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Amniotic Fluid Embolism: Decreased Mortality in a Population-Based Study

From the Department of Obstetrics and Gynecology & Center for Health Services Research in Primary Care, University of California, Davis, and Health Information Solutions, Redwood City, California.

Address reprint requests to: William M. Gilbert, MD University of California, Davis Department of Obstetrics/Gynecology 4860 Y Street, Suite 2500 Sacramento, CA 95817 E-mail: wmgilbert{at}ucdavis.edu

	Abstract

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Objective: To examine the risk factors and pregnancy outcomes associated with 53 cases of amniotic fluid embolism that occurred in California during the 2-year period January 1, 1994 to December 31, 1995.

Methods: Data were obtained from a computerized database that contains linked records from the vital statistics birth certificate and hospital discharge summaries of both mother and newborn. This database covered all singleton deliveries that occurred in 328 civilian acute-care hospitals in California, which represented 98% of all deliveries in California. All cases of amniotic fluid embolism were examined for other pregnancy complications.

Results: There were 1,094,248 deliveries during that 2-year period. Fifty-three singleton gestations had the diagnosis of amniotic fluid embolism, for a population frequency of one per 20,646 deliveries. Fourteen women with amniotic fluid embolism died, for a maternal mortality rate of 26.4%. There were 35 (66%) diagnoses of disseminated intravascular coagulation (DIC), 38 (72%) diagnoses of hemorrhage, and 25 (47%) diagnoses of obstetric shock. Among the 14 women who died, the frequency of DIC (79%) and hemorrhage (71%) was not different compared with that of the survivors (62% and 72%, respectively), but obstetric shock was higher (86%, P = .02) than in survivors (33%). The average maternal length of stay for survivors was 6.5 days (range 3–27 days, median 5 days). The cesarean rate was 60% and the frequency of fetal distress was 49%.

Conclusion: In this population-based study of reported cases of amniotic fluid embolism, the maternal mortality rate (26.4%) was significantly less than previously reported and might reflect a more accurate population frequency. In addition, patients who survived and patients who died had similar pregnancy complications, suggesting that amniotic fluid embolism was present in all cases and not limited to those who died.

Amniotic fluid embolism is an unexpected and rare complication of pregnancy often presenting with sudden maternal cardiovascular collapse, disseminated intravascular coagulation (DIC), and maternal death.^1–5 Historically, the diagnosis of amniotic fluid embolism was made when a woman presented with those findings and at autopsy when fetal squamous and amniotic fluid cells were found within the maternal pulmonary arteries.^1,6,7 The prevailing theory of the cause of amniotic fluid embolism is that amniotic fluid containing fetal cells enters the uterine venous sinuses within the endometrium or endocervix. The fetal cells and amniotic fluid return to the maternal heart through the venous system and enter the lungs in sufficient quantity to cause an embolism or severe pulmonary vasoconstriction.^1–7 The resultant hypoxia causes cardiac and hemodynamic collapse, DIC, and usually maternal death.

Amniotic fluid embolism has been reported to occur in as many as one in 8000 and as few as one in 80,000 pregnancies.^1,2,8 Because amniotic fluid embolism is rare, rapidly progressive, and unpredictable, it is difficult to study. The medical literature on amniotic fluid embolism largely consists of case reports or series collected over many years or even decades.^1–4,8 Clark et al⁴ recently described their national registry of 46 cases of amniotic fluid embolism collected over a 5-year period, in which the maternal mortality rate was 61%, which is consistent with previous reports.^2,3 Little improvement in outcome has occurred since Steiner and Luschbaugh¹ published eight fatal cases in 1941. The Clark et al⁴ national registry has inherent problems with referral bias; physicians might refer only the best- or worst-outcome cases of amniotic fluid embolism, which does not provide a true picture of the disease or its mortality rate. Our study examines a large population of patients who delivered during the 2-year period 1994–1995 in California with the diagnosis of amniotic fluid embolism, thus allowing us to obtain a true population-based frequency.

	Materials and Methods

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A unique database was used that linked maternal and neonatal hospital discharge records to vital statistics birth certificate records. The linkage of vital statistics was established for all single live births in acute-care civilian hospitals (n = 328) that reported to the California Office of Statewide Health Planning and Development between January 1, 1994 and December 31, 1995. This database did not include births from home deliveries, out-of-state deliveries, and birthing centers not reporting to the Office of Statewide Health Planning and Development or deliveries at military facilities (2% of all deliveries in the state). The method successfully linked 98.9% of maternal and 98.6% of neonatal hospital discharge records with the vital statistics birth records, resulting in an overall linkage of 97.9% of reported singleton deliveries. We used data for multiple deliveries from the maternal discharge record only and therefore were unable to obtain information on newborn outcome. All information relates to the singleton pregnancies unless otherwise stated. A database of 1,094,248 deliveries was generated. Using SAS software (SAS Institute, Cary, NC), the database was queried using codes from the International Classification of Diseases, Ninth Revision (ICD-9) and Current Procedural Terminology, which resulted in a specific data set for statistical analysis. Amniotic fluid embolism and other diagnoses were not defined beyond those given in the codebooks. The linked database was searched for the diagnosis of amniotic fluid embolism, (ICD-9 673.1) and all cases were examined with respect to multiple demographic characteristics, as well as antepartum, intrapartum, and postpartum diagnoses. Fisher exact test was used to compare the group of maternal deaths (14 women) with the group of survivors (39 women). A P value of less than .05 was assumed significant unless otherwise stated.

