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Amniotic fluid embolism: Analysis of the national registry

Steven L. Clark, MD, Gary D.V. Hankins, MD, Donald A. Dudley, MD, Gary A. Dildy, MD,
and T. Flint Porter, MD
Salt Lake City, Utah, and San Antonio, Texas

OBJECTIVE: We analyzed the clinical course and investigated possible pathophysiologic mechanisms of
amniotic fluid embolism.
STUDY DESIGN: We carried out a retrospective review of medical records. Forty-six charts were
analyzed for 121 separate clinical variables.
RESULTS: Amniotic fluid embolism occurred during labor in 70% of the women, after vaginal delivery in
1 1%, and during cesarean section after delivery of the infant in 19%. No correlation was seen with
prolonged labor or oxytocin use. A significant relation was seen between amniotic fluid embolism and
male fetal sex. Forty-one percent of patients gave a history of allergy or atopy. Maternal mortality was
61%, with neurologically intact survival seen in 15% of women. Of fetuses in utero at the time of the
event, only 39% survived. Clinical and hemodynamic manifestations were similar to those manifest in
anaphylaxis and septic shock.
CONCLUSIONS: Intact maternal or fetal survival with amniotic fluid embolism is rare. The striking
similarities between clinical and hemodynamic findings in amniotic fluid embolism and both anaphylaxis
and septic shock suggest a common pathophysiologic mechanism for all these conditions. Thus the term
amniotic fluid embolism appears to be a misnomer. (AM J OBSTET GYNECOL 1995;172:1158-69.)

Key words: Amniotic fluid embolism, fetal asphyxia, maternal mortality

Amniotic fluid embolism is an often-devastating ob- medical records of patients who had clinical amniotic
stetric syndrome, occurring in 1 in 8000 to 1 in 80,000 fluid embolism. Criteria for acceptance into the registry
pregnancies.‘, ’ This condition is responsible for are outlined in Table I. Data describing 12 1 clinical
roughly 10% of all maternal deaths in the United States variables were extracted from these charts for descrip-
and is the most common cause of peripartum death.“, 3 tive analysis (a complete list of variables and data is
Because amniotic fluid embolism is uncommon, no available on request).
single practitioner or institution is likely to have suffi- Statistical analysis was accomplished with x2, Mann-
cient experience to determine risk factors, clinical Whitney U, and unpaired t tests. None of these patients
course, pathophysiologic factors, or treatment. To assist has been previously described in the medical literature.
in the understanding of this syndrome, a national reg-
istry for amniotic fluid embolism was established in Results
1988.4 This report is an analysis of that registry. The Sixty-nine charts were submitted to the registry.
purpose of this study was to analyze the clinical course Forty-six met the criteria outlined in Table I. One
and investigate possible pathophysiologic mechanisms additional case of amniotic fluid embolism, which oc-
of this condition. curred before 1983, was excluded to restrict the analysis
to current and uniform methods of diagnosis and treat-
Material and methods ment. Ten patients appeared to have conditions other
In 1988 a registry for amniotic fluid embolism cases than amniotic fluid embolism or had additional clinical
was established under the direction of the principal factors that obscured the diagnosis (see Table II).
investigator.4 Individuals were invited to submit the Twelve patients were believed to have an amniotic fluid
embolism-like syndrome but did not satisfy the strict
criteria outlined in Table I.
From the Department of Obstetrics and Gynecology, University of
Utah School of Medicine; Intermountain Health Care Perinatal Demographic characteristics. Select demographic
Centers at LDS Hospital; and Wilford Hall United States Air Force data are detailed in Tables III and IV.
Medical Center at Lackland Air Force Base. Amniotic fluid embolism timing. The following sta-
Presented by invitation at the Thirteenth Annual Meeting of the
American Gynecological and Obstetrical Society, Hot Springs, Vir- tistics exclude the three patients with second-trimester
ginia, September 8-10, 1994. pregnancy terminations. Thirty women (70%) experi-
Reprint requests: Steven L. Clark, MD, Division of Maternal-Fetal .enced amniotic fluid embolism during labor but before
Medicine, LDS Hospital, 8th Ave. and C St., Salt Lake City, UT
84143. delivery. Three women experienced amniotic fluid em-
616/62&S& bolism during cesarean section for standard obstetric

Volume 172, Number 4, Part 1 Clark et al. 1159
Am J Obstet Gym01

Table I. Amniotic fluid embolism registry entry criteria

1. Acute hypotension or cardiac arrest

2. Acute hypoxia, defined as dyspnea, cyanosis, or respiratory arrest
3. Coagulopathy, defined as laboratory evidence of intravascular consumption or fibrinolysis or severe clinical hemorrhage
in the absence of other explanations*
4. Onset of the above during labor, cesarean section, or dilation and evacuation or within 30 minutes post partum
5. Absence of any other significant confounding condition or potential explanation for the signs and symptoms observed
6. Occurrence within 5 years of registry opening

*Patient meeting all other criteria including abrupt cardrorespiratory arrest who died before coagulopathy could be assessed were
included in the primary analysis.

Table IL Alternative diagnoses in cases Table III. Demographic data for patients with
submitted as amniotic fluid embolism amniotic fluid embolism
No. of Factor Mean + SD
Condition patients
Maternal age (yr) 27 -c 9
Uterine rupture or laceration 3 Gravidity 3?2
Anesthetic accident 2 Parity* 2t2
Sepsis 2 Maternal weight (kg) 73 i- 11
Medication error 1 Maternal weight gain (kg) 13 F 6
Uterine atony 1 Gestational aget (wk) 39 ? 2
Eclampsia 1 Birth weight? (pm) 3519 2 732

*Before index pregnancy, 39% of patients were nulliparous.

tFor 43 patients reaching the third trimester. Three cases
indications after labor; signs and symptoms of amniotic occurred during uterine evacuation between 17 and 20 weeks.
fluid embolism (including acute fetal decompensation)
were not evident before the delivery of the infant. Five
patients manifested amniotic fluid embolism during Table IV. Additional demographic data for
cesarean section after delivery of the infant without patients with amniotic fluid embolism
previous labor. In total, 8 patients (19%) first demon-
No. of
strated evidence of amniotic fluid embolism during
Factor patients
cesarean section after delivery of the infant. Five pa-
tients delivering vaginally first manifested evidence of Race
White 29 (63%)
amniotic fluid embolism in the immediate postpartum Hispanic 8 (17%)
period. In total, 13 patients (30%) experienced amni- Black 7 (15%)
otic fluid embolism after delivery. The mean time from Asian 2 (4%)
Prior elective termination of pregnancy 9 (20%)
delivery to initial signs or symptoms was 8 ? 8 minutes; Prior spontaneous abortion 8 (17%)
9 patients (69%) demonstrating amniotic fluid embo- History of drug allergy or atopy 19 (41%)
lism after delivery did so within 5 minutes of delivery of Male fetus* 25 (67%)t
Twin gestation 1 (2%)
the infant.
Labor characteristics. Thirty-eight patients with am- *Gender available in 37 patients.
niotic fluid embolism who labored had a mean first- tp = 0.05.
stage length of 8.1 2 5 hours. Twenty women experi-
enced amniotic fluid embolism during the first stage of
labor; these patients had a mean first-stage length of Fifteen of 30 patients (50%) who had intrapartum
6.8 + 3.7 hours befrore the amniotic fluid embolism. amniotic fluid embolism were receiving oxytocin at the
Cervical dilatation at the time of symptom onset ranged time of the event. These patients had been receiving
from 0 to 9 cm. Amniotic fluid embolism occurred in 8 oxytocin for a mean of 7.0 + 4.3 hours (range 1.4 to
patients at a cervical dilatation of I 4 cm and in 12 19.2 hours). The mean dose at the time of the event was
patients at 5 to 9 cm. Twelve patients had reached the 12 k 6 mU/min. Examination of the uterine contrac-
stage of fetal engagement, and 8 had fetuses whose tion pattern in these patients revealed the presence of
heads were unengaged at the time of the event. hyperstimulation at any time during labor in only two
Ten patients experienced amniotic fluid embolism instances. There was evidence of a hyperstimulated
during the second stage of labor; these patients had a contraction pattern at the time of the acute event in
mean first-stage duration of 9.2 +- 4.9 hours and a only one patient. However, abrupt uterine tetany devel-
mean second-stage duration before the event of oped in 7 patients either simultaneously with the onset
22 k 26 minutes. of maternal cardiovascular collapse or immediately
1160 Clark et al. April 1995
Am J Obstet Gynecol

