Chapter 14: Amniotic Fluid Embolism

Amniotic fluid embolism (AFE) is a catastrophic syndrome typically occurring during labor and delivery or immediately postpartum. Although presenting symptoms may vary, common clinical features include shortness of breath, altered mental status, followed by sudden cardiovascular collapse, disseminated intravascular coagulation (DIC), and maternal death. The first case report of AFE was published in a 1926 Brazilian medical journal¹ and AFE was recognized as a syndrome in 1941, when 2 investigators described fetal mucin and squamous cells during postmortem examination of the pulmonary vasculature in women who had unexplained obstetric deaths.² Since then, over 1000 studies, case reports, and series have been published in an attempt to elucidate the etiology, risk factors, and pathogenesis of this mysterious obstetric complication.

The incidence of AFE, including both fatal and nonfatal cases, ranges between 1 in 12,953 deliveries in the United States³ to 1 in 50,000 deliveries in the United Kingdom.⁴ The true incidence and mortality rates of AFE are confounded by several factors: (1) the clinical definition of AFE varies across reports, (2) the signs and symptoms of AFE overlap with other more common obstetrical complications such as hemorrhagic shock due to postpartum hemorrhage, (3) there is not a “gold standard” test for the diagnosis of AFE, (4) the diagnosis of AFE is to a great extent a diagnosis of exclusion, and (5) many of the population-based studies relying on hospital discharge diagnostic codes do not ascertain the clinical diagnosis of AFE from the medical record. Diagnostic criteria for AFE as proposed in the US national registry⁵ are summarized in Table 14-1.

There have also been wide variances in the published maternal mortality rates associated with AFE. In the US national registry examining 46 cases of AFE, the maternal mortality rate was 61%, with a neurologically intact maternal survival rate of 15% in cases which occurred in the late 1980s and early 1990s. More recent population-based studies have reported a decreased case fatality rate from AFE (Table 14-2).^{3,4,5,6,7,8,9,10,11,12,13, 14} These improving survival statistics may in part reflect improvement in general and specialized medical care over the recent decades. However, AFE still remains a leading cause of maternal death in the United States.¹⁵ Fetal outcome is poor when AFE occurs before delivery. In the US registry report, the fetal survival rate approached 40%, though with up to half of surviving neonates developing neurologic abnormalities.⁵ As with the maternal mortality statistics, perinatal mortality rates appear to be improving as well over the last several decades.

Although the US national registry⁵ did not find any predictive maternal demographic risk factors for AFE, it was noted that 70% of cases occurred during labor, 19% were recorded during cesarean section, and 11% of cases occurred immediately following vaginal delivery. Other studies have also found an increased frequency of AFE in women who underwent cesarean delivery, with rates of cesarean between 20% and 60%.^10,16 Approximately 50% of these cases were associated with fetal distress, suggesting that amniotic fluid embolus and associated hypoxia preceded cesarean delivery. Rupture of membranes was a consistent finding among 78% of women in the US registry, with onset of symptoms occurring within 3 minutes of amniotomy in 11% of cases.⁵ Another study found maternal age (mean age 33 years) and multiparity (mean parity 2.6) to be associated with AFE.¹⁶ Conflicting data have been reported regarding the association of AFE with multiple gestations. The frequency of twin gestation in the national AFE registry was not increased from baseline population estimates, but was found to be approximately threefold higher in 1 retrospective analysis.¹⁶ Induction of labor has been associated with an increased relative risk of AFE in several studies^4,10 and no association was detected in others.³ Whether this is cause-and-effect versus an association is not clear, nevertheless the increase in absolute risk would seem clinically small assuming there is a valid indication for induction of labor.

The pathogenesis of AFE is poorly understood. Early studies describe the histologic presence of amniotic fluid components in lung tissue during postmortem examination in obstetric patients who had unexplained death.² This finding was followed by reports of amniotic fluid debris found in the maternal circulation in fatal and nonfatal cases of AFE.^17,18 It was hypothesized that embolism of amniotic fluid into the maternal venous circulation caused direct mechanical obstruction of the pulmonary venous circulation resulting in cor pulmonale. However, elements of amniotic fluid have been isolated in the blood of pregnant women who did not have clinical evidence of AFE^19,20 and not all women with “classic AFE” have fetal elements detected in maternal central venous blood or lung histology.⁵

Amniotic fluid contains various concentrations of fetal elements (eg, squamous epithelial cells, lanugo hair, vernix, mucin) and other elements which may incite vasoactive and procoagulant effects (eg, prostaglandins, platelet-activating factor). Possible mechanisms of disease include the direct effects of procoagulants and/or vasoactive substances found in amniotic fluid on maternal systems. Romero and colleagues hypothesize infection/-sepsis as an etiology of AFE based on 2 cases of proposed AFE where supralethal maternal plasma TNF-α levels were present prior to the clinical AFE event.²¹ Laboratory analyses of various substances found in amniotic fluid or thought to be involved in the pathophysiologic response (zinc coproporphyrin, Sialyl Tn antigen, serum tryptase, complement C3 and C4) have been studied and reported, but to date, none appear reliable in predicting or diagnosing AFE.