	Results

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There were 1,094,248 women who delivered during the 2-year period. Fifty-three singleton pregnancies had the diagnosis of amniotic fluid embolism, for a population frequency of one per 20,646 pregnancies. The maternal discharge records noted that four additional cases of amniotic fluid embolism were multiple gestations. Of these four pregnancies, all had DIC, cesarean deliveries, and hemorrhage; two mothers died and two infants had fetal distress. The demographic characteristics of the singleton patients with amniotic fluid embolism are shown in Table 1. Fourteen (26.4%) of the 53 women died during the delivery hospitalization. Table 2 shows the coincident morbidities reported with amniotic fluid embolism grouped by maternal outcome. Most reported frequencies of codiagnoses were similar between the two groups, including hemorrhage and DIC, but obstetric shock was higher in women who died.

	Discussion

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In this population-based study of 1,094,248 pregnancies, we studied maternal and neonatal outcome in 53 cases of amniotic fluid embolism within a 2-year period. The most surprising finding was a maternal mortality rate of 26.4% associated with the diagnosis of amniotic fluid embolism, which is considerably less than rates reported previously (61–80%).^2–4 There are several possible explanations for the differences between the current and previous studies. The first explanation is that our study is the first population-based study with a sufficiently large number of cases of amniotic fluid embolism to be able to obtain an unbiased population-based frequency. Prior studies were largely compiled registries or case reports, which we cannot assume to represent true population frequencies.^1–4,8 If a patient survives an amniotic fluid embolism, it might not be of adequate interest to report a case in the literature or refer to a registry. Second, our study included the 2 years from January 1, 1994, to December 31, 1995. Many previous studies spanned multiple years and were done before widespread use of intensive care units for high-risk patients. The intensive care, multidisciplinary approach to the treatment of very sick patients is becoming more widely available, especially within the past 10 years. Recently, Burrows and Khoo⁸ published a series of ten cases of amniotic fluid embolism with a maternal mortality rate of 22%.⁸ This decrease in maternal mortality rate may reflect these recent developments in intensive care management of these patients.

Clark et al⁴ published an extensive report of their registry of 46 cases of amniotic fluid embolism collected over a 5-year period starting in 1988. They examined 121 clinical variables with strict entry criteria, including acute hypotension or cardiac arrest; acute hypoxia; DIC; and onset during labor, delivery, or within 30 minutes after delivery or pregnancy termination.⁴ They reported dismal maternal outcomes with a maternal mortality rate of 61% and a neurologically intact maternal survival rate of 15%. Neonatal outcome was only marginally better, with a survival rate of undelivered fetuses at the time of amniotic fluid embolism of 79%, in which only 50% of those infants were normal at discharge.⁴ Our results are markedly different from theirs, with a maternal mortality rate of 26.4% and a normal maternal discharge reported in 87% of survivors. The neonatal survival rate was 95% (38 of 40) of known outcomes, and routine discharge was reported in 72% of all cases. We believe the difference in the mortality and morbidity rates results partially from the nature of the case collection process. A registry represents a collection of cases, probably the worst cases, not a population frequency. Our database was limited to information reported on the maternal and neonatal hospital discharge summaries and vital statistics birth certificates. We did not have access to individual medical records and therefore relied on data entered at the time of hospital discharge or death. If a mother or infant was transferred to another facility, the outcome of the subsequent care of that patient would not necessarily be included in the hospital discharge record. Finally, the number of cases in both groups (survivors and deaths) was not large because of the rarity of the condition. Therefore, when small groups are compared, there may be statistically significant differences that might not hold when larger groups are compared.

One concern regarding our database is whether amniotic fluid embolism is overreported. The population frequency (one per 20,646 deliveries) is within the range of frequencies that has been reported in the literature (one per 8000 to one per 80,000 deliveries), indicating that we are not overreporting the frequency of amniotic fluid embolism. Furthermore, the codiagnoses with amniotic fluid embolism were similar between the group of survivors and the group that died (Table 2). Disseminated intravascular coagulation, hemorrhage, and fetal distress were similarly reported between groups, but obstetric shock was higher in the group that died. Whether this difference is a true difference between the groups that survived or died or that the women who survived had lesser degrees of disease is unknown. Others have reported similar frequencies of DIC (45–60%) in cases of fatal amniotic fluid embolism, suggesting that the frequency of codiagnoses in our study is consistent with the diagnosis of amniotic fluid embolism.^9–11 One final point to consider with a maternal death is that physicians and hospitals might include every possible diagnosis to demonstrate the extreme nature of the patient’s condition to help explain the death. The distribution of comorbidity found with the survivors was similar to that found with those who died, strongly confirming the diagnosis of amniotic fluid embolism in the survivors.

