Clinical Expert Series

Amniotic Fluid Embolism

Steven L. Clark, MD

Amniotic fluid embolism remains one of the most devastating conditions in obstetric practicewith an incidence of approximately 1 in 40,000 deliveries and a reported mortality rate rangingfrom 20% to 60%. The pathophysiology appears to involve an abnormal maternal response tofetal tissue exposure associated with breaches of the maternal–fetal physiologic barrier duringparturition. This response and its subsequent injury appear to involve activation of proinflam-matory mediators similar to that seen with the classic systemic inflammatory response syn-drome. Progress in our understanding of this syndrome continues to be hampered by a lack ofuniversally acknowledged diagnostic criteria, the clinical similarities of this condition to othertypes 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 individualchart review by individuals with expertise in critical care obstetrics are likely to both overestimatethe incidence and underestimate the mortality of this condition by the inclusion of women whodid not have amniotic fluid embolism. Data regarding the presence of risk factors for amnioticfluid embolism are inconsistent and contradictory; at present, no putative risk factor has beenidentified that would justify modification of standard obstetric practice to reduce the risk of thiscondition. Maternal treatment is primarily supportive, whereas prompt delivery of the motherwho has sustained cardiopulmonary arrest is critical for improved newborn outcome.

(Obstet Gynecol 2014;123:337–48)

DOI: 10.1097/AOG.0000000000000107

Despite its recognition as a distinct entity for almost100 years, the syndrome commonly referred to

as amniotic fluid embolism remains one of the mostenigmatic and devastating conditions in obstetrics.Although rare in an absolute sense, most contemporaryseries of maternal deaths from developed countriesreport amniotic fluid embolism as a leading cause ofmortality in the pregnant population.1–5 In addition toits clinical importance, amniotic fluid embolism is aclassic example of a condition whose origins wereobscured for many years by less-than-rigorous peerreview and publication of poor-quality case reports

and selective disregard of conflicting data that didnot confirm traditional assumptions regarding thepathophysiology of this syndrome.6,7 Such practicesled investigators seeking to understand, prevent, ortreat this condition on a wild goose chase for morethan half a century. Over the past two decades, morerigorous research efforts have greatly improved ourunderstanding of this condition.

HISTORICAL CONSIDERATIONS

Although the appearance of a syndrome suggestive ofamniotic fluid embolism was reported as early as 1926,this condition received its first systematic descriptionin 1941 in a small series of patients reported by thepathologists Steiner and Luschbaugh.8,9 These authorsreported 32 cases of women dying of “obstetricalshock” during labor. In eight of these women, carefulautopsy examination revealed squamous cells or otherdebris of presumed fetal origin in the maternal pulmo-nary arterial circulation in addition to other findings.Despite widely disparate clinical presentations, theseauthors viewed all patients as having died of a uniqueclinical syndrome based solely on similar pulmonaryhistologic findings. They concluded that the patients

From the Hospital Corporation of America, Women’s and Children’s ClinicalServices, 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, Women’s andChildren’s Clinical Services, The Hospital Corporation of America, P.O. Box404, Twin Bridges, MT 59754; e-mail: Steven.clark1@hcahealthcare.com.

Financial DisclosureThe author did not report any potential conflicts of interest.

© 2014 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/14

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had died as a result of “pulmonary embolism byamniotic fluid,” giving rise to the term amniotic fluidembolism.9

In subsequent decades, the assumptions of theseauthors regarding the pathognomonic nature of suchpulmonary findings and their pathophysiologic impli-cations went largely unchallenged. Patients with path-ologic findings similar to those described in the reportof Steiner and Luschbaugh were often diagnosed ashaving amniotic fluid embolism regardless of clinicalpresentation; reports describing such cellular debrisin the circulation of women with conditions unrelatedto amniotic fluid embolism were largely ignored.6,7,10

As a result, numerous case reports appeared in themedical literature describing an incredible variety ofpresumed clinical presentations of “amniotic fluidembolism” based solely on the detection of fetalcells or other debris of presumed fetal origin in thepulmonary arteries at autopsy.6,7 However, a criticalreview of the clinical details provided in the originalreport of Steiner and Luschbaugh reveals that in sevenof the eight reported cases, the patients appear to havedied from a condition such as sepsis or hemorrhagefrom undiagnosed uterine rupture, yet were consideredas index cases of a new condition (amniotic fluidembolism) based exclusively on pulmonary histologicfindings.6,7,9

With the introduction of the pulmonary arterycatheter into critical care obstetrics in the 1980s, morefrequent examination of pulmonary arterial histo-logic specimens during life became possible. Severalreports in the 1980s documented identical pathologicfindings in pregnant women with a variety ofconditions unrelated to amniotic fluid embolismeither as a result of fetal cells entering the maternalcirculation during uneventful delivery or attributableto the detection of histologically indistinguishableadult squamous cells introduced as a byproduct ofmultiple vascular access sites common in critically illpatients.6,7,11 Such examination led to a collapse ofthe well-intentioned but erroneous diagnostic house ofcards built on the detection of squamous cells in thematernal pulmonary arterial circulation. These findingscast doubt on the validity of cases reported between1941 and 1985 in which the diagnosis of amniotic fluidembolism was based on pathologic findings alone.It appears that an early but generally ignored cautionof Eastman in 1948 was quite prescient: “Let us becareful not to make the diagnosis of amniotic fluidembolism a waste basket for cases of unexplaineddeath during labor.”12

