Venous thromboembolic events (VTEs) in pregnancy refer to deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE). Analysis of administrative data from US hospital admissions including 73,109,789 pregnancy-related hospitalizations (2000 to 2018) suggested a VTE event rate of 6.6 events per 10,000 deliveries. Among these, the DVT event rate (5.1 per 10,000 deliveries) was higher than the PTE event rate (1.7 per 10,000 deliveries). In the United States, 5.3% of maternal mortalities are related to VTE, but the incidence is increasing, as is the number of patients with related risk factors.

The risk for thromboembolic events is elevated during pregnancy. Compared with nonpregnant patients, pregnant women have 5-fold greater odds of thromboembolic events during pregnancy (odds ratio [OR], 4.6; 95% confidence interval [CI], 2.7 to 7.8) and at 60-fold greater odds postpartum (OR, 60.1; 95% CI, 26.5 to 135.9). DVTs are more likely to occur antepartum, with 21%, 23%, and 56% occurring in the first, second, and third trimester, respectively. Most cases of PTE (60% to 80%) occur postpartum. Analysis from a 30-year population-based cohort ( n = 50,080 births) revealed the risk for both DVT and PTE was highest in the first week postpartum, with a progressive decline thereafter. Risk is elevated until at least 12 weeks after delivery.

Although VTE-related mortality, as reported by the Confidential Enquiries into Maternal Deaths and Morbidity in the United Kingdom and Ireland, appeared to have been decreasing a decade ago, more recently, the VTE-associated mortality rate has been stable. VTE was the leading cause of direct maternal deaths with 1.6 deaths per 100,000 births in 2019 to 2021. VTE-related maternal mortality appears to be stable in the United States, at 1.8 deaths per 100,000 births.

Virchow’s triad describes three factors that increase risk for thromboembolism: (1) venous stasis , (2) hypercoagulability , and (3) vascular damage . The incidence of each factor is increased during pregnancy, especially postpartum. Venous stasis occurs as a result of decreased venous flow velocity, venocaval compression, and possibly decreased mobility later in pregnancy. Additionally, pregnancy is a relatively hypercoagulable state, associated with enhanced platelet turnover, coagulation, and fibrinolysis. Thrombin generation and the concentration of clotting factors increase during pregnancy, including factors I (fibrinogen), V, VII, VIII, IX, X, and XII. Fibrinolytic activity decreases during the 48 hours after delivery and enhances clot stability in the early postpartum period. Vascular damage occurs at delivery. Placental separation from the uterine wall traumatizes the endometrium and accelerates the coagulation cascade. This vascular damage, in addition to delivery events that increase the risk of thromboembolism, explains the increased incidence of VTE events postpartum.

Awareness of VTE risk factors and frequent assessment of VTE risk are crucial for identification of patients who require thromboprophylaxis because the risk is not static throughout pregnancy. The assessment of risk should be performed antepartum, at hospital admission, and postpartum. The VTE risk factors can be categorized into maternal characteristics, pregnancy and delivery characteristics, and obstetric complications.

The two most important risk factors for thromboembolic events during pregnancy and postpartum are a previous history of thromboembolism and a diagnosis of thrombophilia. The increased risk is notable, with an increased odds of VTE of 24.8 (95% CI, 17.1 to 36) for women with a history of prior VTE and 51.8 (95% CI, 38.7 to 69.2) for women with thrombophilia. Thrombophilias increase the risk for VTE in pregnancy, for example in women homozygous for the factor V Leiden mutation. Other risk factors include advanced maternal age, race/ethnicity, obesity, anemia, hypertensive disorders, inflammatory bowel disease, and smoking status. Multifetal gestation, hyperemesis, hypertensive disorders of pregnancy, antenatal hospitalization and prolonged bedrest, intrauterine fetal demise, and cesarean delivery also increase the risk for postpartum VTE. In a metaanalysis of 28 studies (pooled n > 53,000 postpartum VTE events), the OR of postpartum VTE after cesarean delivery compared with vaginal delivery was 3.7 (95% CI, 3.0 to 4.6). Greater increases occurred after emergency versus elective cesarean deliveries. Obstetric complications, such as postpartum hemorrhage and postpartum infections, are also associated with increased risk, likely mediated via effects on maternal coagulation and inflammation. The Nationwide Inpatient Sample showed that between 2000 and 2018, the average annual percent change in the proportion of deliveries with one, two, or three VTE risk factors increased by 2.7%, 5.0%, and 7.5%, respectively. Patients with two or more risk factors accounted for over one-fourth of the VTE diagnoses.

