Venous thromboembolism in pregnancy: Epidemiology, pathogenesis, and risk factors

INTRODUCTION — Pregnancy and the postpartum period are well-established risk factors for venous thromboembolism (VTE). During pregnancy and postpartum, VTE can manifest as an isolated lower extremity deep vein thrombosis (DVT) or a clot can break off from the lower extremities and travel to the lung to present as pulmonary embolism (PE), which can be life-threatening. Thus, the detection of DVT during pregnancy is critical to preventing deaths from PE.

The epidemiology, pathogenesis, and risk factors of VTE during pregnancy and the postpartum period will be reviewed here. Other related topics are discussed separately.

●(See "Deep vein thrombosis in pregnancy: Clinical presentation and diagnosis".)

●(See "Pulmonary embolism in pregnancy: Clinical presentation and diagnosis".)

●(See "Venous thromboembolism in pregnancy: Prevention".)

●(See "Venous thromboembolism in pregnancy and postpartum: Treatment".)

●(See "Use of anticoagulants during pregnancy and postpartum".)

EPIDEMIOLOGY

Overall — VTE is diagnosed in 1 per approximately 500 to 2000 pregnancies [1-8]. While the overall incidence is low, VTE in pregnancy has a reported incidence that is 4 to 50 times higher compared with nonpregnant females [1-3,9-12]. It is also a significant cause of pregnancy-associated mortality. Based on data from the Pregnancy Mortality Surveillance System conducted by the Centers for Disease Control and Prevention (CDC) between 2017 and 2019, thrombotic pulmonary or other embolism contributed to 10.5 percent of all pregnancy-related deaths [13]. (See "Overview of maternal mortality", section on 'Causes'.)

VTE is more common during the postpartum compared with the antepartum period, as demonstrated in most (but not all) studies [2,12,14-22]. In a five-year retrospective crossover-cohort analysis of an insurance claims database that examined rates of thrombosis during the first year following delivery, the risk of thrombosis was highest in the first six weeks postpartum (25 per 100,000 deliveries) and declined to lower but still elevated rates at 7 to 12 weeks (6 per 100,000 deliveries) [20]. Rates approximated that of the general population by 13 to 18 weeks (3 and 2 per 100,000 deliveries, respectively).

Deep vein thrombosis (DVT) is also approximately three times more common than pulmonary embolism (PE) in pregnancy [2,8,23]. In a cross sectional analysis of the National Inpatient Sample from 2000 to 2018 and including more than 73 million deliveries in the United States, more delivery-associated hospitalizations were complicated by DVT than PE (5.1 versus 1.7 per 10,000 deliveries) [23]. No studies describe an increased incidence of upper extremity DVT during pregnancy or the postpartum period.

Data on trends in incidence of VTE in pregnancy and postpartum are conflicting. While some retrospective studies have reported decreased rates of VTE (particularly in the postpartum period) [2,15], others have reported increasing rates [24]. In the cross sectional analysis of the National Inpatient Sample from 2000 to 2018, rates of VTE increased among patients with vaginal births (average annual percent change 2.5 percent, 95% CI 1.5-3.5 percent), but not among those with cesarean births [23].

Compared with White females, Black females have a higher risk of VTE (odds ratio 1.5) [25] and deaths from VTE [13]. Social and structural determinants of health (eg, disparities in access to care, perceived racism) are thought to contribute to this disparity rather than race itself. (See "Racial and ethnic inequities in obstetric and gynecologic care and role of implicit biases".)

Pelvic thrombosis — Pelvic vein thrombosis is also more commonly diagnosed during pregnancy and the postpartum period than in the nonpregnant population. However, its true incidence during pregnancy is unknown. This may be due to the poor sensitivity of proximal vein compression ultrasound (CUS) for the diagnosis of thrombosis in the pelvic veins [26]. In an analysis of the DVT-Free Registry enrolling 5451 consecutive patients with CUS-confirmed DVT, rates of isolated pelvic vein thrombosis were higher in antepartum and postpartum patients than in nonpregnant patients (12 and 11 percent versus 1 percent, respectively) [12]. Another retrospective study of 124 pregnant patients showed 64 percent of proximal DVTs were restricted to the iliac and/or femoral vein [27].

PATHOGENESIS — Pregnancy and the postpartum period are marked by the presence of all three components of Virchow's triad: venous stasis, endothelial injury, and a hypercoagulable state [1]. All features likely contribute to the increased risk of VTE in pregnancy.

Venous stasis — Venous stasis of the lower extremities occurs during pregnancy because of several factors:

●Pregnancy-associated changes in venous capacitance – Although blood volume and total venous return are increased in pregnancy, the linear flow velocity in the lower extremity veins is decreased due to hormonally induced dilation of capacitance veins, leading to venous pooling and valvular incompetence [28]. (See "Maternal adaptations to pregnancy: Cardiovascular and hemodynamic changes".)

●Compression of large veins by the gravid uterus – Changes in venous capacitance are amplified by inferior vena cava (IVC) and iliac vein compression by the gravid uterus, especially later in pregnancy [28,29]. In one prospective study including 24 pregnant individuals undergoing monthly CUS examinations of the lower extremities, progressive dilation of the deep veins of the legs was observed with increasing gestation [30]. This corresponded to a decreased flow velocity in the left common femoral vein and IVC that was most severe in the supine position (eg, during cesarean birth).

●Compression of the left iliac vein by the right iliac artery is thought to contribute to the predilection for left-sided deep vein thrombosis during pregnancy [9,31]. (See "Deep vein thrombosis in pregnancy: Clinical presentation and diagnosis", section on 'Clinical presentation'.)