The confusion surrounding the pathophysiologicnature of amniotic fluid embolism was compounded

by a large number of animal studies published in thedecades after the initial description of this condition(Table 1).6,7,13–16 These studies generally involved adescription of pathophysiologic changes resulting fromthe injection of whole or filtered human amniotic fluidor meconium into the central circulation of variousanimal species6,7 (Table 1). Most studies assumed asimple, mechanical mechanism of injury, based on theoriginal assumptions of Steiner and Luschbaugh, thatcan be summarized as follows: amniotic fluid is some-how forced into the maternal circulation resulting inobstruction of pulmonary arterial blood flow as amni-otic fluid cellular debris is filtered by the pulmonarycapillaries. Such obstruction leads to hypoxia, rightheart failure, and death.

Despite this assumption, these studies actually dem-onstrated an incredibly heterogenous group of physio-logic changes in the animal subjects; unfortunately,those findings that did not comport with the assumedtraditional mechanism of injury were generally eitherignored or viewed as aberrations.6,7,10 Most dramati-cally, the only two studies carried out in primates usingautologous or homologous amniotic fluid demonstratedno adverse physiologic effects at all despite the infusionin one series of a volume of amniotic fluid thatwould represent 80% of the entire uterine volume.13,14

Also largely ignored was a report in which terminallyill women with ovarian carcinoma were injected withhuman amniotic fluid, again, with no ill effects.15

Perhaps the fairest evaluation of these studies wouldbe to conclude that the injection of large amounts ofamniotic fluid or fetal fecal material from one speciesinto the central circulation of small mammals of a dif-ferent species sometimes causes adverse physiologiceffects; the relevance of this observation to the humansyndrome of amniotic fluid embolism is dubious atbest. An objective evaluation of this body of evidencedemonstrates quite clearly that the entrance ofhomologous amniotic fluid into the central circulationof primates and humans is generally innocuous, evenin large volumes.13–15 More recent carefully conductedanimal studies using homologous and autologous fetalinjectate also have yielded physiologic findings quitedifferent from the traditional model described here.7,16

Against this background of erroneous diagnosticcriteria and flawed animal models, it is not surprisingthat little progress was made for decades in theunderstanding of this condition, its diagnosis, or treat-ment. The modern era of amniotic fluid embolism washeralded in the 1980s with the publication of severalstudies made possible by the development of clinicaltechniques for pulmonary artery catheterization ofcritically ill women, basic science investigations into

338 Clark Amniotic Fluid Embolism OBSTETRICS & GYNECOLOGY

maternal–fetal physiology, and the establishment ofthe first systematic case registry of amniotic fluid em-bolism.10,11,17–19 These studies revealed several sur-prising results that led to a reevaluation and rejectionof earlier theories of pathogenesis.

PATHOPHYSIOLOGY

Carefully performed central hemodynamic monitoringof women with classic amniotic fluid embolism revealsa hemodynamic picture much different and morecomplex than the original model involving simplepulmonary arterial bed obstruction.18–20 The physio-logic origin of this sequence of hemodynamic alter-ations is incompletely understood but appears toinvolve a complex sequence of pathophysiologicreactions resulting from abnormal activation ofproinflammatory mediator systems similar to the

systemic inflammatory response syndrome (SIRS),which follows the nearly universal entry into thematernal circulation of fetal antigens during thedelivery process6,7,10,21,22 (Fig. 1). Case reports inwhich transesophageal echocardiography was rap-idly available as well as carefully constructed animalmodels indicate the presence of an initial, transientperiod of pulmonary and systemic hyperten-sion.16,23 Thereafter, profound depression of leftventricular function with normal pulmonary arterialpressures appear to be the dominant hemodynamicalterations in human amniotic fluid embolism inwomen who survive long enough for central hemo-dynamic monitoring to be instituted.18–20 Such myo-cardial depression may involve myocardial hypoxiasecondary to amniotic fluid embolism-induced pul-monary injury or cardiac arrest or may involve

Table 1. Animal Models of Amniotic Fluid Embolism

StudyAuthor Year Animal Anesthetized Pregnant

Effects

Filtered AF Whole AF AF SpeciesHemodynamic

Changes Coagulopathy*

Steiner 1941 Rabbitor dog

No No No Yes Human Not examined(death)

No

Cron 1952 Rabbit No No Not examined Yes Human Not examined(death)

No

Schneider 1953 Dog No No Not examined Yes Human Not examined(death)

Yes

Jacques 1960 Dog Yes No Not examined Yes Human ordog

Yes Yes

Halmagyi 1962 Sheep Yes No No Yes Human Yes NoAttwood 1965 Dog Yes No Yes Yes Human Yes YesStolte 1967 Monkey Yes Yes No No Human or

monkeyNo No

Macmillan 1968 Rabbit No No No Yes Human Not examined(death)