Fig. 1. Fetal heart rate tracing in a patient with amniotic fluid embolism. Maternal symptoms began
just before onset of spontaneous uterine hypertonus and fetal bradycardia.

thereafter (see Fig. 1). Each of these patients either was maternal collapse was observed within 3 minutes of
not receiving oxytocin or was receiving a steady-state membrane rupture or intrauterine manipulation. In all
dosage with infrequent contractions before the mother’s cases the antecedent procedure appeared to be indi-
collapse. In one case a mother was awaiting a repeat cated, and there was no evidence of inappropriate
cesarean section in apparent prodromal labor with technique.
irregular contractions, and sudden tetany developed de Clinical features of amniotic fluid embolism syn-
novo in association with fetal bradycardia and cardio- drome. The frequency of various signs and symptoms is
respiratory arrest. outlined in Table V. The most common presenting
Membrane, placenta, and amniotic fluid status. features among women collapsing before delivery were
Thirty-eight of 43 patients (78%) experienced amniotic a seizure or seizure-like activity (9 patients, 30%), dys-
fluid embolism at some point after spontaneous pnea (8 patients, 27%), fetal bradycardia (5 patients,
(n = 12) or artificial (n = 26) rupture of membranes. 17%), hypotension (4 patients, 13%), and cyanosis in 1
Only 5 patients (12%) had the syndrome onset with patient. Difficult ventilation was noted in 5 patients,
intact membranes. and wheezes were auscultated in another, suggesting a
In 6 patients with amniotic fluid embolism and living component of bronchospasm in these patients. All
fetuses, meconium staining was noted before the event. mothers undelivered at the time of the amniotic fluid
Two additional patients were known to have dead embolism onset experienced fetal bradycardia or -the
fetuses. In 5 women the fluid was clear but meconium abrupt onset of severe variable decelerations leading
staining was noted at delivery after maternal cardiovas- within minutes to bradycardia.
cular collapse and fetal bradycardia. Amniotic fluid was Of the 46 patients, 8 died before the clotting status
clear in the other 29 women (69%). In one patient the could be assessed by either clinical or laboratory tech-
nature of the amniotic fluid was not recorded. Among niques. Four of the remaining 38 patients had a clinical
women who had amniotic fluid embolism in association coagulopathy but died before laboratory assessment
with meconium-stained fluid and a live fetus or with a could be made. Thirty-four patients had laboratory
dead fetus (8 patients), none survived neurologically evidence of a coagulopathy with or without clinical
intact, compared with 6 of 37 (16%) who had amniotic signs. The extent of laboratory evaluation varied
fluid embolism with clear amniotic fluid. No significant greatly, principally depending on the length of patient
difference was noted in interval from onset to cardiac survival and degree of clinical hemorrhage. Among the
arrest, maternal death rate, or neonatal outcome 34 patients with laboratory assessment of coagulopathy,
among women with clear as opposed to meconium- fibrinogen levels ranged from < 10 to 295 mg/dl. Only
stained fluid. 2 patients had fibrinogen levels exceeding 200 mgidl;
Hydramnios was present in only 2 of 43 patients both had additional laboratory evidence of intravascu-
(5%). The placenta was anterior in 8 patients, posterior lar consumption but neither died.
in 8 patients, and unknown in the remaining cases. Seventeen patients had fibrinogen levels below 100
There was a striking temporal association between mgidl, and 8 of these patients had undetectable levels
maternal cardiovascular collapse and artificial rupture or levels below the lowest reporting value of the labo-
of the membranes and/or placement of an intrauterine ratory. Twenty-one patients had assessment of fibrin
pressure catheter in 6 patients (14%). In each, acute degradation products or o-dimer; all results were ab-
Volume 172, Number 4, Part 1 Clark et al. 1161
Am J Obstet Gynecol

Table V. Signs and symptoms noted in Table VI. Initial dysrhythmia in patients with
patients with amniotic fluid embolism amniotic fluid embolism
No. of No. of
Sign or symptom patients 9% Dysrhythmia patients %

