: 1416–1423.

22. Karumanchi SA & Epstein FH. Placental ischemia and soluble fms-like tyrosine kinase 1: cause or con-

sequence of preeclampsia? Kidney Int 2007; 71: 959–961.

23. Lopez-Novoa JM. Soluble endoglin is an accurate predictor and a pathogenic molecule in pre-eclampsia.

Nephrol Dial Transplant 2007; 22: 712–714.

24. Levine RJ, Maynard SE, Qian C et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J

Med 2004; 350: 672–683.

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: 168–180.

26. Baumwell S & Karumanchi SA. Pre-eclampsia: clinical manifestations and molecular mechanisms. Neph-

ron 2007; 106: c72–c81.

27. Poston L. Endothelial dysfunction in pre-eclampsia. Pharmacol Rep 2006; 58(Suppl): 69–74.

28. von Dadelszen P, Menzies J, Gilgoff S et al. Evidence-based management for preeclampsia. Front Biosci

2007; 12: 2876–2889.

*29. Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: evidence from randomized trials. Clin Obstet

Gynecol 2005; 48: 478–488.


*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: 818–822.

31. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol 2005; 105: 402–410.

32. Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver

enzymes, and low platelet count. Obstet Gynecol 2004; 103: 981–991.

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: 914–934.

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: 1591–1598.

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: 1210–1213.

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: 40–44.

37. Xenakis EM, Piper JM, Field N et al. Preeclampsia: is induction of labor more successful? Obstet Gynecol

1997; 89: 600–603.

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: 389–395.

39. Mjahed K, Charra B, Hamoudi D et al. Acute fatty liver of pregnancy. Arch Gynecol Obstet 2006; 274:

349–353.

40. Pockros PJ, Peters RL & Reynolds TB. Idiopathic fatty liver of pregnancy: findings in ten cases. Medicine

(Baltimore) 1984; 63: 1–11.

41. Fesenmeier MF, Coppage KH, Lambers DS et al. Acute fatty liver of pregnancy in 3 tertiary care cen-

ters. Am J Obstet Gynecol 2005; 192: 1416–1419.

42. Schoeman MN, Batey RG & Wilcken B. Recurrent acute fatty liver of pregnancy associated with a fatty-

acid oxidation defect in the offspring. Gastroenterology 1991; 100: 544–548.

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: 1723–1731.

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: 211–216.

45. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J

Gastroenterol 2006; 12: 7397–7404.

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: 1183–1188.

*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: 2050–2055.

48. Brar SS, Khan SS, Sandhu GK et al. Incidence, mortality, and racial differences in peripartum cardiomy-

opathy. Am J Cardiol 2007; 100: 302–304.

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: 1005–1010.

50. Sliwa K, Skudicky D, Bergemann A et al. Peripartum cardiomyopathy: analysis of clinical outcome, left ven-

tricular function, plasma levels of cytokines and Fas/APO-1. J Am Coll Cardiol 2000; 35: 701–705.

51. O’Connell JB, Costanzo-Nordin MR, Subramanian R et al. Peripartum cardiomyopathy: clinical, hemo-

dynamic, histologic and prognostic characteristics. J Am Coll Cardiol 1986; 8: 52–56.

52. Bultmann BD, Klingel K, Nabauer M et al. High prevalence of viral genomes and inflammation in peri-

partum cardiomyopathy. Am J Obstet Gynecol 2005; 193: 363–365.

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: 49–52.

54. Demakis JG & Rahimtoola SH. Peripartum cardiomyopathy. Circulation 1971; 44: 964–968.

55. Demakis JG, Rahimtoola SH, Sutton GC et al. Natural course of peripartum cardiomyopathy. Circulation

1971; 44: 1053–1061.

56. Hu CL, Li YB, Zou YG et al. Troponin T measurement can predict persistent left ventricular dysfunction

in peripartum cardiomyopathy. Heart 2007; 93: 488–490.


*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: 38C–44C.

59. Amos AM, Jaber WA & Russell SD. Improved outcomes in peripartum cardiomyopathy with contem-

porary. Am Heart J 2006; 152: 509–513.

60. Chapa JB, Heiberger HB, Weinert L et al. Prognostic value of echocardiography in peripartum cardio-

myopathy. Obstet Gynecol 2005; 105: 1303–1308.

*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: 1567–1571.

