Pathophysiology of Amniotic Fluid Embolism: new considerations and remarks for syndrome diagnosis
Bouchè C. MD1; Casarotto M, MD2; Wiesenfeld U. MD1 Bussani R. MD3 ; Addobati R.4 ; Bogatti P. MD1
1 Dipartimento Ostetricia e Ginecologia Istituto per l’Infanzia Burlo Garofolo; Clinica Ostetrica e Ginecologica Università di Trieste.
2 Dipartimento Materno-Infantile Ospedale S. Maria degli Angeli Pordenone; Divisione di Ostetricia e Ginecologia.
3 Dipartimento di Patologia e Medicina Legale; Istituto di Anatomia ed Istologia Patologica Università di Trieste.
4 Dipartimento di Medicina di Laboratorio Istituto per l’Infanzia Burlo Garofolo Trieste.
Corrispondence to: Dr. Carlo Bouchè Istituto per l’Infanzia di Trieste; Clinica Ostetrica e Ginecologica , via dell’Istria 65/1 34100 Trieste.
E-mail; carlobouche@tiscali.it.
Even today amniotic fluid embolism (AFE) can be responsible for maternal death with a frequency that ranges between 1/8000 and 1/80000 of all pregnancies.
The discrepancy of reported observations leads to one important consideration: this still enigmatic syndrome can manifest itself in sudden, subclinical, mild or in the classical severe forms reported in Literature. Therefore, disease incidence and even more so maternal mortality can vary widely if diagnosis is performed with accurate clinical criteria and the rigorous fulfillment of diagnostic procedures.
Cases are reported in literature in which the diagnosis had been solely made by exclusion of other disorders which did not generally show any of the typical AFE syndrome signs or symptoms4,125, 39, 103 .
Various observers of the AFE syndrome believe that many forms of coagulopathy and subsequent post-partum hemorrhage are associated with moderate forms of amniotic fluid embolism. The majority of these forms, however, are often undiagnosed and sometimes the coagulopathy is attributed to blood loss due to uterine atony.
Hemodynamic alterations in these AFE forms can be transitory121 or absent. This, however, does not exclude a severe form of coagulopathy - generally classified as acute disseminated intravascular coagulation (DIC) and associated with copious hemorrhage – that may be the cause of death in some cases before the appearance of the syndrome’s cardiopulmonary symptoms94.
Another factor that has led to the various reported incidence has been the different importance that was attributed to histopathological findings for diagnosis in the 1940s, 1950s and 1960s and the value these findings have today.
Additionally some cases, characterized by severe obstetric hemorrhage secondary to coagulopathy, can favor the development of an hemorrhagic or hypovolemic shock, triggering in turn cardiac and respiratory symptoms. Moreover some potentially life-threatening maternal diseases, such as placenta accreta, placental abruption and uterine rupture, have been found to be significantly associated with AFE74,90.
AFE is a syndrome with a significant incidence of fetal or neonatal deaths or of bad outcomes for them. When maternal symptoms manifest themselves during labor, they are almost often accompanied by acute fetal distress, which is often the onset symptom 63,25,29,36,83,8. In many cases, the fetus is already dead 29,90.
The diagnosis of AFE is mainly based on clinical signs and symptoms, which develop during the evolution of the syndrome. Histology performed at autopsy or on samples of organs and tissues of survived women is useful to confirm the diagnosis.
The frequently reported symptoms of the classical forms of AFE are characterized by sudden cardiovascular collapse in the course of labor or post-partum, which may be preceded by respiratory distress that rapidly leads to shock and coma. The clinical picture may be complicated by neurological manifestations, such as tonic-clonic seizures and rigor, which in some cases may precede other signs or symptoms.
Half of the patients die within the first hour of onset of symptoms and those who survive the first phase usually develop significant coagulopathy. In at least 40% of cases, alteration of coagulation manifest itself through acute DIC with massive consumption of coagulation factors and genital hemorrhage. Development of coagulopathy is generally subsequent to cardiorespiratory symptoms. Nonetheless, aberration of one single district may prevail in the evolution of AFE with peculiar onset of other signs and symptoms. There are, however, some prodromic signs which can often precede the classical picture of this disease. They are:
1. restlessness or agitation83,84,100,3,86,95,63,124,45
2. change of behavior 122,124
3. anxiety100,71
4. numbness
5. pallor
6. tachypnea or breathing alteration124
7. inability to answer questions 40
8. mental confusion112,71
9. perception of bad taste 20
These clinical elements can certainly be related to a condition of maternal partial hypoxia and, since they are not specific, they can “a posteriori” aid in the clinical diagnosis of AFE.
These evidences confirm a possible prodromic phase of the syndrome and justify the fact that classical onset of symptoms occurs in the post-partum phase in a relevant number of cases, supporting the concept that the embolic event often does not coincide with the evident onset of symptoms.
Case reports
Case 1
A patient was admitted in labor at 40 weeks of gestation. After amniotomy meconium staining (grade 2) become evident. Repeated fetal heart rate decelerations appeared in the CTG tracing. An emergency cesarean section was performed. The lower segment appeared intact and the operation ended with a blood loss of around 200 cc. After about one hour from the end of the operation, the uterus was dilated and atonic. Abundant coagulated blood, approximately 1000 cc, was squeezed out. Despite the intravenous administration of oxytocin and PGE2 and the continuous bimanual massage, the uterus remained strongly atonic with a loss of other 1000 cc of very liquid blood. Blood transfusion was started and fresh frozen plasma was given. After 5 minutes, it was decided to perform a total hysterectomy due to persistent uterine atony and hemorrhage. On reopening the peritoneum, the uterus presented with good suture retention and no intraperitoneal hemorrhage. The operation did not raise any particular problem apart from diffuse oozing. The results of coagulation analysis suggested the presence of an acute DIC.
Despite an estimated total blood loss of about 3000 cc, the patient did not present with a condition of particular hemodynamic instability and was discharged after six days.
AFE was immediately suspected, due to absence of other clinical elements that could justify an acute post-partum DIC.
Macroscopically, the cervix showed an area of hemorrhagic infarction with mild laceration of the decidua. There were no areas of hemorrhagic suffusion in the hysterotomy.
The microscopic examination of the cervix showed consistent presence of acid mucopolysaccharides, and thus debris of meconial origin, in a vein of medium caliber. Moreover, the vessel was completely thrombosed, while inclusions on the hysterotomic incision did not show any element of fetal origin and the patency of venous vessels could be easily demonstrated.
A blood sample, taken during the operation to determine the concentration of zinc-coproporphyrin - a meconium component - resulted negative for generalized embolization.
Case 1: Alcian Blue PAS magnification X 20: deposit of acid mucopolysaccharidic matter into a cervical vein.
Case 1: Azan-Mallory magnification X 60: endovascular occlusive clot of cervical vein.
Case 1: Alcian Blue PAS magnification X 20: deposit of acid mucopolysaccharidic matter in some cervical veins.
Case 1: Alcian Blue PAS magnification X 40: deposit of acid mucopolysaccharidic matter in a cervical vein.
We measured the concentration of zinc coproporphyrin I (ZnCP-I), a characteristic component of meconium, in maternal plasma by fluorometry after HPLC.
Zinc coproporphyrin I (ZnCP-I), which is present in high concentration in meconium [4], can be detected in maternal plasma, and it was found to be high in the plasma of patients with amniotic fluid embolus.
We found a particular case of AFE with non-detectable level of ZnCP-I.
Reagents
CP-III dihydrochloride and ZnCP-I were purchased from Frontier Scientific (
HPLC-grade acetonitrile, reagent grade acetic acid, KH2PO4 and other reagents were all obtained from Sigma Aldrich.
Procedures
High-performance liquid chromatography of ZnCP-I.
The HPLC system consisted of a series 200 lc Perkin Elmer biocompatible pump equipped with a Perkin Elmer autosampler, a fluorimeter LS 50 B Perkin Elmer and a pc station with Turbochrome as data processor software. Samples were injected into a Rheodyne injector with a 200 ɥl loop.
For ZnCP-I analysis we used an 4.6 x
Assay of ZnCP-I content of plasma.
ZnCP-I concentration was assayed by HPLC with synthetic ZnCP-I as the standard and Cp-III as the internal standard.
Internal standard was added to calibrator solutions and plasma solutions.
For analysis for ZnCP-I, we followed the spectrofluorometric method used by Gourley et al. [1] that has showed a sensibilty of about 0.6 pmol/100ɥL.
