**3.2 Risk factors**

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

AFE was first described in the 1920s by J.R. Meyer. It was later recognized as a syndrome in 1941 when Steiner and Lushbaugh reported autopsy findings of 32 women who died suddenly during childbirth. The common histopathological finding among these women was the presence of amniotic fluid debris in the pulmonary vasculature [1]. Therefore, the historical hypothesis was based on an obstruction of the pulmonary arteries from amniotic fluid or fetal debris [1, 3]. Medical advancements in the 1980s allowed for more frequent use of the pulmonary artery catheter to obtain arterial histologic specimens from living patients [1]. There were several reports of pathologic findings that were previously thought to be diagnostic of AFE found in pregnant women that did not have AFE. These findings called into question previous cases diagnosed as AFE that were based solely on pathologic findings. The second and more commonly accepted theory is that AFE results from a complex sequence of reactions involving an abnormal activation of proinflammatory mediators in the host leading to an immunologic response [1–7]. This response is similar to the systemic inflammatory response syndrome (SIRS). Amniotic fluid contains several procoagulant factors including platelet-activating factor, leukotrienes, bradykinin, cytokines, thromboxane, and arachidonic acid, which aids in the understanding of why disseminated intravascular coagulation (DIC) is observed in 80% or more of women diagnosed with AFE [1, 7, 8]. In conjunction with these responses, a profound hemodynamic change leads to the maternal collapse and death in patients with AFE. Thus, during the first minutes, a sudden increase in pulmonary vascular resistance as a result of an inflammatory/anaphylactoid vasoconstriction leads to a right ventricular dysfunction with dilation of the right ventricular chambers, with a left shift of the interventricular septum and a decrease of the left ventricular filling pressures, with hypotension and cardiovascular collapse [9]. This severe pulmonary vasoconstriction produces an oxygen shunt, with ventilation-perfusion mismatching and severe hypoxia. Finally, left ventricular failure may be present as a consequence of myocardial

injury secondary to some inflammatory mediators or myocardial ischemia [10]. Complement activation is thought by some to play a role in the pathophysiology of AFE. Virtually all patients diagnosed with AFE develop some degree of acute respiratory distress syndrome (ARDS). Various case series evaluating serum complement levels in patients with AFE have noted significantly decreased levels of C3 and C4 compared to a control group of normal laboring patients who all had complement levels within the normal range [7]. Decreased levels of C3 are thought

The true incidence of amniotic fluid embolism is unknown. Discrepancies in diagnosis as well as inconsistencies in reporting practices lead to a wide range of estimates. AFE incidence ranges between 1 in 8000 and 1 in 80,000 pregnancies [8, 11, 12]. In 2012, Knight et al. reviewed available data sources from Australia, Canada, the Netherlands, the United Kingdom, and the United States to investigate incidence rates and identify variations in methodology in diagnosis of AFE. Their analysis found a reported incidence of AFE ranging from 1.9 cases per 100,000 in the United Kingdom to 6.1 cases per 100,000 cases in Australia. Differences in the reported incidence were attributed to a lack of internationally accepted diagnostic

criteria for nonfatal cases of AFE as well as variance in methodology.

to be consistent with complement activation.

**3. Incidence and risk factors**

**3.1 Incidence**

**2. Pathophysiology**

**132**

Review of various data registries reveals a wide range of conflicting data regarding identifiable risk factors for AFE. Historically, risk factors associated with AFE included situations where there was an increased likelihood of exchange of maternal and fetal components [1, 2, 13]. Events such as cesarean delivery, operative vaginal delivery, cervical trauma, placenta previa, and abruption were frequently reported [9, 13–16].

Knight et al. in 2012 reviewed data sources on incidence of AFE in Australia, Canada, the Netherlands, the United Kingdom, and the United States. Where data was available, they also examined risk factors associated with AFE. There were only two associations that were consistent across all five countries: induction of labor and maternal age [2]. In the Netherlands the association with age was not statistically significant. This may be a result of the limited power of the study given that all reported cases occurred in women who were 29 years of age or older. The data from Canada showed an association between AFE and all methods of medical induction of labor, while in the United Kingdom, there was only a statistically significant association with induction of labor using vaginal prostaglandins [2]. In the United States, all methods of induction of labor showed an increased odds ratio; however, this was not statistically significant [2]. Increased odds of AFE associated with placental previa and placental abruption was also observed. In the United Kingdom there was a statistically significant association between cesarean section when the amniotic fluid embolism occurred after delivery. There was no association with forceps or vacuum delivery; however, only a small subset of women underwent an operative vaginal delivery, so there is limited power to detect this association [2].