No

Reis 1969 Sheep Yes Yes Yes Yes Sheep Yes NoDutta 1970 Rabbit Yes No Not examined Yes Human Not examined

(death)No

Adamsons 1971 Monkey Yes Yes Not examined No Monkey No NoKitzmiller 1972 Cat Yes No No Yes Human Yes NoSpence 1974 Rabbit No Yes No No Rabbit No NoReeves 1974 Calf No No Not examined Yes Calf Yes Not examinedAzegami 1986 Rabbit No No No Yes Human Not examined

(death)No

Richards 1988 Rat† Yes No Yes NE Human Coronary flow Not examinedHankins 1993 Goat Yes Yes Yes Yes Goat Yes NoPetroianu 1999 Minipig Yes Yes Yes Yes Minipig Not examined YesRannou 2011 Rabbit Yes Yes No Yes Rabbit No Yes

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;360–8; modified from Dildy GA, Belfort MA, Clark SL. Anaphylactoid syndrome ofpregnancy (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. 466–74; 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 Perinatol1986;13:801–11.

* In the majority of patients.† Isolated heart preparation.

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coronary artery spasm and direct myocardial ische-mia as demonstrated in the rat model of thisdisease.10,24

Pulmonary manifestations of hypoxia appear tohave their origin in an initial period of profoundshunting often followed (in survivors) by lung injurypatterns consistent with acute respiratory distresssyndrome. Importantly, the cardiac and pulmonarymanifestations of this condition cannot be viewed asdistinct from one another—dysfunction in either organsystem will generally affect the other.

Patients whose initial clinical manifestations donot include fatal cardiac arrest often develop a coagul-opathy, which may ultimately be the principle causeof death. Coagulopathy is the third leg of the classictriad of signs and symptoms comprising the amnioticfluid embolism syndrome.6,7,10 Consistent with thevariable nature of clinical manifestations of amnioticfluid embolism, a number of patients have also beenobserved who developed acute, severe disseminatedintravascular coagulation in isolation at the time of deliv-ery and exsanguinated without any discernible clinical

evidence of primary cardiopulmonary dysfunction.6,7

The nature of this coagulopathy remains incompletelyunderstood and the evidence contradictory. Amnioticfluid has been shown to shorten in vitro clotting timeand induce both platelet aggregation and the release ofplatelet factor III as well as activate both factor X andthe compliment cascade.6,7 Amniotic fluid is alsoa source of the coagulation initiator tissue factorand has been shown to induce transient thrombocy-topenia in the rabbit model.25,26 However, investigatorshave reached contradictory conclusions as to whetherthe amount of procoagulant in clear amniotic fluidis sufficient to cause clinically significant coagulop-athy.6,7,25 High levels of tissue factor pathway inhibitorfound in amniotic fluid during late pregnancy wouldinhibit procoagulant activity and may actually contrib-ute to the rarity of this condition.27

It is striking that the only two conditions inobstetrics classically known to cause acute, severeconsumptive (as opposed to dilutional) coagulopathyare amniotic fluid embolism and rare cases of massiveplacental abruption, both of which presumably involverelease of fetal tissue, placental thromboplastin, or bothinto the maternal circulation. One must presume thatthe coagulopathy in both of these cases has similarpathophysiologic mechanisms. It is also intriguing thata number of cases of placenta accreta involve maternalcardiovascular collapse and coagulopathy that occurbefore a degree of blood loss or shock normallyrequired for their development, suggesting the lineamong placenta accreta, placental abruption, andamniotic fluid embolism is not always distinct andmay involve a similar sequence of inflammatorymediator, coagulation cascade activation, or both inresponse to exposure to fetal antigens.

When one considers the spectrum of clinical andlaboratory manifestations of classic amniotic fluidembolism syndrome, the similarities between amnioticfluid embolism and conditions such as anaphylacticshock or endotoxin-mediated shock are striking.7,10,22

All appear to involve an abnormal host response to ex-posure to various foreign antigens with the subsequentrelease of endogenous mediators, which drive thepathophysiology of the specific clinical syndrome.Indeed, traumatic fat embolism, once considered toinvolve a simple, obstructive mechanism similar tothat originally postulated for amniotic fluid embolism,is now known to be much more complex and involvessimilar release and response to endogenous inflamma-tory mediators.28 In one animal model of amniotic fluidembolism, pretreatment of patients with an inhibitor ofleukotriene synthesis was shown to prevent death.29

Thus, it appears that amniotic fluid embolism is,

Disruption ofmaternal–fetal barrier

during delivery

Fetal and infectioustissue enter into the maternal circulation

SIRS-likeactivation of proinflammatory

mediators in susceptiblematernal–fetal pairs

Inflammatory mediators andendogenous catecholamines

induce transient systemicand pulmonary hypertension

and uterine hypertonus

Activation of coagulationcascade

Inflammatory mediator andhypoxia induce myocardialdepression, pulmonary and

central nervous system injury

Disseminated intravascularcoagulation and hemorrhage

Fig. 1. Proposed mechanism of amniotic fluid embolism.SIRS, systemic inflammatory response syndrome.