The linear regression of calibration curve was R2=0.997.
As Gourley et al. outlined, we did not even detect ZnCP-I in any samples unrelated to pregnancy.
Here below the unexpected non-detectable level of ZnCP-I of AFE diagnosed patient compared to one of the standard solutions of plasma doped with ZnCP-I, used for calibration.
Case 2
Labor was induced via oxytocin administration in a patient at 41 weeks + 6 days of gestation, after a normal pregnancy. After a normal labor, sudden persistent fetal bradycardia, with meconial grade 3 amniotic fluid, prompted a vacuum delivery. A newborn with normal weight and in good conditions was extracted.
Before the delivery of the placenta, about ten minutes after birth, blood loss was about 700 cc.
After the third stage diffuse fluid blood oozing from small lacerations in the vagina and cervix was observed. They were sutured, but nonetheless genital hemorrhage persisted with outflow of fluid blood from the birth canal.
Coagulation tests suggested an acute DIC with platelet count rapidly decreasing to 139,000.
Total hysterectomy and bilateral ligation of the hypogastric arteries were performed due to the persistent hemorrhage. Hemoglobin level was 6.7 g/dl and platelet count 69,000.
The patient maintained good hemodynamic stability. She was administered 26 units of concentrated erythrocytes, 2 units of platelets, 8 units of fresh frozen plasma, 6000 IU of antithrombin III and 2.4 mg of activated factor VII. After several hours, clotting was under control. The patient was discharged without sequels after 11 days.
In this case too the clinical diagnosis of AFE was made by exclusion of the other possible causes of coagulopathy.
During hospitalization blood samples were taken from the pulmonary artery to determine the presence of mucin, vernix caseosa and fetal squames. Twenty-three cytological sections (12 with whole blood and 11 after lysis of erythrocytes) were variably fixed (Delaunoi, Citofix and air) and variably stained (Papanicolau, Emocolor and May-Grunwald-Giemsa). Fetal debris was not found in any specimen.
The removed uterus microscopically showed vascular thrombotic formations. For the microscopic examination inclusions on the body, decidua, lower uterine segment and cervix were carried out. A massive hemorrhagic necrosis of the endometrium was evident, with recent, isolated, endovasal thrombi. Thrombotic formations were observed in the cervical venous vessels, together with Alcian-PAS positive material compatible with fetal debris.
Case 2: H.&E. ( hematossilin-eosin ) magnification X 60 : venous myometrial vessel with an occlusive clot.
Case 2: H.&E. magnification X 40: fetal debris into venous cervical vessel.
Case 2: Alcian magnification X 60: mucin into a venous cervical vessel.
Case 2: PAS ( Periodic Acid Schiff ) magnification X 20: mucin into a venous cervical vessel.
PATHOGENESIS AND PATHOPHYSIOLOGY OF AMNIOTIC FLUID EMBOLISM: NEW ISSUES AND SOME CONSIDERATIONS
Amniotic Fluid Embolism is a typical disorder of delivery labor or abortive labor. However, we have reports of some cases where the presence of myometrial contraction could not be demonstrated3, even though a certain degree of hypertone or uterine contraction may have preceded the phase of embolization. Amniotic fluid may also enter maternal circulation in the course of either an elective or emergency cesarean section22,120,101. In any case, the pressure gradient pushing the amniotic fluid into the venous vessels opened by hysterotomy can be determined by the development of myometrial contractions appearing during fetal extraction or immediately after. Similarly, there are published cases occurring after amnioinfusion80,126,44,37, amniocentesis43,89,109,62, insertion of intrauterine transducer5, removal of cervical suture59, presence of intrauterine device at term118, an attempt of external cephalic version64, uterine manipulation35, feticide or termination of pregnancy48,110 and after abdominal trauma49,98,66,91,88.
The sites of entry of amniotic fluid into maternal circulation are well known and universally and almost unanimously shared by various researchers. For amniotic fluid to overcome the resistance of maternal venous pressure the presence of a pressure gradient, facilitating its flow into the maternal circulation, is necessary and it is represented by uterine contraction.
In AFE cases a large fetal part, mostly the cephalic extremity, may close the pelvic cavity like a sort of “plug” preventing amniotic fluid outflow from genitals and redirecting it towards open venous sinuses. This mechanism may be more understandable in the phase of comparison of cephalic extremity and pelvis, particularly during internal rotation, when the myometrial tissue of the lower segment and the cervix is compressed between the presenting part and the maternal pelvic bone and particularly stretched during contraction. For the hematoplacental barrier to break, amniochorial membranes too need to be broken, although AFE cases with integral membranes have been reported.
In the absence of labor, the pressure gradient in AFE cases, which allows amniotic fluid to enter the maternal circulation, may be due to transitory alterations of the uterine tone and to the simultaneous opening of a uterine venous sinus, probably associated with premature separation of amniochorial membranes or partial placental abruptio. Alternatively anaphylactic or anaphylactoid reaction may occur due to antigen stimulation, unrelated to amniotic fluid such as in the case of feto-maternal transfusion, and the clinical picture may be related to a reaction to antigenically incompatible blood transfusion65.
Various researchers have objected that uterine activity, particularly hypertonia, can carry amniotic fluid into the maternal venous system. They have in fact underlined that venous sinuses in the myometrium are mechanically closed during the peak of uterine contractions: they believe it is difficult to correlate an increase in intra-amniotic pressure with the passage of amniotic fluid into the venous vessels.
Nonetheless, this concept can only be valid for the uterine venous system, but is less valid for the lower segment and is completely absent for the uterine cervix108. Indeed, the two latter anatomical structures have much less muscular tissue, compared to the uterine myometrium, and are subject to distension, rather than shortening, during uterine contraction, thus potentially favoring the opening of lacerated venous sinuses105,95. This concept confirms what has been supposed by many authors: endocervix and lower segment veins are the most probable portals of entry of amniotic fluid into maternal circulation during labor. However the concurrent role of membrane rupture and premature placental separation have been clearly illustrated by Peterson and Taylor90, who have observed this possible mechanism of amniotic fluid entry into the maternal circulation in a significant percentage of their 40 reported AFE cases. When myometrial veins are the portal of amniotic fluid entry, as it occurs in cases of abruptio or premature separation of the placenta, the accompanying, persistent uterine contraction may prevent the amniotic fluid from entering the uterine venous circulation. In these cases embolization could occur either in the initial phase of contraction or, most likely, during the relaxation phase, when an endouterine depression occurs, favoring aspiration of the amniotic fluid through open venous sinuses.
It is very important to underline that the penetration of amniotic fluid into the maternal circulation is always described as a pathological condition in the Literature111,102 , although some researchers have a different opinion and assume that small quantities of amniotic fluid can rather frequently enter the maternal circulation without causing the syndrome. They have supposed that the syndrome linked to amniotic fluid embolism is due to the release of pathogenic, toxic or antigenically incompatible amniotic fluid into the maternal circulation25,27,22,52. However, if amniotic fluid were able to enter the maternal circulation with extreme ease, we should observe some cases in which the syndrome relapses in next pregnancies of surviving patients. Howewer, in no reported case has the syndrome reappeared79,28,41,114,47,31,1 .
Many studies have been performed on animal models by injecting the homologous or heterologous amniotic fluid, either filtered or not, through a peripheral vein. In contrast to the studies by Steiner and Lushbaugh112, who have reproduced the syndrome mostly by injecting pure or diluited human meconium into monkeys and dogs, subsequent studies have found contrasting results and the signs and symptoms of the syndrome have been detected only in some cases.
Some considerations could be made on these results:
1) By overlooking the uterine circulation, researchers have only considered eventual systemic effects of the amniotic fluid, not considering that some pathophysiological mechanism may have occurred in the uterine vessels, interfering with final results.
2) The amniotic fluid has been injected through a large peripheral vein, which is a condition that does not apply to the uterus where amniotic fluid is very likely to enter the maternal circulation through small or medium sized venous sinuses.
3) The filtering of amniotic fluid, the administration of human amniotic fluid, the non-pregnant state of some animals and the possible general anesthesia prior to euthanasia may have strongly affected results.
Although many studies have not been able to reproduce the syndrome on experimental animals, other numerous in vivo and in vitro studies have confirmed that amniotic fluid has a certain effect on maternal coagulation127,34.
