Venous Thromboembolism in Pregnancy

Amy Archer

Mary Callis

OVERVIEW

Pregnancy and the puerperium result in a 5-fold greater risk of venous thromboembolism (VTE) compared to nonpregnant states.¹ Given the physiologic changes that occur with pregnancy and the potential risks of diagnostic testing to both mother and fetus, the diagnosis and management of VTE can be challenging.

Background and Importance

VTE complicates 0.5 to 2.2 per 1000 deliveries.² Eighty percent of VTE cases in pregnancy are isolated deep vein thrombosis (DVT) and approximately 20% are pulmonary embolism (PE) or a combination of DVT/PE.¹ The risk increases during each trimester of pregnancy, with 12.4% of VTEs being diagnosed in the first trimester, 15.3% during the second trimester, and 72.3% in the third trimester.² The postpartum period is associated with a 2- to 5-fold increased risk for VTE compared to the antepartum period, with 70% of all pregnancy-associated VTEs occurring during the postpartum period.³^,⁴^,⁵ The highest risk is in the first 6 weeks postpartum and declines thereafter, reaching the nonpregnant level by 13 to 18 weeks. Although the overall rate of PE in pregnancy is low, it is a significant cause of maternal mortality in developed countries, contributing to 9.2% of maternal deaths in the United States.⁶^,⁷

Risk Factors

Risk factors for VTE in pregnancy are classified by antepartum and postpartum periods (Table 3.1). During the antepartum period, the risk for VTE includes personal history of VTE, thrombophilia, maternal age 35 years or older, multiple gestation, preeclampsia/eclampsia, medical comorbidities (preexisting diabetes, varicose veins, inflammatory bowel disease, sickle cell disease), and the use of assisted reproductive technology (ART).¹^,⁸ In addition, body mass index (BMI) ≥ 30 kg/m², smoking, and urinary tract infection may increase the risk for antepartum VTE.⁸ There is an increased risk of VTE in ART, particularly in the first trimester. Many of these cases have been attributed to the presence of ovarian hyperstimulation syndrome (OHSS).¹^,⁹ OHSS is a complication of ART that occurs in 3% to 8% of successful in vitro fertilizations.⁹ The syndrome is accompanied by supraphysiologic estradiol concentrations and is correlated with VTE in unusual locations, such as in the upper extremities and in the internal jugular veins.¹⁰

TABLE 3.1 Risk Factors for Vte in the Antepartum and Postpartum Period

Antepartum Period	Postpartum Period
Previous VTE	C-section
Thrombophilia	Multiple gestation
Medical comorbidities	Obstetric hemorrhage
Maternal age ≥ 35 years	Preterm delivery
BMI ≥ 30 kg/m²	Stillbirth
Multiple gestation	Medical comorbidities
Smoking	Maternal age ≥ 35 years
Preeclampsia/eclampsia	BMI ≥ 30 kg/m²
Acute systemic infection	Smoking
Assisted reproductive technology	Surgical procedure
BMI, body mass index; VTE, venous thromboembolism.
Data from Linnemann B, Bauersachs R, Rott H, et al.; Working Group in Women’s Health of the Society of Thrombosis and Haemostasis. Diagnosis of pregnancy-associated venous thromboembolism—position paper of the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH). Vasa. 2016;45(2):87-101; Sultan AA, Tata LJ, West J, et al. Risk of first venous thromboembolism in pregnant women in hospital: population based cohort study from England. Blood. 2013;121:3953-3961.

Hereditary thrombophilia increases the risk of pregnancy-associated VTE by 34-fold however, not all thrombophilias carry the same risk.¹¹ A meta-analysis of pregnant women with antithrombin deficiency, homozygous prothrombin G20210A mutation, protein C/S deficiency, and homozygous factor V Leiden recommends antepartum and postpartum thromboprophylaxis.¹¹ A previous history of VTE in a pregnant patient can increase pregnancy-associated VTE by 10% if the patient does not receive thromboprophylaxis.¹²

Postpartum risk factors for VTE include cesarean section, multiple gestation, obstetric hemorrhage, preterm delivery at or before 37 weeks, stillbirth, medical comorbidities (varicose veins, cardiac disease, inflammatory bowel disease), smoking, BMI ≥ 30 kg/m², and maternal age 35 years or older.⁸ Cesarean section itself carries a 4 times greater risk for VTE as compared to vaginal delivery (3 in 1000 women), independent of other VTE risk factors.¹³

Pathophysiology

Pregnancy is an independent risk factor for VTE. Hypercoagulability in pregnancy is believed to be an evolutionary adaptation conferring survival benefit to pregnant women facing the trauma of childbirth. Three changes involving blood coagulation and fibrinolysis that result in a procoagulant state occur in pregnant women. First, is an increase in fibrinogen, factors VII, VIII, C, and IX as well as von Willebrand factor. Second, is reduced coagulation inhibitors in the form of acquired resistance to activated protein C, decrease in protein S, and antithrombin activities. Finally, fibrinolysis is inhibited by an increase in plasminogen activator inhibitors 1 and 2.¹

The venous system in the lower extremities is prone to thrombosis for several reasons. There is venous dilatation hormonally induced by progesterone, which leads to venous pooling and valvular incompetence. In addition, there is compression of the iliac veins and inferior vena cava (IVC) by the gravid uterus.¹^,¹⁴ At delivery, endothelial damage to the iliac veins may contribute to the increased risk of VTE in the immediate postpartum period.