Anesthesia and obstetric providers should work together to develop and implement strategies to reduce VTE. Systems should be developed to identify at-risk women for whom peripartum mechanical or pharmacologic thromboprophylaxis is indicated. Given the recent expansion of indications for pharmacologic thromboprophylaxis, it is imperative that there is communication between anesthesia and obstetric providers regarding timing of delivery, plans for neuraxial analgesia and/or anesthesia, and plans for postpartum anticoagulation.

Several risk assessment tools provide guidance on antepartum and postpartum anticoagulation management. Currently, there is not one validated and clinically accepted scoring tool, and controversy exists regarding the VTE risk level at which patients should be anticoagulated. The ACOG Practice Bulletin on thromboembolism in pregnancy summarizes which patients should receive prophylactic versus therapeutic anticoagulation. Patients with a previous history of thrombosis, certain high-risk populations (e.g., patients with acquired or inherited thrombophilia), or patients with a mechanical heart valve should be anticoagulated during pregnancy as well as postpartum. The American College of Chest Physicians has defined major and minor risk factors for postcesarean VTE ( Box 38.1 ). The National Partnership for Maternal Safety published a consensus bundle on VTE in 2016. This bundle broadens the indications for antepartum and postpartum pharmacologic anticoagulation beyond the ACOG practice guidelines, including recommending daily thromboprophylaxis for antepartum patients hospitalized for longer than 72 hours. This has anesthetic implications (see later discussion). All women with a new-onset thromboembolic event in pregnancy should be therapeutically anticoagulated.

Mechanical thromboprophylaxis should be initiated in women with contraindications to pharmacologic anticoagulation, and after all cesarean births. Intermittent pneumatic compression stockings are cost-effective versus no thromboprophylaxis after cesarean delivery ; however, compliance has been shown to be suboptimal. For women in whom significant risk factors persist after delivery, extended prophylaxis (6 to 8 weeks postpartum) is recommended. Women are at the highest risk for thrombotic events in the first week postpartum ; therefore, careful postdischarge planning and evaluation of VTE risk are equally as important as inpatient management.

The incidence of AFE is difficult to establish because (1) there are no universally accepted diagnostic criteria, (2) differing ascertainment methods yield divergent rates of AFE, and (3) there are no serum or histologic markers that are specific for AFE, making AFE a clinical diagnosis that is ultimately a diagnosis of exclusion. The dependence on clinical criteria has likely resulted in both over- and under-diagnosis; mild cases without permanent sequelae may not be reported, and many reports, particularly those based on administrative codes, likely include inappropriate diagnoses of AFE in women who become critically ill from other causes. As AFE is considered the least preventable cause of maternal mortality, there may be medical-legal pressure to diagnose AFE in some cases of maternal mortality or severe morbidity. The lack of uniform diagnostic criteria is a significant barrier to furthering our understanding of AFE.

In an effort to standardize diagnosis and reporting of AFE for research purposes, in 2016 an expert panel convened by the Society for Maternal-Fetal Medicine (SMFM) and the AFE Foundation proposed diagnostic criteria for AFE. Notably, this definition requires documentation of coagulopathy to confirm diagnosis and excludes patients who were febrile during labor. It is intentionally biased toward specificity in an effort to standardize reporting; thus, even some cases considered by experts to represent true cases of AFE do not meet all components of this definition. Similar, but slightly more liberal definitions of AFE, have been established by the International Network of Obstetric Survey Systems (INOSS), the UK Obstetric Surveillance System (UKOSS), and by consensus in Japan (see Table 38.4 ).