As underlined by Bick18, lipid content, cell count, fetal debris, procoagulant activity and amniotic fluid viscosity increase with evolution of pregnancy, reaching their peak on delivery. He emphasizes the in vitro effect of amniotic fluid, such as the acceleration of prothrombin time, activation of thromboplastin partial time, acceleration of coagulation of factor VII deficient plasma and thromboplastin effects. The author believes that not only does the amniotic fluid act as total thromboplastin, but even as activator of the tissue phase, with direct activation of factor X.
Let us thus consider a given fact: amniotic fluid has some effect on blood coagulation78,106,77,61,123,92.
The majority of studies have been performed to identify the DIC-causing biochemical mediator, while amniotic fluid is very likely to accelerate coagulation and possibly lead to the formation of a venous thrombus.
DIC, on the other hand, could be a secondary effect. This is the starting point for fully understanding the pathophysiological mechanism, which begins with exposure of the amniotic fluid in uterine veins, before interpreting and justifying the reasons that trigger the syndrome!
In 1990, Kool73 reaffirmed that the procoagulant effect of amniotic fluid on stagnant blood, which can be observed in the pelvic vessels of a pregnant patient close to term, is greater and can thus cause a thrombus formation. These concepts had already emerged from other studies115,34 .
It can thus be hypothesized that in the majority of embolic events, amniotic fluid does not pass over the uterine venous circulation because a rapid activation of the local coagulant system occurs, leading to immediate thrombotic occlusion of venous vessels. The effect of embolization would thus be limited to one blood compartment and could be mainly identified as a potential cofactor of a local coagulopathy. Platelet activation and the formation of a platelet thrombus would occur first, followed by the transformation into a fibrin thrombus. Uterine venous thrombosis, induced by the mixture of amniotic fluid with maternal coagulation system, may be a form of protection preventing amniotic fluid components from reaching the general circulation and thus potentially triggering the syndrome.
On the other hand, uterine or cervical venous vessels thrombosis, secondary to amniotic embolization, may exert some action also on uterine arterious vessels, and specifically a vasoconstriction, with remarkable reduction of flow and consequent local ischemia and then hypoxia, which in turn is responsible for fetal asphyxia, post-partum coagulopathy, and uterine atony.
Theoretically, the thrombotic obstruction may allow the amniotic fluid also to reflow from the site through which it entered, when the pressure gradient stops, thus limiting disease severity. If the venous thrombotic formations will not rapidly deteriorate, the stagnant amniotic fluid might be re-absorbed in its liquid form. Coagulopathy can extend to the general circulation only in a marginal way, through the arrival of blood containing some products of the locally activated coagulation. The way can be through collateral uterine venous vessels that have not been affected by the thrombotic event. An alteration of some laboratory parameters of coagulation (fibrin degradation products or FDP) can then be the only evident, generalized phenomenon, while local effects may be a lot more severe.
Courtney33,34 supports this possibility by emphasizing the concepts that had already been discussed by Basu10. It was assumed that FDP concentrations in the uterine venous circulation were higher than in the general circulation, thus justifying the myorelaxing effects on the myometrium56. Courtney also assumed that amniotic fluid can have a two-fold effect on uterine musculature, the first being hyperstimulation to contract and the second myometrial inhibition causing organ atony.
Uterine atony can be a final consequence of all these mechanisms, but in our opinion it mainly results from uterine ischemia, due to the concomitant vasoconstriction of uterine arteries. The direct action of factors found in amniotic fluid or FDPs10,33,34,21,127,55 , which reach the capillary circulation with retroactive flow due to venous obstruction, may increase the duration and severity of this anomaly.
These concepts justify the fact that many cases, diagnosed as post-partum hemorrhage, where coagulopathy is attributed to the often conspicuous blood loss, are rather the expression of an association between uterine atony and coagulopathy secondary to amniotic embolization that occurred during labor or delivery.
There are also reported cases where clinical onset is represented by fetal asphyxia, followed by fatal DIC, which caused substantial post-partum hemorrhage96,75 and sometimes led to patient death94. The death of these patients can be related to the hemorrhage only and we will never know if these women would have later developed an anaphylactic or anaphylactoid syndrome if they had survived. In other cases9 the anaphylactic reaction to amniotic fluid can have a late onset and coagulopathy can have a two-fold origin.
Katcky68 published 58 cases of patients who underwent emergency post-partum hysterectomy. The number of blocks was not always considered adequate if it was lower than 10. Debris was observed in seven patients. Out of the nine cases where uterine atony was an indication for hysterectomy, four were positive for the presence of debris, but only one had clinical evidence of AFE.
Liban and Raz76 performed the clinical and histological assessment in 14 cases of women that died due to AFE, all confirmed by detection of squames and mucus in the blood, lung sections and in nearly all uterine sections. In a control group encompassing 22 uteri removed at peripartum for various reasons, squames were observed in two cases and mucoid material was found in one case.
Thompson and Budd119 described six cases and emphasized that AFE may also be wrongly diagnosed. Nevertheless in one of the reported cases, in which AFE was refuted, the venous vessels of the lower uterine segment were dilated and thrombosed and this process affected the pelvic vessels too.
Steiner and Lushbaugh113, during their experimental studies on animal models, observed the presence of vernix caseosa and thrombosis of the jugular vein in a monkey that had been administered 5 cc of amniotic fluid and subsequently another 20 cc of the same fluid. The most relevant data is that the animal did not die after fluid administration, but was killed after 72 hours from the first injection, while three other monkeys died within six hours from administration of one or three cc of meconium-stained amniotic fluid. While the deceased monkeys showed significant alterations of the pulmonary microcirculation, the lung sections of the monkey, which was killed after 72 hours from the first injection, showed the presence of a normal pulmonary condition, with only a slight alveolar edema and sporadic vascular thrombosis.
Cheung and Luk23 published two obstetric cases that developed a DIC post-partum. The histological examination of the cervix in both cases showed not only the presence of amniotic residue, but also confirmed the presence of recently thrombosed venous vessels.
Kern and Duff69 reported on a case where the only documented clinical manifestation was the isolated thrombosis of the right ovarian vein, in which, once the adnexa was removed, a significant presence of debris was observed. The patient did not develop either symptoms of cardio-respiratory failure, or a severe coagulopathy. The authors believe that the mechanism preventing the entry into the pulmonary circulation may have been related to a venous vasospastic reaction after the exposure of meconial elements to the interior surface of the vessels.
Amniotic fluid may be trapped in the uterine veins and then released after delivery explaining the numerous cases where the temporal relation between embolic event and maternal signs and symptoms is desynchronized, in other words that symptoms often appear late in their most acute picture 97,85.
Courtney32 first and Margarson82 later assumed, with different theories, that amniotic fluid could be trapped in uterine veins and then released. Courtney assumed that the amniotic, fluid penetrating the circulation while the fetus is still in utero, is then released gradually with a post-partum decreased uterine tone. Howewer he could not explain the mechanism underlying this vascular aberration. Similar conclusions were drawn by Margarson, who hypothesized that amniotic fluid is trapped, due to spinal blockade after administration of bupivacaina, and later mobilized with restored sympathetic tone after local anesthesia.
Stolte115, on the other hand, believed that the amniotic fluid that penetrated in the uterine venous vessels was channelled towards the general venous circulation only during the pauses between contractions, since the venous flow stopped under the phase of increased uterine tone and until after the peak of contraction.
Spapen110 published the case of a gravida undergoing an emergency cesarean section, without complications, due to fetal distress. However, after surgery, the patient suffered from massive genital hemorrhage, mild arterious hypotension and dyspnea. A second laparotomy was performed, but the uterus was intact and atonic. Coagulation showed the presence of a DIC; a Swan-Ganz catheter placed in the pulmonary artery showed data that were not suggestive of AFE: increase in pressure in the pulmonary arteries, elevated pulmonary capillary wedge pressure and left hearth failure, namely a hemodynamic picture of anemia and hypovolemic shock.
These hypotheses state that the embolization process may occur a few hours before the onset of real cardiorespiratory and neurological symptoms. The presence of a prodromic phase of the syndrome, often characterized by light neurological symptoms, justifies the fact that classical onset of symptoms occurs post-partum in a certain number of cases, but embolization is precocious.
Clark25,29 believes that amniotic fluid can easily penetrate the maternal venous circulation during labor without causing major consequences for the mother and fetus. In fact, Clark presupposes that amniotic fluid reaches the pulmonary circulation unhindered, without taking into account that amniotic fluid may not reach the general circulation. On the contrary, the influential researcher states that the presence of squames in the pulmonary circulation is due to a possible maternal contamination.
