Continuing Education Activity
Amniotic fluid embolism (AFE) is a rare entity, but one which has very high mortality and morbidity rates. This article will explain the clinical presentation of AFE, including a detailed description of the pathophysiology, and the very complicated evaluation and treatment modalities. This activity reviews the evaluation and management of AFE and highlights the role of the interprofessional team in evaluating and improving care for patients with this condition.
- Identify the underlying risk factors for amniotic fluid embolism.
- Describe the triggering pulmonary pathology that initiates the syndrome of amniotic fluid embolism.
- Outline correct methods of analyzing coagulation parameters and how to treat them once they are determined.
- Explain the importance of improving care coordination amongst the interprofessional team to enhance the delivery of care for a woman who has sustained amniotic fluid embolism.
Amniotic fluid embolism (AFE) is a life-threatening obstetric emergency characterized by sudden cardiorespiratory collapse and disseminated intravascular coagulation. Amniotic fluid embolism (AFE) represents the second leading cause of peripartum maternal death in the United States and the number one cause of peripartum cardiac arrest. The presentation is abrupt, usually with sudden cardiorespiratory collapse followed by severe coagulopathy and refractory resuscitation. Survivors are frequently left with serious cardiac renal neurologic and pulmonary dysfunction. In the United States, AFE occurs in 2 to 8 per 100,000 deliveries and is the cause of maternal mortality between 7.5% to 10%.
Steiner and Luschbaugh first described amniotic fluid embolism in 1941, after they found fetal cells in the maternal pulmonary circulation, who died during labor. Data from the National Amniotic Fluid Embolism Registry suggest that the process resembles anaphylaxis more than to embolism, and the terminology of "anaphylactoid syndrome of pregnancy" has been recommended because fetal tissue or amniotic fluid components are not always found in women who present with signs and symptoms attributable to amniotic fluid embolism.
The diagnosis of AFE has been established at autopsy when fetal squamous cells are found in the maternal pulmonary artery blood; however, fetal squamous cells are also sometimes present in the circulation of laboring women who do not develop AFE. The diagnosis is of exclusion based on clinical presentation. Other causes of hemodynamic instability should be ruled out.
Amniotic fluid embolism (AFE) is unpredictable, with an unknown cause. Risk factors for the development of AFE are advanced maternal age, multiparity, male fetuses, and trauma. It has been found that the induction of labor increases the risk of AFE. Fong et al. found that women with cerebrovascular disorders and cardiac disease have 25 fold and 70 fold higher risk of AFE, respectively. There is also a strong association of AFE with cesarean delivery, placenta previa, eclampsia, placental abruption, polyhydramnios, dilatation and curettage, and renal disease.
The introduction of amniotic fluid and fetal components into the maternal circulation has been shown to create intense pulmonary vasoconstriction and bronco constriction. These effects are considered to be caused not only by physical obstruction but also by the liberation of intense inflammatory cytokines reactant to the foreign material. These inflammatory mediators are also believed to trip the coagulation and fibrinolytic pathways, creating a form of disseminated intravascular coagulation (DIC) syndrome.
The incidence of amniotic fluid embolism (AFE) is estimated at 1 case per 8000 to 30,000 pregnancies. The exact prevalence is not known due to inaccurate diagnosis and not reporting the nonfatal cases. In Germany, AFE was the leading cause of death during parturition in 2011. AFE is identified as the leading direct cause of maternal mortality in Australia from 1 in 8000 to 1 in 80,000 deliveries. In the UK, the estimated incidence is 1.9 per 10000 to 7.7 per 10000 births.
The setting for amniotic fluid embolism (AFE) is a disruption of the placenta-amniotic interface with the subsequent entry of amniotic fluid and fetal elements (such as hair, meconium, squama, and mucin) into the maternal circulation. Portals of entry may include the placental attachment, the cervical veins, or uterine surgical incisions. Upon entering the pulmonary arterial tree, intense pulmonary vasoconstriction occurs. This may be associated with concomitant bronchoconstriction. The hemodynamic result is acute pulmonary arterial obstruction, dilatation of the right ventricle and the right atrium, and significant tricuspid regurgitation.
The right ventricular enlargement causes the intraventricular septum to bow into the left ventricle creating obstruction and systolic dysfunction, further raising pulmonary artery pressure and decreasing cardiac output. Hypoxemia and hypotension lead to sudden cardiovascular collapse. Normally, pregnancies are procoagulant, to begin with, having increased levels of clotting factors X, IX, VIII, von Willebrand factor (VWF), and tissue factor pathway inhibitor (TFPI). The introduction of amniotic fluid and fetal elements trigger inflammatory mediators such as platelet-activating factor, tissue necrosis factor-alpha (TNF-alpha), interleukin-six, interleukin-one, phospholipase A2, endothelin, plasminogen activators, thromboplastins, and complement factors.
