Amniotic fluid embolism (AFE) is one of the most catastrophic complications of pregnancy. Passage of amniotic fluid into the maternal circulation was first reported by Meyer1 in 1926, and the syndrome was first described by Steiner and Lushbaugh2 in 1941. However, the condition is exceedingly rare and the exact pathophysiology is still unknown. Common presenting symptoms include dyspnea, nonreassuring fetal status, hypotension, seizures and disseminated intravascular coagulation (DIC). Early recognition of AFE is critical to a successful outcome. However, despite intensive efforts at resuscitation, outcomes are frequently poor for both infant and mother. Aggressive management with the use of recombinant factor VIIa (rfVIIa) and a ventricular assist device,3 inhaled nitric oxide,4 cardiopulmonary bypass,5 and intraaortic balloon pump with extracorporeal membrane oxygenation (ECMO)6 have recently been reported with successful outcomes.
To better understand the risk factors and clinical presentation of women with AFE, two registries were developed, one by Clark et al.7 in the United States and one by Tuffnell8 in the United Kingdom (UK). Entry criteria were the same in both registries and included: 1) acute hypotension or cardiac arrest, 2) acute hypoxia, 3) coagulopathy, and 4) onset during labor, cesarean delivery or dilation and evacuation or within 30 min of evacuation of the uterus. Both of these registries have limitations since they depend on self-reporting and limited numbers of patients were entered, 46 in the United States registry published in 1995 and 44 in the UK registry published in 2005.
Incidence and Outcome
The true incidence of AFE is unknown but is estimated to occur between 1 in 8000 and 1 in 80,000 deliveries,7–9 with reported mortality rates in older reports as high as 60% even with aggressive and immediate treatment.7 Maternal morbidity is also high and only 15% of survivors may be neurologically intact. More recent data suggest a lower mortality rate can be achieved, 27% in a population-based study performed in 199910 and 37% in the UK registry from 2005.8 It is unclear if the improved mortality rate is related to better critical care management or an artifact related to different reporting techniques yielding a larger denominator. Neonatal outcome is generally poor with a mortality rate of 20%–25% and, of the survivors, only 50% may be neurologically intact.7,8 There are no proven risk factors to the development of AFE and its onset cannot be predicted.
The pathophysiology of AFE is poorly understood as human study is obviously limited. Experimental animal studies into the pathogenesis and treatment of AFE have produced mixed results. Some models have failed to reproduce the syndrome even with direct intravascular injection of amniotic fluid,11,12 and some have only been able to do so when the injected amniotic fluid was stained with meconium.13,14
AFE, as a clinical syndrome, was first characterized by the presence of amniotic fluid debris in the maternal pulmonary circulation, and the amniotic fluid was thought to cause an embolic phenomenon.2,15 Steiner and Lushbaugh,2 in their original description of AFE, reported the presence of mucin, amorphous eosinophilic material and squamous cells in women with AFE, consistent with the presence of amniotic fluid. They hypothesized that amniotic fluid was forced into the maternal circulation during contractions leading to the embolic event. The theory was supported by analyzing the women in their series who developed AFE. Most cases of AFE occurred in multiparous women who delivered vaginally during a tumultuous or hyperstimulated labor. However, knowledge of uterine physiology and results of other studies have called this theory into question. During contractions, especially forceful ones, when uterine pressure increases above maternal venous pressure, maternal-placental exchange decreases or ceases, but certainly does not increase. Therefore, Clark et al.7 speculated that the least likely time for transfer of amniotic fluid is during tumultuous labor or during uterine tachysystole. Furthermore, Lee et al.16 demonstrated that fetal squamous cells can be found in the pulmonary circulation of women without clinical evidence of AFE, and other investigators could not reproduce the syndrome in two separate animal models, mini-pigs and monkeys, by injecting amniotic fluid directly into their circulation.11,12 Finally, Clark et al.7 found that 19% of women in their registry first manifested symptoms during cesarean delivery when there is no tumultuous labor.
Clark et al.7 recognized that the clinical course and hemodynamic changes of AFE were similar to patients with anaphylactic shock and proposed that AFE was more of an immunologic than embolic phenomena. Amniotic fluid contains many vasoactive and procoagulant substances, such as platelet activating factor, cytokines, bradykinin, thromboxane, leukotrienes and arachidonic acid, and entrance of even minute amounts of these substances into the maternal circulation could cause the syndrome.17 This would explain why fetal cells were not always found in women who suffered AFE. They further recommended changing the name of the syndrome from AFE “to the anaphylactoid syndrome of pregnancy.” In support of this “immunologic” theory is the finding that AFE seems to be more common in women carrying male fetuses, and these women are also at increased risk for Rh isoimmunization, another immunologic-based condition.18 Some have suggested that plasma tryptase levels, a mast cell enzyme, may be helpful in the diagnosis of AFE.19,20 Further support for an immune basis is that complement activation, another component of the immune response, may play a role in the pathogenesis of AFE. Specifically, C3 and C4 levels are markedly decreased in women with AFE.21
AFE usually occurs intrapartum or in the immediate postpartum period. The symptoms are often sudden and protean. Clark et al.7 found the most common presenting signs and symptoms were hypotension and signs of nonreassuring fetal status (100%), pulmonary edema or respiratory symptoms (93%), cardiac arrest (87%), cyanosis (83%), and coagulopathy (83%) (Table 1). Tuffnell8 found that the most common presentation was a sudden change in either the maternal or fetal condition, but he did not specify the exact symptom.