Hypotension 43 100 Electromechanical dis- 11 24

Fetal distress* 30 100 sociation
Pulmonary edema or 28 93 Bradycardia 10 22
adult respiratory dis- Ventricular tachycardia 8 17
tress syndrome? or fibrillation
Cardiopulmonary 40 87 Asystole 6 13
arrest Undescribed 3 7
Cyanosis 38 83 None s 17
CoagulopathyJ 38 83 TOTAL 46 100
Dyspneas 22 49
Seizure 22 48
Atony 11 23
Bronchospasmli 15
Transient hypertension r
11 tension as the initial hemodynamic manifestation of am-
Cough ; 7 niotic fluid embolism.
Headache 3 7
Twenty-eight patients had arterial blood gas assess-
Chest pain 2
ment within 1 hour of the acute event. All were receiv-
*n = 30. Includes all live fetuses in utero at time of event. ing an FIO, of 100%. Partial oxygen pressures reflecting
tn = 30. Eighteen patients did not survive long enough for profound shunting were generally seen. Seventeen pa-
these diagnoses to be confirmed.
tients were studied within 30 minutes of the acute
in = 38. Eight patients did not survive long enough for this
diagnosis to be confirmed. event; for these patients the mean f SD PO, was
On = 45. One patient was intubated at the time of the event 105 -C 140 mm Hg. In 11 patients the PO, was <30
and could not be assessed. mm Hg; 3 patients had a PO, of 12 mm Hg. In 5
l/Difficult ventilation was noted during cardiac arrest in 6 patients dramatic correction of initial profound hypoxia
patients, and wheezes were auscultated in 1 patient.
to normal levels was observed within a short period of
time (see Table VII). Only 4 women had an initial PO,
in excess of 500 mm Hg while receiving a 100% FIO,; in
normal. In 29 patients activated partial thromboplastin these cases the time intervals from event to blood gas
time was assessed; 2 had normal activated partial measurement were 12, 50, 55, and 68 minutes.
thromboplastin time values, and the remainder were Maternal outcome. Twenty-eight women died, for an
abnormal, with 11 values of infinity. Prothrombin time overall maternal mortality of 61%. Death occurred from
was measured in 30 patients, and the values were 30 minutes to 2 months after the initial event. However,
abnormal in 28. Platelets were measured in 34 patients only 7 patients (15%) survived neurologically intact.
and were below 100,000/m1 in 19. In 1 patient the Because long-term follow-up is not available for most
platelet count was reported as “low.” Platelet counts surviving patients, it is possible that some with perma-
were below 50,00O/ml in only 6 patients. nent neurologic injury have died or eventually will die
Forty patients (87%) experienced cardiac arrest, and second to the amniotic fluid embolism. Although most
an additional four manifested a serious dysrhythmia patients died of refractory cardiopulmonary arrest, in
without frank arrest. The nature of the initial dysrhyth- six instances hemodynamic and ventilatory support was
mia is detailed in Table VI. The time interval between withdrawn after the diagnosis of brain death. Of the 28
onset of symptoms and cardiac arrest varied from patients who died, 11 (36%) did so within 2 hours of the
< 1 minute to 18 hours. In 15 of the 40 arrest occurred event and 18 (63%) within 5 hours. In these cases the
within 5 minutes from symptom onset. Only 2 patients interval between cardiac arrest and death was depen-
initially had cardiac arrest > 1 hour from symptom dent on the duration of the resuscitative efforts. It was
onset, at 1% hours and 18 hours, both after prolonged generally prolonged in such young women and prob-
periods of hemodynamic instability. ably does not reflect the true natural history of the
Nine patients underwent central hemodynamic moni- condition.
toring. However, in no case was monitoring instituted Twelve patients with cardiac arrest were successfully
within 2 hours of the amniotic fluid embolism. In gen- resuscitated and survived. However, only 3 of 40 (8%)
eral, cardiac outputs were low (mean + SD 5.3 * with cardiac arrest survived neurologically intact. Four
3 Wmin). However, because all these patients were re- of 6 patients not having cardiac arrest in conjunction
ceiving pharmacologic agents with profound hemody- with the initial event survived; two had residual neuro-
namic effects, no additional conclusions can be drawn. logic damage and two (33%) survived neurologically
Five patients experienced a transient episode of hyper- intact.
1162 Clark et al. April 1995
Am J Obstet Gynecol

Table VII. Resolution of hypoxia after amniotic fluid embolism

Initial Time from amniotic Next PO, Time from amniotic
Pataent No. (mm Hg) fluid embolism (min) (mm 49 &id embolirm (min)

2 34 11 242 62
4 19 20 587 40
12 98 21 388 45
22 24 60 128 75
25 12 37 484 96

Table VIII. Cardiac arrest-to-delivery interval (38%) patients with clear fluid before the amniotic fluid
and neonatal outcome embolism. This difference did not reach statistical sig-
nificance. Histologic debris of presumed fetal origin
Intewal Survival Intact survival
(min) (No.) (No.) included squamous cells, hair, fat droplets, tropho-
blasts, “nonspecific cellular debris,” and nonspecific
<5 313 213 (67%)
5-15 313 213 (67%)
proteinaceous, keratinaceous, or mutinous material. In
16-25 215 215 (40%) only 1 patient, a woman with meconium-stained amni-
26-35 314 114 (25%) otic fluid, were the histologic findings described as
36-54 Oil Oil (0%)
“vessels occluded with squames.”

Neonatal outcome. Twenty-eight patients had amni- Comment

otic fluid embolism while the fetus was alive in utero. In 1941 Steiner and Luschbaugh,’ pathologists at the
Twenty-two fetuses survived (79%); however, only 11 of University of Chicago, reported detailed histologic and
these fetuses (50%) were neurologically normal. Overall cursory clinical findings in 42 women who died during
neurologically intact survival was 39%. The interval from the third trimester of pregnancy. Nine of these women
initial symptoms or signs to delivery was available for 26 exhibited unique histopathologic findings in the pul-
of 28 fetuses. The mean t SD time from initial clinical monary vasculature consisting of mucin, amorphous
manifestation to delivery was 27 ? 12 minutes. Twenty- eosinophilic material, and in some cases squamous
five patients had cardiac arrest while the fetus was alive in cells. Squamous cells were described in a semiquantita-
utero. Seventeen fetuses survived (68%), but only 9 fe- tive manner, and ranged from absent to ” + + + .”
tuses (32%) had normal neurologic outcome. In 16 pa- These authors’ discussion focused on 8 of 9 women in
tients with cardiac arrest while the fetus was in utero, whom these described histologic findings were most
precise arrest-to-delivery time was available. The prominent and who formed what became the “classic”
mean + SD arrest-to-delivery time was 16 + 15 min- amniotic fluid embolism group.
utes. Table VIII demonstrates survival and neurologi- It is notable that 7 of the 8 patients carried clinical
tally intact survival statistics according to arrest-to- diagnoses other than amniotic fluid embolism that were
delivery interval. not materially different from the diagnoses of the 34
Arterial cord blood analysis was available for 11 neo- “control” patients. The most common clinical diagnosis
nates in utero at the time of the maternal amniotic fluid in the amniotic fluid embolism group was postpartum
embolism. The mean i. SD pH was 6.79 + 0.2. All pH hemorrhage. One patient in the amniotic fluid embo-
values were % 7.0, with one value of 6.4 recorded. Um- lism group had a clinical course complicated by sepsis,
bilical arterial cord blood Pco, was available in 6 of these and another was found at autopsy to have an unrecog-
patients; all had pure respiratory acidosis with Pco, val- nized uterine rupture. Only 1 of the original 8 patients
ues ranging from 92 to 221 mm Hg (mean f SD died of “obstetric shock” without an additional clinical
137 + 45). Nine of the neonates in whom arterial blood diagnosis. These clinically heterogeneous patients were
gas values were measured survived without evidence of grouped together on the basis of similar histopatho-
neurologic impairment, despite profound respiratory logic findings and formed the basis for the syndrome of
acidosis, with pH values ranging from 6.4 to 7.0. amniotic fluid embolism. Seven of the 8 patients were
Histologic findings. Autopsy was performed in 22 of multiparous, and some had abdominal pain that ac-
46 patients. Presumed fetal elements were identified in companied the initial respiratory symptoms.
the pulmonary vasculature in 16 of 22 patients (73%). From the sketchy and heterogeneous clinical descrip-
Fetal elements were sought by histologic examination tions of these 8 patients, a description emerged of a
of distal port pulmonary artery catheter blood in 8 cases syndrome occurring in older, multiparous patients after
and were detected in 4 of 8 (50%). Positive findings “tumultuous” or “hyperstimulated” labor and charac-
were encountered in 3 of 6 patients (50%) with meco- terized by the detection of (presumably fetal) squamous
nium staining before the event compared with 13 of 34 cells in the maternal pulmonary arteries. These have
Volume 172, Number 4, Part 1 Clark et al. 1163
Am J Obstet Gynecol