The coagulation cascade and fibrinolytic systems are thus activated. Amniotic fluid in the maternal circulation activates platelet factor III, stimulates platelet aggregation, and activates clotting factor Xa. The superimposed pathologic activation of the coagulation and fibrinolytic pathways create a severe coagulopathy. Disseminated intravascular coagulation (DIC) occurs in approximately 80% of patients with AFE. This may be immediate at the time of the cardiopulmonary collapse or delayed. Bleeding may be severe, unrelenting, and fatal. Amniotic fluid and fetal elements are also known to infiltrate the uterus, causing severe uterine atony, which further exacerbates the hemorrhage. Autopsies on women succumbing to AFE show pulmonary edema, amniotic component emboli in the lungs, and alveolar hemorrhage. Myocardial infarction, acute renal failure from acute tubular necrosis, and cerebral infarctions are also found.
History and Physical
The prior medical history or history of present illness of the patient who sustains an amniotic fluid embolism (AFE) may reveal advanced maternal age, multiple pregnancies, placenta accreta, placenta abruption, placenta previa, preeclampsia, gestational diabetes, polyhydramnios, amniocentesis, amnioinfusion, mechanical rupture of membranes, or any surgery to the gravid uterus. The classic history is that woman in the late stages of labor becomes acutely short of breath with hypotension. There may be agitation or feeling of impending doom before the onset of other symptoms. She may experience seizures followed by cardiac arrest. Massive DIC-associated hemorrhage follows and then death. Mostly die within an hour of onset. Data shows that 53% of females with AFE present at the time of delivery or even before it and remaining presented by an average of nineteen minutes after delivery.
The physical exam will show a patient in cardiovascular collapse with marked hypoxemia, hypotension, and cyanosis. The classic triad of AFE is hypoxia, hypotension, and coagulopathy. The temperature will be normal. The funduscopic exam may reveal minute bubbles in the retinal arteries. The patient would be tachypneic, perhaps with the classic holosystolic high-pitched murmur of tricuspid regurgitation. This murmur is loudest at the lower left sternal border and radiates to the right sternal edge. Hemorrhage may range from massive to minimal. The uterus frequently is atonic (83%), which further accentuates bleeding. Initial bleeding is generally from the vagina but may also be first seen in surgical incisions. Full-blown DIC is seen in approximately 80% of patients. The neurologic exam usually reveals a dysphoric and encephalopathic patient. Tonic-clonic seizures (10-50%) may complicate the picture.
No reliable, definitive test exists for amniotic fluid embolism (AFE). The suspicion of AFE is suggested by the sudden appearance of dyspnea, dysphoria, hypotension, cardiovascular collapse, and coagulopathy following some action during the peripartum period-, e.g., active labor, rupture of membranes, vaginal delivery, or cesarean section. AFE has also been seen during or after elective pregnancy terminations (induced or surgical). The initial evaluation for AFE is usually done during aggressive cardiopulmonary resuscitation. This evaluation is tailored to the two main system failures, which are hemodynamic and hematologic. Bedside measurement of pulmonary wedge pressure, cardiac output, central venous pressure, pulse oximetry, arterial waveform, electrocardiography, and chest radiography should start the initial hemodynamic evaluation.
Transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) is essential to the diagnosis. If stability is acquired, TEE is preferred. Significant findings of AFE are right ventricle dilatation, hypokinesis, and overload, tricuspid regurgitation, and right atrial enlargement. Early cardiac thrombi may be detected in the enlarged right ventricle or right atrium. Highly associated with this syndrome is bowing of the intraventricular septum into the left ventricle, creating left ventricular obstruction and systolic dysfunction. The echocardiographic appearance of this bowing resembles the letter ‘D.’ Blood should be obtained immediately for urgent type and crossmatch, complete blood count, comprehensive metabolic panel, and a full coagulation panel to include platelets, prothrombin time, partial thromboplastin time, bleeding time, fibrinogen, d-dimer, and fibrin degradation products (FDPs).