Clark. Amniotic Fluid Embolism. Obstet Gynecol 2014.

340 Clark Amniotic Fluid Embolism OBSTETRICS & GYNECOLOGY

from a pathophysiologic standpoint, similar to theSIRS common to conditions such as septic shock,in which an abnormal host response rather than theintrinsic nature of the inciting antigen is primarilyresponsible for clinical manifestations.30 The natureof the antigenic challenge and of the host endogenousmediator release may determine both similarities anddifferences in the clinical manifestations of these con-ditions and also appear to influence the clinical severityof amniotic fluid embolism. Alternately, an abrupt dis-inhibition of the generalized immunosuppression seenin pregnancy by exposure to inflammatory cytokineshas a recognized physiologic basis and could contributeto the “immunologic storm” that appears to be operativein amniotic fluid embolism.31 Because the passageof some fetal tissue into the maternal circulationappears to be ubiquitous during delivery, even earlyin pregnancy, future efforts to prevent this conditionmay rely on identification of women at risk for thisabnormal response.22

Because amniotic fluid itself is innocuous, and thepathophysiology of this syndrome is not embolic innature, it seems reasonable to conclude that the termamniotic fluid embolism is a misnomer. Given theapparent relationship of this condition to abnormalendogenous mediator release with clinical similaritiesto SIRS-like conditions such as severe sepsis and ana-phylaxis, in 1995 we proposed a new term emphasiz-ing the anaphylactic-like clinical manifestations of thesyndrome, anaphylactoid syndrome of pregnancy.10

Although this term makes sense from a clinicaland physiologic standpoint, it has not been widelyadopted; even among the authors of the original paper,“amniotic fluid embolism” seems to roll off the tongueeasier. Like the terms “heart attack,” “stroke,” or“Grave’s disease,” amniotic fluid embolism seems toodeeply embedded in the language of medicine to bechanged despite the availability of more precisely de-scriptive terms. Accordingly, the original term, amnioticfluid embolism, is used throughout this article.

INCIDENCE

Although uncommon in an absolute sense, in thepopulation of women who have died during preg-nancy, amniotic fluid embolism is common, and inthe population of women who die after unexpectedcardiovascular collapse during labor, amniotic fluidembolism is statistically the most likely diagnosis.1–6

The reported incidence of amniotic fluid embolismvaries widely with rates varying from 1.9 per 100,000to 6.1 per 100,0003,5,10,32–42 The reported rate appears tobe closely related to the data source; series based ondetailed review of individual case records generally

detect a much lower rate than those based on birthand death certificates or discharge databases.7,40 In someseries, 30–60% of cases originally submitted as amnioticfluid embolism were found, after careful case review byexperts, to not meet accepted diagnostic criteria.10,41

Even with careful chart review, rates will vary de-pending on clinical criteria required for acceptanceas amniotic fluid embolism.40 For example, mostpatients reported in the series of Gilbert et al hadclinical presentations that would not have qualifiedfor inclusion in the earlier series of Clark et al, inwhich all features of classical amniotic fluid embolismsyndrome were required.10,36 The demonstrateddiscrepancy between case ascertainment by carefulmedical record review and that arrived at usingdeath certificate or discharge codes suggests thatthe latter source probably overestimates the incidenceof amniotic fluid embolism. A rate of approximately1 in 40,000 seems reasonable given current data.Importantly, a more precise knowledge of the absoluteincidence of amniotic fluid embolism is unlikely to leadto any clinical benefit; in the general population ofpregnant women, the prospective risk of amniotic fluidembolism is too rare to seriously consider, whereas inthe population of women who die unexpectedly duringlabor, it should generally be a priority in the differentialdiagnosis.

Several case reports exist of successful pregnancyafter survival of amniotic fluid embolism.7 However,definitive conclusions regarding recurrence risk cannotbe drawn from such sparse data, particularly given thevagaries of case identification, discussed previously.Although available evidence as well as extrapolationfrom our current understanding of the pathophysiologyof amniotic fluid embolism does not suggest a significantrecurrence risk, neither should be viewed as tremen-dously reassuring given the potentially fatal nature of thissyndrome. What is a woman’s risk of recurrent amnioticfluid embolism? We just do not know.

