Clinical Expert Series

Amniotic Fluid Embolism

Steven L. Clark,
MD

Amniotic fluid embolism remains one of the most devastating conditions in obstetric practice with an incidence of approximately 1 in 40,000 deliveries and a reported mortality rate ranging from 20% to 60%. The pathophysiology appears to involve an abnormal maternal response to fetal tissue exposure associated with breaches of the maternalfetal physiologic barrier during parturition. This response and its subsequent injury appear to involve activation of proinflammatory mediators similar to that seen with the classic systemic inflammatory response syndrome. Progress in our understanding of this syndrome continues to be hampered by a lack of universally acknowledged diagnostic criteria, the clinical similarities of this condition to other types of acute critical maternal illness, and the presence of a broad spectrum of disease severity. Clinical series based on population or administrative databases that do not include individual chart review by individuals with expertise in critical care obstetrics are likely to both overestimate the incidence and underestimate the mortality of this condition by the inclusion of women who did not have amniotic fluid embolism. Data regarding the presence of risk factors for amniotic fluid embolism are inconsistent and contradictory; at present, no putative risk factor has been identified that would justify modification of standard obstetric practice to reduce the risk of this condition. Maternal treatment is primarily supportive, whereas prompt delivery of the mother who has sustained cardiopulmonary arrest is critical for improved newborn outcome.
(Obstet Gynecol 2014;123:33748) DOI: 10.1097/AOG.0000000000000107

espite its recognition as a distinct entity for almost 100 years, the syndrome commonly referred to as amniotic fluid embolism remains one of the most enigmatic and devastating conditions in obstetrics. Although rare in an absolute sense, most contemporary series of maternal deaths from developed countries report amniotic fluid embolism as a leading cause of mortality in the pregnant population.15 In addition to its clinical importance, amniotic fluid embolism is a classic example of a condition whose origins were obscured for many years by less-than-rigorous peer review and publication of poor-quality case reports
From the Hospital Corporation of America, Womens and Childrens Clinical Services, Nashville, Tennessee. Continuing medical education for this article is available at http://links.lww. com/AOG/A466. Corresponding author: Steven L. Clark, MD, Medical Director, Womens and Childrens Clinical Services, The Hospital Corporation of America, P.O. Box 404, Twin Bridges, MT 59754; e-mail: Steven.clark1@hcahealthcare.com. Financial Disclosure The author did not report any potential conflicts of interest. 2014 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/14

and selective disregard of conflicting data that did not confirm traditional assumptions regarding the pathophysiology of this syndrome.6,7 Such practices led investigators seeking to understand, prevent, or treat this condition on a wild goose chase for more than half a century. Over the past two decades, more rigorous research efforts have greatly improved our understanding of this condition.

HISTORICAL CONSIDERATIONS
Although the appearance of a syndrome suggestive of amniotic fluid embolism was reported as early as 1926, this condition received its first systematic description in 1941 in a small series of patients reported by the pathologists Steiner and Luschbaugh.8,9 These authors reported 32 cases of women dying of obstetrical shock during labor. In eight of these women, careful autopsy examination revealed squamous cells or other debris of presumed fetal origin in the maternal pulmonary arterial circulation in addition to other findings. Despite widely disparate clinical presentations, these authors viewed all patients as having died of a unique clinical syndrome based solely on similar pulmonary histologic findings. They concluded that the patients

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had died as a result of pulmonary embolism by amniotic fluid, giving rise to the term amniotic fluid embolism.9 In subsequent decades, the assumptions of these authors regarding the pathognomonic nature of such pulmonary findings and their pathophysiologic implications went largely unchallenged. Patients with pathologic findings similar to those described in the report of Steiner and Luschbaugh were often diagnosed as having amniotic fluid embolism regardless of clinical presentation; reports describing such cellular debris in the circulation of women with conditions unrelated to amniotic fluid embolism were largely ignored.6,7,10 As a result, numerous case reports appeared in the medical literature describing an incredible variety of presumed clinical presentations of amniotic fluid embolism based solely on the detection of fetal cells or other debris of presumed fetal origin in the pulmonary arteries at autopsy.6,7 However, a critical review of the clinical details provided in the original report of Steiner and Luschbaugh reveals that in seven of the eight reported cases, the patients appear to have died from a condition such as sepsis or hemorrhage from undiagnosed uterine rupture, yet were considered as index cases of a new condition (amniotic fluid embolism) based exclusively on pulmonary histologic findings.6,7,9 With the introduction of the pulmonary artery catheter into critical care obstetrics in the 1980s, more frequent examination of pulmonary arterial histologic specimens during life became possible. Several reports in the 1980s documented identical pathologic findings in pregnant women with a variety of conditions unrelated to amniotic fluid embolism either as a result of fetal cells entering the maternal circulation during uneventful delivery or attributable to the detection of histologically indistinguishable adult squamous cells introduced as a byproduct of multiple vascular access sites common in critically ill patients.6,7,11 Such examination led to a collapse of the well-intentioned but erroneous diagnostic house of cards built on the detection of squamous cells in the maternal pulmonary arterial circulation. These findings cast doubt on the validity of cases reported between 1941 and 1985 in which the diagnosis of amniotic fluid embolism was based on pathologic findings alone. It appears that an early but generally ignored caution of Eastman in 1948 was quite prescient: Let us be careful not to make the diagnosis of amniotic fluid embolism a waste basket for cases of unexplained death during labor.12 The confusion surrounding the pathophysiologic nature of amniotic fluid embolism was compounded

