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CLINICAL OBSTETRICS AND GYNECOLOGY Volume 53, Number 2, 322328 r 2010, Lippincott Williams & Wilkins

Amniotic Fluid Embolism

STEVEN L. CLARK, MD8 Womens and Childrens Clinical Services, Clinical Services Group, Hospital Corporation of America, Nashville, Tennessee
Abstract: Amniotic fluid embolism (AFE) remains an enigmatic, but devastating obstetrical condition associated with significant maternal and newborn morbidity and mortality. Although our understanding of this condition is incomplete, research over the past 2 decades has altered traditional concepts of both the causation and pathophysiology of AFE. Although maternal treatment remains primarily supportive, prompt delivery of the fetus can substantially improve neonatal outcome after AFE-induced cardiac arrest. Newer biochemical markers may in the future enhance the specificity and sensitivity of this clinical diagnosis and could potentially lead to improved therapy. Key words: amniotic fluid embolism, anaphylactoid syndrome of pregnancy, maternal cardiac arrest, systemic inflammatory response syndrome

double tragedy, as its onset during labor often results in a catastrophic outcome for both mother and fetus. Although several pieces of this clinical puzzle remain missing, research in the past 2 decades has resulted in significant advances in our understanding of the clinical presentation, pathophysiology, diagnosis, and treatment of AFE.

Definition, Incidence, and Outcomes

In its classic and most lethal form, AFE consists of the triad of hypoxia resulting from acute lung injury and transient pulmonary vasospasm, hypotension or cardiac arrest, and a consumptive coagulopathy, all occurring during labor or pregnancy termination or shortly after delivery, and in the absence of reasonable alternative explanations.1,3 However, several authors have reported the existence of a partial AFE syndrome in which one or more of these features were absent.3,6,7 The incidence of AFE will clearly be greater, and the outcomes generally better in the latter group of patients than in the former. Given the absence of any single confirmatory test proving the existence of AFE, and the multitude of conditions
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Amniotic fluid embolism (AFE) remains one of the greatest enigmas in obstetrics. It has been described as the medical equivalent of being struck by lightning. Unlike a lightning strike, however, no clinically useful risk factors or effective preventative measures are known. In addition, although quite uncommon in an absolute sense, AFE is one of the leading causes of maternal death in developed countries.15 This condition is often a

Correspondence: Steven L. Clark, MD, Medical Director, P.O. Box 404, Twin Bridges, MT 59754. E-mail: steven.clark@mountainstarhealth.com

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Amniotic Fluid Embolism in laboring women that may individually give rise to hypoxia, hypotension, or coagulopathy, great caution must be exercised in diagnosing this condition in its less than classic form and in analyzing data in which cases have been selected on the basis of death certificate or discharge diagnosis coding without a thorough chart review or other verifying evidence. The need for caution in accepting the results of such studies was recently emphasized in a review by Conde-Agudelo and Romero.5 Indeed, almost 1 of 3 patients initially reported to a US AFE registry were found, upon examination of the complete medical records, to have conditions other than AFE.1 Nevertheless, most authorities do acknowledge the existence of partial AFE syndromes in which other conditions can been reasonably excluded. The incidence of AFE has historically been estimated to be between 1 in 7000 and 1 in 80,000 deliveries.3 Recent evidence from the United States suggests an incidence of approximately 1 in 13,000 deliveries, whereas a report from the UK demonstrated an incidence closer to 1 in 50,000 deliveries.8,9 An incidence of roughly 1 in 20,000 births would seem to be a reasonable estimation taking into account both complete and partial forms of the syndrome. Maternal mortality rates in developed countries range from 61% in women with the more severe form of AFE to 13% to 44% in other series, most of which did not involve complete chart review, or in which some patients did not have all of the features of the classic, fulminate AFE syndrome.1,5,7 Ten percent or less of women with AFE and cardiac arrest survive neurologically intact, a figure not significantly different than observed with other causes of in-hospital cardiac arrest. Fetal injury is also common in cases that occur during labor, but may be favorably influenced by delivery decisions, as will be discussed below.