CLINICAL MANIFESTATIONS

Like with any condition resulting from a complexinteraction of foreign antigens and a host of potentialendogenous inflammatory mediators, specific clinicalmanifestations of amniotic fluid embolism withinthe general triad of hypoxia, hypotension, andcoagulopathy are protean. Box 1 lists signs andsymptoms associated with amniotic fluid embolismand the exact frequency of any sign or symptomsdepending largely on the clinical criteria requiredfor acceptance as amniotic fluid embolism.6,7,10

In its most classic form, a woman in labor or shortlyafter vaginal or cesarean delivery sustains acute dyspnea,

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desaturation, or dyspnea and desaturation followedby sudden cardiovascular collapse. This is commonlyfollowed by cardiac arrest, coagulopathy, or cardiacarrest and coagulopathy; the latter may be the causeof death despite successful management of cardiorespi-ratory collapse and expert management of bleedingand component replacement. In women sustainingcardiac arrest, any of the three classic lethal patternsof dysrhythmia (ventricular fibrillation, asystole, andpulseless electrical activity) has been described,probably reflecting different mechanisms of arrest,including hypoxia, direct myocardial depression, andexsanguination from severe coagulopathy.10 In womenwho survive the initial hemodynamic collapse andcoagulopathy, lung injury and acute respiratory distresssyndrome are often seen. In women whose initial courseinvolves cardiac arrest, multiorgan failure, includinghypoxic brain injury, is common.

If the fetus is in utero at the onset of amniotic fluidembolism syndrome, fetal heart rate manifestations ofhypoxia are almost universal. These may include latedecelerations or, more commonly, acute prolonged

decelerations10 (Fig. 2). Like with any form of massivehemodynamic insult, the mother will initially shuntoxygenated blood from the peripheral and splanchnicvascular beds to her own central circulation to maintainperfusion of brain and heart, unfortunately at theexpense of uterine blood flow.6,10 Thus, fetal heartrate abnormalities resulting from such hypoperfusionnot uncommonly accompany or even precede recog-nizable maternal signs and symptoms of amnioticfluid embolism.10

DIAGNOSIS

The diagnosis of amniotic fluid embolism is primarilybased on clinical observations and, as described inthe discussion of signs and symptoms, is oftenunmistakable. The classic triad of sudden hypoxia,hypotension, and coagulopathy with an onset duringlabor or immediately after delivery forms the hallmarkof amniotic fluid embolism diagnosis.10 However, it isclear that there exist many cases of “form fruste” amni-otic fluid embolism, in which one or more componentsof this triad may be minimal or absent.6,36,40 In suchcases, the diagnosis is more difficult and must includecareful exclusion of plausible alternative diagnoses.Identical signs and symptoms may herald amnioticfluid embolism after both first- and second-trimesterpregnancy termination, consistent with the observationthat an abnormal maternal response to fetal tissuerather than the volume of tissue itself underlies thiscondition.6,7,42

Although the detection of fetal squamous cells inthe maternal pulmonary circulation was once considereddiagnostic of amniotic fluid embolism, more recentstudies of distal port (pulmonary artery) aspirates from

Box 1. Common Early Signs and Symptoms ofAmniotic Fluid Embolism

HypotensionDyspneaCyanosisFrothing from mouthFetal heart rate abnormalitiesLoss of consciousnessCardiac arrestBleeding from uterus, incisions, or intravenous sitesUterine atonySeizure-like activity

Fig. 2. Fetal heart rate tracing in a woman with amniotic fluid embolism. Note spontaneous uterine tachysystole in con-junction 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 ObstetGynecol 1995;172:1158–69, with permission from Elsevier. Modification courtesy of Advanced Practice Solutions.

Clark. Amniotic Fluid Embolism. Obstet Gynecol 2014.

342 Clark Amniotic Fluid Embolism OBSTETRICS & GYNECOLOGY

pulmonary artery catheters in patients with a variety ofcritical illnesses including complicated preeclampsia,cardiac disease, and septic shock revealed that squamouscells and trophoblasts are frequently transported toand may be recovered from the pulmonary arterialbed of such patients.6,7,11 With sufficient histologicsampling and special stains, identification of suchcells is quite common.11 Although available data dosuggest a fetal origin for some of these squamous cells,identification of indistinguishable adult squamous cellsin similar samples drawn from critically ill adult malessuggests a component of desquamation from vascularaccess lines and ports as well.11 Regardless of theirorigin, the detection of squamous cells or other debrisof presumed fetal origin in the pulmonary arterialbed of pregnant women is no longer considered diag-nostic of amniotic fluid embolism; such studies are notgenerally useful in either the diagnosis of exclusion ofthis condition.7,10,11

Several investigators have proposed the existenceof more specific laboratory or autopsy findings toconfirm the diagnosis of amniotic fluid embolism.These include various arachidonic acid metabolites,tryptase, urinary histamine, insulin-like growth factorbinding protein-1, various markers of complementactivation and postmortem immunohistologic stainingfor Sialyl Tn antigen, zinc coproporphyrin, or otherevidence of pulmonary mast cell degranulation.6,7,21,42–44

Unfortunately, such studies are difficult to interpret;index cases are often chosen based on clinical findings,which were interpreted by the authors to be diagnosticof amniotic fluid embolism but which are generallyreported in insufficient detail to allow the reviewerto be assured of the accuracy of the diagnosis. Theseproblems are further compounded by the use of normalpregnant women as control participants rather thancritically ill pregnant women in whom acute-phaseinflammatory reactants would be expected to rise,regardless of the diagnosis.21 Thus, although thesedescriptions of laboratory findings appear to be gener-ally supportive of an inflammatory-based mechanismof disease in amniotic fluid embolism, to date none ofthese findings is of significant diagnostic or clinicaluse. Although the search for specific histologic orlaboratory markers of amniotic fluid embolism con-tinues, this condition remains primarily a clinicaldiagnosis of exclusion.