by a large number of animal studies published in the decades after the initial description of this condition (Table 1).6,7,1316 These studies generally involved a description of pathophysiologic changes resulting from the injection of whole or filtered human amniotic fluid or meconium into the central circulation of various animal species6,7 (Table 1). Most studies assumed a simple, mechanical mechanism of injury, based on the original assumptions of Steiner and Luschbaugh, that can be summarized as follows: amniotic fluid is somehow forced into the maternal circulation resulting in obstruction of pulmonary arterial blood flow as amniotic fluid cellular debris is filtered by the pulmonary capillaries. Such obstruction leads to hypoxia, right heart failure, and death. Despite this assumption, these studies actually demonstrated an incredibly heterogenous group of physiologic changes in the animal subjects; unfortunately, those findings that did not comport with the assumed traditional mechanism of injury were generally either ignored or viewed as aberrations.6,7,10 Most dramatically, the only two studies carried out in primates using autologous or homologous amniotic fluid demonstrated no adverse physiologic effects at all despite the infusion in one series of a volume of amniotic fluid that would represent 80% of the entire uterine volume.13,14 Also largely ignored was a report in which terminally ill women with ovarian carcinoma were injected with human amniotic fluid, again, with no ill effects.15 Perhaps the fairest evaluation of these studies would be to conclude that the injection of large amounts of amniotic fluid or fetal fecal material from one species into the central circulation of small mammals of a different species sometimes causes adverse physiologic effects; the relevance of this observation to the human syndrome of amniotic fluid embolism is dubious at best. An objective evaluation of this body of evidence demonstrates quite clearly that the entrance of homologous amniotic fluid into the central circulation of primates and humans is generally innocuous, even in large volumes.1315 More recent carefully conducted animal studies using homologous and autologous fetal injectate also have yielded physiologic findings quite different from the traditional model described here.7,16 Against this background of erroneous diagnostic criteria and flawed animal models, it is not surprising that little progress was made for decades in the understanding of this condition, its diagnosis, or treatment. The modern era of amniotic fluid embolism was heralded in the 1980s with the publication of several studies made possible by the development of clinical techniques for pulmonary artery catheterization of critically ill women, basic science investigations into

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Table 1. Animal Models of Amniotic Fluid Embolism

Effects Study Author
Steiner Cron

Year Animal Anesthetized Pregnant Filtered AF Whole AF AF Species

Rabbit or dog 1952 Rabbit Dog Dog 1941 No No No Yes Yes Yes Yes No Yes Yes Yes Yes No No No Yes Yes Yes Yes No No No No No No Yes No Yes No Yes No Yes No No No Yes Yes Yes No Not examined Not examined Not examined No Yes No No Yes Not examined Not examined No No Not examined No Yes Yes Yes No Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes No Yes Yes NE Yes Yes Yes Human Human Human Human or dog Human Human Human or monkey Human Sheep Human Monkey Human Rabbit Calf Human Human Goat Minipig Rabbit

Hemodynamic Changes Coagulopathy*

Not examined (death) Not examined (death) Not examined (death) Yes Yes Yes No Not examined (death) Yes Not examined (death) No Yes No Yes Not examined (death) Coronary flow Yes Not examined No No No Yes Yes No Yes No No No No No No No Not examined No Not examined No Yes Yes

Schneider 1953 Jacques 1960

Halmagyi 1962 Sheep Attwood 1965 Dog Stolte 1967 Monkey Macmillan 1968 Reis Dutta Adamsons Kitzmiller Spence Reeves Azegami Richards Hankins Petroianu Rannou 1969 1970 Rabbit Sheep Rabbit

1971 Monkey 1972 Cat 1974 Rabbit 1974 Calf 1986 Rabbit 1988 Rat 1993 Goat 1999 Minipig 2011 Rabbit

AF, amniotic fluid. Adapted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health: Clark SL. New concepts of amniotic fluid embolism: a review. Obstet Gynecol Surv 1990;3608; modified from Dildy GA, Belfort MA, Clark SL. Anaphylactoid syndrome of pregnancy (amniotic fluid embolism). In: Belfort M, Saade G, Foley M, Phelan J, Dildy G, editors. Critical care obstetrics. 5th ed. Oxford (UK): Wiley-Blackwell; 2010. p. 46674; modified from Clark SL Amniotic fluid embolism. In: Clark SL, Phelan JP, Botton DB, editors. Critical care obstetrics; Oradell (NJ): Medical Economics; 1987; and modified from Clark SL. Amniotic fluid embolism. Clin Perinatol 1986;13:80111. * In the majority of patients. Isolated heart preparation.

maternalfetal physiology, and the establishment of the first systematic case registry of amniotic fluid embolism.10,11,1719 These studies revealed several surprising results that led to a reevaluation and rejection of earlier theories of pathogenesis.