Although AFE typically occurs during labor and delivery or immediately postpartum, rare cases of AFE have been reported after termination, transabdominal amniocentesis, trauma, and saline amnioinfusion.^{22,23,24,25, 26} Classic presenting signs and symptoms of AFE include respiratory distress, altered mental status, profound hypotension, coagulopathy, and death.⁶ Historical studies have described the presenting symptom as primarily respiratory distress, whereas other studies describe the most common presenting symptom before delivery to be altered mental status. Seizure or seizure-like activity was reported as the initial symptom of 30% of patients involved in the US national registry, followed by dyspnea (27%), fetal bradycardia (17%), and hypotension (13%).⁵ Classic signs and symptoms are listed in Table 14-3. The interval between the onset of symptoms and collapse reportedly varies between almost immediately to over 4 hours later. Other signs and symptoms include nausea, vomiting, fever, chills, and headache.

Clinical features of AFE include profound cardiovascular changes. According to the US national registry, all patients who had AFE experienced hypotension.⁵ Most women (93%) had some level of pulmonary edema or adult respiratory distress syndrome along with hypoxia. One explanation for these findings includes the possibility of severe bronchospasm related to the presence of fetal elements in the pulmonary vasculature; however, only 15% of patients were found to have bronchospasm. Transesophageal echocardiography and pulmonary artery catheterization studies have demonstrated transiently elevated pulmonary artery pressures in cases of AFE along with left ventricular dysfunction, supporting the notion that these pulmonary findings are consistent with cardiogenic shock. There have also been reports of isolated right ventricular dysfunction with high right-sided pressures and tricuspid regurgitation.^{27,28,29,30,31, 32} In several cases where transesophageal echocardiography was performed during the early course of AFE, left ventricular failure was secondary to impaired left ventricular filling caused by dilation of the right ventricle with deviation of the interventricular septum. Available evidence suggests that the hemodynamic response to AFE initially presents with increased pulmonary vascular resistance, and right ventricular failure followed by left ventricular dysfunction.²⁷ A summary of pulmonary artery catheter hemodynamic studies following AFE is presented in Table 14-4. Myocardial hypoxic injury may be related to decreased cardiac output and impaired filling, resulting in decreased coronary artery perfusion. This vasoconstriction is often followed by profound hypotension and shock, most likely resulting from cardiogenic or obstructive causes as described earlier. After initial survival, hypoxia relates more to noncardiogenic shock, whereby severe alveolar-capillary membrane leak leads to an increase in pulmonary edema and a decrease in oxygenation.²⁷

DIC is a common feature of AFE and often further complicates the management of the patient who has AFE. According to the US registry, 83% of patients demonstrated laboratory abnormalities or clinical findings consistent with DIC, regardless of mode of delivery.⁵ Onset was variable, with 50% of cases occurring within 4 hours of presentation, often within 20 to 30 minutes of symptom onset. The presence of clotting factors in amniotic fluid has been linked with the possible activation of the clotting cascade ^33,34 In the US national registry, 75% of patients who presented with hemorrhage and isolated coagulopathy died despite appropriate resuscitative efforts.

Due to the vast overlap of AFE symptomatology with other disease states, consideration for the differential diagnosis of AFE is warranted. A differential diagnosis for possible AFE is shown in Table 14-5.

Management of AFE is aimed to support acute multisystem dysfunction. Initial diagnostic testing to consider in a patient whose differential diagnosis includes AFE is summarized in Table 14-6. With or without evidence of hemorrhage as a presenting symptom, blood products should be ordered expeditiously in anticipation of profound bleeding and DIC. Cardiac enzymes may be elevated and arterial blood gas levels will demonstrate hypoxemia. Electrocardiogram may demonstrate tachycardia with possible right ventricular strain. Chest radiography may demonstrate nonspecific increased opacities and transesophageal echocardiography can reveal severe pulmonary hypertension, acute right ventricular failure, and deviation of the interventricular septum.