Another group of researchers who conducted a population-based cohort study on 3 million birth records in the United States from 1999 to 2003 found AFE was associated with maternal age greater than 35 (OR 2.2, 95% CI 1.5–2.1). However, they did not find that AFE was significantly associated with induction of labor. They also reported an association of placenta previa (OR 30.4, 95% CI 15.4–60.1) and cesarean delivery (OR 5.7, 95% CI 3.7–8.7) [16].

Maternal risk factors [1, 3, 5, 6, 8, 9, 11, 13–16]:


Fetal risk factors [15, 16]:


Obstetrical factors [1, 3, 5, 6, 8, 9, 11, 13–16]:


### **4. Diagnosis**

There should be a high level of suspicion of AFE for a pregnant or postpartum woman with an acute onset of cardiopulmonary compromise, DIC, and altered mental status. The diagnosis of AFE is one of exclusion and is based upon clinical findings of sudden onset of hypoxia, cardiovascular compromise, and/or coagulopathy. The differential diagnosis of AFE includes, but is not limited to, pulmonary embolism, anaphylaxis, placental abruption, myocardial infarction, eclampsia, aspiration, and septic shock [1, 4, 5]. To date there are no specific laboratory tests available to diagnosis AFE. Some recent publications have suggested an insulin-like growth factor binding protein-1 as a useful biomarker for AFE diagnosis, with high sensitivity and specificity; however, this is not extensively used [6].

The Society of Maternal-Fetal Medicine (SMFM) and the Amniotic Fluid Embolism Foundation proposed a definition of AFE based on four diagnostic criteria, which are all required to be present. This definition was specifically developed for research purposes.


Although there are no specific tests that are currently recommended to confirm the diagnosis of amniotic fluid embolism, there are test that may help to support the

**135**

**6. Management**

*Amniotic Fluid Embolism*

earlier intervention [4, 9].

**5. Clinical presentation**

*DOI: http://dx.doi.org/10.5772/intechopen.85726*

diagnosis. Initial evaluation should always include assessment of arterial blood gas to determine the degree of hypoxemia. In addition to arterial blood gas measurements, serial complete blood counts and coagulation studies should be trended in order to detect early coagulopathy [9]. These studies can aid in the early identification of DIC. Abnormalities often include a prolonged prothrombin time (PT) which is due to consumption of clotting factors as well as a decreased fibrinogen. Intervention is often indicated if the PT is 1.5 times the normal limit. Activated partial thromboplastin time may not be as helpful as values may be within normal reference range. Additional laboratory tests proposed include various markers of C3 and C4 complement activation, serum tryptase, insulin-like growth factor binding protein-1, urinary histamine, and arachidonic acid metabolites [1, 4, 9]. Tryptase is a serine protease that has a half-life of several hours and has been useful in the diagnosis of anaphylaxis. Given the similarities of the reported pathophysiology of AEF and anaphylaxis, elevated levels of serum tryptase may aid in diagnosis. There have been reports of the use of immunostaining techniques of the monoclonal TKH-2 antibodies in maternal serum and lung tissue. Although data is limited, there are a few studies that have evaluated the use of serum sialyl Tn (STn) which is a fetal antigen in meconium as well as amniotic fluid that can be detected with TKH-2 monoclonal antibodies. TKH-2 reacts with fetal components (meconium and mucin) which stain the lung tissue of women with AFE [4, 5, 9]. Researchers found that serum levels of sialyl Tn greater than 50 U/ml had a sensitivity between 78 and 100% and a specificity between 97 and 99% [9]. Another biomarker of interest is zinc coproporphyrin, which is also a component of amniotic fluid found

in maternal serum and can be elevated in women with AFE [1, 4, 9].

coagulopathy within 4 hours of initial symptoms [2].

Radiographic findings are nonspecific and not diagnostic. The most common radiographic abnormalities in AFE are bilateral interstitial and alveolar infiltrates with areas of increased opacity which is indistinguishable from pulmonary edema [4, 9]. The use of bedside transesophageal echocardiography may aid in early identification of acute pulmonary vasoconstriction or left heart failure precipitating

The classic presentation of AFE is often described as an acute onset of respiratory distress, hypoxia, hypotension (including cardiac arrest), seizures, and DIC either during labor, during delivery, or in the immediate postpartum period. If AFE occurs during labor, electronic fetal heart tracings frequently demonstrate acute changes characteristic of fetal hypoxia. There is often a rapid progression from the time of onset of the initial signs and symptoms to end organ damage and death. Severe consumptive coagulopathy is seen in only two obstetric conditions, AFE and massive placental abruption [4]. DIC is present in approximately 80% of patients with AFE and may develop at any time; however, half of affected patients develop