Endothelial injury — Delivery is associated with vascular injury and changes at the uteroplacental surface, which probably contribute to the increased risk of VTE in the immediate postpartum period. Forceps, vacuum extraction, or cesarean birth can exaggerate vascular intimal injury and amplify this phenomenon [9].

Hypercoagulability — Pregnancy is a hypercoagulable state associated with progressive increases in several coagulation factors, including factors I, II, VII, VIII, IX, and X, along with a decrease in protein S [5,9,32]. A progressive increase in resistance to activated protein C is normally observed in the second and third trimesters [33], and high resistance to activated protein C was shown in one study to be associated with an increased risk for pregnancy-related VTE [34]. Activity of the fibrinolytic inhibitors plasminogen activator inhibitor (PAI)-1 and PAI-2 is increased during pregnancy, although total fibrinolytic activity may not be impaired [35,36].

RISK FACTORS

●Pregnancy and postpartum – Pregnancy, in itself, is a risk factor for the development of VTE (see 'Pathogenesis' above). Commonly cited antepartum and postpartum risk factors associated with VTE during pregnancy are listed in the table (table 1) [6,14,15,18-23,37-41].

Most studies report equal distribution of VTE across the trimesters of pregnancy [1,9,14-18,42]. However, two large conflicting retrospective studies reported a predominance in the first trimester (50 percent before 15 weeks) and third trimester (60 percent) [19,43].

The risk of VTE in the postpartum period is higher than at any point in pregnancy; the risk is highest in the first six weeks postpartum and declines to rates that approximate that of the general population by about 13 to 18 weeks [20]. (See 'Epidemiology' above.)

Risk factor models for VTE in pregnancy and postpartum have been proposed, but have not been widely accepted [4,44].

●Inherited thrombophilias – The risk of VTE is further magnified in pregnant patients who have inherited thrombophilias (eg, factor V Leiden; antithrombin III, protein S, or protein C deficiency; antiphospholipid syndrome) [5,11,45-50].

The variable range in risk of VTE in pregnant patients with the most common inherited thrombophilias is illustrated by the following studies:

•Compared with the general population, the thrombotic risk is three times higher for pregnant patients with factor V Leiden [5]. Further augmenting that risk in pregnant patients with factor V Leiden deficiency and G20210A prothrombin-gene mutation is a history of prior VTE in the patient or an affected first-degree relative (up to 50-fold) [50]. (See "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A", section on 'Obstetric issues'.)

•When compared with pregnant patients without a known thrombophilia, pregnant patients with an inheritable deficiency of antithrombin III, protein S, or protein C had an eightfold increased risk of VTE in the antepartum and postpartum periods combined [45]. (See "Antithrombin deficiency" and "Protein S deficiency" and "Protein C deficiency".)

•Among patients with known antiphospholipid syndrome, one prospective study described a 5 percent risk of thrombosis during pregnancy [51]. (See "Clinical manifestations of antiphospholipid syndrome".)

This is discussed in more detail separately. (See "Inherited thrombophilias in pregnancy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism" and "Society guideline links: Anticoagulation in pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Deep vein thrombosis (blood clot in the leg) (The Basics)")

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical significance – During pregnancy and postpartum, venous thromboembolism (VTE) can manifest as an isolated lower extremity deep vein thrombosis (DVT) or a clot can break off from the lower extremities and travel to the lung to present as pulmonary embolism (PE), which can be life-threatening. Thus, the detection of DVT during pregnancy is critical to preventing deaths from PE. (See 'Introduction' above.)

●Epidemiology (see 'Epidemiology' above)

•While the overall incidence of VTE in pregnancy is low, VTE in pregnancy has a reported incidence that is 4 to 50 times higher compared with nonpregnant females.

•VTE is more common postpartum than during pregnancy.

•During pregnancy and postpartum, DVT is approximately three times more common than PE.

●Pathogenesis – Pregnancy and the postpartum period are marked by the presence of all three components of Virchow's triad; all likely contribute to the increased risk of VTE in pregnancy (see 'Pathogenesis' above):

•Venous stasis – Venous stasis of the lower extremities occurs during pregnancy because of changes in venous capacitance and compression of large veins by the gravid uterus. Compression of the left iliac vein by the right iliac artery is thought to contribute to the predilection for left-sided DVT during pregnancy. (See 'Venous stasis' above.)

•Endothelial injury – Delivery is associated with vascular injury and changes at the uteroplacental surface, which probably contribute to the increased risk of VTE in the immediate postpartum period. (See 'Endothelial injury' above.)

•Hypercoagulable state – Pregnancy is a hypercoagulable state associated with progressive increases in several coagulation factors. (See 'Hypercoagulability' above.)

●Risk factors

•Pregnancy and postpartum – Pregnancy, in itself, is a risk factor for the development of VTE. Most studies report equal distribution of VTE across the trimesters of pregnancy; however, data are conflicting. The risk of VTE in the postpartum period is higher than at any point in pregnancy. The risk is highest in the first six weeks postpartum and declines to rates that approximate that of the general population by about 13 to 18 weeks. Antepartum and postpartum risk factors for VTE are listed in the table (table 1). (See 'Risk factors' above.)

•Inherited thrombophilias – The risk of VTE is further magnified in pregnant patients who have inherited thrombophilias (eg, factor V Leiden; antithrombin III, protein S, or protein C deficiency; antiphospholipid syndrome). (See 'Risk factors' above and "Inherited thrombophilias in pregnancy".)