persisted for >50 years, supported only by anecdotal tetanic contraction at the time of onset of other symp-
reports with little objective data, toms of amniotic fluid embolism. Synthetic oxytocin was
In the ensuing decades several investigators at- not available for clinical use in 1941, yet a presumptive
tempted to develop animal models of amniotic fluid causative relation between oxytocin and amniotic fluid
embolism, usually by injecting large volumes of fecal embolism has developed and persisted in the ensuing
material from foreign species into the central circula- years. The concept that oxytocin causes amniotic fluid
tion of various animals3 Hemodynamic data based on embolism was retited on statistical grounds by Morgan*
these models were extrapolated to apply to the syn- in 1971, who found, in a review of 272 reported cases,
drome described by Steiner and Luschbaugh. Subse- tumultuous labor or tetanic uterine contractions in only
quent hemodynamic assessment of women with amni- 28% and oxytocin use in only 22% of cases. In our series
otic fluid embolism, however, suggested a hemody- we observed no relation between oxytocin or anteced-
namic picture markedly different from that seen in ent hyperstimulation and amniotic fluid embolism. Fifty
animal models.4. 5 Only recently have carefully per- percent of the patients in the current series received
formed studies involving the administration of homolo- oxytocin at some time during labor. Although national
gous meconium preparations yielded hemodynamic statistics regarding the frequency of oxytocin use are
data that resemble those seen in humans.’ not available, during 1993, 5 1% of patients delivering at
In this analysis we attempted to describe the clinical LDS Hospital (a tertiary-level center with an annual
spectrum of an obstetric syndrome of acute peripartum delivery base of 3500 women and a cesarean section
cardiovascular collapse and coagulopathy without pre- rate of 18%) received oxytocin during labor. Thus the
conceived notions regarding cause or additional diag- prevalence of oxytocin use in patients experiencing
nostic criteria. It was hoped that this approach would amniotic fluid embolism does not appear to be greater
shed new light on this enigmatic condition. As with any than that observed in the general obstetric population.
data derived from a registry, the principal weakness is the It is important, however, that the current series sheds
possibility that the data submitted may not be represen- light on the association between amniotic fluid embo-
tative of the population as a whole; precise numeric con- lism and hypertonic contractions.
clusions must therefore be made with caution. Uterine hypoxia appears to induce myometrial hy-
An analysis of the data presented reveals no demo- pertonus.’ During the early stages of shock of any
graphic maternal risk factors predisposing to amniotic cause, the normal human hemodynamic response in-
fluid embolism. Age, race, parity, obstetric history, cludes a dramatic outpouring of catecholamines and
weight gain, and blood pressure were no different from shunting of blood from the splanchnic (including uter-
those expected in the general obstetric population. ine) vasculature to maintain perfusion of vital organs.
Whereas it has been speculated that maternal-fetal red In addition, norepinephrine exerts a direct effect on
blood cell antigen incompatibility might contribute to uterine activity resulting in tetanic contractions, an
the clinical manifestations of this syndrome, this could effect commonly seen during eclamptic seizures.’ The
be excluded in 3 of 4 patients in whom the data on fetal patient in Fig. 1 is enlightening in this regard. An
blood type were available. analysis of this series suggests that the hypertonus that
Steiner and Luschbaugh found that all 8 “amniotic frequently accompanies the symptoms of amniotic fluid
fluid embolism” patients delivered vaginally. In con- embolism is a result of the initial maternal hemody-
trast, we found that 19% of patients first manifested the namic response to a profound cardiovascular insult
syndrome during cesarean section. These differences and, as in eclampsia, is a result rather than a cause of
most likely reflect the prevailing cesarean section rates that insult.
today, as compared with 50 years ago. Given the na- Steiner and Luschbaugh postulated that the uterine
tional cesarean section rate during the lo-year period tetany observed in some of their patients may force
of case collection, we conclude that route of delivery amniotic fluid into the maternal circulation. This theory
does not appear to affect risk of amniotic fluid em- was supported by the fact that none of their 8 patients
bolism. underwent cesarean section, which in their words pre-
Our patients exhibiting amniotic fluid embolism dur- vented “powerful uterine contractions on enclosed am-
ing the first stage of labor had a mean first stage of 6.8 niotic fluid.” Subsequent investigations into human pla-
hours; those with amniotic fluid embolism after com- cental and uterine physiologic characteristics clearly
plete cervical dilatation had a mean first stage of 9.2 demonstrated the absence of direct vascular communi-
hours and a mean second stage of 22 minutes. These cation between mother and fetus. Further, when intra-
observations suggest that previous descriptions of am- uterine pressure is increased to values above the mean
niotic fluid embolism commonly occurring after long, pressure of maternal venous blood flow, maternal-fetal
hard labors are not valid. exchange ceases.’ This is believed to occur at pressures
Several of the patients initially described by Steiner exceeding 25 to 35 mm Hg.’ Thus, far from acting as a
and Luschbaugh experienced abdominal pain or a “pump” for amniotic fluid from mother to fetus, uterine
1164 Clark et al. April 1995
Am J Obstet Cynecol