The challenges of applying definitions to AFE are evident from studies that have combined expert case review with application of various consensus criteria. In an analysis of cases submitted to the US AFE Registry, 12% of cases were considered atypical because they did not meet the full research criteria, but on expert review were considered to represent AFE. A retrospective observational study confirmed that a larger number of cases are classified as AFE using Japanese criteria compared with US or UKOSS criteria. In an international cohort study that included a comparison of criteria, the INOSS found that 31% of cases collected by member institutions met INOSS, but not SMFM criteria, with a lack of evidence for disseminated intravascular coagulation (DIC) being the most common reason for not meeting SMFM criteria. Similarly, in the French Confidential Enquiry into Maternal Deaths (2007 to 2011), documentation of coagulopathy was missing for 14 of 39 deaths. Practically, while obtaining laboratory studies to assess coagulation status can be essential in the management of a critically ill patient, it may not occur in the appropriate time frame in the context of ongoing resuscitation.

While a rate of up to 6 per 100,000 pregnancies has been recently reported in the United States based on data from the National Inpatient Sample, this discrepancy likely represents the result of ascertaining cases using administrative codes versus diagnostic criteria rather than geographical variation. Overdiagnosis of AFE in administrative data has been identified in studies from a regional surveillance system in Australia that has the capacity to systematically review records for all cases identified from administrative data. By only counting women using a validated case identification system, the reported incidence of AFE decreased from 6.3 to 3.3 cases per 100,000 pregnancies. The largest international study of the epidemiology of AFE suggested a much lower event rate of 0.8 to 1.8 per 100,000 pregnancies, with a lower rate when the SMFM criteria are applied and a higher rate using the more liberal UKOSS criteria.

Maternal demographic factors, including older age and maternal race or ethnicity, have been associated with AFE in population-based studies. Other obstetric factors such as abnormal placentation, placenta previa, placental abruption, eclampsia, multiple gestation, induction of labor (particularly with prostaglandins), artificial or spontaneous rupture of membranes, fetal demise, and operative delivery have also been associated with AFE. Notably, 66% of women in the US AFE registry had a history of atopy, latex, medication, or food allergy. This potentially may reflect a predilection for immunologic hyperreactivity in patients with AFE.

Because nonreassuring fetal heart rate (FHR) tracings can complicate AFE in labor, cesarean delivery may be a consequence, rather than a cause, of intrapartum AFE. Nonetheless, there was a strong association between cesarean birth and postpartum AFE in the INOSS data set, with an adjusted OR (aOR) of 14.02 ; notably, 61% of women did not labor prior to their cesarean delivery, and 33% of cesarean deliveries complicated by postpartum AFE were elective. In the US registry, of the patients who had a cesarean delivery and AFE, only 27.5% underwent emergency cesarean delivery in response to AFE. Overall these results suggest that the association between cesarean birth and AFE is not solely a consequence of emergency intrapartum cesarean delivery prompted by nonreassuring fetal well-being as a result of maternal hemodynamic collapse.

Despite possible association between AFE and maternal demographic characteristics, obstetric complications, and labor outcomes, the rarity of AFE and the tenuous nature of the described associations means that none of the potentially identified risk factors carry clinical utility for prediction or risk stratification of AFE.

In 1941, Steiner and Lushbaugh described eight autopsies after fatal intrapartum shock in which examination of lung tissue revealed embolic material of squamous cells, mucin, meconium, and amorphous eosinophilic material. Because all of these patients were described as having tumultuous labors with stronger than usual uterine contractions, it was presumed that the forceful contractions loosened or tore the placenta and forced the emboli into the maternal circulation. Yet, periods of uterine tachysystole are the least likely times for maternoplacental exchange of embolic material to occur as uterine blood flow ceases. The tachysystole is probably a result of endogenous norepinephrine (noradrenaline) release and, therefore is likely temporally related to, but not causative for, embolic material transfer.