Clinical Presentation
In its most classic form, AFE is diagnosed when a woman in labor experiences sudden dyspnea, hypotension, and cardiac arrest, accompanied by evidence of acute fetal hypoxia. Pulmonary thromboembolism and conduction anesthetic accident or medication reaction should be initially considered, as specific therapy is available for these conditions (Table 1). These initial signs and symptoms are often followed in short order by a severe consumptive coagulopathy which may result in exanguination even if the hypoxia and cardiac arrest are successfully treated. Consumptive coagulopathy is generally not a component of most alternative conditions and its appearance in this clinical setting often confirms the diagnosis of AFE. Indeed, AFE and massive placental abruption are the only 2 obstetric conditions that give rise to acute, severe consumptive coagulopathy. Although cardiac arrest or shock of any etiology may result in subclinical laboratory evidence of coagulopathy, these conditions alone are not generally associated with a degree of coagulopathy sufficient to result in acute, severe derangements of the clotting profile or clinical hemorrhage. In contrast, primary severe hemorrhage of any etiology may eventually result in a dilutional coagulopathy which further aggravates the bleeding and may lead secondarily to hypoxia, hypotension, and cardiac arrest. Thus the temporal


Conditions to Consider in the Differential Diagnosis of Amniotic Fluid Embolism

Anesthetic complications, especially high spinal/ epidural block Medication reaction/allergy Pulmonary thromboembolism Myocardial infarction Eclampsia Placental abruption Postpartum hemorrhage of any etiology



Clark assumption that the finding of cells of fetal origin in the maternal pulmonary circulation either during life, or at autopsy was pathognomonic for AFE. In the years after the initial widespread recognition of this condition, this assumption led to a plethora of case reports and small series describing a variety of supposed clinical presentations of AFE, based upon such histologic findings alone.3 Subsequent documentation that fetal cells may be commonly found in the maternal circulation, given the utilization of a sufficient number of special stains on a sufficient number of histologic sections has thrown the validity of many earlier case reports into questionmany of these patients clearly had conditions other than AFE.3,12,13 Indeed, a review of the brief case reports accompanying the early, classic description of AFE by the pathologists Steiner and Luschbaugh14 (a series defined by unselected maternal deaths in which fetal debris was found in the central circulation at autopsy) reveals that most of these original patients seemed to have died from clinical conditions unrelated to AFE. Finally, the older assumption that AFE is the result of a massive forcing of amniotic fluid debris into the maternal circulation by hypertonic uterine contractions is now known to be at odds with the physiology of maternal/fetal circulatory exchange. Uterine blood flow ceases with contractions exceeding 40 mm Hg, a modest level universally exceeded during normal labor.1,15 Thus, a period of uterine hyperstimulation is the least likely time for any exchange between the fetal compartment and the maternal circulation. The hypertonic contractions commonly seen in association with the onset of AFE are generally a manifestation of the earliest maternal response to impending cardiovascular collapse, probably as a result of endogenous norepinephrine release. An identical situation has been described with eclamptic seizures.16

sequence of cardiorespiratory deterioration and coagulopathy, as well as the severity of the latter is often helpful in making the diagnosis of AFE. The statement of Eastman10 in 1948 remains worth heeding: Let us be careful not to make (the diagnosis of AFE) a wastebasket for cases of unexplained death during labor. In contrast, it is critical to remember that despite its rarity in the general population of pregnant women, this condition accounts for 5% to 15% of maternal deaths from all causes in developed countries.5 In fact, AFE is probably the most common diagnosis in the population of women suffering sudden cardiac arrest during labor or the immediate postpartum period.13,5

Two decades ago, AFE was felt to be the result of the infusion of amniotic fluid cells and other debris into the maternal circulation by forceful uterine contractions, resulting in physical obstruction of the pulmonary circulation and cardiovascular collapse. Today, each component of this view has been thoroughly discredited based upon sound data and a better understanding of maternal/fetal physiology.3 Unfortunately, no useful animal model of this condition has been developed. Most of the earlier studies examining experimental AFE in animals consisted of little more than the infusion of fetal material from one species into the central circulation of another, and bear no resemblance to clinical AFE in humans. Indeed, those studies using the experimental infusion of even relatively large volumes of clear amniotic fluid from an individual of one species (including humans!) into a same-species recipient generally resulted in no adverse hemodynamic or physiologic effects.1,3,11 This situation has historically been made even more confusing by the false www.clinicalobgyn.com

