The majority of women (55, 92%) had ruptured membranes at or before the time of presentation with amniotic-fluid embolism. In those women who had amniotic-fluid embolism before delivery, the amniotic-fluid embolism presented a median of 45 minutes after membrane rupture (range 0 minutes to 6 days after); in four women the amniotic-fluid embolism presented at the time of membrane rupture, and a further three women presented within 10 minutes of membrane rupture. An obstetrician was present at the time of presentation in 28 cases (47%) and an anesthetist in 27 (45%); neither was present in 26 cases (43%) (Table 1).
Twenty-eight women (85%) who presented with amniotic-fluid embolism at or before delivery were delivered by cesarean. A range of management strategies were used after amniotic-fluid embolism in addition to supportive therapies (Table 4). Supportive therapies alone, defined as fluids and blood products only, were used in 35 women (58%); 15 women (25%) had hysterectomy to control hemorrhage, and 15 women (25%), including one who also had a hysterectomy, were treated with factor VIIa. In total, five women (8%) had a combination of different treatment strategies in addition to supportive therapies. Women were transfused a median of 6.5 units of blood (range 0–62 units).
Twelve women died (case fatality rate 20%, 95% CI 11–32%) (Table 1). All the women died within 1 day of the amniotic-fluid embolism at a median of 1 hour, 40 minutes after the acute event (range 0 minutes to 23 hours, 18 minutes). Women who died were significantly more likely to be from an ethnic-minority group than were those who survived (OR 4.64, 95% CI 1.11–19.5); this association persisted after adjustment for differences in age, socioeconomic status, body mass index, and parity (adjusted OR 11.8, 95% CI 1.40–99.5). There were no other significant differences between fatal and nonfatal cases, although this analysis has limited power to detect differences. Eight women who survived had other severe morbidities: four had cerebral neurologic injury, two suffered a thrombotic event, one had septicemia, and one had renal failure. Forty-five of the 48 women who survived (94%) were admitted to intensive care. Only 3 of the 12 women who died (25%) were admitted to intensive care; the remainder died before admission. The median length of stay in intensive care was 3 days (range 1–39 days).
There was one stillbirth and four neonatal deaths (all due to asphyxia before birth) among the 37 neonates for whom outcomes are known and who were born to mothers who had amniotic-fluid embolism at or before delivery, giving a perinatal mortality rate of 135 per 1,000 total births (95% CI 45–288). Neither mother nor neonate survived in three cases. None of the neonates born to mothers who had amniotic-fluid embolism after delivery died.
The incidence of amniotic-fluid embolism as estimated by this 4-year prospective national study is 2.0 per 100,000 maternities (95% CI 1.5–2.5), which is significantly lower than the rate documented in retrospective reviews of population-based hospital discharge databases in Canada (6.1 cases per 100,000 deliveries, 95% CI 5.3–7.14) and the United States (7.7 cases per 100,000 births, 95% CI 6.7–8.73). As we demonstrated, amniotic-fluid embolism is difficult to diagnose; of 86 nonduplicate cases reported, further examination of the records revealed a more likely diagnosis in 26 (30%). Hospital discharge databases do not allow for examination of sufficiently detailed clinical information to either confirm or refute the diagnosis of amniotic-fluid embolism and, therefore, are likely to be subject to a degree of overreporting. Neither of the previous studies undertook validation of the diagnosis by examining medical charts. The authors of the Canadian report cite their observed associations of amniotic-fluid embolism with complications including eclampsia, placenta previa, and abruption as evidence of overreporting; similar associations were observed in the U.S. study.
Although a possibility, we believe that our lower incidence estimate is unlikely to be due to underreporting of cases because the UK Obstetric Surveillance System is an active, prospective surveillance system in which we require negative reports, ie, participating hospitals return a report card every month, regardless of whether there are cases to report. We thus can be confident that reports of “no cases” from an individual hospital are true negative reports. Furthermore, all of the fatal cases reported to the Centre for Maternal and Child Enquiries in the study period had been reported to the UK Obstetric Surveillance System. If the true incidence in the U.K. population were the same as that estimated in Canada (6.1 per 100,000), there would have been 186 cases in total, implying that we had missed 126 nonfatal cases and that the case fatality rate was only 6% (12 of 186); levels of both missing cases and fatalities that seem highly improbable.
A third explanation for the threefold difference in incidence estimates is that this reflects a true difference in incidence in the United Kingdom compared with North America. Given that the population-proportional attributable risk associated with cesarean delivery is 62% and that the cesarean-delivery rate in the United States is 50% higher than in the United Kingdom, one might indeed anticipate a higher rate of amniotic-fluid embolism in the United States than in the United Kingdom.