Large intravenous boluses of human meconium suspended in human amniotic fluid can precipitate cardiovascular collapse in rabbits and dogs, but injection of autologous amniotic fluid fails to reproduce the AFE syndrome in many animal models, including primates. Passage of fetal squames, lanugo hair, and mucin into the maternal pelvic vasculature appears to be a common event at term, and fetal material has been identified in pulmonary arterial samples aspirated from critically ill women who did not have AFE. Furthermore, in a goat model of AFE, histopathologic analysis of the lungs after injection of autologous amniotic fluid failed to demonstrate evidence for amniotic debris in 19 of 29 animals. Therefore, the presence of fetal tissue in the lungs is neither sensitive nor specific for the diagnosis of AFE.

The trigger for development of AFE, as well as the pathophysiology driving the associated cardiovascular collapse and coagulopathy, are all unknown. Given that AFE appears to be a systemic inflammatory response, its pathophysiology may include the inappropriate release of endogenous inflammatory mediators, such as arachidonic acid metabolites (i.e., thromboxane, prostaglandins, leukotrienes), although a role for these inflammatory mediators in AFE has not yet been definitively established.

The large proportion of women in AFE registries with a history of allergy or atopy has led to suggestions of an anaphylactoid mechanism. In support of this theory, the symptoms of AFE were blocked by the administration of a leukotriene inhibitor in a rabbit model. However, a series of case reports suggested that levels of tryptase and histamine are not dramatically or universally elevated among women with AFE. While mast cell degranulation may play a role in the pathophysiology of AFE, this may be a secondary product of the inflammatory cascade, rather than causal, and thus the term anaphylactoid syndrome of pregnancy may be a misnomer.

Other immune-mediated mechanisms may be potential mediators of AFE. A case-control study demonstrated low levels of the complement components C3 and C4 among women diagnosed with AFE compared with controls, suggesting that complement activation may also contribute to the inflammatory cascade. Levels of C1 esterase inhibitor (C1INH), a regulator of the complement pathway, have also been shown to be decreased in AFE compared with controls. These studies should be considered preliminary; it is unknown whether complement plays a primary, secondary, or no role in AFE.

Coagulopathy develops in the majority of women who survive initial cardiovascular collapse. In vitro studies using amniotic fluid and viscoelastic testing suggested that amniotic fluid may accelerate thrombin production and increase platelet activation, leading to a consumptive coagulopathy, although the in vivo relevance of these findings has not been established. One proposed mechanism for the coagulopathy in AFE involves tissue factor. As pregnancy progresses, increasing amounts of tissue factor, a potent procoagulant, accumulates in the amniotic fluid. Tissue factor binds factor VII, thus activating the extrinsic pathway and triggering clotting by activating factor X, with the subsequent development of a consumptive coagulopathy. A second possible mechanism is that amniotic fluid has a thromboplastin-like effect, which induces platelet aggregation, releases platelet factor III, and activates the clotting cascade. Other components of amniotic fluid, the amniochorion, and the placenta have also been implicated in contributing to the coagulopathy. Uterine atony, from a specific myometrial depressant or from uterine hypoperfusion, may exacerbate hemorrhage and the consumptive coagulopathy seen in AFE. While these studies suggest that the bleeding seen in AFE is due primarily to a consumptive coagulopathy, conflicting evidence suggests that the coagulopathy may primarily be due to hypofibrinogenemia. Specifically, reports of viscoelastic testing conducted early in AFE suggest that, at least in some cases, the initial coagulopathy may result from isolated hyperfibrinolysis and hypofibrinogenemia.

AFE presents clinically as cardiorespiratory collapse and coagulopathy during labor, immediately postpartum, or very rarely after abdominal trauma or abortion.

AFE most often occurs during labor; intrapartum events comprised 46% of cases in the INOSS registry and 70% of cases in the initial cohort of the US registry. With the caveat that milder cases may not be as reliably reported, severe initial presentations are common: 50% of cases in the INOSS registry presented with cardiac arrest, 67% of cases in an Israeli retrospective study presented with sudden loss of consciousness, and 97% of cases in the US registry presented with hypotension. AFE may also be accompanied by cough, cyanosis, or seizures, and some cases are accompanied by nonspecific premonitory symptoms such as restlessness or agitation. Maternal symptoms may precede FHR changes. Fetal bradycardia, or the abrupt onset of variable decelerations that progress to fetal bradycardia, may also herald AFE in labor ( Fig. 38.2 ).