RISK FACTORS

A review of multiple registry series reveals a wide rangeof conflicting conclusions regarding the presence ofidentifiable risk factors for amniotic fluid embolism.32–41

Advanced maternal age and parity, male fetus, medical

induction of labor, cesarean delivery, instrumentaldelivery, cervical trauma, placenta previa and abrup-tion, and ethnic minority status have been found tobe both significantly associated with amniotic fluidembolism and not associated with amniotic fluidembolism in various studies.32–41 For example, inan initial Canadian study, labor induction was deter-mined to be a significant risk factor.38 However, asubsequent publication of a large series of patientsin the United States by the same research groupcontradicted the original finding.39 In addition,based on investigations of maternal–fetal exchange,the frequency of oxytocin use, and the rarity ofamniotic fluid embolism, most investigators struggleto find biologic plausibility for a causative link betweenoxytocin and other uterine stimulants and amnioticfluid embolism.6,7,10,17 As early as 1976, investigationsinto maternal–fetal oxygen transport during uterinecontractions demonstrated a complete cessation ofuteroplacental exchange as intrauterine pressuresexceed 40 mmHg.17 Thus, a contraction, especially ahypertonic contraction, is the least likely event duringall of labor to induce entrance of amniotic fluid andfetal tissue into the maternal circulation.10 However, aninitial period of uterine tachysystole or tetany is in factcommonly observed just before, or in association with,the onset of maternal hemodynamic collapse in womenwith amniotic fluid embolism6,10 (Fig. 2). This apparentparadox is explained by the realization that endoge-nous norepinephrine released as part of the normalhuman hemodynamic response to any major physio-logic insult has significant uterotonic effects; thus, theincreased uterine activity commonly seen at or evenjust preceding the onset of discernible maternal or fetalphysiologic response is a manifestation of evolvingamniotic fluid embolism syndrome rather than beingcausative.45 These observations confirm earlier statisti-cal observations by Morgan based on the frequency ofoxytocin use and the rarity of amniotic fluid embolismas well as conclusions of the American College ofObstetricians and Gynecologists that there is no caus-ative link between uterine stimulation and amnioticfluid embolism.32,46

In addition, many studies examining risk factorshave a common weakness, namely a shotgun approachto risk factor identification. Using a cutoff for signifi-cance of P,.05, any examination of 20 potential riskfactors is likely to falsely identify one as being statisti-cally significant. This observation is not intended as acriticism of this approach as an initial attempt to deter-mine where to focus further investigation. However, asit stands today, no demographic or clinical risk factorhas been identified that justifies any prospective

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alteration of standard obstetric practice to reduce therisk of amniotic fluid embolism. Furthermore, noneof these potential risk factors and no action or inac-tion of patient or health care provider has a suffi-ciently established causative link to justifya conclusion that were it not for this factor, the amni-otic fluid embolism would not have occurred in anyindividual patient. As it stands today, amniotic fluidembolism remains both unpredictable andunpreventable.

OUTCOME

Estimates of maternal mortality vary greatly and appearto be largely dependent on criteria required for the in-clusion of cases as true amniotic fluid embolism.7,10,40,42

Series restricted to patients in whom all classic signsand symptoms of amniotic fluid embolism are presentsuggest mortality rates exceeding 60%.10 In cases com-plicated by cardiac arrest, survival is even worse withmost series reporting that fewer than 10% of adultssustaining in-hospital cardiac arrest of any origin aredischarged alive.47 On the other hand, when less sickpatients are included, particularly in population-based,death certificate, or discharge code-dependent series inwhich many patients do not actually have amnioticfluid embolism, reported mortality rates will be muchlower, in some cases below 20%.7,40,42 Although it isclear that expert critical care management will improvethe likelihood of survival in some women, prognosisultimately appears to be more closely linked to diseaseseverity and the occurrence of concomitant cardiacarrest than to any specific treatment modality.

MANAGEMENT

Fortunately, it is not necessary to make the diagnosisof amniotic fluid embolism to treat it appropriately,because treatment is primarily supportive and basedon observable pathophysiology. After cardiac arrest,standard Basic Cardiac Life Support and AdvancedCardiac Life Support algorithms should be applied.With maternal hypotension short of arrest, bloodpressure should be supported with fluids and pressoragents when necessary. Dyspnea, hypoxia, or bothare managed with oxygen administration; althoughintubation is not required in every case, a clinicalsuspicion of possible amniotic fluid embolism shouldprompt immediate anesthesia attendance, becauseintubation is commonly indicated. Oxygen deliveryshould be guided by pulse oximetry, arterial blood gasassessment, or both. Isolated reports of survivalassociated with the use of extracorporeal membraneoxygenation, intraaortic balloon counterpulsation, con-tinuous hemodiafiltration, cardiopulmonary bypass,

right ventricular assist device, and nitric oxide haveall been reported; however, such techniques must becurrently regarded as unproven and experimental.7,10,48