The crossing of the uterine venous bed by the amniotic fluid may depend on several factors, such as a missing or late thrombotic-occlusive effect on uterine venous vessels.
Other hypothesis is related on a possible maternal inability, even partial, to activate platelet aggregation and the coagulation system. This anomaly may be due to the congenital absence in the mother of some coagulation factor or to the fact that the quantity of fluid entering the circulation is particularly elevated. Another possibility, underlined by several researchers, is that amniotic fluid may have atypical characteristics. In our hypothesis, it may be unable to activate coagulation locally or it may do so late or it may activate a simultaneous hyperfibrinolysis or it may not control it and thus amniotic fluid may reach the pulmonary circulation and cause cardio-respiratory symptoms. In other words, an early or rapid lysis of uterine venous thrombi or the their failed formation may pave the way for amniotic fluid reaching the pulmonary circulation. In these cases, however, severe respiratory distress or cardiac arrest cannot be due to the activation of coagulation in the pulmonary vessels and thus to the development of thrombi, because if no such response occurs precociously in the uterine veins, it is less likely to occur in other areas. This hypothesis is in agreement with the fact that coagulopathy or DIC in a significant number of severe AFE cases is an epiphenomenon following the first phase of disease (second AFE phase).
Morgan86 observed that detection of fibrin thrombi at autopsy in AFE’s cases is rare and reported a case published by Bowman in 1955: a patient collapsed during labor, a venous varix was cut on her ankle and a significant presence of thrombi was observed. At autopsy thrombosed veins were no longer present and blood was completely fluid.
The DIC that is associated with AFE is known to be often characterized by a massive fibrinolytic process12,13,61, which often continues after death87,107,58 to the extent that a paradoxically poor detection of fibrin thrombi in vessels occurs at the autopsy of some clinical cases with frank DIC104,12,13,3,18 and some cases show a form of primitive hyperfibrinolysis induced by biochemical mediators that are found in anomalous concentrations in the amniotic fluid12,19,127.
The DIC consequent to amniotic embolization may therefore have a two-fold genesis. In cases where the embolic process stops in the uterine venous circulation, the DIC may develop from the combination of thrombotic effect on uterine venous vessels, venous vasoconstriction, insult on endothelium and capillary bed, myometrial richness of the tissue factor, insufficient action of myometrial and placental TFPI (tissue factor pathway inhibitor), ischemic reaction of uterus induced by the consequent arterious vasoconstriction. In these cases, the third stage, even when it is physiological, may be the moment when DIC symptoms appear, that is when uterine hemorrhage is observed. Viceversa, in cases where amniotic fluid immediately reaches the pulmonary circulation, the mechanism may be primarily related to anaphylactic response and complement activation.
It may be assumed that the uterine pathogenetic mechanism prevails in cases of frank DIC onset, causing rapid evolution of the hemocoagulative disorder; greater effects are determined by genital hemorrhage which is nearly always worsened by uterine atony. There can often be a discrepancy between coagulation laboratory parameters, extent of hemorrhage and poor therapeutic efficacy.
On the other hand, in classical AFE forms, DIC occurs from half an hour to several hours after collapse and may be directly related to the synergic effect between amniotic fluid thrombo-platelet activity and the effects secondary to anaphylaxis, mast cell activation and complement activation14.
In the forms where the antigenically incompatible amniotic fluid reaches late the pulmonary circulation, both mechanisms may overlap and greater effects may be sinergically determined by fluid quantity localized in the uterine veins, and the patient’s degree of anaphylactic response.
The mechanism whereby the presence of antigenically incompatible amniotic fluid does not trigger an anaphylactic response when the fluid stagnates in the uterine venous plexus remains to be clarified. The rapid formation of platelet thrombus may isolate the antigens responsible for maternal anaphylactic response; therefore, the amniotic fluid and its components, even if antigenically incompatible, are trapped within the thrombus. The pregnant uterus may also be unresponsive to the immune response and thus be tolerant towards external antigens as it tolerates the placenta14. Much information has been published on cases where maternal, symptoms secondary to anaphylactic response, are delayed in relation to the time of embolization. Therefore this type of response is very likely to occur only when the amniotic fluid reaches the pulmonary circulation and not when the fluid is confined to the uterine venous plexus, showing its inability to trigger an anaphylactic syndrome when it is confined to that area.
It is thus very likely that an anaphylactic or anaphylactoid response occurs only when the amniotic fluid manages to cross the uterine venous vascular plexus and reaches the pulmonary arterioles.
DISCUSSION
In the 1940s, 1950s and 1960s many published studies emphasized the role of the uterine factor in the syndrome’s pathogenesis.
Many other published cases have described the presence of coagulopathy or DIC as the main or sole dysfunction associated with AFE.
As less diagnostic importance has been gradually attributed to the detection of squames in the pulmonary vasculature, major work has mainly focused on understanding the hemodynamic aberrations caused by the syndrome and the description of case reports. Studies on animal models have also followed this direction.
In fact, over the past decades studies have no longer focused on understanding the underlying pathophysiological process of the syndrome that is the possible hemodynamic and functional changes that occur when the amniotic fluid enters the mother’s uterine venous circulation.
We have managed to demonstrate that amniotic fluid stops in the uterine venous circulation, where it exercises its pathogenic effect. Any systemic effects, such as hemorrhagic shock or DIC, result from this initial aberration. At the same time, we have emphasized the fact that no maternal sensitivity to fetal antigens is developed in case of incompatibility, if the amniotic fluid remains confined to the uterus.
Our first described case developed a condition of fetal distress during labor, making it necessary to resort to an emergency cesarean section. Soon after the operation, the patient developed coagulopathy and uterine atony with subsequent genital hemorrhage not responsive to therapy. A hysterectomy was thus necessarily performed. The coagulopathy could not have been induced by other disorders, which were all accurately excluded. The only remaining hypothesis was that of a meconium-amniotic fluid embolic process. The histological examination confirmed this hypothesis since it resulted positive for the presence of acid mucopolysaccharides in a diffusely thrombosed venous branch of the cervix. A blood sample was taken during the mother’s critical stage to measure zinc- coproporphyrin, which was within the normal range. The normal levels of serum zinc- coproporphyrin, which is found in meconium and amniotic fluid, showed that the embolic process stopped in the uterine cervix and the uterus, inducing local effects (fetal distress, uterine atony and genital hemorrhage linked to coagulopathy), without leading to evident hemodynamic, systemic effects, despite massive genital blood loss ( 3000 c.c. ).
Similarly, in the second case, the amniotic fluid that entered the cervical venous vessels contributed to the formation of local thrombi, which prevented the fluid from flowing towards the pulmonary circulation. The absence of debris in the numerous cytological sections of pulmonary arterious blood could confirm this analysis. The negative cytological examination of pulmonary arterious blood plays a negative predictive role, relevant for diagnostic purposes in suspected cases54.
We have thus assumed that the amniotic fluid entering and stagnating in the uterine venous vessels during labor can induce a local thrombosis, which in turn can be responsible for a process of local coagulopathy. This condition may result in local disseminated intravascular coagulation with evident maternal genital hemorrhage, with specific systemic symptoms being related only to the consequences of the hemorrhage. Should this disorder occur during labor, uterine venous thrombosis can cause an arterious vasospasm, generally and rapidly leading to fetal hypoxia with acute fetal distress. In many of these cases, immediate removal of the uterus could help to resolve every problem, since this operation would also remove any amniotic fluid stagnating in the uterine vessels and favoring local coagulopathy. In other cases, coagulation affects the areas adjacent to the uterus, and hemorrhage extends to the visceral peritoneum and utero-ovaric ligaments. In these cases, histology or immunoistochemistry could confirm the presence of debris in the vessels where amniotic fluid has entered or where it has stagnated.
Uterine atony is another event secondary to the effects of local coagulopathy and myometrial hypoxia. We believe that more or less severe AFE forms localized in the genital area may have a far greater prevalence, since uterine atony and consequent genital hemorrhage is the first or second most frequent indication for emergency post-partum hysterectomy53,6,67. In AFE forms with anaphylactoid or anaphylactic syndrome, uterine atony may result from shock, generalized maternal hypoxia, which means it can be related to the reduced quantity of blood, mainly desaturated, reaching the uterus113,90 . The development of DIC or a late fibrinolytic process in these cases may worsen this condition due to the direct inhibition of fibrin degradation products on the myometrial fibre.