Fetal Heart Rate Tracing in a Patient With Amniotic Fluid Embolism. Maternal symptoms began just before the onset of spontaneous uterine tachysystole and fetal bradycardia.

Modified from Clark SL, Hankins GDV, Dudley DA, et al. Amniotic fluid embolism: analysis of the national registry. Am J Obstet Gynecol . 1995;172:1158–1167.

Point-of-care echocardiography has established that the cardiovascular collapse that heralds the onset of AFE is typically accompanied, and likely caused, by acute right ventricular failure. While right ventricular failure in AFE is thought to be mediated by acute pulmonary hypertension, the molecular mediators causing increased pulmonary vascular resistance are unknown. Echocardiographic findings include a dilated, akinetic right ventricle and a normally contracting left ventricle with a nearly obliterated cavity. Right ventricular failure results in an underfilled left ventricle, decreased systemic cardiac output, and hypotension.

Patients who survive the initial cardiorespiratory collapse associated with AFE subsequently develop profound coagulopathy. This has classically been described as DIC, and numerous reports document thrombocytopenia with prolonged prothrombin time and aPTT in addition to hypofibrinogenemia or “flatline” viscoelastic testing suggesting global hemostatic failure. More recent reports, however, suggest that hyperfibrinolysis and severe hypofibrinogenemia may be the hallmarks of coagulation failure in AFE, with less prominent decreases in factor V and preservation, at least initially, of other components of the coagulation cascade. It is unclear whether the global hemostatic failure that has been described represents progression of the disease process or a more severe variant of AFE-induced coagulopathy. The coagulopathy described in some cases of AFE is indistinguishable from cases of severe placental abruption. It is unclear whether they share a common inciting mechanism or whether this represents a common pathway in acute obstetric coagulopathy.

Because many of the signs and symptoms of AFE are nonspecific, AFE must be distinguished from other life-threatening causes of cardiovascular collapse in obstetric patients ( Box 38.2 ). In an analysis of cases submitted to the US AFE Registry, obstetric hemorrhage was most commonly misdiagnosed as AFE. While severe obstetric hemorrhage may cause life-threatening hypotension and coagulopathy, it can be distinguished from AFE by the sequence of presentation; massive blood loss precedes cardiovascular collapse in hemorrhage, whereas cardiovascular collapse precedes blood loss in AFE. Furthermore, except in cases of placental abruption, massive blood loss typically precedes development of a coagulopathy in obstetric hemorrhage, whereas a coagulopathy precedes significant blood loss in AFE. Reflecting this, the hemoglobin/ fibrinogen ratio, when assessed early, has been suggested as a potential tool for differentiating AFE from postpartum hemorrhage from other sources. The fibrinogen level often decreases earlier than hemoglobin in AFE, leading to a high hemoglobin/fibrinogen ratio Sepsis is associated with hypotension and can cause both hypoxia and coagulopathy, but typically is insidious in onset and frequently is associated with maternal hyper- or hypothermia. Anaphylaxis can cause hypotension and hypoxia, but is not associated with a coagulopathy and occurs in association with exposure to an allergen. Furthermore, in cases of anaphylaxis, tryptase levels remain elevated 1 to 2 hours following suspected anaphylactic reactions, whereas serum tryptase levels are not elevated in cases of AFE. High neuraxial block can cause hypotension and respiratory compromise, but does not include coagulopathy. While pulmonary or air embolism can cause hypotension and hypoxia, they are not typically associated with coagulopathy. Similarly, hemodynamic collapse from a primary cardiac etiology, such as an acute myocardial infarction, does not present with coagulopathy and typically occurs in the clinical context of patients with known risk factors or recognized cardiac pathology.

Box 38.2

Differential Diagnosis of Amniotic Fluid Embolism

Nonobstetric

• •

  Myocardial infarction

• •

  Pulmonary embolism

• •

  Aspiration

• •

  Sepsis

• •

  Anaphylaxis

• •

  Venous air embolism

Obstetric

• •

  Placental abruption

• •

  Eclampsia

• •

  Uterine rupture or laceration

• •

  Obstetric hemorrhage

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