Coagulopathy and ensuing hemorrhage are man-aged by aggressive blood and component replacement;widely available massive transfusion protocols areoften helpful in this regard.49 Although several reportsexist describing the use of recombinant factor VIIain amniotic fluid embolism, recombinant VIIa cancombine with circulating tissue factor to enhancethe formation of intravascular clots; a recent reviewsuggests that such patients have significantly worseoutcomes than cohorts who received componentreplacement only.50 Although such patients were notrandomized, and those receiving recombinant factorVIIa may have been sicker than those receivingconventional component therapy, the available datasuggest that recombinant factor VIIa should probablybe reserved for women with severe coagulopathy whocontinue to bleed heavily despite adequate componenttherapy.50 If the fetus is undelivered and of a viablegestational age, prompt delivery is indicated, as dis-cussed subsequently. Although scattered, anecdotalcase reports exist in which delivery appears to haveimproved the maternal condition, and although suchan effect is physiologically plausible as a result of therelease of venacaval obstruction by the gravid uterus,a conclusion that in any individual case delivery wouldhave altered the maternal outcome would be unjustified.Given the dismal maternal prognosis associated withamniotic fluid embolism and cardiac arrest even afterprompt delivery, and an ascertainment bias that favorscase reports of apparent miraculous, but vanishinglyrare maternal recovery after delivery with amniotic fluidembolism, an objective, evidence-based assessmentof this issue must conclude that delivery confers nomaternal benefit. Neither does delivery, however,confer significant additional maternal risk after car-diopulmonary arrest.10,51 As discussed subsequently,prompt delivery is, from the fetal standpoint,vital.7,10,51

Two large series of mothers undergoing cardiacarrest before delivery highlight the importance ofprompt delivery in such cases10,51 (Table 2). Becausecardiac output achieved by optimally performedcardiopulmonary resuscitation (CPR) is only aboutone third of normal, and optimal CPR performanceduring term pregnancy is, because of venacaval obstruc-tion by the uterus, always problematic, uteroplacentalperfusion during CPR in late pregnancy probablyapproaches zero.10,51 It follows that for maternal cardiacarrest of any etiology, emergent perimortem delivery isindicated if the fetus has reached an age of viability.

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Indeed, the only evidence-based conclusions that maybe drawn regarding efficacy of treatment of amnioticfluid embolism is that with maternal cardiac arrest,prompt delivery improves the likelihood of a goodnewborn outcome.10,51

Despite these observations, the acute managementof amniotic fluid embolism is not entirely reactive.The available evidence would suggest a number ofproactive steps that may be taken when amnioticfluid embolism is suspected. These may be institutedsimultaneously with the essential resuscitative effortsdescribed previously and may be summarized asfollows:

1. Red blood cells, fresh-frozen plasma, or cryopre-cipitate and platelets may be prepared even beforeclinical manifestations of coagulopathy or labora-tory confirmation of clotting deficits.

2. If the patient is unconscious or experiencingsignificant hypoxia or desaturation, intubationand ventilation with 100% oxygen is vital—thesewomen often sustain hypoxic central nervoussystem damage seemingly out of proportion tothe duration of cardiac arrest or the documenteddegree of hypoxia.

3. During CPR and preparations for delivery, lateraldisplacement of the uterus may improve maternalvenous return and cardiac output.

4. Although rapid infusion of crystalloid solutionis an essential component of advanced cardiaclife support with amniotic fluid embolism, themanaging physician should be cognizant of thelikelihood of acute lung injury and pulmonaryedema in surviving patients.

FUTURE RESEARCH DIRECTIONS

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

amniotic fluid embolism.32–42 It is unlikely that addi-tional data of this type will be useful. On the otherhand, the rarity and unpredictable nature of thissyndrome and its high rate of mortality hinder thebasic science investigations necessary to further explorethe etiology of this condition and potentially developeffective means of prevention and treatment. Perhapsmost promising in this regard is an internationalAmniotic Fluid Embolism Patient Registry thathas been established at Baylor College of Medicine(aferegistry@bcm.edu) in partnership with the AmnioticFluid Embolism Foundation (http://afesupport.org), aninternational nonprofit patient advocacy organization.These investigators aim to study the relationshipsbetween various biochemical and immunologicfeatures of women who survived amniotic fluidembolism and their children from both affectedand unaffected pregnancies.

CONCLUSIONS

For the past 30 years I have studied, published, andreviewed hundreds of clinical cases of women whodied of amniotic fluid embolism and spent a good dealof my life caring for critically ill pregnant women witha variety of disease conditions. Despite this, theultimate inciting pathophysiologic process leadingto the often unmistakable syndrome of sudden intra-partum cardiorespiratory collapse and coagulopathyremains frustratingly just out of reach. Although theresearch methodology of Steiner and Luschbaugh was,from our current standpoint, flawed, and although theliterature is cluttered with case reports, small series, andlarge population data-based registries of amniotic fluidembolism in women who clearly did not have amnioticfluid embolism, sufficient good-quality data as well asclinical experience seem to confirm the following:

1. The syndrome of sudden peripartum hypoxia,cardiovascular collapse, and coagulopathy isreal but has nothing to do directly with eitheramniotic fluid or embolization. The recovery ofcellular debris of fetal origin from the maternalcirculation may be a marker of this event but isneither sufficiently sensitive nor specific to be ofdiagnostic use because entry of amniocytes orother cells of fetal origin is commonly seen innormal pregnancy.