PATHOPHYSIOLOGY
Carefully performed central hemodynamic monitoring of women with classic amniotic fluid embolism reveals a hemodynamic picture much different and more complex than the original model involving simple pulmonary arterial bed obstruction.1820 The physiologic origin of this sequence of hemodynamic alterations is incompletely understood but appears to involve a complex sequence of pathophysiologic reactions resulting from abnormal activation of proinflammatory mediator systems similar to the

systemic inflammatory response syndrome (SIRS), which follows the nearly universal entry into the maternal circulation of fetal antigens during the delivery process6,7,10,21,22 (Fig. 1). Case reports in which transesophageal echocardiography was rapidly available as well as carefully constructed animal models indicate the presence of an initial, transient period of pulmonary and systemic hypertension.16,23 Thereafter, profound depression of left ventricular function with normal pulmonary arterial pressures appear to be the dominant hemodynamic alterations in human amniotic fluid embolism in women who survive long enough for central hemodynamic monitoring to be instituted.1820 Such myocardial depression may involve myocardial hypoxia secondary to amniotic fluid embolism-induced pulmonary injury or cardiac arrest or may involve

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Disruption of maternalfetal barrier during delivery

Fetal and infectious tissue enter into the maternal circulation

SIRS-like activation of proinflammatory mediators in susceptible maternalfetal pairs

Inflammatory mediators and endogenous catecholamines induce transient systemic and pulmonary hypertension and uterine hypertonus

Activation of coagulation cascade

Inflammatory mediator and hypoxia induce myocardial depression, pulmonary and central nervous system injury

Disseminated intravascular coagulation and hemorrhage

Fig. 1. Proposed mechanism of amniotic fluid embolism. SIRS, systemic inflammatory response syndrome.
Clark. Amniotic Fluid Embolism. Obstet Gynecol 2014.

coronary artery spasm and direct myocardial ischemia as demonstrated in the rat model of this disease.10,24 Pulmonary manifestations of hypoxia appear to have their origin in an initial period of profound shunting often followed (in survivors) by lung injury patterns consistent with acute respiratory distress syndrome. Importantly, the cardiac and pulmonary manifestations of this condition cannot be viewed as distinct from one anotherdysfunction in either organ system will generally affect the other. Patients whose initial clinical manifestations do not include fatal cardiac arrest often develop a coagulopathy, which may ultimately be the principle cause of death. Coagulopathy is the third leg of the classic triad of signs and symptoms comprising the amniotic fluid embolism syndrome.6,7,10 Consistent with the variable nature of clinical manifestations of amniotic fluid embolism, a number of patients have also been observed who developed acute, severe disseminated intravascular coagulation in isolation at the time of delivery and exsanguinated without any discernible clinical

evidence of primary cardiopulmonary dysfunction.6,7 The nature of this coagulopathy remains incompletely understood and the evidence contradictory. Amniotic fluid has been shown to shorten in vitro clotting time and induce both platelet aggregation and the release of platelet factor III as well as activate both factor X and the compliment cascade.6,7 Amniotic fluid is also a source of the coagulation initiator tissue factor and has been shown to induce transient thrombocytopenia in the rabbit model.25,26 However, investigators have reached contradictory conclusions as to whether the amount of procoagulant in clear amniotic fluid is sufficient to cause clinically significant coagulopathy.6,7,25 High levels of tissue factor pathway inhibitor found in amniotic fluid during late pregnancy would inhibit procoagulant activity and may actually contribute to the rarity of this condition.27 It is striking that the only two conditions in obstetrics classically known to cause acute, severe consumptive (as opposed to dilutional) coagulopathy are amniotic fluid embolism and rare cases of massive placental abruption, both of which presumably involve release of fetal tissue, placental thromboplastin, or both into the maternal circulation. One must presume that the coagulopathy in both of these cases has similar pathophysiologic mechanisms. It is also intriguing that a number of cases of placenta accreta involve maternal cardiovascular collapse and coagulopathy that occur before a degree of blood loss or shock normally required for their development, suggesting the line among placenta accreta, placental abruption, and amniotic fluid embolism is not always distinct and may involve a similar sequence of inflammatory mediator, coagulation cascade activation, or both in response to exposure to fetal antigens. When one considers the spectrum of clinical and laboratory manifestations of classic amniotic fluid embolism syndrome, the similarities between amniotic fluid embolism and conditions such as anaphylactic shock or endotoxin-mediated shock are striking.7,10,22 All appear to involve an abnormal host response to exposure to various foreign antigens with the subsequent release of endogenous mediators, which drive the pathophysiology of the specific clinical syndrome. Indeed, traumatic fat embolism, once considered to involve a simple, obstructive mechanism similar to that originally postulated for amniotic fluid embolism, is now known to be much more complex and involves similar release and response to endogenous inflammatory mediators.28 In one animal model of amniotic fluid embolism, pretreatment of patients with an inhibitor of leukotriene synthesis was shown to prevent death.29 Thus, it appears that amniotic fluid embolism is,