Metabolic and respiratory acidosis is common. This should be evaluated by an arterial blood gas, as well as an end-tidal carbon dioxide (etCO2) measurement. The International Society on Thrombosis and Hemostasis (ISTH) has a formal scoring system (10) to determine the presence of DIC in pregnancy. The score is based on platelet count, international neutralization ratio (INR), and fibrinogen level. Scores of more than 3 are indicative of DIC in pregnancy. Determining strict criteria for the diagnosis of AFE has been trying since there is no single definitive test to clinch the diagnosis. Internationally, various standards have appeared defining AFE. The American Society for Maternal-Fetal Medicine, after a consensus symposium has created its criteria for AFE, which require the following:
- Sudden cardiopulmonary collapse, or hypotension (systolic blood pressure <90 mmHg) with hypoxia (SpO2<90%)
- DIC, according to ISTH definition
- Symptomatology either during labor or during placental delivery (or up to 30 minutes later)
- No fever
They specifically note that there are cases outside of these parameters (such as during pregnancy terminations) and emphasize that their goal was to establish standardized research reporting criteria. They freely admit that there would be countless outlier cases using their standards, but hopefully, not many.
Treatment / Management
The cornerstone of the management of an acute amniotic fluid embolism (AFE) is prompt and effective cardiopulmonary resuscitation of the mother and rapid evacuation of the fetus. For the mother, this, of course, would include securing the airway, effective ventilation, ideal fluid management, and the appropriate use of vasopressors. Initially, after intubation, large-bore intravenous catheters should be instituted for infusions. Pulmonary wedge catheters (Swan Ganz) will directly measure left atrial and pulmonary artery pressures as well as cardiac output through thermal dilution. Pulmonary artery blood aspirants may reveal the presence of fetal components. Intra-arterial lines are useful to facilitate minute to minute pressure measurement and frequent arterial blood gas samplings. A central venous pressure line may assist in assessing right-sided preload. Urethral catheterization facilitates urine output documentation. Crystalloid fluids are generally given judiciously but must be limited if coagulopathy ensues. Copious fluid administration dilutes clotting factors making bleeding worse. For this reason, the decision to move to vasopressors should be considered earlier as compared to significant bleeding from other etiologies.
The general sequence of vasopressors support starts with dopamine, dobutamine, or epinephrine, but may be switched to norepinephrine for persistent hypotension. Vasopressin may be added at this point to augment cardiac output. Ideal management is to maintain mean arterial pressure (MAP) >65mmHg, a cardiac index of more than 2L per meter square, an adequate urine output of 40-50 ml/hr, and a PaO2/FiO2 ratio more than 250. Ventilation using inhaled nitric oxide assists in reducing RV afterload. Sildenafil is utilized for its pulmonary arterial vasodilatation. Extracorporeal membrane oxygenation (ECMO) has been used successfully for refractory cardiogenic shock secondary to amniotic fluid embolus. Any patient who remains in persistent cardiopulmonary collapse should have femoral arterial and venous 4Fr sheaths placed in anticipation of ECMO. Patients may need to be transferred to tertiary facilities capable of ECMO. This mandates early decision-making and knowledge of local capabilities. Once ECMO is instituted, it is recommended to remove arterial and venous catheters once cardiovascular stability has been obtained. Intravascular catheters exacerbate an ongoing coagulopathy.
The management of the coagulopathy (DIC) of AFE has classically been to empirically administer units of packed red blood cells (pRBCs), fresh frozen plasma (FFP), and platelets in a 1:1:1 ratio until bleeding is controlled. Cryoprecipitate contains concentrated clotting factors, including factor VIII, von Willebrand factor, and fibrinogen. It is also given to maintain fibrinogen levels >200mg/dl. Tranexamic acid is given for fibrinolysis. Standard laboratory turnaround times for important clotting parameters such as prothrombin time, partial thromboplastin time, clotting factor analysis, and fibrinogen tend to be excessive. The use of viscoelastic tests such as thromboelastography (TEG) and rotational thromboelastometry (ROTEM), when done at the bedside (point of care) by a trained specialist, offers the capability of a minute to minute evaluation of fibrinogen level, platelet count and function, as well as evaluation of the entire extrinsic clotting pathway. Algorithms derived from these measurements dictate appropriate administration of cryoprecipitate, fibrinogen, prothrombin complex concentrates, platelets, FFP, pRBCs, and tranexamic acid (TXA). Anecdotal reports in the literature cite the use of rivaroxaban, a factor Xa inhibitor, as successfully reversing the DIC of AFE. Other anecdotal reports suggest the use of ketorolac to inhibit thromboxane, which activates platelets in AFE. Besides, ondansetron has been utilized to block serotonin receptors in the lung. Serotonin is thought to be a potent pulmonary vasoconstrictor.