The entry of amniotic fluid in the uterine venous circulation may thus accelerate the coagulation process leading to the formation of venous thrombi. However, the coagulopathy or DIC may have a more complex genesis due to the interaction of several factors, even if the process is started by the entry of amniotic fluid into the maternal venous circulation.
In AFE forms where amniotic fluid rapidly crosses the uterine venous circulation, without locally activating the coagulation process, the effects on the coagulative state may appear late and after complement activation.
Therefore, in agreement with Benson and Ratten15,17,99, the severity of coagulopathy in AFE cases may be directly proportional to the quantity of amniotic fluid entering the circulation. Other factors such as the patient’s gestational age and labor can strongly condition the procoagulant effect of amniotic fluid.
Amniotic fluid can thus cross the uterine venous tree and reach the maternal circulation. If the fluid is antigenically compatible, it does not cause any significant systemic symptom other than a possible, paucisymptomatic or transitory obstructive activity on the pulmonary circulation and a significant coagulative disorder that is secondary only to a possible initial thrombotic-obstructive involvement of the uterine venous circulation. In some cases, respiratory distress due to mere obstruction and consequent right heart disorder, which may require intensive care, may occur after a moderate embolic flow of amniotic fluid42,72. .
When the amniotic fluid is trapped in the uterine veins, sometimes it can gradually be released into the circulation during labor and particularly post-partum, due to precocious interruption of the protective barrier created by uterine venous thrombosis, as it occurrs with hyperfibrinolysis or conspicuous embolism. The passage may initially be of a low quantity or gradual in time. If the amniotic fluid is antigenically incompatible, once it has reached the pulmonary vessels, even in small quantities, it can initially generate prodromic neurological signs and symptoms of mild cerebral hypoxia.
The antigenically compatible amniotic fluid may thus enter the circulation and trigger a uterine venous thrombosis, and therefore severe localized coagulopathy, subsequent massive hemorrhage and be thus potentially fatal. Therefore, the cause of death in these cases ought to be attributed more to the consequences of rapid and conspicuous hypovolemia than to the alterations secondary to an anaphylactic process99 .
Small quantities of amniotic fluid entering the uterine circulation generally have a modest effect on the local vascular system and can thus be asymptomatic.
On the contrary, even small quantities of antigenically incompatible amniotic fluid which, for the above reasons, can rapidly pass over the uterine venous system, can trigger AFE syndrome and the severity of symptoms will depend on maternal immune response.
The anaphylactic response may also be roused to the maternal pulmonary vessels exposure to trophoblastic antigens, particularly if they are the expression of placental anomalies. Therefore, also in these cases coagulopathy is related to the effects of maternal immune response, rather than the direct thromboplastin-like action of the trophoblast tissue or of the amniotic fluid 25 ,108 .
As a consequence of what has been stated so far, another possible cause of maternal death related to the penetration of amniotic fluid in the venous circulation, may be the mobilization of one or more uterine venous thrombi11,93, extended to the pelvic vessels , that developed due to the procoagulant effects of amniotic fluid and are saved by fibrinolytic process. This could lead to severe or fatal thrombo-embolism post-partum or during puerperium50. Bauer11 in fact demonstrated the coexistence of AFE clinical signs and symptoms and thrombo-embolism, respectively, confirmed histologically, in a fatal AFE case .
Malvino81 later reported an AFE case presenting with tonic-clonic seizures and DIC and a large thrombus, which was detected during insertion of a catheter in the pulmonary artery and was in part rechannelled mechanically.
It is thus recommended that, in case of hysterectomy, histochemical and immnuhistochemical examinations are systemically performed on uterus inclusions from all the possible entry sites of amniotic fluid. This procedure is particularly important because not only does uterine histology show the portal of entry of amniotic fluid, but it also helps detect the presence of venous thrombosis, which is often still present since the fibrinolytic process that generally develops after DIC and genital hemorrhage has not yet been able to dissolve the previously formed thrombi. Paradoxically, thrombotic formations in the uterine venous network may be occasional or even absent in cases where histological examination is performed at autopsy. This is due to the fact that the fibrinolytic process may have dissolved the thrombi during the patients’ hospitalization and even after death.
Similarly, in cases of maternal death due to thrombo-embolism, debris ought to be searched in pulmonary thrombotic formations, particularly in cases of negative medical history or with no thrombophilic risk, in subjects who die under heparin prophylaxis and in cases that simultaneously present with a coagulation disorder or other complications during delivery.
CONCLUSIONS
In many ways, little is known about AFE which shares severe, often fatal and less severe forms that are more difficult to diagnose, mainly because symptoms are often less intense or only limited to a form of coagulopathy.
The effects of amniotic embolization can be very different and depend on whether amniotic fluid reaches the pulmonary circulation and whether it is antigenically incompatible or not.
We have assumed that in “milder forms” amniotic fluid remains confined to the uterine venous vessels, causing thrombosis which prevents its entry into the general circulation. The following effects would be limited to the uterus and/or the fetus, if it is still in. In some of these cases, coagulopathy can generate a massive genital hemorrhage that can also lead to exitus.
The third stage of delivery may be the event when the symthoms of hemorrhage generated by coagulopathy start to manifest themselves.
The failure of this protective mechanism is likely to allow amniotic fluid to flow beyond uterine veins and reach the pulmonary circulation.
In light of our observations, AFE may be classified as a “minor form” in cases where embolization is confined to the uterine or pelvic venous vessels and as a “major form“ in cases presenting with signs and symptoms of an anaphylactoid or anaphylactic response.
As AFE “major”, in AFE “minor forms”, a coagulopathy induced by amniotic fluid embolization of uterine veins is an unforeseeable event. The often consequent hemorrhage is frequently characterized by sudden onset and massive genital hemorrage, often non responsive to medical treatment. In such cases, it is fundamental, in a medical-legal setting, to carefully establish the cause of hemorrhage and also consider aspects of above, particularly in cases where the uterus was removed or particularly in fatal cases.
Finally, on basis of our considerations, further data are needed to identify the true reason that let amniotic fluid to reach quickly the pulmonary circulation. Some forms of hereditary platelet disorders, such as von Willebrand’s disease, may in fact play a precise role in the development of severe forms. Platelet inactivation after the arrival of amniotic fluid procoagulants and the consequent lack of platelet thrombi formation in the small uterine venous vessels may pave the way for amniotic fluid towards the pulmonary circulation, with all the possible aforementioned consequences.
SUMMARY
The authors describe two clinical cases presenting with an atypical form of amniotic fluid embolism characterized by rapid onset of DIC without apparent severe hemodynamic instability. The histological examination of the removed uterus showed the presence of debris and thrombotic formations in some uterine veins.
The authors thus supposed that in some cases the embolic process does not reach the general circulation, but remains confined to the uterus and, if this phenomenon is of a considerable quantity, it can be responsible for local pathogenic effects such as fetal distress, coagulopathy and uterine atony.
Classical AFE appears in cases when amniotic fluid reaches the pulmonary circulation unhindered or when it manages, even partially, to cross the obstacle of uterine thrombotic formations induced by amniotic fluid procoagulant factors and is at the same time antigenically incompatible.
The entry of amniotic fluid into the central venous circulation may be justified by the maternal inability to develop a platelet or a fibrin clot. Subsequent symptoms may depend on the degree of maternal response and fetal antigenic compatibility.
Similarly, fetal asphyxia may have a different pathogenetic mechanism. It may originate from a state of hypoxia induced by concomitant arterious vasoconstriction in those forms which are localized in the uterus. In generalized forms this condition may be generated by maternal hypoxia successive to spasm of pulmonary arterioles or to cardiogenic shock.
BIBLIOGRAPHY
1. Abecassis P.; Benhamou D.: “ Is amniotic fluid embolism likely to recur in a subsequent pregnancy ? “15 (1): 90.
2. Abenhaim H.A.; Azoulay L.; Kramer M.S.; Leduc L.: “ Incidence and risk factors of amniotic fluid embolisms: a population-based study on 3 million births in the United States “ Am. J. Obstet. Gynecol. 2008; 199: 49e1-49e8.
3. Anderson D.: “ Amniotic fluid embolism : A re-evaluation “ Am. J. Obstet. Gynecol. 1967; 98 (3): 336-348.
4. Awad IT; Shorten GD: " Amniotic fluid embolism and isolated coagulopathy: atypical presentation of amniotic fluid embolism " Eur. J. Anaesth 2001; 18: 410-413.