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from a pathophysiologic standpoint, similar to the SIRS common to conditions such as septic shock, in which an abnormal host response rather than the intrinsic nature of the inciting antigen is primarily responsible for clinical manifestations.30 The nature of the antigenic challenge and of the host endogenous mediator release may determine both similarities and differences in the clinical manifestations of these conditions and also appear to influence the clinical severity of amniotic fluid embolism. Alternately, an abrupt disinhibition of the generalized immunosuppression seen in pregnancy by exposure to inflammatory cytokines has a recognized physiologic basis and could contribute to the immunologic storm that appears to be operative in amniotic fluid embolism.31 Because the passage of some fetal tissue into the maternal circulation appears to be ubiquitous during delivery, even early in pregnancy, future efforts to prevent this condition may rely on identification of women at risk for this abnormal response.22 Because amniotic fluid itself is innocuous, and the pathophysiology of this syndrome is not embolic in nature, it seems reasonable to conclude that the term amniotic fluid embolism is a misnomer. Given the apparent relationship of this condition to abnormal endogenous mediator release with clinical similarities to SIRS-like conditions such as severe sepsis and anaphylaxis, in 1995 we proposed a new term emphasizing the anaphylactic-like clinical manifestations of the syndrome, anaphylactoid syndrome of pregnancy.10 Although this term makes sense from a clinical and physiologic standpoint, it has not been widely adopted; even among the authors of the original paper, amniotic fluid embolism seems to roll off the tongue easier. Like the terms heart attack, stroke, or Graves disease, amniotic fluid embolism seems too deeply embedded in the language of medicine to be changed despite the availability of more precisely descriptive terms. Accordingly, the original term, amniotic fluid embolism, is used throughout this article.

detect a much lower rate than those based on birth and death certificates or discharge databases.7,40 In some series, 3060% of cases originally submitted as amniotic fluid embolism were found, after careful case review by experts, to not meet accepted diagnostic criteria.10,41 Even with careful chart review, rates will vary depending on clinical criteria required for acceptance as amniotic fluid embolism.40 For example, most patients reported in the series of Gilbert et al had clinical presentations that would not have qualified for inclusion in the earlier series of Clark et al, in which all features of classical amniotic fluid embolism syndrome were required.10,36 The demonstrated discrepancy between case ascertainment by careful medical record review and that arrived at using death certificate or discharge codes suggests that the latter source probably overestimates the incidence of amniotic fluid embolism. A rate of approximately 1 in 40,000 seems reasonable given current data. Importantly, a more precise knowledge of the absolute incidence of amniotic fluid embolism is unlikely to lead to any clinical benefit; in the general population of pregnant women, the prospective risk of amniotic fluid embolism is too rare to seriously consider, whereas in the population of women who die unexpectedly during labor, it should generally be a priority in the differential diagnosis. Several case reports exist of successful pregnancy after survival of amniotic fluid embolism.7 However, definitive conclusions regarding recurrence risk cannot be drawn from such sparse data, particularly given the vagaries of case identification, discussed previously. Although available evidence as well as extrapolation from our current understanding of the pathophysiology of amniotic fluid embolism does not suggest a significant recurrence risk, neither should be viewed as tremendously reassuring given the potentially fatal nature of this syndrome. What is a womans risk of recurrent amniotic fluid embolism? We just do not know.

CLINICAL MANIFESTATIONS
Like with any condition resulting from a complex interaction of foreign antigens and a host of potential endogenous inflammatory mediators, specific clinical manifestations of amniotic fluid embolism within the general triad of hypoxia, hypotension, and coagulopathy are protean. Box 1 lists signs and symptoms associated with amniotic fluid embolism and the exact frequency of any sign or symptoms depending largely on the clinical criteria required for acceptance as amniotic fluid embolism.6,7,10 In its most classic form, a woman in labor or shortly after vaginal or cesarean delivery sustains acute dyspnea,

INCIDENCE
Although uncommon in an absolute sense, in the population of women who have died during pregnancy, amniotic fluid embolism is common, and in the population of women who die after unexpected cardiovascular collapse during labor, amniotic fluid embolism is statistically the most likely diagnosis.16 The reported incidence of amniotic fluid embolism varies widely with rates varying from 1.9 per 100,000 to 6.1 per 100,0003,5,10,3242 The reported rate appears to be closely related to the data source; series based on detailed review of individual case records generally