contractions are a highly effective barrier to uterine A detailed discussion of the pathophysiologic features
venous blood flow and exchange; a tetanic contraction of anaphylactic and septic shock is beyond the scope of
is the least likely time for transfer of any substance this manuscript. However, both septic and anaphylactic
between mother and fetus. The initial speculations of shock involve the entrance into the circulation of a
Steiner and Luschbaugh more than half a century ago foreign substance (bacterial endotoxin or specific anti-
are understandable. However, the concept that tetanic gens), which then, directly or indirectly, results in the
contractions act as a pump for amniotic fluid is one that release of various primary and secondary endogenous
should have been abandoned in light of subsequent mediators.“-” It is the release of these mediators that
developments in the understanding of uterine blood results in the principal physiologic derangements char-
flow and placental transfer. Our observations appear to acterizing these syndromes, including profound myo-
refute the concept of a causative relation between oxy- cardial depression and decreased cardiac output, de-
tocin and amniotic fluid embolism on a clinical basis, scribed in experimental animals and man; pulmonary
supporting the statement of The American College of hypertension, demonstrated in lower primate models of
Obstetricians and Gynecologists that “. . such a rela- anaphylaxis; and disseminated intravascular coagula-
tionship has been refuted on both statistical and theo- tion, also described in human anaphylactic reactions
retical grounds.“Y and septic shock.‘O-‘X These same clinical and hemody-
Five of 40 patients (13%) exhibited a striking tempo- namic derangements are virtually identical to those
ral relationship between artificial rupture of the mem- seen in amniotic fluid embolism.
branes or placement of an intrauterine pressure cath- The list of involved mediators is extensive and in-
eter and acute cardiovascular collapse. This observa- cludes histamine, bradykinin, cytokines, prostaglandins,
tion, in conjunction with the description of amniotic leukotrienes, thromboxane, and many others.‘“W”. ”
fluid embolism occurring in several patients during The temporal sequence of hemodynamic decompensa-
cesarean section, suggests that amniotic fluid embolism tion and recovery seen in experimental amniotic fluid
is not related to the entrance of amniotic fluid into the embolism is also virtually identical to that described in
maternal system under pressure. Rather, simple expo- canine anaphylaxis.” An anaphylactoid response is also
sure of the maternal circulatory system to even small well described in man and involves the nonimmuno-
amounts of amniotic fluid contents may, under the right logic release of the same mediators.‘” The ability of
circumstances, initiate the amniotic fluid embolism syn- arachidonic acid metabolites to cause the same physi-
drome. This scenario explains the well-documented ologic and hemodynamic changes observed in human
occurrence of fatal amniotic fluid embolism during amniotic fluid embolism has been previously noted.‘O
first-trimester pregnancy termination, at a time when Further, in the rabbit model of amniotic fluid embolism,
neither the volume of fluid nor positive intrauterine pretreatment with an inhibitor of leukotriene synthesis
pressures could be contributing factors.’ has been shown to prevent death.” Individual host
In 6 cases symptoms of abruptio placentae were reaction to foreign antigen exposure also plays a major
coincident with cardiovascular collapse, and partial role in determining the severity of clinical symptoms.
abruptio placentae was confirmed post partum. Al- The clinical observations presented here suggest that in
though the patient’s sudden death could not be attrib- some patients intravenous exposure to certain material
uted to abruptio placentae, the coexistence of these of fetal origin may initiate a similar pathophysiologic
events is probably not coincidental. It is likely that the cascade (see Fig. 2). It is especially intriguing that
disruption of the uteroplacental bed occurring with amniotic fluid embolism appears to be significantly
abruptio placentae provides another opportunity for more common in women carrying a male fetus. A
exposure of the maternal circulation to fetal tissue. similar preponderance of male fetuses is seen in primi-
In analyzing in detail the medical records of 46 gravid women who are Rh isoimmunized, thus support-
patients with amniotic fluid embolism over a short ing a possible immunologic role in the pathogenesis of
period of time, perhaps the most striking observation amniotic fluid embolism.22 Although the prevalence of
was the remarkable similarity of the clinical course and actual drug allergy in the obstetric population is un-
the hemodynamic and laboratory findings between known, the observation that 41% of patients with am-
women with amniotic fuid embolism syndrome and niotic fluid embolism had a known history of drug
patients with anaphylactic or septic shock (Table V). allergy or atopy further invites comparison of this
Clearly, the clinical manifestations of these conditions condition to human anaphylaxis, as does the temporal
are not identical; fever is unique to septic shock, and relation between intrauterine manipulation and deliv-
cutaneous manifestations are more common in anaphy- ery and the onset of amniotic fluid embolism.
laxis. Nevertheless, the marked similarities of these In 1993 Hankins et al.” described an initial phase of
conditions suggest similar pathophysiologic mecha- transient hypertension in a carefully prepared goat
nisms. model of amniotic fluid embolism, after the intravenous
Volume 172, Number 4, Part 1 Clark et al. 1165
Am J Obstet Gym01

Anaphylaxis Sepsis Amniotic Fluid Embolism

UgE) (Endotoxin) (various fetal elements)

Endogenous mediator release

Clinical manifestations

Fig. 2. Proposed pathophysiologic relation between amniotic fluid embolism, septic shock, ahd
anaphylactic shock. Each syndrome may also have specific direct physiologic effects (for example,
fever in endotoxin-mediate2 sepsis). ’

injection of a homologous meconium preparation. On have an undiagnosed uterine rupture, and another had
the basis of the experimental observations of these sepsis. The frequency with which cellular debris may be
investigators, we carefully examined initial blood pres- detected centrally after maternal exposure to amniotic
sure responses to amniotic fluid embolism. In many fluid must be influenced by the volume of exposure and
cases early blood pressure recordings were not available the cellular content of the fluid; thick meconium is
because of the sudden nature of the hemodynamic clearly different in this regard from clear, relatively
collapse. In 5 patients, however, early blood pressure hypocellular amniotic fluid. In the registry patients a
recordings revealed an initial, transient hypertension, trend was observed suggesting both a shorter time from
consistent with the experimental findings described. initial symptoms to cardiac arrest and an increased risk
This initial pressor response is intriguing but poorly of maternal neurologic damage or death in the pres-
understood, and the actual frequency of this response ence of meconium or a dead fetus. No such patient
in human amniotic fluid embolism remains to be deter- survived neurologically intact. These observations sug-
mined. gest that substances in meconium or the fluid associated
In this series elements of presumed fetal origin were with a dead fetus may be more likely to initiate a severe
detected in 73% of those undergoing autopsy and 50% reaction than when clear flluid is involved, a finding
of those in whom such evidence was sought during life, supported by several animal studies.3. ’ However, most
by examination of pulmonary artery catheter aspirate. patients dying of amniotic fluid embolism had clear
Although such findings were more prevalent in patients amniotic fluid. Thus the detection of cellular or aceullar
with meconium staining before the event than in debris of presumed fetal origin in the central maternal
women with clear amniotic fluid, the difference did not circulation may in some cases be a marker of fetal tissue
reach statistical significance. The true prevalence of exposure but is neither sensitive nor specific for the
such findings is unknown; in several published cases diagnosis of the syndrome.
fetal elements were detected only with the use of special This study confirms the abysmal maternal and peri-
stains not routinely used in clinical practice. Although natal outcome of women with amniotic fluid embolism
many have in the past focused on the detection of even with ideal care. Eighty-five percent of women with
squamous cells in the pulmonary circulation in patients amniotic fluid embolism died or lived with permanent
with amniotic fluid embolism, such cells are not uncom- neurologic damage. In 6 women complete physiologic
monly detected in normal patients and the differentia- stabilization was achieved, but life support was discon-
tion of maternal from fetal squames is problematic.‘3 tinued after the diagnosis of brain death. We were
The detection of squamous cells in the pulmonary surprised at the rapidity with which patients had brain
vessels of a patient initially submitted as having an damage after the onset of symptoms and the frequency
amniotic fluid embolism but who likely died of an with which seizures were an initial manifestation. The
anesthetic mishap and in a woman who died of an profound degree of initial hypoxia seen in these pa-
undiagnosed uterine rupture confirms these earlier tients is probably of significance in this regard. Earlier
observations. Indeed, at least two of the original 8 studies suggesting an 86% mortality rate for amniotic
patients described by Steiner and Luschbaugh in whom fluid embolism, with half of all deaths occurring in the
debris of presumably fetal origin was found would not first hour. The apparently improved mortality seen in
have met clinical criteria for inclusion in this study: One this series (61%) with only 36% dying in the first 2 hours
died of postpartum shock and was found at autopsy to may reflect improved care of the critically ill gravid
1166 Clark et al. April 1995
AmJ Obstet Gynecol