62. Sliwa K, Forster O, Zhanje F et al. Outcome of subsequent pregnancy in patients with documented

peripartum cardiomyopathy. Am J Cardiol 2004; 93: 1441–1443. A10.

63. Porat S, Leibowitz D, Milwidsky A et al. Transient intracardiac thrombi in amniotic fluid embolism. Br J

Obstet Gynaecol 2004; 111: 506–510.

64. Morgan M. Amniotic fluid embolism. Anaesthesia 1979; 34: 20–32.

65. Clark SL, Hankins GD, Dudley DA et al. Amniotic fluid embolism: analysis of the national registry. Am J

Obstet Gynecol 1995; 172: 1158–1167. discussion 67–69.

66. Gilbert WM & Danielsen B. Amniotic fluid embolism: decreased mortality in a population-based study.

Obstet Gynecol 1999; 93: 973–977.

*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: 2187–2203.

69. Resnik R, Swartz WH, Plumer MH et al. Amniotic fluid embolism with survival. Obstet Gynecol 1976; 47:

295–298.

70. James CF, Feinglass NG, Menke DM et al. Massive amniotic fluid embolism: diagnosis aided by emer-

gency transesophageal echocardiography. Int J Obstet Anesth 2004; 13: 279–283.

71. Clark SL. New concepts of amniotic fluid embolism: a review. Obstet Gynecol Surv 1990; 45: 360–368.

72. Oi H, Kobayashi H, Hirashima Y et al. Serological and immunohistochemical diagnosis of amniotic fluid

embolism. Semin Thrombosis Hemostasis 1998; 24: 479–484.

73. Benson MD, Kobayashi H, Silver RK et al. Immunologic studies in presumed amniotic fluid embolism.

Obstet Gynecol 2001; 97: 510–514.

74. Robillard J, Gauvin F, Molinaro G et al. The syndrome of amniotic fluid embolism: a potential contribu-

tion of bradykinin. Am J Obstet Gynecol 2005; 193: 1508–1512.

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: 163–166.

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: 269–273.

77. Clarke J & Butt M. Maternal collapse. Curr Opin Obstet Gynecol 2005; 17: 157–160.

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 em-

bolism. Paediatr Perinat Epidemiol 2005; 19: 173–176.

80. Kramer MS, Rouleau J, Baskett TF et al. Amniotic-fluid embolism and medical induction of labour: a ret-

rospective, population-based cohort study. Lancet 2006; 368: 1444–1448.

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: 324–332.

82. El Kady D. Perinatal outcomes of traumatic injuries during pregnancy. Clin Obstet Gynecol 2007; 50:

582–591.

83. Pearlman MD. Motor vehicle crashes, pregnancy loss and preterm labor. Int J Gynaecol Obstet 1997; 57:

127–132.

84. Green W, Robinson LM, Rizzo AG et al. Pregnancy is not a sufficient indicator for trauma team acti-

vation. J Trauma Inj Infect Crit Care 2007; 63: 550–555.


85. Patel SJ, Reede DL, Katz DS et al. Imaging the pregnant patient for nonobstetric conditions: algorithms

and radiation dose considerations. RadioGraphics 2007; 27: 1705–1722.

86. Cusick SS & Tibbles CD. Trauma in pregnancy. Emerg Med Clin N Am 2007; 25: 861–872.

87. Barraco R, Chiu W, Clancy Tet 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: 555–583.

89. Gunter JJ. Intimate partner violence. Obstet Gynecol Clin N Am 2007; 34: 367–388, 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: 1104–1108.

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: 664–672.

92. Weiss HB, Songer TJ & Fabio A. Fetal deaths related to maternal injury. JAMA 2001; 286: 1863–1868.

93. Cahill AG, Bastek JA, Stamilio DM et al. Minor trauma in pregnancy – is the evaluation unwarranted? Am

J Obstet Gynecol 2008; 198: 208e1–5.

*94. ACOG Educational Bulletin. Obstetric aspects of trauma management. Washington D.C: American Col-

lege 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: 1094–1098.

96. Pearlman MD & Phillips ME. Safety belt use during pregnancy. Obstet Gynecol 1996; 88: 1026–1029.

http://www.east.org/tpg/pregnancy.pdf

Documents

Critical care in obstetrics: pregnancy-speciﬁc conditions Care in... · Critical care in obstetrics: pregnancy-speciﬁc conditions ... elevated in 85–100% and at least 93% of