The primary management goals include rapid maternal cardiopulmonary stabilization with prevention of hypoxia and maintenance of vascular perfusion. This may require endotracheal intubation to keep oxygen saturation at 90% or greater. Treatment of hypotension should include optimization of preload with infusion of crystalloid solutions. In cases of refractory hypotension, vasopressors such as dopamine or norepinephrine may be necessary. Central monitoring of cardiovascular function may assist in these endeavors.

Eighty-seven percent of patients in the national AFE registry suffered cardiac arrest.⁵ Of these, 40% occurred within 5 minutes of symptom onset. The most common dysrhythmia was found to be electromechanical dissociation, followed by bradycardia and ventricular tachycardia or fibrillation. Inotropic agents may need to be administered to improve myocardial function. In these cases, administration of all conventional cardiac support measures, including medications used in resuscitation, should be used without delay. The patient should be placed in the left lateral position before chest compressions to avoid compression of the inferior vena cava by the gravid uterus. In cases in which asystole or malignant arrhythmia is present for greater than 4 minutes, perimortem cesarean delivery should be considered. In such women, it is unlikely that cesarean section would adversely affect maternal outcome. Even properly performed cardiopulmonary resuscitation, difficult at best in a pregnant woman, provides only a maximum of 30% of normal cardiac output. Under these circumstances, it is fair to assume that the proportion of blood directed to the uterus and other splanchnic beds is minimal. Thus, the fetus will be profoundly hypoxic at all times following maternal cardiac arrest. For the pregnant patient, the standard ABCs of cardiopulmonary resuscitation should be modified to include a fourth category, D for delivery.

When AFE occurs prior to delivery, there is a significant chance of perinatal death, and a substantial risk of permanent neurodevelopmental deficits among surviving infants. There is a clear relationship between neonatal outcome and event-to-delivery interval in those women suffering cardiac arrest (Table 14-7). Intact fetal survival has been shown to be highest when delivery is accomplished within 5 minutes of maternal cardiac arrest; however, the decision to deliver should not be abandoned if determined beyond the 5-minute mark.

In a mother who is hemodynamically unstable but has not yet undergone cardiac arrest, maternal considerations must be weighed carefully against those of the fetus. The decision to subject such an unstable mother to a major surgical procedure (cesarean section) is a difficult one, and each case must be individualized. However, it is axiomatic in these situations that where a choice must be made, maternal well-being must take precedence over that of the fetus.

Selective arterial embolization has been reported in cases of AFE, but efficacy remains unproven.³⁵ Recombinant factor VII has been used and reported in cases of severe coagulopathy resistant to conventional blood and product replacement.^36,37 Other case reports have described the use of continuous hemodiafiltration, extracorporeal membrane oxygenation, and intra-aortic balloon counterpulsation in cases of AFE.^{38,39, 40} In 1 report, early transesophageal echocardiogram demonstrating severe pulmonary vasoconstriction and cor pulmonale lead to successful rescue using cardiopulmonary bypass. Nitric oxide appeared to be of benefit in 1 case report.⁴¹ The roles of these interventions in managing AFE remain unknown.

Significant maternal morbidity is associated with AFE. Over 75% of patients in the UK registry required intensive care management, with an average length of stay of 5 days among survivors and an average of 34 units of blood products was required in these patients. In the US AFE registry, only 15% of patients who had cardiac arrest survived neurologically intact. Other sequelae include liver hematoma, renal and multisystem failure, and ischemic encephalopathy. Overall morbidity and mortality of AFE has improved with early recognition of the syndrome and improved resuscitative efforts involving multiple disciplines of medicine. In cases recorded within the UK registry, women who survived AFE had a shorter time frame between symptom onset and treatment (42 vs 108 minutes).^42,43

There have been reported cases of successful pregnancies following AFE, and no reported recurrences to our knowledge. Although data is limited, there is no evidence to suggest that there is a recurrence risk for AFE in future pregnancies.

Although there are many new research developments in this field, the etiology and the pathogenesis of AFE remain unclear. Thus, currently, there is no “gold standard” diagnostic test or a specific therapy for AFE. AFE remains a diagnosis of exclusion, dependent on bedside evaluation and judgment. Ideal management includes prompt evaluation and intervention for each of the pathologic features found in this complex obstetric condition. Because AFE is an unpredictable and rare event, its study at any single obstetric institution is impractical. Future research efforts will be dependent upon collaborative efforts by national programs such as the United Kingdom Obstetric Surveillance System (https://www.npeu.ox.ac.uk/ukoss) and nonprofit entities such as the AFE Foundation (http://www.afesupport.org) which currently operates an international registry in partnership with Baylor College of Medicine.