Amniotic Fluid Embolism The percentage of women who experience the onset of AFE during cesarean delivery mirrors the incidence of AFE delivery in the general population. Cesarean delivery does not prevent AFE in susceptible mother-infant pairs.1 One recent report from Canada by Kramer et al17 suggesting an increased risk of AFE associated with labor induction was refuted 2 years later in a study from the US (which included the same author).8 Given the nature of this data and the seeming biologic implausibility of a causative relationship between labor induction and AFE, it would be inappropriate at present to conclude that labor induction is causally associated with AFE. Demographic, clinical, and physiologic data all suggest the absence of a causative relationship between oxytocin stimulation of labor and AFE.1,3,5,8,18 AFE seems to be an example of the systemic inflammatory response syndrome associated with the inappropriate release of endogenous inflammatory mediators.1,3,5 This basic observation is suggested by the similarity of clinical signs and symptoms seen in the classic AFE syndrome to those observed in conditions in which the specific mediators have been better defined, such as septic or anaphylactic shock.1,3 The exact trigger for this reaction in women with AFE is not well understood, but is presumed to involve a rare, abnormal maternal immune response to the fetal antigen exposure common to virtually all laboring women. This assumption is based on the known complex barriers to maternal-fetal immunologic interaction during most of pregnancy and the frequent occurrence of AFE during active labor, pregnancy termination, or cesarean delivery, times during which this barrier is known to be commonly breached.1,3 Although a history of allergy seems to be more common in women with AFE than in the general population, this finding is neither sensitive nor specific. At present, there are no known useful pre-


dictors of AFE, and no patient is either at significantly higher or lower risk than the general population regardless of medical or obstetric history, natural, augmented, or hyperstimulated labor, vaginal birth, or cesarean delivery.1,3,5 As the known pathophysiology of AFE involves neither amniotic fluid per se, nor an embolic phenomenon, the term anaphylactoid syndrome of pregnancy has been proposed as a more physiologic descriptive term for this condition.1 AFE however remains in common usage. It is interesting to note that in nonobstetric fat embolism syndrome, earlier suppositions regarding a purely mechanical/embolic pathophysiologic mechanism have also been recently replaced with an understanding of the role of acute phase reactants in the production of this condition.19 The abnormal mediator release associated with AFE often results in acute lung injury, manifested by clinical dyspnea and hypoxia, and blood gas evidence of intrapulmonary shunting or later radiographic evidence of pulmonary capillary leak or acute respiratory distress syndrome. An element of transient pulmonary vasospasm probably contributes to the initial hypoxia.1,3,5 Left ventricular function is also acutely depressed, and may contribute to systemic hypoxia.1,3,5,20 Such ventricular depression may be the result of the initial pulmonary vasospasm, secondary to hypoxia, or perhaps as a direct effect of various endogenous mediators. The thromboplastic effects of endogenous mediators to the coagulopathy observed with AFE is better understood, and is probably similar to that observed in cases of severe placental abruption.3

In women with AFE, squamous cells and other debris of presumed fetal origin may be found, either at autopsy or during life in a distal port aspirate of a pulmonary www.clinicalobgyn.com


Clark port should follow established basic and advanced cardiac life support protocols. In surviving patients, coagulopathy is generally treated with component and blood replacement. Although the bolus administration of steroids was suggested as a possible approach on a theoretical basis by this author over a decade ago, experience since that time has failed to document improved outcomes with steroid treatment.1 Several case reports exist in which newer treatment modalities were used in women with AFE and the patient survived. These include cardiopulmonary bypass, inhaled aerosolized prostacyclin, the administration of nitric oxide, and the use of recombinant factor VII for coagulopathy associated with AFE.3,5 Although intriguing, it should be emphasized that none of these treatments has been demonstrated to lead directly to, or contribute to survival in AFE patients; thus the use of these techniques might be considered in selected patients but are not mandated by the standard of care. Unfortunately, the ultimate maternal outcome for women with AFE is primarily related to the nature and severity of the initial presentation. There exists no data to support the contention that any specific form of treatment either improves or worsens the outcomes in women with AFE, beyond the rather dismal statistics that apply to patients with cardiac arrest managed with general basic and advanced cardiac life support protocols. The same does not apply to newborn outcome. With AFE and maternal cardiac arrest before delivery, neurologically intact neonatal survival is directly related to the cardiac arrest to delivery interval1,3 (Table 2). Even this relationship, however, is inconsistent and probably relates to variability in the onset and intensity of uterine hypoperfusion associated with maternal cardiovascular decompensation preceding the ultimate lethal dysrhythmia. Reports exist of neurologically intact fetuses being delivered beyond 15 minutes