Induction of labor was associated with a population-attributable risk of 35% in our study, suggesting that, assuming causality, if induction of labor were no longer performed, 35% of cases of amniotic-fluid embolism could be prevented. The practice of inducing labor, with its many potential benefits, clearly will continue, and amniotic-fluid embolism remains a very rare complication; nevertheless, clinicians should be aware of both the risks and benefits of induction because more restricted use may result in a decrease in the number of women suffering a potentially fatal amniotic-fluid embolism.
Both Canadian and U.S. studies show an increased rate of cesarean delivery among women with amniotic-fluid embolism, which the authors of the U.S. study interpret as causal. However, as the investigators discuss, one of the limitations of administrative databases is that they do not indicate whether the amniotic-fluid embolism occurred before, during, or after delivery. Our prospectively collected data include timing of all the events, and we found that 56% of women had amniotic-fluid embolism at or before delivery, with 44% after delivery. More than 80% of women who had amniotic-fluid embolism at or before delivery subsequently were delivered by cesarean; clearly, in these cases, the cesarean delivery was a consequence and not a cause of amniotic-fluid embolism. However, we also found more than an eightfold increase in the odds of amniotic-fluid embolism associated with cesarean delivery in the group who had amniotic-fluid embolism after delivery, suggesting that there indeed may be a causal relationship. The clinical message from this study thus echoes other studies in noting that cesarean delivery is not risk-free7 and that all risks and benefits should be assessed before a decision for cesarean delivery is made.
Older maternal age was also an important factor in all the studies, although, in our population, having adjusted for confounders, the increase in risk with age was limited to ethnic-minority women. The small number of older ethnic-minority women with amniotic-fluid embolism means that we do not have sufficient power to investigate this association further, but continued surveillance through the UK Obstetric Surveillance System may allow us to address this in the future. In the meantime, clinicians should be aware of the increased risk when caring for older pregnant women who are ethnic-minorities.
All the women in our study experienced at least one of the cardinal features of shortness of breath, hypotension, hemorrhage, coagulopathy, and premonitory symptoms at the time of amniotic-fluid embolism, and all cases were consistent with the reporting criteria used in a U.S. amniotic-fluid embolism registry.13 Premonitory symptoms such as numbness, tingling, and agitation were the most common initial presenting feature, although acute fetal compromise was the first feature noted in 36% of antenatal cases. Fetal compromise was noted first as a fetal heart rate abnormality in the majority of cases; clinicians should consider amniotic-fluid embolism as part of the differential diagnosis of a sudden, unexplained deterioration in the fetal heart rate even in the absence of maternal symptoms or signs.
The mainstay of the management of amniotic-fluid embolism remains supportive therapy, and this study shows that high-quality supportive care can result in a good maternal outcome in the majority of cases. The results also highlight the use of a number of therapies for amniotic-fluid embolism previously described only in case reports. Coagulopathy is a common feature of amniotic-fluid embolism (occurring in more than 60% of our cases), and, therefore, use of recombinant factor VIIa, a procoagulant leading to increased thrombin formation, has been proposed, with individual reports of its success.14–16 In our study, 14 women were treated with factor VIIa for coagulopathy; 13 survived.
Seven women were treated with exchange transfusion or plasma exchange, a therapy first described more than 20 years ago.17 Authors have suggested variously that clinical improvement is related to the removal of red cell debris and hemoglobin from the circulation17 or that the process removes amniotic fluid and cytokines from the circulation and corrects metabolic acidosis.18 Thus, these therapies should be regarded as an extension of supportive care and not as a substitute. All seven women treated with these therapies survived, although the small numbers involved means that we should not assume that this form of therapy is more effective than any other; survival to the point where these techniques are possible may put the women in a more favorable prognosis group.
One fifth of women with amniotic-fluid embolism and 1 in 10 of their newborns died. Maternal fatality was comparable with that in the Canadian and U.S. studies (13% [95% CI 9–19%] and 22% [95% CI 16–28%], respectively). This confirms the view that maternal fatality in large, unselected populations is lower than previously suggested. We found that women who died were significantly more likely to come from ethnic-minority groups than were survivors, an association that could not be explained by differences in age, socioeconomic status, body mass index, or parity. In previous UK Obstetric Surveillance System studies,11 we found that the incidence of severe maternal morbidity is higher among ethnic-minority women, and we postulate that this may be due to differences in underlying medical conditions or access to care. It is possible that these factors also may play a role in the increased risk of fatality from amniotic-fluid embolism for these women.
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© 2010 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.
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