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Box 1. Common Early Signs and Symptoms of Amniotic Fluid Embolism

Hypotension Dyspnea Cyanosis Frothing from mouth Fetal heart rate abnormalities Loss of consciousness Cardiac arrest Bleeding from uterus, incisions, or intravenous sites Uterine atony Seizure-like activity

decelerations10 (Fig. 2). Like with any form of massive hemodynamic insult, the mother will initially shunt oxygenated blood from the peripheral and splanchnic vascular beds to her own central circulation to maintain perfusion of brain and heart, unfortunately at the expense of uterine blood flow.6,10 Thus, fetal heart rate abnormalities resulting from such hypoperfusion not uncommonly accompany or even precede recognizable maternal signs and symptoms of amniotic fluid embolism.10

DIAGNOSIS
The diagnosis of amniotic fluid embolism is primarily based on clinical observations and, as described in the discussion of signs and symptoms, is often unmistakable. The classic triad of sudden hypoxia, hypotension, and coagulopathy with an onset during labor or immediately after delivery forms the hallmark of amniotic fluid embolism diagnosis.10 However, it is clear that there exist many cases of form fruste amniotic fluid embolism, in which one or more components of this triad may be minimal or absent.6,36,40 In such cases, the diagnosis is more difficult and must include careful exclusion of plausible alternative diagnoses. Identical signs and symptoms may herald amniotic fluid embolism after both first- and second-trimester pregnancy termination, consistent with the observation that an abnormal maternal response to fetal tissue rather than the volume of tissue itself underlies this condition.6,7,42 Although the detection of fetal squamous cells in the maternal pulmonary circulation was once considered diagnostic of amniotic fluid embolism, more recent studies of distal port (pulmonary artery) aspirates from

desaturation, or dyspnea and desaturation followed by sudden cardiovascular collapse. This is commonly followed by cardiac arrest, coagulopathy, or cardiac arrest and coagulopathy; the latter may be the cause of death despite successful management of cardiorespiratory collapse and expert management of bleeding and component replacement. In women sustaining cardiac arrest, any of the three classic lethal patterns of dysrhythmia (ventricular fibrillation, asystole, and pulseless electrical activity) has been described, probably reflecting different mechanisms of arrest, including hypoxia, direct myocardial depression, and exsanguination from severe coagulopathy.10 In women who survive the initial hemodynamic collapse and coagulopathy, lung injury and acute respiratory distress syndrome are often seen. In women whose initial course involves cardiac arrest, multiorgan failure, including hypoxic brain injury, is common. If the fetus is in utero at the onset of amniotic fluid embolism syndrome, fetal heart rate manifestations of hypoxia are almost universal. These may include late decelerations or, more commonly, acute prolonged

Fig. 2. Fetal heart rate tracing in a woman with amniotic fluid embolism. Note spontaneous uterine tachysystole in conjunction with fetal heart rate deceleration several minutes before maternal cardiovascular collapse. Modified from Clark SL, Hankins DV, Dudley DA, Dildy GA, Porter TF. Amniotic fluid embolism: analysis of the national registry. Am J Obstet Gynecol 1995;172:115869, with permission from Elsevier. Modification courtesy of Advanced Practice Solutions.
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pulmonary artery catheters in patients with a variety of critical illnesses including complicated preeclampsia, cardiac disease, and septic shock revealed that squamous cells and trophoblasts are frequently transported to and may be recovered from the pulmonary arterial bed of such patients.6,7,11 With sufficient histologic sampling and special stains, identification of such cells is quite common.11 Although available data do suggest a fetal origin for some of these squamous cells, identification of indistinguishable adult squamous cells in similar samples drawn from critically ill adult males suggests a component of desquamation from vascular access lines and ports as well.11 Regardless of their origin, the detection of squamous cells or other debris of presumed fetal origin in the pulmonary arterial bed of pregnant women is no longer considered diagnostic of amniotic fluid embolism; such studies are not generally useful in either the diagnosis of exclusion of this condition.7,10,11 Several investigators have proposed the existence of more specific laboratory or autopsy findings to confirm the diagnosis of amniotic fluid embolism. These include various arachidonic acid metabolites, tryptase, urinary histamine, insulin-like growth factor binding protein-1, various markers of complement activation and postmortem immunohistologic staining for Sialyl Tn antigen, zinc coproporphyrin, or other evidence of pulmonary mast cell degranulation.6,7,21,4244 Unfortunately, such studies are difficult to interpret; index cases are often chosen based on clinical findings, which were interpreted by the authors to be diagnostic of amniotic fluid embolism but which are generally reported in insufficient detail to allow the reviewer to be assured of the accuracy of the diagnosis. These problems are further compounded by the use of normal pregnant women as control participants rather than critically ill pregnant women in whom acute-phase inflammatory reactants would be expected to rise, regardless of the diagnosis.21 Thus, although these descriptions of laboratory findings appear to be generally supportive of an inflammatory-based mechanism of disease in amniotic fluid embolism, to date none of these findings is of significant diagnostic or clinical use. Although the search for specific histologic or laboratory markers of amniotic fluid embolism continues, this condition remains primarily a clinical diagnosis of exclusion.