artery catheter.3 Although once felt to be pathognomonic for this condition, such debris may also be found in women with other types of critical illness. Indeed, squamous cells are commonly identifiable from distal port pulmonary artery aspirates from critically ill male patientsour inability to distinguish squamous cells of fetal origin from those related to obtaining vascular access further complicate this issue.12 Conversely, as many as a quarter of women with classic AFE syndrome may have negative pulmonary histologic examinations for squamous cells or other fetal debris, in part depending upon the degree of special staining of these specimens undertaken.1 Thus, at the present time, the diagnosis of AFE must be made clinically; it can neither be confirmed nor refuted based on histologic studies of lung tissue.1,3 In recent years, attention has turned to the identification of biochemical markers of AFE. Such proposed markers include zinc coproporphyrin, Sialyly Tn antigen, and complement C3 and 4.5 Many such studies are problematic, however, given the frequent misdiagnosis of AFE discussed above. Data collection from patients whose diagnosis is not based upon strict, objective, predetermined clinical criteria must be viewed with skepticism, particularly when the control group consists of normal pregnant women, rather than critically ill women in whom acute phase reactants would be expected to rise, regardless of the diagnosis.

The maternal of AFE is general and supportive. Hypoxia is treated with oxygen supplementation and, when necessary, intubation. Circulatory support is accomplished by optimizing cardiac preload and Starlings forces with rapid fluid infusion and, when necessary, the administration of pressor agents. In cases of cardiac arrest, respiratory and circulatory supwww.clinicalobgyn.com

Amniotic Fluid Embolism

TABLE 2. Maternal Cardiac Arrest-to-delivery Interval and Neonatal Outcome After Predelivery Maternal Amniotic Fluid Embolism
Survival 3/3 3/3 5/10 Intact Survival (%) 2/3 (67) 2/3 (67) 3/10 (33)


Interval (min) <5 6-15 16-54

lead to immediate perimortum cesarean, at the bedside if an operating suite is not immediately available. For a pregnant woman whose fetus has reached an age of ex-utero viability, the standard ABCs (Airway, Breathing, and Circulation) of basic cardiac life support should be augmented by a Ddelivery.

Modified from Am J Obstet Gynecol. 1995;172:1158.

At present, 9 case reports exist documenting successful pregnancy after survival from AFE.5 Given the possibility of misdiagnosis, and in the absence of a single gold standard for determining the presence of AFE in the index pregnancy, the number of survivors after actual AFE is probably even less than sparse case report data would suggest. However, 3 factors suggest that the recurrence risk should be very small. First, fetal tissue or antigen exposure per-se cannot underlie the occurrence of AFE given its near universal presence around the time of delivery, the rarity of the condition and the fact that AFE is not a disease primarily of primiparous women. Second, subsequent pregnancies of a given set of parents are antigenically dissimilar. Finally, recurrence after exposure to different fetal antigens is not consistent with the current view of AFE as a systemic inflammatory response syndrome-related condition. Indeed, recurrence of confirmed AFE has apparently not been reported. However, in counseling such women regarding recurrence risk, it is important to emphasize both the gravity of the condition, and the paucity of data to support any information regarding recurrence risk.

of cardiac arrest, and the author has personally seen hypoxic brain death in a newborn delivered in within 5 minutes of a witnessed cardiac arrest in a woman with AFE. Nevertheless, several generalizations are valid. First, during any period of maternal hemodynamic instability that precedes frank asystole, ventricular fibrillation, or pulseless electrical activity cesarean delivery itself may precipitate cardiac arrest. In a situation in which both mother and fetus are deteriorating in this manner, but the mother has not yet reached the point of frank arrest, as defined by one of these dysrythmias, no clear standard of care exists regarding intervention, and a decision to operate or not can only appropriately be made by the obstetrician on the scene, and not in hindsight. In such cases, the general obstetric axiom that the welfare of the mother takes precedence over that of the fetus should be kept in mind. However, in a mother who is manifesting one of the patterns of lethal dysrythmia commonly termed cardiac arrest, the situation become quite different. Under such circumstances, intact maternal survival follows the general pattern of adult cardiac arrest, and is typically less than 10%. Further, given the pathophysiology of AFE, it is highly unlikely that a cesarean delivery would be the deciding factor in maternal survival or death. Finally, maternal resuscitative efforts may be theoretically enhanced by the complete release of vena caval compression associated with delivery. Thus, maternal cardiac arrest should