5. Ayoub C.M.; Zreik T.G.; Dabbous A.S.; Baraka A.S.: “ Amniotic fluid embolus: can we affect the outcome ?” Curr. Opin. Anesthesiol. 2003; 16: 257-261.
6. Bakshi S.; Meyer B.A.: “ Indications foe and Outcomes of Emergency Peripartum Hysterectomy “ J. Reprod. Med. 2000; 45 (9): 733-737.
7. Bannister M.: “ Amniotic fluid embolism “ Can. J. Anesth. 2000; 47: 381.
8. Barrows J.J.: “ A documented case of amniotic fluid embolism presenting as acute fetal distress “ Am. J. Obstet. Gynecol. 1982; 143: 599-600.
9. Bastien J.L.; Graves J.R.; Bailey S.: " Atypical Presentation of Amniotic Fluid Embolism " Anesth. Analg. 1998; 87: 124-126.
10. Basu H.: “ Fibrinolysis and abruption placentae “ J. Obstet. Gynaec. Brit. Cwith. 1969; 76: 481.
11. Bauer P.; Lelarge P.; Hennequin L.; Lambert H.; Larcan A. : “ Thrombo-embolism during amniotic fluid embolism “ Intensive Care Med. 1995; 21: 384.
12. Beller F.K.; Douglas G.W. Debrovner C.H. et al: “ The fibrinolytic system in amniotic fluid embolism “ Am. J. Obstet. Gynecol. 1963; 87: 48-55.
13. Beller F.K.; Uszynski M.: “ Disseminated intravascular coagulation in pregnancy “ Clin. Obstet. Gynecol. 1974; 17 (4): 250-278.
14. Benson M.D.: “ A hypothesis regarding complement activation and amniotic fluid embolism “ Med. Hypoth. 2007; 68 (5): 1019-1025.
15. Benson M.D.: “ Nonfatal amniotic fluid embolism: three possible cases and new clinical definition “ Arch. Far. Med. 1993; 2: 989-994.
16. Benson M.D.; Kobayashi H.; Silver R.K.; Ohi H.; Greenberger P.A.; Terao T: “ Immunologic studies in presumed amniotic fluid embolism “ Obstet. Gynecol. 2001; 97 (4): 510-514.
17. Benson M.D.; Lindberg R.E.: “ Amniotic fluid embolism, anaphylaxis and tryptase “ Am. J. Obstet. Gynecol. 1996; 175: 737.
18. Bick R.L.; Frenkel E.P.; Baker W.F.; Sarode R.: “ Hematological Complications in Obstetrics, Pregnancy, and Gynecology “ Cambridge University Press, 2006.
19. Biron-Andreani C.; Morau E.; Schved J.F.; Hédon B.; Dechaud H.: “ Amniotic Fluid Embolism with Haemostasis Complications: Primary Fibrinogenolysis or Disseminated Intravascular Coagulation ? “ Pathophysiol. Of Haemostasis and Thrombosis 2003; 33: 170-171.
20. Blanc P.L.; Bethenod J.M.; Muguet D.; Gerard M.; Robert D.: “ Un signe prodromique d’embolie amniotique ?” La Presse Médicale 1985; 14 (41): 2107.
21. Boulton F.E.; Letsky E.: « Obstetric haemorrhage : causes and management « 1985; 14 (3) : 683-728.
22. Burrows A.; Khoo S.K.: “ The amniotic fluid embolism syndrome: 10 years’ experience at a Major Teaching hospital “ Austr. N.Z. Obstet. Gynecol. 1995; 35 (3): 245-250.
23. Cheung A.N.; Luk S.C.: ” The importance of extensive sampling and examination of cervix in suspected cases of amniotic fluid embolus “ Arch. Gynecol. Obstet. 1994; 255 (2): 101-105.
24. Choi D.M.A.; Duffy B.L.: ” Amniotic Fluid Embolism ” Anaesth. Intens. Care 1995; 23 (6): 741-743.
25. Clark S.L.: “ Amniotic fluid embolism “ Crit. Care Clin. 1991; 7: 877-882.
26. Clark S.L.: “ Amniotic Fluid Embolism “ Clin. Perinatol. 1986; 13: 801-811.
27. Clark S.L.: “ New concepts of amniotic fluid embolism: A review “ Obstet Gynecol. Surv. 1990; 45: 360-368.
28. Clark S.L.: “ Successful pregnancy outcomes after amniotic fluid embolism “ Am. J. Obstet. Gynecol. 1992; 167 (2): 511-512.
29. Clark S.L.; Hankins G.D.V.; Dudley D.; Dildy G.A.; Porter T.F.: “ Amniotic fluid embolism: analysis of a national registry “ Am. J. Obstet. Gynecol. 1995; 172: 1158-1167.
30. Clark S.L.; Pavlova Z.; Greenspoon J.;Horestein J.; Phelan J.P. : “ Squamous cells in the maternal pulmonary circulation “ Am. J. obstet. Gynecol. 1986; 154: 104-106.
31. Collier C.: “ Recurring amniotic fluid embolism “ Anaesth. Int. Care 1998; 26 (5): 599-600.
32. Courtney L.D.: “ Amniotic fluid embolism “ Obstet Gynecol. Surv. 1974; 29: 169-177.
33. Courtney L.D.: “ Coagulation failure in pregnancy “ Br. Med. J. 1970; 1: 691.
34. Courtney L.; Allington M.: “ Effects of amniotic fluid on blood coagulation “ Br. J. Haematol. 1972; 22: 353-355.
35. Cragun J.M.; Ellestad S.C.; Panni M.K.: “ Amniotic fluid embolism presenting after uterine manipulation under general anesthesia: A case with a positive outcome “ Resuscitation 2008; 77 (1): 145-146.
36. Dashow E.E.; Cotterill R.; Benedetti T.J.: “ Amniotic fluid embolus: A report of two cases resulting in maternal survival “ J. Reprod. Med. 1989; 34: 660-666.
37. Davey A.M.; Becker J.D.; Davis J.M.: “ Possible amniotic fluid embolism associated with amnioinfusion “ J. Mat. Fetal Med. 1992; 146: 1287-1293.
38. Davies S.: “ Amniotic fluid embolus: a review of the literature “ Can. J. Anaesth. 2001; 48: 88-98.
39. Davies S.: “ Amniotic fluid embolism and isolated disseminated intravascular coagulation “ Can J. Anaesth. 1999; 46 (5): pt 1: 456-459.
40. Davis D.: “ Amniotic Fluid Embolism: Exploring This Rare but Typically Fatal Condition “ AWHONN Lifelines 2003; 7 (2): 127-131.
41. Demianczuk C.E.; Corbett T.F.: “ Successful pregnancy after amniotic fluid embolism: a case report “ J. Obstet. Gynaecol. Can. 2005; 27 (7): 699-701.
42. Devriendt J.; Machayekhi S.; Staroukine M.: ” Amniotic fluid embolism: another case with non-cardiogenic pulmonary edema ” Int. Care Med. 1995; 21 (8): 698-699.
43. Dodgson J.; Martin J.; Boswell J.; Goodall H.B.; Smith R.: “ Probable amniotic fluid embolus precipitated by amniocentesis and treated by exchange transfusion “ Br. Med. J. 1987; 294: 1322-1333.
44. Dorairajan G.; Soundararaghavan S.: “ Case report: Maternal death after intrapartum saline amnioinfusion – report of two cases “ Br. J. Obstet Gynaecol. 2005; 112: 1331-1333.
45. Dorne R.; Pommier C.; Emery J.C.; Dieudonnè F.; Bongiovanni J.P.: “ Embolie de liquide amniotique: evolution favourable après embolisation thérapeutique des artères utérines “ ANN. Fr. Anesth. Réanim. 2002; 21: 431-435.
46. Ducloy-Bouthors A.S.; Wantellet A.; Tournoys A.; Depret S.; Krivosic-Horber R.: “ Amniotic fluid embolism suspected in a case of seizure and mild uterine haemorrhage with activation of coagulation and fibrinolysis “ Ann. Fr. Anesth. Reanim. 2004; 23: 149-152.
47. Duffy B.L.: “ Does amniotic fluid embolism recur? “ Anaesth Int. Care 26 (3): 333, 1998.
48. Edwards G.J.; Davies N.J.: “ Amniotic fluid embolism following feticide –a cautionary tale “ J. Obstet. Gynaecol. 2000; 20 (2): 191.
49. Ellingsen C.L.; Eggebo T.M.; Lexow K.: “ Amniotic fluid embolism after blunt abdominal trauma “ Resuscitation 2007; 75 (1): 180-183.