2. The timing of most such events during deliveryor pregnancy termination as well as the relation-ship between this syndrome and other conditionsknown to involve abnormal invasion or releaseof fetal material into the maternal circulation(placental abruption and placenta accreta)

Table 2. Cardiac Arrest-to-Delivery Interval andNeurologic Outcome

Arrest toDelivery(min)

NeurologicallyIntact

NeurologicallyImpaired

% WithoutNeurologicImpairment

0–5 11 1 9115–15 4 47 50More thanthan 15

7 12 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 JObstet Gynecol 1995;172:1158–69 and Katz V, Balderston K,DeFreest M. Perimortem cesarean delivery: were our assump-tions correct? Am J Obstet Gynecol 2005;195:1916–20.

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suggest that a breach of the normal physiologicbarrier between fetus and mother is involved.

3. Clinically identical activation of the coagulationcascade known to result from amniotic fluidembolism, placental abruption, and placentaaccreta cannot realistically be viewed as coin-cidental or unrelated. Given the well-describedthromboplastin-like effects of placental tropho-blastic tissue, it is reasonable to conclude thatthe coagulopathy seen with amniotic fluid embo-lism often also involves trophoblastic-derivedantigens.

4. This syndrome involves a series of recognizableclinical signs, symptoms, and central hemody-namic changes similar to those seen in manycases of anaphylaxis or SIRS and septic shock,suggesting the involvement of similar endogenousproinflammatory mediator and procoagulantactivation or release in response to foreignantigenic substances.

5. Neither the precise nature of the stimulusinvolved nor the inflammatory mediator responseis uniform, consistent with the variable clinicalexpression of this syndrome. Rather, this condi-tion may be the final common expression of aunique maternal immunologic response to var-ious foreign antigenic stimuli originating in thefetal compartment, which may be fetal or infec-tious in origin. Alternately, bacterial endotoxinor exotoxin could potentiate the endogenousmediator response in immunologically susceptiblematernal–fetal pairs. Romero posed the prescientquery “amniotic fluid embolism or septic shockdue to intrauterine infection?”22 The ultimateanswer may well be “both.” Because entry ofsome fetal tissue into the maternal circulation atsome point in the delivery process is common,if not universal, amniotic fluid embolism iscurrently unpreventable in susceptible maternal–fetal pairs. Amniotic fluid embolism has noidentifiable risk factors of sufficient strengthto warrant alteration in standard obstetric practiceto avoid or reduce the risk of this condition.

6. Data linking stimulated or augmented labor toamniotic fluid embolism are weak and conflictingand lack biologic plausibility. Given the frequencyof stimulated or augmented labor and the infre-quency of amniotic fluid embolism, a causativelink in any individual case would be scientificallyunjustified.

7. The diagnosis of amniotic fluid embolism is aclinical one. Identification of elements ofthe classic triad of hypotension, hypoxia, and

coagulopathy and the careful exclusion ofother conditions are essential for the diagnosis.Diagnosis based on specific biochemical indicesremains investigational.

8. Treatment of amniotic fluid embolism in themother is primarily supportive and directed atobservable physiologic abnormalities.

9. In the mother who has undergone cardiac arrestas a result of amniotic fluid embolism, emergentdelivery is indicated. Prompt delivery mayimprove newborn outcome and will not jeopar-dize maternal recovery. However, in the motherwho is hemodynamically unstable but has notdeveloped one of the lethal dysrhythmia patternscommonly considered under the category“cardiac arrest,” the decision for delivery mayindeed affect maternal outcome. Given thedisparate needs of the mother and fetus in thissituation, no uniform standard of care exists.These decisions are the most difficult in all ofmedicine and cannot realistically be made byanyone not on the scene and in charge of careat the time.

10. Case selection not based on careful individualchart review will likely result in the inclusion ofpatients who do not have amniotic fluid embo-lism. Such misdiagnosis has already hinderedprogress in amniotic fluid embolism researchfor more than 50 years. It is suggested that futureresearch into specific diagnostic or therapeuticapproaches to amniotic fluid embolism be lim-ited to patients who exhibit the classic triad ofhypotension, hypoxia, and coagulopathy or inwhom alternative diagnoses have been excludedby careful and skeptical medical records review.

11. Although much remains to be learned aboutthe mechanism of amniotic fluid embolism,the wild goose chase alluded to at the beginningof this article appears to be over. With carefulinvestigative approaches examining the role ofantigenic response and endogenous or inflamma-tory mediators in the genesis of amniotic fluidembolism, we appear to be at last on the righttrack.

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