RISK FACTORS
A review of multiple registry series reveals a wide range of conflicting conclusions regarding the presence of identifiable risk factors for amniotic fluid embolism.3241 Advanced maternal age and parity, male fetus, medical

induction of labor, cesarean delivery, instrumental delivery, cervical trauma, placenta previa and abruption, and ethnic minority status have been found to be both significantly associated with amniotic fluid embolism and not associated with amniotic fluid embolism in various studies.3241 For example, in an initial Canadian study, labor induction was determined to be a significant risk factor.38 However, a subsequent publication of a large series of patients in the United States by the same research group contradicted the original finding.39 In addition, based on investigations of maternalfetal exchange, the frequency of oxytocin use, and the rarity of amniotic fluid embolism, most investigators struggle to find biologic plausibility for a causative link between oxytocin and other uterine stimulants and amniotic fluid embolism.6,7,10,17 As early as 1976, investigations into maternalfetal oxygen transport during uterine contractions demonstrated a complete cessation of uteroplacental exchange as intrauterine pressures exceed 40 mmHg.17 Thus, a contraction, especially a hypertonic contraction, is the least likely event during all of labor to induce entrance of amniotic fluid and fetal tissue into the maternal circulation.10 However, an initial period of uterine tachysystole or tetany is in fact commonly observed just before, or in association with, the onset of maternal hemodynamic collapse in women with amniotic fluid embolism6,10 (Fig. 2). This apparent paradox is explained by the realization that endogenous norepinephrine released as part of the normal human hemodynamic response to any major physiologic insult has significant uterotonic effects; thus, the increased uterine activity commonly seen at or even just preceding the onset of discernible maternal or fetal physiologic response is a manifestation of evolving amniotic fluid embolism syndrome rather than being causative.45 These observations confirm earlier statistical observations by Morgan based on the frequency of oxytocin use and the rarity of amniotic fluid embolism as well as conclusions of the American College of Obstetricians and Gynecologists that there is no causative link between uterine stimulation and amniotic fluid embolism.32,46 In addition, many studies examining risk factors have a common weakness, namely a shotgun approach to risk factor identification. Using a cutoff for significance of P,.05, any examination of 20 potential risk factors is likely to falsely identify one as being statistically significant. This observation is not intended as a criticism of this approach as an initial attempt to determine where to focus further investigation. However, as it stands today, no demographic or clinical risk factor has been identified that justifies any prospective

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alteration of standard obstetric practice to reduce the risk of amniotic fluid embolism. Furthermore, none of these potential risk factors and no action or inaction of patient or health care provider has a sufficiently established causative link to justify a conclusion that were it not for this factor, the amniotic fluid embolism would not have occurred in any individual patient. As it stands today, amniotic fluid embolism remains both unpredictable and unpreventable.

OUTCOME
Estimates of maternal mortality vary greatly and appear to be largely dependent on criteria required for the inclusion of cases as true amniotic fluid embolism.7,10,40,42 Series restricted to patients in whom all classic signs and symptoms of amniotic fluid embolism are present suggest mortality rates exceeding 60%.10 In cases complicated by cardiac arrest, survival is even worse with most series reporting that fewer than 10% of adults sustaining in-hospital cardiac arrest of any origin are discharged alive.47 On the other hand, when less sick patients are included, particularly in population-based, death certificate, or discharge code-dependent series in which many patients do not actually have amniotic fluid embolism, reported mortality rates will be much lower, in some cases below 20%.7,40,42 Although it is clear that expert critical care management will improve the likelihood of survival in some women, prognosis ultimately appears to be more closely linked to disease severity and the occurrence of concomitant cardiac arrest than to any specific treatment modality.

MANAGEMENT
Fortunately, it is not necessary to make the diagnosis of amniotic fluid embolism to treat it appropriately, because treatment is primarily supportive and based on observable pathophysiology. After cardiac arrest, standard Basic Cardiac Life Support and Advanced Cardiac Life Support algorithms should be applied. With maternal hypotension short of arrest, blood pressure should be supported with fluids and pressor agents when necessary. Dyspnea, hypoxia, or both are managed with oxygen administration; although intubation is not required in every case, a clinical suspicion of possible amniotic fluid embolism should prompt immediate anesthesia attendance, because intubation is commonly indicated. Oxygen delivery should be guided by pulse oximetry, arterial blood gas assessment, or both. Isolated reports of survival associated with the use of extracorporeal membrane oxygenation, intraaortic balloon counterpulsation, continuous hemodiafiltration, cardiopulmonary bypass,