woman. Unfortunately, this potential improvement in 2. This syndrome appears to be initiated after ma-
mortality appears to translate into prolonged survival of ternal intravascular exposure to fetal tissue. Such
more women with hypoxia-induced neurologic injury, a exposure may occur during the course of normal
dubious achievement. Overall, the 15% intact survival labor and delivery, after potentially minor trau-
matic events such as intrauterine pressure catheter
rate seen in this series is virtually identical to traditional
placement, or during cesarean section. Because
estimates of maternal mortality and appeared unrelated
fetal-to-maternal tissue transfer is common at
to the care administered after the event.
some time during the labor and delivery process,
Fetal outcome was also poor with amniotic fluid actions by the health care providers such as intra-
embolism onset before delivery. Although perinatal uterine manipulation or cesarean delivery may
mortality was only 21%, 50% of survivors had perma- affect the timing of the exposure; however, no
nent neurologic injury. Intact survival appeared to be evidence exists to suggest that such exposure can
related to cardiac arrest-to-delivery interval (see Table be avoided by altering clinical management.
VIII), confirming an earlier review by Katz et al.‘4 3. In a small percentage of women such exposure
However, fetal outcome was extremely variable; delivery results in the initiation of a complex pathophysi-
within 5 minutes did not guarantee an intact fetus, and ologic chain of events resulting in death in a high
one fetus delivered 32 minutes after cardiac arrest percentage of cases. Variations in nature and se-
verity of the clinical syndrome may be dependent
survived without apparent neurologic sequelae.
on variations in antigenic exposure and in indi-
Although profound respiratory acidosis was observed
vidual response, consistent with other anaphylac-
in all fetuses who were delivered after maternal cardiac toid reactions in humans.
arrest and in whom cord gas values were obtained, none 4. Analysis of these data suggests no causative link
of these fetuses had residual neurologic damage. This between hypertonic contractions and the occur-
confirms the generally accepted belief that even severe rence of amniotic fluid embolism. Prior anecdotal
fetal respiratory acidosis does not result in neurologic observations of a temporal association between
injury. However, only 2 of 11 fetuses who survived with uterine tetany and symptom onset are better ex-
residual neurologic injury had a 5-minute Apgar score plained on the basis of the catecholamine response
of 5 3, whereas the remaining 9 had an Apgar score of to catastrophic physiologic insult, as well as the
4 to 6. These observations suggest that the Apgar score frequent association of seizures with the onset of
symptoms. These observations are in agreement
criteria for hypoxic-ischemic neurologic injury estab-
with basic uteroplacental physiologic concepts; a
lished by The American College of Obstetricians and
complete cessation of uterine venous blood flow
Gynecologists and the American Academy of Pediatrics, during even moderate contractions suggests that a
while valid in fetuses with subacute or chronic injury, maternal exposure to fetal tissue is least likely to
may not apply in cases of acute, near-total fetal as- occur during a hypertonic contraction. Any relation
phyxia.25 between oxytocin and this syndrome has been
We arbitrarily limited inclusion of postpartum pa- refuted on theoretical, statistical, and clinical
tients in this study to cases of amniotic fluid embolism grounds.
occurring within 30 minutes of delivery. It should be 5. Care of the mother with amniotic fluid embolism
noted, however, that cases of syndrome onset much is nonspecific and supportive but should include
high concentrations of oxygen. Despite optimal
later than 30 minutes have been reported. We do not
care, however, most patients with this syndrome
know if such cases actually represent amniotic fluid
die, and most of the survivors are neurologically
embolism or whether prior misconceptions regarding
the pathognomonic nature of central squamous cell 6. Profound acidemia, initially of a respiratory na-
detection lead to misdiagnosis. We have no evidence, ture, develops in fetuses of mothers with this
however, to suggest that this syndrome could not be syndrome who have cardiac arrest. Earlier delivery
first manifest at a later time; indeed, a delayed reaction appears to improve prognosis, although fetal neu-
caused by the “slow-reacting substance of anaphylaxis” rologic injury may occur even with delivery within
(predominantly leukotrienes C3 and D4) is well estab- 5 minutes of the arrest. Intact maternal survival
lished in human anaphylaxis. after cardiac arrest is rare, and delivery may, on
An analysis of this registry and previously published theoretical grounds, actually be of benefit to the
data suggests the following conclusions. mother undergoing cardiopulmonary resuscita-
tion.‘* For these reasons we recommend that peri-
1. The syndrome of peripartum cardiovascular col- mortem cesarean section be initiated as soon as
lapse and coagulopathy is, from a clinical, hemo- possible after maternal cardiac arrest in patients
dynamic, and hematologic standpoint, similar to with clinical amniotic fluid embolism.
anaphylaxis and septic shock and suggests the
possibility of a common underlying pathophysi- Whereas much has been written about the impor-
ologic mechanism (see Fig. 2). tance to the fetus of an immunologic “barrier” between
Volume 172, Number 4, Part 1 Clark et al. 1167
Am J Obstet Gynecol

the mother and the antigenically different products of 14. Smedegard G, Revenas B, Lundberg C, Arfors KE. Ana-
conception, little attention has been paid to the poten- phylactic shock in monkeys passively sensitized with hu-
man reaginic serum. I. Hemodynamics and cardiac per-
tial importance of this barrier to maternal well-being. formances. Acta Physiol Stand 1981;111:239-47.
Our observations suggest that breaches of this barrier 15. Kapin MA, Ferguson JL. Hemodynamic and regional
may, under certain circumstances and in susceptible circulatory alterations in dog during anaphylactic chal-
lenge. Am J Physiol 1985;249:H430-7.
maternal-fetal pairs, be of immense significance to the 16. Wong S, Dykewicz MS, Patterson R. Idiopathic anaphy-
mother. Previous experimental evidence in both ani- laxis-a clinical summary of 175 patients. Arch Intern
mals and humans unequivocally demonstrates that the Med 1990;150:1323-8.
17. Silverman HJ, Van Hook C, Haponik EF. Hemodynamic
intravenous administration of amniotic fluid per se is changes in human anaphylaxis. Am J Med 1984;77:341-4.
generally innocuous, even in large amounts.’ Further, 18. Lee W, Clark SL, Cotton DB, et al. Septic shock during
the clinical findings described in our analysis of the pregnancy. AM J OBSTET GYNECOL 1988;158:410-6.
19. Parker CW. In: Clinical immunology. Philadelphia: WB
registry are not consistent with an embolic event, as it is Saunders, 1980:1208-18.
commonly understood. Thus the term amniotic jZuid 20. Clark SL. Arachidonic acid metabolites and the patho-
embolism appears to be a misnomer that has led to nhvsiolow of amniotic fluid embolism. Semin Renrod
Bnhocri& 1985;3:253.
confusion and possibly hindered our understanding of 21. Azegami M, Mori N. Amniotic fluid embolism and leuko-
this condition and the construction of meaningful in- trienes. AM J OBSTET GYNECOL 1986;155: 1119-23.
vestigative approaches. We suggest that, given our cur- 22. Scott JR, Beer AE, Guy LR, Liesch M, Elbert G. Patho-
genesis of Rh isoimmunization in primigravidas. Obstet
rent understanding of this condition, the name amniotic Gynecol 1977;49:9-14.
fluid embolism should be discarded, and the syndrome of 23. Clark SL, Pavlova A, Greenspoon J, Horenstein J, Phelan
acute peripartum hypoxia, hemodynamic collapse, and JP. Squamous cells in the maternal pulmonary circulation.
AM J OBSTET GYNECOL 1986;154:104-6.
coagulopathy should be designed in a more descriptive 24. Katz VJ, Dotters DJ, Droegemueller W. Perimortem cesar-
manner as anaphylactoid syndrome of pregnancy. Addi- ean delivery. Obstet Gynecol 1986;68:571-6.
tional investigations will be necessary to define more 25. American College of Obstetrics and Gynecologists. Fetal
and neonatal neurologic injury. Washington: American
clearly the biochemical nature of this maternal re- College of Obstetricians and Gynecologists, 1992 Jan;
sponse. Technical bulletin 163.