Obstetrical management must include the rapid evacuation of the fetus, usually by cesarean section. The Society for Maternal-Fetal Medicine recommends this for all fetuses over 23 weeks gestational age. Ongoing resuscitation of the mother in the obstetrical operating room with an anesthesiologist or critical care physician running the cardiovascular resuscitation must go on during the extraction of the infant. It is recommended to shift the gravid uterus to the left, therefore, relieving aortocaval compression. This multidisciplinary team must be able to initiate neonatal resuscitation and should include a neonatologist because the majority of these infants are born with low Apgar’s. The infant will likely need rapid suctioning, intubation, and vascular access. The obstetrician may elect several different procedures to alleviate the ongoing uterine hemorrhage. Uterine artery ligation or embolization has been documented with some success. Circumferential B-Lynch, Hayman, or Pereira compression sutures have been utilized to compress the atonic uterus and staunch bleeding. However, in the setting of massive hemorrhage and an atonic uterus, the best course is emergency hysterectomy.
The differential diagnosis of a woman who sustains complete cardiovascular collapse during or close to the time of delivery and then subsequently develops major hemorrhage should include
- Pulmonary embolism (PE)
- Peripartum cardiomyopathy
- Septic shock
- Myocardial infarction
- Venous air embolism
- Cephalad spread of spinal anesthetic
Amniotic fluid embolism (AFE) mimics pulmonary embolus to a degree, but an ongoing coagulopathy is not seen in PE. Postpartum cardiomyopathy would likely have significant ST-T wave changes on electrocardiography, with left-sided congestive heart failure symptoms predominating. Bedside echocardiography (TEE or TTE) should easily be able to make this differential with the classic right ventricular dilatation and overload pattern and septal bowing into the left ventricle seen in AFE.
Septic shock should show the classic systemic inflammatory response syndrome (SIRS) picture with elevated or depressed body temperature and is unlikely to present with sudden cardiovascular collapse. Myocardial infarction, unless antecedent to the cardiac arrest, would show typical ST-T wave changes and elevation of serial cardiac enzymes. Bedside echocardiography would show characteristic ventricular wall motion abnormalities of myocardial infarction. Venous air embolism usually presents with wheezing, gasping, and chest pain before the cardiovascular collapse. Eclampsia would be suggested by hypertension, edema, proteinuria, headaches, or seizures before the collapse. Anaphylaxis should have premonitory symptoms of wheezing, dyspnea, rash, urticaria, and a period of hypotension before cardiovascular decompensation. Cephalad distribution of spinal anesthetic would present with an elevated sensory level, weakness of the upper extremities, difficulty in speaking, dysphagia, and bradycardia.
Amniotic fluid embolism (AFE) itself is rare, with the prevalence in the United States approximately one in 25,000 deliveries. However, the case mortality rate varies somewhere between 40 to 60%. A study in California showed that 26.4% of women died while 66% developed DIC. Maternal survival is uncommon, although the prognosis is improved with early recognition and prompt resuscitation. The United Kingdom AFE registry has reported 37% mortality, and 7% of those who survived were neurologically impaired.
Two-thirds of women surviving AFE are left with serious neurologic, pulmonary, and cardiovascular deficits. The risk of recurrence is unknown. Successful subsequent pregnancies have been reported. The recommendations for elective cesarean delivery during future pregnancies in an attempt to avoid labor is controversial. The mortality rate for the infant is slightly lower at approximately 30%. Then there is a high risk of hypoxic-ischemic encephalopathy, cerebral palsy, and other cognitive disabilities in survivors.
The major complications for the mother who survives amniotic fluid embolism (AFE) are
- Renal failure
- Prolonged respiratory failure with adult respiratory distress
- Myocardial infarction
- Congestive heart failure
- Left ventricular systolic dysfunction
- Prolonged coagulopathy
- Liver failure
- Anoxic encephalopathy
- Other cognitive impairments
- Infants delivered precipitously during maternal AFE frequently sustain hypoxic-ischemic encephalopathy (HIE). The usual result is a markedly cognitively impaired child who may go on to have chronic epilepsy, motor impairment, and developmental delay.
Enhancing Healthcare Team Outcomes
The very complicated nature of the sudden onset of cardiovascular collapse and subsequent severe coagulopathy in the mother, as well as the need for neonatal resuscitation of the infant, make amniotic fluid embolism (AFE) challenging to any interdisciplinary team. Coordination between obstetrician, maternal-fetal specialist, anesthesiologist, labor and delivery nurses, neonatologist, intensivist, hematologist, perfusionist, respiratory therapists, and neonatal intensive care unit nurses is mandatory for successful maternal and infant survival outcomes.