right ventricular assist device, and nitric oxide have all been reported; however, such techniques must be currently regarded as unproven and experimental.7,10,48 Coagulopathy and ensuing hemorrhage are managed by aggressive blood and component replacement; widely available massive transfusion protocols are often helpful in this regard.49 Although several reports exist describing the use of recombinant factor VIIa in amniotic fluid embolism, recombinant VIIa can combine with circulating tissue factor to enhance the formation of intravascular clots; a recent review suggests that such patients have significantly worse outcomes than cohorts who received component replacement only.50 Although such patients were not randomized, and those receiving recombinant factor VIIa may have been sicker than those receiving conventional component therapy, the available data suggest that recombinant factor VIIa should probably be reserved for women with severe coagulopathy who continue to bleed heavily despite adequate component therapy.50 If the fetus is undelivered and of a viable gestational age, prompt delivery is indicated, as discussed subsequently. Although scattered, anecdotal case reports exist in which delivery appears to have improved the maternal condition, and although such an effect is physiologically plausible as a result of the release of venacaval obstruction by the gravid uterus, a conclusion that in any individual case delivery would have altered the maternal outcome would be unjustified. Given the dismal maternal prognosis associated with amniotic fluid embolism and cardiac arrest even after prompt delivery, and an ascertainment bias that favors case reports of apparent miraculous, but vanishingly rare maternal recovery after delivery with amniotic fluid embolism, an objective, evidence-based assessment of this issue must conclude that delivery confers no maternal benefit. Neither does delivery, however, confer significant additional maternal risk after cardiopulmonary arrest.10,51 As discussed subsequently, prompt delivery is, from the fetal standpoint, vital.7,10,51 Two large series of mothers undergoing cardiac arrest before delivery highlight the importance of prompt delivery in such cases10,51 (Table 2). Because cardiac output achieved by optimally performed cardiopulmonary resuscitation (CPR) is only about one third of normal, and optimal CPR performance during term pregnancy is, because of venacaval obstruction by the uterus, always problematic, uteroplacental perfusion during CPR in late pregnancy probably approaches zero.10,51 It follows that for maternal cardiac arrest of any etiology, emergent perimortem delivery is indicated if the fetus has reached an age of viability.

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Table 2. Cardiac Arrest-to-Delivery Interval and Neurologic Outcome

Arrest to Delivery (min)
05 1515 More than than 15

% Without Neurologically Neurologically Neurologic Impairment Intact Impaired

11 4 7 1 47 12 91 50 37

Data are n unless otherwise specified. Data from Clark SL, Hankins DV, Dudley DA, Dildy GA, Porter TF. Amniotic fluid embolism: analysis of the national registry. Am J Obstet Gynecol 1995;172:115869 and Katz V, Balderston K, DeFreest M. Perimortem cesarean delivery: were our assumptions correct? Am J Obstet Gynecol 2005;195:191620.

Indeed, the only evidence-based conclusions that may be drawn regarding efficacy of treatment of amniotic fluid embolism is that with maternal cardiac arrest, prompt delivery improves the likelihood of a good newborn outcome.10,51 Despite these observations, the acute management of amniotic fluid embolism is not entirely reactive. The available evidence would suggest a number of proactive steps that may be taken when amniotic fluid embolism is suspected. These may be instituted simultaneously with the essential resuscitative efforts described previously and may be summarized as follows: 1. Red blood cells, fresh-frozen plasma, or cryoprecipitate and platelets may be prepared even before clinical manifestations of coagulopathy or laboratory confirmation of clotting deficits. 2. If the patient is unconscious or experiencing significant hypoxia or desaturation, intubation and ventilation with 100% oxygen is vitalthese women often sustain hypoxic central nervous system damage seemingly out of proportion to the duration of cardiac arrest or the documented degree of hypoxia. 3. During CPR and preparations for delivery, lateral displacement of the uterus may improve maternal venous return and cardiac output. 4. Although rapid infusion of crystalloid solution is an essential component of advanced cardiac life support with amniotic fluid embolism, the managing physician should be cognizant of the likelihood of acute lung injury and pulmonary edema in surviving patients.

amniotic fluid embolism.3242 It is unlikely that additional data of this type will be useful. On the other hand, the rarity and unpredictable nature of this syndrome and its high rate of mortality hinder the basic science investigations necessary to further explore the etiology of this condition and potentially develop effective means of prevention and treatment. Perhaps most promising in this regard is an international Amniotic Fluid Embolism Patient Registry that has been established at Baylor College of Medicine (aferegistry@bcm.edu) in partnership with the Amniotic Fluid Embolism Foundation (http://afesupport.org), an international nonprofit patient advocacy organization. These investigators aim to study the relationships between various biochemical and immunologic features of women who survived amniotic fluid embolism and their children from both affected and unaffected pregnancies.