AFE is a common cause of maternal death during labor. Although the condition remains incompletely understood, the past 2 decades have seen significant advances in our understanding of this condition. Many older theories, (such as www.clinicalobgyn.com


fluid embolism: a population-based study on 3 million births in the United States. Am J Obstet Gynecol. 2008;199:49.e149.e8. Knight M, UKOSS. Amniotic fluid embolism: active suveillance versus retrospective database review. Am J Obstet Gynecol. 2008;199:e9. Eastman NJ. Editorial comment. Obstet Gynecol Surv. 1948;3:35. Sparr RA, Pritchard JA. Studies to detect the escape of amniotic fluid into the maternal circulation during parturition. Surg Gynecol Obstet. 1958;107:550. Clark SL, Pavlova Z, Horenstein J, et al. Squamous cells in the maternal pulmonary circulation. Am J Obstet Gynecol. 1986;154:104. Lee W, Ginsburg KA, Cotton DB, et al. Squamous and trophoblastic cells in the maternal pulmonary circulation identified by invasive hemodynamic monitoring during the peripartum period. Am J Obstet Gynecol. 1986;155:999. Steiner PE, Luschbaugh CC. Maternal pulmonary embolism by amniotic fluid as a cause of obstetric shock and unexpected deaths in obstetrics. JAMA. 1941;117:12451254, 13411345. Towell ME. Fetal acid-base physiology and intrauterine asphyxia. In: Goodwin JW, Godden JO, Chance GW, eds. Perinatal Medicine. Baltimore: Williams and Wilkins; 1976:200. Paul RH, Koh BS, Bernstein SG. Changes in fetal heart rate: uterine contraction patterns associated with eclampsia. Am J Obstet Gynecol. 1978;130:165. Kramer MS, Rouleau J, Baskett TF, et al; Maternal Health Study Group of the Canadian Perinatal Surveillance System. Amniotic-fluid embolism and medical induction of labour: a retrospective population-based cohort study. Lancet. 2006;368:14441448. ACOG. Prologue. Amniotic fluid embolism syndrome. In: Obstetrics. 3rd ed. Washington DC: American College of Obstetricians and Gynecologists; 1993:94. Parisi DM, Koval K, Egol K. Fat embolism syndrome. Am J Orthop. 2002;31:507512. Clark SL, Montz FJ, Phelan JP. Hemodynamic alterations in amniotic fluid embolism: a reappraisal. Am J Obstet Gynecol. 1985;151:617.

a causative association between uterine hyperstimulation and AFE) have been solidly discredited based on a more complete understanding of maternal/fetal physiology, whereas new questions (such as the precise nature and identify of the involved endogenous mediators) have arisen. The condition remains unpredictable and unpreventable. The prognosis for the mother with a complete manifestation of the syndrome remains poor, whereas the prognosis for the fetus may be somewhat improved with prompt delivery. Several decades after its initial description, the analogy with a lightning strike remains appropriate.


10. 11.



1. Clark SL, Hankins GDV, Dudley DA, et al. Amniotic fluid embolism: analysis of a national registry. Am J Obstet Gynecol. 1995;172:1158. 2. Clark SL, Belfort MA, Dildy GA, et al. Maternal death in the 21st century. Prevention and relationship to cesarean delivery. Am J Obstet Gynecol. 2008;199:36e136e5. 3. Dildy GA, Belfort MA, Clark SL. Anaphylactoid syndrome of pregnancy (Amniotic fluid embolism). In: Dildy GA, Belfort MA, et al, eds. Critical Care Obstetrics. 5th ed. 4. Tuffnell DJ. United Kingdom amniotic fluid embolism register. BJOG. 2005;112:16251629. 5. Conde-Agudelo A, Romero R. Amniotic fluid embolism: an evidence based review. Am J Obstet Gynecol. 2009;201:445. e1445.e13. 6. Porter TF, Clark SL, Dildy GA, et al. Isolated disseminated intravascular coagulation and amniotic fluid embolism. Society of Perinatal Obstetricians 16th Annual Meeting, Poster Presentation, Kona, Hawaii, January 1996. 7. Gilbert WM, Danielsen B. Amniotic fluid embolism: decreased mortality in a population-based study. Obstet Gynecol. 1999; 93:973977. 8. Aberhaim HA, Axoulay L, Kramer MS, et al. Incidence and risk factors of amniotic 14.





19. 20.