The demographic characteristics of our patients with amniotic fluid embolism are different from those of women with normal deliveries in California.¹² Our patients were older (mean age 33 years, Table 1), more likely to be non-Hispanic white and less likely to be Hispanic (in California in 1994, 36% of births were non-Hispanic white, 7% black, 45% Hispanic, 10% Asian, 2% other) and more likely to be multiparous (mean parity after delivery 2.6), which is consistent with other reports of amniotic fluid embolism.^2,4 Clark et al⁴ found an increase in male offspring (67%) in their registry that was not seen in our population (51%). The cesarean rate in this population was markedly higher (60%) than that of the total population during this time period (22.8%) and was not different between the total group of women with amniotic fluid embolism and those that died (Table 2). Lau and Chui¹¹ also found a high (50%) cesarean rate in 10 fatal cases of amniotic fluid embolism. Because the exact time of the onset of amniotic fluid embolism in our cases cannot be determined from the data set, we are unable to determine accurately the timing of the cesarean. The higher frequency of cesareans is most likely the result of the increased diagnosis of fetal distress (49%).

There were four cases of multiple gestation (four of 57 cases, 7%), which is higher than that in the general population (1–2%). Clark et al⁴ did not find higher rate of twin gestations (2%). The finding of more twin gestations in our population is consistent with the theory that uterine overdistension is a risk factor associated with amniotic fluid embolism.² If one twin ruptured its membranes, with the second twin’s membranes still intact, the amniotic fluid could more easily enter the maternal venous system causing an amniotic fluid embolism. Amniotic fluid embolism has been reported to be consistent with an allergic (anaphylactic) reaction instead of a true embolism. Steiner and Lushbaugh¹ attributed death to an "anaphylactoid reaction" which has been mentioned by others.^1,2,13 Morgan² believed that an allergic reaction as a cause of amniotic fluid embolism was less likely because of inconsistencies between histamine-related anaphylaxis and clinical amniotic fluid embolism. Recently, however, there has been renewed interest in allergy as a cause of amniotic fluid embolism.^4,14,15 The commonality between immunoglobulin E-mediated anaphylaxis, endotoxin-mediated sepsis, and amniotic fluid embolism supports this interest. In addition, experimentally induced amniotic fluid embolism can be prevented by the administration of a 5-lipoxygenase inhibitor, a leukotriene-blocking agent.¹⁶ This finding strongly indicates the effect of leukotrienes in amniotic fluid embolism.¹⁶ Clark et al⁴ proposed renaming the syndrome to "anaphylactoid syndrome of pregnancy" because of the similarities between anaphylaxis and amniotic fluid embolism. An allergic reaction requires sensitization to an antigen before the allergic response can occur. Seventy-five percent of the women with amniotic fluid embolism were multiparous at the time of delivery and therefore could have been previously exposed to fetal antigens.

The exact progression of maternal signs and symptoms in the initial phase of amniotic fluid embolism has been difficult to identify because of the rarity of the condition and lack of monitoring from the onset. Fava and Galizia¹⁷ described a case of amniotic fluid embolism that occurred during cesarean using general anesthesia in which the patient’s oxygen saturation decreased from 100% to 70% within 30 seconds. The hypoxia was followed within seconds by an initial increase in blood pressure, with subsequent decrease to hypotensive levels, suggestive of left atrial and ventricular failure.¹⁷ They concluded that an initial pulmonary vasospasm caused the hypoxia and subsequent cardiovascular collapse, and treating the hypoxia and hemodynamic factors was important for the patient to survive.¹⁷ Disseminated intravascular coagulation was a common finding in most of the women with amniotic fluid embolism (Table 2). The exact mechanism by which DIC develops in cases of amniotic fluid embolism is not known. It is unlikely that DIC is a component of an allergic or anaphylactic reaction because normally it does not occur with either. Tissue factor, a primary biologic initiator of coagulation, is found in increasing amounts in amniotic fluid as gestation advances.¹⁸ Lockwood et al¹⁸ postulated that the large quantities of active tissue factor in amniotic fluid could explain the changes in coagulation accompanying amniotic fluid embolism.

	Footnotes

 
PII S0029-7844(99)00004-6

Received July 21, 1998. Received in revised form November 18, 1998. Accepted November 25, 1998.

	References

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12. Gilbert WM, Nesbitt TS, Danielsen B. Childbearing beyond age 40: Pregnancy outcome in 24,032 cases. Obstet Gynecol 1999;93:9–14.[Abstract/Free Full Text]

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