50. Esposito R.A.; Grossi E.A.; Coppa G.; Giangola G.; Ferri D.P.; Angelides E.M.; Andriakos P.: “ Successful treatment of post partum shock caused by amniotic fluid embolism with cardiopulmonary bypass and pulmonary artery thromboembolectomy “ Am. J. Obstet. Gynecol. 1990; 163: 572-574.
51. Fineschi V.; Gambassi M.; Gherardi M.; Turillazzi E.: “ The diagnosis of amniotic fluid embolism: an immunohistochemical study for quantification of pulmonary mast cell tryptase “ Int. J. Legal Med. 1998; 111 (5): 238-243.
52. Fletcher S.J.; Parr M.J.A.: “ Amniotic fluid embolism: a case report and review “ Resuscitation 2000; 43: 141-146.
53. Forna F.; Miles A.; Jamieson D.J.: “ Emergency peripartum hysterectomy: A comparison of caesarean and postpartum hysterectomy “ Am. J. Obstet. Gynecol. 2004; 190: 1440-1444.
54. Gamerre L.; Tramoni G.; Lhuillier F.; Boisson C.; Clement H.J.; Viale J.P.: " Embolie de liquide amniotique: évolution favorable d'une CIVD isolée et diagnostic biologique précoce " Ann. Fr. Anesth. Reanim. 2006; 25: 633-637.
55. Gillie M.H.; Hughes S.C.: “ Amniotic Fluid Embolism “ Anesth. Clin. North Amer. 1993; 11 (1): 55- 78.
56. Gilmore D.; Wakim J.; Secrest J.; Rawson R.: “ Anaphylactoid syndrome of pregnancy: A review of the literature with latest management and outcome data “ AANA J. 2003; 71 (2): 120-126.
57. Gogola J.; Hankins G.D.V.: Amniotic Fluid Embolism in Progress: A Management Dilemma ! “ Am. J. Perinat. 1998; 15 (8): 491-493.
58. Haba K.; Kumano O.; Mohri M.; Takemaru H.; Kawanishi K.; Tobe S.; Kamada T.; Ueno S.: “ Post-mortem activation of human blood fibrinolytic enzyme in sudden and natural deaths “ Acta Med. Okayama 1963; 17: 279-288.
59. Haines J.; Wilkes R.G.: “ Non-fatal amniotic fluid embolism after cervical suture removal “ Br. J. Anaesth. 2003; 90 (2): 244-247.
60. Hankins G.D.V.; Snyder R.R.; Clark S.L. et al: “Acute hemodynamic and respiratory effects of amniotic fluid embolism in the pregnant goat model “ Am. J. Obstet. Gynecol. 1993; 168: 1113-1130.
61. Harnett M.J.P.; Hepner D.L.; Datta S.; Kodali B.S.: “ Effect of amniotic fluid on coagulation and platelet function in pregnancy: an evaluation using thromboelastography “ Anaesth. 2005; 60: 1068-1072.
62. Hasaart T.H.; Essed G.G.: “ Amniotic fluid embolism after transabdominal amniocentesis “ Eur. J. Obstet. Gynecol. Reprod. Biol. 1983; 16: 25-30.
63. Hogberg U.; Joelsson I.: “ Amniotic Fluid Embolism in Sweden, 1951-1980 “ Gynecol. Obstet. Invest. 1985; 20: 130-137.
64. Hussain S.A.; Sondhi D.S.; Munir A.; Rosner F.: “ Amniotic Fluid Embolism with Late Respioratory Failure “ Hospital Physician 2001; 40-43.
65. Ishiyama I.; Mukaida M.; Komuro E.; Keil W.: “ Analisys of a Case of Generalized Amniotic Fluid Embolism by Demostrating the Fetal Isoantigen ( A Blood Type ) in Maternal Tissued of B Bllod Type, Using Immunoperoxidase Staining “ Am. J. Clin. Pathol. 1986; 85: 239-241.
66. Judich A.; Kuriansky J.; Engelberg I.; Haik J.; Shabtai M.; Czerniak A.: “ Amniotic fluid embolism following blunt abdominal trauma in pregnancy “ Iniury 1998; 29 (6): 475-477.
67. Kastner E.S.; Figueroa R.; Garry D.; Maulik D.: “ Emergency Peripartum Hysterectomy: Experience at a Community Teaching Hospital “ Obstet. Gynecol. 2002; 99 (6): 971-975.
68. Katchy K.C.; Ziad F.; Al Nashmi N.; Diejomaoh M.F.E.: “ Emergency obstetric hysterectomy in Kuwait: a clinico pathological analysis “ Arch. Gynecol. Obstet. 2006; 273: 360-365.
69. Kern S.B.; Duff P.: “ Localized Amniotic Fluid Embolism Presenting as Ovarian Vein Thrombosis and Refractory Postoperative Fever “ Am. J. Clin. Path. 1981; 76 (4): 476-480.
70. Khong T.Y.: “ Expression of endothelin-1 in amniotic fluid embolism and possible pathophysiological mechanism “ J. Obstet. Gynecol. 1998; 105 ( 7): 802-804.
71. Killam A.:” Amniotic Fluid Embolism “ Clin. Obstet. Gynecol. 1985; 28: 32-36.
72. Koegler A.; Sauder P.; Marolf A.; Jaeger A.: “ Amniotic fluid embolism: a case with non-cardiogenic pulmonary edema “ Int. Care Med. 1994; 20 (1): 45-46.
73. Kool M.J.: Letters To the Editors. Am. J. Obstet. Gynecol. 1991; 164 (2): 701-702.
74. Kramer M.; Rouleau J., Baskett T.F.; Joseph K.S.: “ Amniotic-fluid embolism and medical induction of labour: a retrospective, population-based cohort study “ Lancet 2006; 368: 1444-1448.
75. Levy R.; Furman B.; Hagay Z.J.: " Fetal bradycardia and disseminated coagulopathy: atypical presentation of amniotic fluid embolism " Acta Anaesth. Scand. 2004; 48: 1214-1215.
76. Liban E.; Raz S.: “ A clinicopathologic study of forteen cases of amniotic fluid embolism “ Am. J. Clin. Pathol. 1969; 51: 477-486.
77. Liu E.H.C.; Shailaja S.; Koh S.C.L.; Lee T.L.: “ An assessment of the effects on coagulation of mid-trimester and final-trimester amniotic fluid on blood by Thromboelastograph analisys “ Anesth. Analg. 2000; 50: 333-336.
78. Lookwood C.J.; Bach R.; Guha A.; Zhou X. ; Miller W.A.; Nemerson Y.: “ Amniotic fluid contains tissue factor, a potent initiator of coagulation “ Am. J. Obstet. Gynecol. 1991; 165: 1335-1341.
79. Lumley J.; Owen R.; Morgan M.: “ Amniotic fluid embolism: a report of three cases “ Anaesthesia 1979; 34: 33-36.
80. Maher J.E., Wenstrom K.D.; Hauth J.C.; Meis P.J.: “ Amniotic fluid embolism after saline amnioinfusion: two cases and review of the literature “ Obstet. Gynecol. 1994; 83: 851-854.
81. Malvino E.; Korin J.; Bruno M.; Medrano J.; Miano J.: “ Angiografìa pulmonar en un caso de embolia de lìquido amniòtico y revisiòn de la literatura “ Medicina Intensiva 2002; 18 (2): 52-57.
82. Margarson M.P.: “ Delayed amniotic fluid embolism following Caesarean section under spinal anaesthesia “ Anaesthesia 1995; 50: 804-806.
83. Martin R.W.: “Amniotic Fluid Embolism “ Clin. Obstet. Gynecol. 1996; 39 (1): 101-106.
84. Masson R.G.: “ Amniotic fluid embolism “ Clin. Chest Med. 1992; 13 (4): 657-665.
85. Masson R.G.; Ruggieri J.; Siddiqui M.M.: “ Pulmonary microvascular cytology. A new diagnosis application of the pulmonary artery catheter “. Chest 1985; 88: 908-914.
86. Morgan M.: “ Amniotic.Fluid Embolism “ Anaesthesia 1979; 34: 20-32.
87. Morioka H.; Haba K.; Tanaka M.; Takemaru H.; Kawanishi K.; Tobe S.; Kamada T.; Ueno S.: “ Studies on fluidity of blood on the basis of fibrinolysis. II. Fibrinolytic activity of post-mortem blood in death from disease “ Nihon Hoig. Zasshi 1965; 19: 58-67.