Clark et al.22 proposed a biphasic model of the hemodynamic consequences of AFE. The initial response is acute pulmonary hypertension and vasospasm leading to right ventricular failure, hypoxia, and cardiac arrest. If one survives this initial insult, then the pulmonary hypertension is generally not sustained and may be replaced with left ventricular failure and pulmonary edema. Increased pulmonary artery pressure has not been consistently reported probably because this finding may be short-lived.23 When cardiac pressures are measured early in the process, pulmonary and right ventricular pressures have been found to be elevated.5 Hankins et al.14 demonstrated in a goat model that injecting 2.5 mL/kg of homologous amniotic fluid IV increased right heart and systemic vascular resistance. They also demonstrated that the presence of meconium was needed to produce left heart failure and hypoxia. These findings were confirmed by Petroianu et al.13 and might explain a role for meconium as the putative cause for mast cell degranulation and inflammatory response. This would explain why in Clark et al.’s7 series the worst maternal outcomes were in those with meconium-stained amniotic fluid. It is also possible that meconium does not cause the syndrome, but is simply present because it is a nonspecific marker of either maternal or fetal stress.
Coagulation disorders are a prominent feature of the amniotic fluid syndrome. DIC is present in more than 83% of patients with AFE. The onset can occur as quickly as 10–30 min from onset of symptoms or may be delayed by as many as 4 h.24 Amniotic fluid contains tissue factor that acts as a procoagulant and may account for the coagulopathy.25 Tissue factor binds with Factor VII and activates the extrinsic coagulation pathway. Alternatively, the coagulopathy may be related to fibrinolysis due to increased levels of plasminogen activation inhibitor 1 in amniotic fluid.26
The differential diagnoses of AFE include obstetric, nonobstetric and anesthetic etiologies (Table 2).27 Although each of the disorders listed has symptoms consistent with AFE, sudden onset of dyspnea in the face of cardiovascular collapse and DIC should lead the clinician to suspect AFE and initiate treatment. Since squamous cells have been found in the circulation of patients with and without the AFE syndrome, the diagnosis is one of exclusion based on presenting symptoms and clinical course, not based on laboratory or pathology findings.
Early recognition of AFE is critical to a successful outcome. Management is primarily resuscitative and should be directed toward controlling the airway, maintaining vital signs and correcting coagulopathy. AFE is always associated with hypoxia. Therefore, control of the airway with tracheal intubation and administration of 100% O2 with positive pressure ventilation should be performed as soon as possible. Venous access with large bore IV catheters should be accomplished without delay. Arterial catheterization should also be considered for accurate arterial blood pressure monitoring and frequent blood sampling.
If the presentation is before delivery, providers should consider expeditious delivery of the fetus. Early delivery of the fetus in the resuscitation process may increase the chances of perinatal survival without neurologic sequelae.7 Also, delivery of the fetus aids in the maternal resuscitation efforts by improving venous return to the right heart.
Echocardiography is a sensitive tool to evaluate cardiac function and intravascular volume status. Both transthoracic and transesophageal modalities have been used by some clinicians in the diagnosis and management of AFE.5,28 Verroust et al.28 documented the presence of amniotic fluid in the right heart by echocardiography, which had a different appearance on echocardiography than blood. Care must be taken when inserting the transesophageal echocardiography probe in the coagulopathic patient.
Vasopressors and inotropic support are generally needed to varying degrees in AFE. Central venous access should be established for vasopressor infusion and monitoring. Choice of vasopressor drug depends on the clinical scenario. Phenylephrine, a pure α 1 agonist, is often an excellent choice early in the treatment of AFE because at that time point systemic vasodilation is the most prominent circulatory abnormality. Later in the course of the process, inotropic support is commonly needed, and drugs, such as norepinephrine, epinephrine, and dopamine, should be considered. Vasopressin may be used as primary therapy or as an adjunct to other inotropic therapies and has the benefit of sparing the pulmonary vasculature from vasoconstriction, especially at low doses.29 In the face of right heart failure, milrinone or other phosphodiesterase inhibitors should be considered.
Blood and blood products, including fresh frozen plasma, platelets and cryoprecipitate, must be available and administered early in the resuscitation phase of AFE.30 The successful use of rfVIIa has been reported,3,31,32 although it has also been associated with massive intravascular thrombosis.33 Aprotinin has also been effective in reducing hemorrhage with AFE.34 However, after the results of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study of patients undergoing coronary artery bypass surgery that demonstrated an increased mortality with aprotinin as compared with lysine analogues, the drug is no longer available.35 Other antifibrinolytic drugs, such as aminocaproic acid and tranexamic acid, have been described in the management of obstetric hemorrhage36 and menorrhagia37 and might also be considered during AFE. However, the authors are unaware of published reports in which these drugs were used specifically for treatment of the AFE-associated coagulopathy.
Other novel approaches for the treatment of AFE have been successfully used. Inhaled nitric oxide has been used in the treatment of right-sided heart failure and pulmonary hypertension.4 The use of cardiopulmonary bypass5 and placement of an intraaortic balloon pump counter pulsation with ECMO have also been described in the management of severe hypoxia and left heart failure associated with AFE.6 We recently reported the successful management of AFE with a right ventricular assist device and rfVIIa.3
AFE is a rare but often fatal complication of pregnancy and its onset can neither be predicted nor prevented. Early recognition of AFE with prompt intervention is paramount to a successful outcome. Management is resuscitative, geared toward maintaining vital signs and treating hemodynamic and coagulopathic derangements as they occur. A team approach among obstetrician, anesthesiologist and intensivist is necessary for a successful outcome. Despite early intervention, maternal and fetal mortality remain high. Aggressive management with novel products and devices, such as rfVIIa, cardiopulmonary bypass, ventricular assist device and ECMO, has been reported and should be considered.
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