CONCLUSIONS
For the past 30 years I have studied, published, and reviewed hundreds of clinical cases of women who died of amniotic fluid embolism and spent a good deal of my life caring for critically ill pregnant women with a variety of disease conditions. Despite this, the ultimate inciting pathophysiologic process leading to the often unmistakable syndrome of sudden intrapartum cardiorespiratory collapse and coagulopathy remains frustratingly just out of reach. Although the research methodology of Steiner and Luschbaugh was, from our current standpoint, flawed, and although the literature is cluttered with case reports, small series, and large population data-based registries of amniotic fluid embolism in women who clearly did not have amniotic fluid embolism, sufficient good-quality data as well as clinical experience seem to confirm the following: 1. The syndrome of sudden peripartum hypoxia, cardiovascular collapse, and coagulopathy is real but has nothing to do directly with either amniotic fluid or embolization. The recovery of cellular debris of fetal origin from the maternal circulation may be a marker of this event but is neither sufficiently sensitive nor specific to be of diagnostic use because entry of amniocytes or other cells of fetal origin is commonly seen in normal pregnancy. 2. The timing of most such events during delivery or pregnancy termination as well as the relationship between this syndrome and other conditions known to involve abnormal invasion or release of fetal material into the maternal circulation (placental abruption and placenta accreta)

FUTURE RESEARCH DIRECTIONS

Several large national registries have examined clinical findings, outcomes, and risk factors associated with

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suggest that a breach of the normal physiologic barrier between fetus and mother is involved. 3. Clinically identical activation of the coagulation cascade known to result from amniotic fluid embolism, placental abruption, and placenta accreta cannot realistically be viewed as coincidental or unrelated. Given the well-described thromboplastin-like effects of placental trophoblastic tissue, it is reasonable to conclude that the coagulopathy seen with amniotic fluid embolism often also involves trophoblastic-derived antigens. 4. This syndrome involves a series of recognizable clinical signs, symptoms, and central hemodynamic changes similar to those seen in many cases of anaphylaxis or SIRS and septic shock, suggesting the involvement of similar endogenous proinflammatory mediator and procoagulant activation or release in response to foreign antigenic substances. 5. Neither the precise nature of the stimulus involved nor the inflammatory mediator response is uniform, consistent with the variable clinical expression of this syndrome. Rather, this condition may be the final common expression of a unique maternal immunologic response to various foreign antigenic stimuli originating in the fetal compartment, which may be fetal or infectious in origin. Alternately, bacterial endotoxin or exotoxin could potentiate the endogenous mediator response in immunologically susceptible maternalfetal pairs. Romero posed the prescient query amniotic fluid embolism or septic shock due to intrauterine infection?22 The ultimate answer may well be both. Because entry of some fetal tissue into the maternal circulation at some point in the delivery process is common, if not universal, amniotic fluid embolism is currently unpreventable in susceptible maternal fetal pairs. Amniotic fluid embolism has no identifiable risk factors of sufficient strength to warrant alteration in standard obstetric practice to avoid or reduce the risk of this condition. 6. Data linking stimulated or augmented labor to amniotic fluid embolism are weak and conflicting and lack biologic plausibility. Given the frequency of stimulated or augmented labor and the infrequency of amniotic fluid embolism, a causative link in any individual case would be scientifically unjustified. 7. The diagnosis of amniotic fluid embolism is a clinical one. Identification of elements of the classic triad of hypotension, hypoxia, and

8.

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10.

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coagulopathy and the careful exclusion of other conditions are essential for the diagnosis. Diagnosis based on specific biochemical indices remains investigational. Treatment of amniotic fluid embolism in the mother is primarily supportive and directed at observable physiologic abnormalities. In the mother who has undergone cardiac arrest as a result of amniotic fluid embolism, emergent delivery is indicated. Prompt delivery may improve newborn outcome and will not jeopardize maternal recovery. However, in the mother who is hemodynamically unstable but has not developed one of the lethal dysrhythmia patterns commonly considered under the category cardiac arrest, the decision for delivery may indeed affect maternal outcome. Given the disparate needs of the mother and fetus in this situation, no uniform standard of care exists. These decisions are the most difficult in all of medicine and cannot realistically be made by anyone not on the scene and in charge of care at the time. Case selection not based on careful individual chart review will likely result in the inclusion of patients who do not have amniotic fluid embolism. Such misdiagnosis has already hindered progress in amniotic fluid embolism research for more than 50 years. It is suggested that future research into specific diagnostic or therapeutic approaches to amniotic fluid embolism be limited to patients who exhibit the classic triad of hypotension, hypoxia, and coagulopathy or in whom alternative diagnoses have been excluded by careful and skeptical medical records review. Although much remains to be learned about the mechanism of amniotic fluid embolism, the wild goose chase alluded to at the beginning of this article appears to be over. With careful investigative approaches examining the role of antigenic response and endogenous or inflammatory mediators in the genesis of amniotic fluid embolism, we appear to be at last on the right track.

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