The management of women diagnosed with AFE is centered on supportive care. Unfortunately, even with prompt recognition and appropriate treatment, maternal morbidity and mortality remain high. The Society for Maternal-Fetal Medicine (SMFM) recommends a multidisciplinary team approach consisting of anesthesiology, critical care medicine, respiratory therapy, and maternal-fetal

#### *Amniotic Fluid Embolism DOI: http://dx.doi.org/10.5772/intechopen.85726*

*Clinical Management of Shock - The Science and Art of Physiological Restoration*

There should be a high level of suspicion of AFE for a pregnant or postpartum woman with an acute onset of cardiopulmonary compromise, DIC, and altered mental status. The diagnosis of AFE is one of exclusion and is based upon clinical findings of sudden onset of hypoxia, cardiovascular compromise, and/or coagulopathy. The differential diagnosis of AFE includes, but is not limited to, pulmonary embolism, anaphylaxis, placental abruption, myocardial infarction, eclampsia, aspiration, and septic shock [1, 4, 5]. To date there are no specific laboratory tests available to diagnosis AFE. Some recent publications have suggested an insulin-like growth factor binding protein-1 as a useful biomarker for AFE diagnosis, with high

sensitivity and specificity; however, this is not extensively used [6].

peripheral capillary oxygen saturation < 90%)

4.Absence of fever (≥38°C) during labor" [6, 14].

The Society of Maternal-Fetal Medicine (SMFM) and the Amniotic Fluid Embolism Foundation proposed a definition of AFE based on four diagnostic criteria, which are all required to be present. This definition was specifically developed

2.Documentation of overt DIC after appearance of these initial signs or symptoms, using this scoring system of the Scientific and Standardization Committee on DIC of the International Society on Thrombosis and Hemostasis (ISTH), modified for pregnancy. Coagulopathy must be detected before loss of sufficient blood to itself account for *dilutional* or shock-related consumptive

3.Clinical onset during labor or within 30 minutes of delivery of placenta

Although there are no specific tests that are currently recommended to confirm the diagnosis of amniotic fluid embolism, there are test that may help to support the

1. "Sudden onset of cardiorespiratory arrest, or both hypotension (systolic blood pressure < 90 mm Hg) and respiratory compromise (dyspnea, cyanosis, or

Obstetrical factors [1, 3, 5, 6, 8, 9, 11, 13–16]:

• Induction or augmentation of labor

• Cervical or abdominal trauma

• Operative vaginal delivery

• Placenta previa/accreta

• Placental abruption

• Eclampsia

for research purposes.

coagulopathy

**4. Diagnosis**

• Premature rupture of membranes

• Cesarean section

**134**

diagnosis. Initial evaluation should always include assessment of arterial blood gas to determine the degree of hypoxemia. In addition to arterial blood gas measurements, serial complete blood counts and coagulation studies should be trended in order to detect early coagulopathy [9]. These studies can aid in the early identification of DIC. Abnormalities often include a prolonged prothrombin time (PT) which is due to consumption of clotting factors as well as a decreased fibrinogen. Intervention is often indicated if the PT is 1.5 times the normal limit. Activated partial thromboplastin time may not be as helpful as values may be within normal reference range.

Additional laboratory tests proposed include various markers of C3 and C4 complement activation, serum tryptase, insulin-like growth factor binding protein-1, urinary histamine, and arachidonic acid metabolites [1, 4, 9]. Tryptase is a serine protease that has a half-life of several hours and has been useful in the diagnosis of anaphylaxis. Given the similarities of the reported pathophysiology of AEF and anaphylaxis, elevated levels of serum tryptase may aid in diagnosis. There have been reports of the use of immunostaining techniques of the monoclonal TKH-2 antibodies in maternal serum and lung tissue. Although data is limited, there are a few studies that have evaluated the use of serum sialyl Tn (STn) which is a fetal antigen in meconium as well as amniotic fluid that can be detected with TKH-2 monoclonal antibodies. TKH-2 reacts with fetal components (meconium and mucin) which stain the lung tissue of women with AFE [4, 5, 9]. Researchers found that serum levels of sialyl Tn greater than 50 U/ml had a sensitivity between 78 and 100% and a specificity between 97 and 99% [9]. Another biomarker of interest is zinc coproporphyrin, which is also a component of amniotic fluid found in maternal serum and can be elevated in women with AFE [1, 4, 9].

Radiographic findings are nonspecific and not diagnostic. The most common radiographic abnormalities in AFE are bilateral interstitial and alveolar infiltrates with areas of increased opacity which is indistinguishable from pulmonary edema [4, 9]. The use of bedside transesophageal echocardiography may aid in early identification of acute pulmonary vasoconstriction or left heart failure precipitating earlier intervention [4, 9].