Steiner PE, Luschbaugh CC. Maternal pulmonary embo- Discussion
lism by amniotic fluid. JAMA 1941;117:1245-54, 1341-5.
Morgan M. Amniotic fluid embolism. Anesthesia 1979;34: DR. JOHN F. HUDDLESTON, Atlanta, Georgia. The
20-32. thanktilly rare syndrome Clark et al. described can
Clark SL. New concepts of amniotic fluid embolism: a surely be one of the most frightening and therapeuti-
review. Obstet Gynecol Surv 1990;45:360-8. cally disappointing encounters in obstetrics. Most of us
Clark SL, Cotton DB, Gonik B, et al. Central hemody-
namic observations in amniotic fluid embolism. AM J have probably been at least tangentially involved in
OBSTET GYNECOL 1988;158:1124-6. such a case, and some of us have been present when
5. Clark SL, Montz FJ, Phelan JP. Hemodynamic alterations symptoms began unexpectedly.
associated with amniotic fluid embolism: a reappraisal. AiM One afternoon in the spring of 1982, I was on .the
J OBSTET GYNECOL 1985;151:617-21.
6. Hankins GDV, Snyder RR, Clark SL, Schwartz L, Patterson
labor floor at the University Hospital in Birmingham,
WR, Butzin CA. Acute hemodynamic and respiratory ef- Alabama, and was discussing case management with’my
fects of amniotic fluid embolism in the pregnant goat chief resident and the attending obstetric anesthesiolo-
model. AM J OBSTET GYNECOL 1993;168:1113-30. gist, The nurse working in the adjacent labor room
7. Paul RH, Koh BS, Bernstein SG. Changes in fetal heart
abruptly and urgently summoned the three of us to the
rate: uterine contraction patterns associated with eclamp-
sia. AM J OBSTET G~ECOL 1978;130:165-9. bedside of her patient, an obese, multiparous woman
8. Towel1 ME. Fetal acid-base physiology and intrauterine undergoing an internally monitored, low-dose oxytocin
asphyxia. In: Goodwin JW, Godden JO, Chance GW, eds. induction of labor for ruptured membranes with clear
Perinatal Medicine. Baltimore: Williams & Wilkins, 1976: fluid. Her term pregnancy had previously been uncom-
9. American College of Obstetricians and Gynecologists Pro- plicated. At 5 cm dilatation and without evidence of
logue. Amniotic fluid embolism syndrome. In: Obstetrics: uterine hyperstimulation the patient had suddenly be-
3rd ed. Washington: American College of Obstetricians come restless, then dyspneic, then apneic with the
and Gynecologists 1993:94-5. peripheral pulse undetectable. A full-scale resuscitation,
10. Raoer RF. Fisher MM. Profound reversible mvocardial including intubation, was underway within the minute,
deiression after anaphylaxis. Lancet 1988;1:38$-8.
11. Parrillo JE. Pathogenic mechanisms of septic shock. but we were unsuccessful. Both the mother and her
N Engl J Med 1993;328:1471-7. fetus died, despite what might be considered ideal
12. Enjeti S, Bleecker ER, Smith PL, Rabson I, Permutt S, circumstances for promptly recognizing and combating
Traystman RJ. Hemodynamic mechanisms in anaphylaxis. cardiopulmonary arrest. There was laboratory evidence
Circ Shock 1983;11:297-307.
13. Smith PL, Kagey-Sobotka A, Bleecker ER, et al. Physi-
of coagulopathy. Autopsy was retised, but squamous
ologic manifestations of human anaphylaxis. J Clin Invest cells and mucin were demonstrated in blood aspirated
1980;66:1072-80. from the right side of the heart.
1168 Clark et al. April 1995
Am J Obstet Gynecol

In an obviously labor-intensive project, Clark et al. would also like them to comment on the statement in
have collected in a registry 46 cases meeting their the article that all 11 babies with cord arterial blood gas
stringent requirements for what has been known for analyses showed a “pure respiratory acidosis.” I was
more than a half century as amniotic fluid embolism but surprised that a significant metabolic component was
what the authors rather compellingly now suggest be not found, because the pH values averaged 6.79 and
termed anaphylactoid syndrome of pregnancy. Such a col- the time from cardiac arrest until delivery averaged 16
lection of this uncommon syndrome could only be minutes, during which time the fetuses were likely
accomplished by means of a registry, and the authors’ hypoxic.
foresight in creating such, now 6 years ago, is com- Finally, because the finding of presumably fetal ele-
mendable. The critical analysis of many variables from ments in maternal blood seems unrelated to the amni-
each record has shed new light on possibly pathophysi- otic fluid embolism syndrome, is a search for these
ologic mechanisms. Much of what Clark et al.‘, 3, 4 and currently indicated with clinical suspicion of this diag-
Hankins et al.” now report reinforces their previous nosis?
research, which, in part, is a series of studies that have I congratulate Clark et al. on an important contribu-
bolstered our understanding of gestational physiologic tion to our clinical knowledge.
and pathophysiologic characteristics5 In particular,
support is provided to refute beliefs still commonly held REFERENCES
regarding the pathophysiologic causes of this syn- 1. Clark SL, Cotton DB, Gonik B, et al. Central hemody-
drome. namic observations in amniotic fluid embolism. AM J OBSTET
The vaginal route of birth, the use of oxytocin, and GYNECOL 1988;158:1124-6.
the intense uterine activity resulting in pressure-related 2. Hankins GDV, Snyder RR, Clark SL, Schwartz L, Patterson
transfer of amniotic contents into the maternal circula- WR, Butzin CA. Acute hemodynamic and respiratory effects
of amniotic fluid embolism in the pregnant goat model. AM
tion have been considered common associations with J OBSTET GYNECOL 1993;168:1113-30.
the syndrome. Even the current (1993) edition of Wil- 3. Clark SL, Pavlova A, Greenspoon I, Horenstein I, Phelan
liams’ Obstetrics notes rapid or tumultuous labor leading JP. Squamous cells in the maternai pulmonary c&ulation.
to the pumping of meconium-laden amniotic fluid into AM I OBSTET GYNECOL 1986:154:104-6.
4. ClaGk SL. Arachidonic acid metabolites and the pathophysi-
the maternal circulation and causing severe pulmonary ology of amniotic fluid embolism. Semin Reprod Endo-
vascular obstruction with acute car pulmonale.6 crinol 1985;3:253-61.
Clark et al., citing previous work and using registry 5. Clark SL, Cotton DB, Lee W, et al. Central hemodynamic
data for support, lucidly argue that neither delivery assessment of normal third-trimester pregnancy. AM J
OBSTET GYNECOL 1989;161:1439-42.
route, use of oxytocin, nor excessive uterine activity
6. Cunningham FG, MacDonald PC, Gant NF, Leveno KJ,
before the clinical event is a likely antecedent. Indeed, Gilstrap LC. Williams’ obstetrics. 19th ed. Norwalk,
during intense uterine activity the uterine venous out- Connecticut: Appleton & Lange, 1993:843-5.
flow is occluded. In this study even meconium did not
emerge as statistically significantly associated with this
syndrome. In addition, the concept of pulmonary arte- DR. STEVEN G. GABBE, Columbus, Ohio. I enjoyed this
rial obstruction is challenged. presentation. You pointed out that 41% of the women
What is supported by these findings is the prior had a history of atopy or allergy. I wonder if you could
conclusion of dismal clinical outcome. There was a 61% tell us what features of the chart review led you to
maternal mortality, a 26% maternal survival with neu- establish that diagnosis.
rologic damage, and only a 11% intact maternal sur- DR. ROBERT CEFALO, Chapel Hill, North Carolina.
vival. Although 79% of babies alive at the onset of First of all, I want to thank Dr. Clark for his many
maternal symptoms survived, half of them had perma- contributions in attempting to dissect this obstetric
nent neurologic sequelae. emergency.
Thus we are left with a very rare clinical syndrome Air embolism occurs not infrequently, particularly
with essentially no definable predisposing factors and during a cesarean delivery. Given the fact that you
little chance of successful treatment, even if treatment excluded coagulopathy in some patients and given the
considered appropriate is initiated promptly. There fact that 19% of cases occurred during a cesarean
almost seems a lethal predestination for the majority of delivery, how did you exclude the possibility that air
affected women. This is certainly not reassuring infor- embolism occurred rather than an amniotic fluid em-
mation. bolism?
However, the arguments that compare these findings DR. 0. RICHARD DEPP, Philadelphia, Pennsylvania. In
with anaphylaxis and septic shock are enlightening and a number of the cases where amniotic fluid embolus was
encouraging both for prospects of future understand- a diagnostic consideration, the differential diagnosis
ing and for possible effective therapies. has included the question of whether a recently admin-
Clark et al. have advised us that currently manage- istered epidural anesthetic could have played a role in
ment is nonspecific and supportive and is based on the generation of a similar picture of hypotension.
attempts to maintain maternal oxygenation. I ask them Was an epidural anesthetic administered within 15
to speculate as to what therapies might prove useful if minutes or so of the embolism in any of the cases?
this syndrome is proved to be due to anaphylaxis. I DR. JAMES H. MCGREGOR, Denver, Colorado. I too
Volume 172, Number 4, Part 1 Clark et al. 1169
Am J Obstet Gym01