88. Olcott C.O.; Robinson A.J.; Maxwell T.M et al. : “ Amniotic fluid embolism and disseminated intravascular coagulation after blunt maternal trauma “ J. Trauma 1973; 13: 737-740.
89. Paterson W.G.; Grant K.A.; Grant J.M.; McLean N.: “ The pathogenesis of amniotic fluid embolism with particular reference to transabdominal amniocentesis “ Eur. J. Obstet. Gynecol. Repr. Biol. 1977; 7: 319-324.
90. Peterson E.P.; Taylor H.B.: “ Amniotic Fluid Embolism: an analysis of 40 cases “ Obstet. Gynaecol. 1970; 35: 787-793.
91. Petrone P.; Asensio J.A.: “ Trauma in pregnancy: assessment and treatment “ Scand. J. Surg. 2006; 95 (1): 4-10.
92. Philips L.L.; Davidson E.C.: “ Procoagulant properties of amniotic fluid “ Am.J. Obstet. Gynecol. 1972; 113: 911-919.
93. Porat S.; Leibowwitz D.; Milwidsky A.; Valsky D.V.; Yagel S.; Anteby E.Y.: “ Transient intracardiac thrombi in amniotic fluid embolism “ Br. J. Obstet. Gynaecol. 2004; 111: 506-510.
94. Porter TF; Clark SL; Dildy GA; Hankins GDV: " Isolated disseminated intravascular coagulation and amniotic fluid embolism " Am. J. Obstet. Gynec. 1997; 174: 486.
95. Price T.M.; Baker V.V.; Cefalo R.C.: “ Amniotic Fluid Embolism. Three Case Reports with a Review of the Literature “ Obstet. Gynecol. Surv. 1985; 40 (7): 462-465.
96. Prosper S.C.; Goudge C.S.; Lupo V.R.: “ Recombinant Factor VIIa to Successfully Manage Disseminated Intravascular Coagulation From Amniotic Fluid Embolism “ Obstet. Gynecol. 2007; 109 (2): part 2; 524-525.
97. Quance D.: “ Amniotic Fluid Embolism: Detection by Pulse Oximetry “ Anesthesiology 1988; 68: 951-952.
98. Raijnio J.; Penttila A.: “ Amniotic fluid embolism as cause of death in a car accident- A case report “ Forensic Sci. Int. 2003; 137: 231-234.
99. Ratten G.J.. “ Amniotic Fluid Embolism – 2 Case Reports and a Review of Maternal Deaths From This Cause in Australia “ Austr. N.Z. J. Obstet. Gynecol. 1988; 28: 33-35.
100. Resnik R.: “ Amniotic fluid embolism “ Contemporary OB/GYN Archive, 1996.
101. Ricou B.; Reper P.; Suter P.M.: “ Rapid diagnosis of amniotic fluid embolism causing severe pulmonary failure “ Intens. Care Med. 1989; 15: 129-131.
102. Roche W.D.; Norris H.J.: “ Detection and significance of maternal pulmonary amniotic fluid embolism “ Obstet. Gynecol. 1974; 43: 729-731.
103. Rufforny-Doudenko I.; Sipp C.; Shehata B.M.: " Pathologic Quiz Case: A 30-Year-Old Woman With Severe Disseminated Intravascular Coagulation During Delivery " Arch. Pathol. Lab. Med. 2002; 126: 869-870.
104. Rushton D.I.; Dawson I.M.P.: “ The maternal autopsy “ J. Clin. Pathol. 1982; 35: 909-921.
105. Russell W.; Jones W.N.: “ Amniotic Fluid Embolism: a review of the Syndrome with a Report of 4 Cases “ Obstet. Gynecol. 1965; 26 (4): 476-485..
106. Salem H.H.; Walter W.A.; Perkin J.L.: “ Aggregation of human platelets by amniotic fluid “ Br. J. Obstet. Gynaecol.1982; 89: 733.
107. Senianskaia N.L.: “ Electron microscopic study of post-mortem fibrinolysis “ Arkh. Patol. 1985; 47 (2): 58-65.
108. Shnider S.L.; Moya F.: “ Amniotic Fluid Embolism “ Anesthesiology 1961; 22 (1): 108-119.
109. Shojai R.; Chau C.; Boubli L.; d’Ercole C. : « Amniotic fluid embolism during late term termination of pregnancy « Pren. Diagn. 2003; 23: 944-951.
110. Spapen H.: “ Use of the Swan-Ganz catheter in amniotic fluid embolism “ Int. Care Med. 1988; 14 (6): 678.
111. Sparr R.A.; Pritchard J.A.: “ Studies to detect the escape of amniotic fluid into the maternal circulation during parturition “ Surg. Gynecol. Obstet. 1958; 107: 560-564.
112. Stafford I.; Sheffield J.: “ Amniotic Fluid Embolism “ Obstet. Gynecol. Clin. North Am. 2007; 34: 545-553.
113. Steiner P.E.; Lushbaugh C.C.: “ Maternal pulmonary embolism by amniotic fluid as a cause of obstetric shock and unexpected death in obstetrics “ J.A.M.A. 1941; 117: 1245-1254, 1341-1345.
114. Stiller R.J.; Siddiqui D.; Laifer S.A.; Tiakowski R.L.; Whetham J.C.: “ Successful pregnancy after suspected anaphylactoid syndrome of pregnancy ( amniotic fluid embolus ). A case report “ J. Reprod. Med. 2000; 45 (12): 1007-1009.
115. Stolte L.; Lim H.T.; Van Arkel C.; Eskes T.K.A.B.; van Kessel H.: “Activation of coagulation, stasis and amniotic fluid embolism syndrome “ Eur. J. Obstet Gynaecol. 1971; 219 . .
116. Strickland M.A.; Johnson M.P.; Whitworth N.S. et al: “ Procoagulant properties of amniotic fluid from labouring and non-laboring women “ ACOG Annual Clinical Meeting, 1982.
117. Tews G.; Yaman C.; Ebner T.: “ Fatal trophoblastic embolism during cesarean section “ Int. J. Gynecol. Obstet. 2002; 76: 179-180.
118. Thomsen R.J. : “ Pregnancy in the presence of an intrauterine contraceptive device and amniotic fluid embolism: a possible association “ Am. J. Obstet. Gynecol. 1975; 15: 121 (2): 279-280.
119. Thompson W.B.; Budd J.W.: “ Erroneous diagnosis of amniotic fluid embolism “ Am. J. Obstet. Gynecol. 1965; 91: 606-622.
120. Tramoni G.; Valentin S.; Robert M.O.; Sergeant M.V.; Branche P.; Duperret S.; Clement H.J.; Lopez F.; Boisson C.; Audra P.; Rudigoz R.C.; Viale J.P.: “ Amniotic fluid embolism during caesarean section “ 2004; 13 (4): 271-274.
121. Tuffnell D.J.: “ Managing amniotic fluid embolism “ OBGManagement.com 2005.
122. Tuffnell D.J.:” United Kingdom Amniotic Fluid Embolism Register “ Br. J. Obstet. Gynaec. 2005; 112: 1625-1629.
123. Uszynski M.; Zekanowska E.; Uszynski W.; Kuczynski J.: “ Tissue factor ( TF ) and tissue factor pathway inhibitor ( TFPI ) in amniotic fluid and blood plasma: implications for the mechanism of amniotic fluid embolism “ Eur. J. Obstet Gynaecol. Repr. Biol. 2001; 95: 163-166.
124. Vlies R.: “ Amniotic fluid embolism “ Savig Mothers 2003-2005, 86-90.
125. Yang J.I.; Kim H.S.; Chang K.H.; Ryu H.S.; Joo H.J.: " Amniotic fluid embolism with isolated coagulopathy: a case report " J. Reprod. Med. 2006; 51 (1): 64-66.
126. Wegelius G.; Bergstrom M.; Ahlbom L.; Thomassen P.: “ A case of life-threatening pulmonary edema associated with amnioinfusion during labor “ Eur. J. Obstet. Gynaecol. Reprod. Biol. 1996; 65 (2): 237-239.
127. Weiner A.E.; Reid D.E.: “ The pathogenesis of Amniotic Fluid Embolism. III. Coagulant activity of amniotic fluid “ New Engl. J. Med. 1950; 243: 597-598.
CARLO BOUCHE'
All Rights Reserved. The reproduction of the whole test or part of it must be authorized by authors.