thank you for an excellent study that took great effort There were two questions about respiratory acidosis,
to organize and conduct. one from Dr. Huddleston and one from Dr. Gilstrap.
What about the results of autopsies that were done on Yes, we did apply a correction to the high Pco, levels to
the women? And among the survivors were there signs uncover what the underlying metabolic component of
of anaphylaxis? You’ve quite strongly suggested this. that acidosis might be; and in the 11 cases in which cord
Were there signs or findings of anaphylaxis either in gas values were available, the resultant pH and base
survivors or at autopsy, and how do you conceive that deficit that were uncovered were within the range de-
this happens? Does the bag of water break or does it scribed by Dr. Gilstrap and others for laboring patients.
go into a vessel? What do you conceive of as the On the basis of that, we concluded that the acidosis was
mechanism? only respiratory.
DR. RICHARD L. BERKOWITZ, New York, New York. Is As Dr. Huddleston pointed out, the mean time from
there any concern on your part that the registry reflects event to delivery was 16 minutes; but we did not have
a bias in that people were reporting the most dramatic cord gas values available in all of those patients. As a
cases and the ones with the worst outcome? In particu- rule the patients in whom cord gas values were available
lar, do you have data on how the women did who were patients delivered at major medical centers where
underwent rapid cesarean section because of concern extremely rapid intervention was also available.
about the fetus? In other words, did those women do These groups of patients tended to have a shorter
worse than patients who were treated supportively? event-to-delivery time, and that probably explains why
DR. LUIS A. CIBILS, Chicago, Illinois. I’m very inter- the fetuses had not yet had to rely on anaerobic me-
ested in finding out why 30% of the submitted charts tabolism for their cellular energy needs and metabolic
were rejected. Obviously those women had a diagnosis acidosis had not yet developed.
of amniotic fluid embolism by the clinicians who took Dr. Huddleston’s final question addressed the value
care of them. What was the basis for that? How different of histologic findings in the diagnosis of this syndrome.
were these 30% from the 66% or so included in this Several members of this society have demonstrated that
study? the finding of central cellular elements is not very
DR. LARRY C. GILSTRAP, Dallas, Texas. Did you use any specific. These data suggest that the finding of central
kind of correction in defining a metabolic component cellular elements is not very sensitive either; and so,
in the fetus for the very high Pco, values that were there unfortunately, we are left without a pathognomonic
or do you think that’s necessary for the fetus? finding for this condition.
DR. CLARK (Closing). I thank Dr. Huddleston for his The diagnosis has to be made either at classic clinical
comments. In terms of therapy, I think two approaches presentation or less than classic clinical presentation
could be considered: first, a more shotgun approach to after careful exclusion of any other possible factors.
general immune suppression such as is used in anaphy- Dr. Gabbe, atopy or allergy was ascertained by the
laxis. This would be high-dose corticosteroids and/or patient’s history. We had hospital charts for each
epinephrine. Most of these patients will be in cardiac patient; and in most cases they are asked on admission,
arrest, and epinephrine is a first-line treatment for most “Do you have any history of allergies or atopy?” Forty-
forms of lethal cardiac dysrhythmia. So most of them one percent of patients responded positively.
will already be receiving epinephrine. If a case of this Dr. Cefalo, air embolism cannot always be excluded;
nature were to happen to me on a Sunday night, I and I think this is an important point. We are not
would consider the administration of large doses of making any definite conclusions about pathophysi-
corticosteroids. The data are skimpy, and the use of ologic factors. We’re defining a specific clinical syn-
steroids cannot be considered a standard of care; how- drome, with precise pathophysiologic characteristics to
ever, we have very little to lose. be determined later. However, in cases with coagulop-
Specifically, I would probably give 500 mg of hydro- athy and adult respiratory distress syndrome air embo-
cortisone sodium succinate intravenously and repeat it lism would be unlikely.
every 6 hours until the patient either was better or died. Dr. Depp, we did look carefully at the relation of
In terms of specific inhibition of mediators, this is one epidural and any other type of anesthetic agent to this
of the hottest topics in septic shock research. These condition and could find none.
investigators are far ahead of our investigations, of Dr. McGregor, we have not claimed that this is
course, in terms of identifying specific mediators of anaphylactic. We have specifically used the word ana-
sepsis. phyla&d to get away from implying an immunoglobu-
We’re currently gearing up for an animal study in lin-mediated event. Anaphylactoid is a simple clinical
which we will administer various fractions of fetal ele- descriptor.
ments and then measure a whole host of endogenous Dr. Berkowitz, we fully recognize the potential biases
mediators that are released in response. I hope that in inherent in any type of registry information. Patients
the future we may be able to identify specific endog- submitted to the registry may have had better or worse
enous mediators involved, which may help us to tailor outcomes than the population as a whole. However, this
specific therapy; but for now I think it’s basic hemody- is the best information available to date.
namic support and treatment of coagulopathy with Dr. Cibils, patients were rejected if they did not meet
component replacement. entry criteria outlined in Table I of our article.