DIAGNOSTIC TESTING

Clinical prediction rules are applied to assess pretest probability routinely in nonpregnant populations when considering the diagnosis of VTE. These include the Wells’ score, the pulmonary embolism rule-out criteria (PERC rule), and the revised Geneva score (RGS).¹⁵^,¹⁶^,¹⁷ These clinical
prediction rules are not applicable to the pregnant patient given the physiologic changes that occur in pregnancy. Pregnant patients often experience dyspnea, leg swelling, and an increased resting heart rate.¹⁸ All three clinical prediction rules include resting heart rate either more than 100 (PERC and Wells) or more than 95 (RGS).¹⁵^,¹⁶^,¹⁷ Pregnant patients are less likely to have comorbidities listed as risk factors in these models. These clinical prediction rules are not recommended in pregnancy to exclude VTE.¹⁹

D-dimer is a degradation product of cross-linked fibrin and is a sensitive but nonspecific marker for VTE.¹ A negative test is helpful in the exclusion of VTE. In pregnancy, however, there is a steady increase in D-dimer levels, with a peak on the first day after delivery.²⁰^,²¹ Several studies attempted to identify a D-dimer threshold in pregnancy. None of these studies have validated appropriate ranges during each trimester of pregnancy that can be successfully adopted clinically in excluding VTE. However, if the range for D-dimer in nonpregnant patients is applied in pregnancy, normal D-dimers exclude clinically relevant VTE as reliably as in the nonpregnant population.²²

ACUTE DEEP VENOUS THROMBOSIS

Overview

The incidence of DVT in pregnancy is between 7.2% and 8.8%.²⁴^,²⁵ The anatomic distribution of DVT in pregnancy differs from that of nonpregnant patients. Serial compression ultrasounds performed in pregnancy found 65% of DVT cases to be isolated to the iliofemoral veins and 12% isolated to iliac deep veins.²⁶ In contrast, nonpregnant patients most commonly develop DVT in the calf that extends proximally.

Clinical Features

The clinical presentation may be challenging as leg swelling is a frequent finding in pregnancy. Signs and symptoms of DVT are diffuse pain and swelling of the extremity, with possible accompanying erythema, warmth, and tenderness. The majority of DVTs presenting in pregnancy are left-sided, with a reported incidence of 88%.²⁵^,²⁷ There is increased venous stasis in the left leg caused by compression of the left iliac vein by the gravid uterus where it crosses the right iliac artery.²⁷ DVT of the iliac or femoral vein in pregnancy may present with pain in the buttocks, groin, flank, or abdomen.¹ This can be a diagnostic challenge because evaluation of pelvic vein thrombosis by ultrasound is more difficult.¹

Diagnostic Testing

A diagnostic algorithm for suspected DVT in pregnancy is found in Figure 3.1. Compression ultrasound is the method of choice to diagnose DVT in pregnant and nonpregnant patients.¹⁹ There is high sensitivity using compression ultrasound as a single test for the diagnosis of DVT in nonpregnant patients.²⁸ In pregnancy, however, there is increased frequency of isolated iliac or femoral vein thrombosis, which is more difficult to diagnose by compression ultrasound especially with increasing gestational age.²⁷ If a pregnant patient presents with unilateral leg swelling with back or pelvic pain and iliac vein thrombosis is suspected, additional imaging is necessary. A Doppler flow or color-coded duplex ultrasound of the iliac vein should be ordered. A complete ultrasound examination including compression ultrasound of the femoral, popliteal, and calf veins along with duplex ultrasound of the IVC, iliac veins, and small saphenous veins at the junction with the deep venous system results in a 10.5% diagnosis of DVT with a negative predictive value (NPV) of 98.2% (95% confidence interval [CI] 94.9%-99.4%).²⁹

If a patient has a negative or nonconclusive compression ultrasound, and clinical suspicion for DVT remains, there are several options. If clinical suspicion is not high, serial ultrasound and clinical follow-up are done on days 3 and 7. A prospective study of pregnant women with suspected DVT found 7.2% had a DVT diagnosed after compression ultrasound and Doppler imaging of the external iliac vein. The risk of VTE during a 3-month follow-up period (during ongoing pregnancy or at least 6 weeks postpartum) was 0.49% (95% CI 0.09%-2.71%), with a NPV of 99.5% and a sensitivity of 94.1%.²⁶

Figure 3.1: Diagnostic algorithm for suspected deep vein thrombosis in pregnancy. CUS, compression ultrasound; PE, pulmonary embolism; VTE, venous thromboembolism. (Data from Linnemann B, Bauersachs R, Rott H, et al.; Working Group in Women’s Health of the Society of Thrombosis and Haemostasis. Diagnosis of pregnancy-associated venous thromboembolism—position paper of the Working Group in Women’s Health of the Society of Thrombosis and Haemostasis (GTH). Vasa. 2016;45(2):87-101; Kline JA, Kabrhel C. Emergency evaluation for pulmonary embolism, part 2: diagnostic approach. J Emerg Med. 2015;49(1):104-117; Tan M, Huisman MV. The diagnostic management of acute venous thromboembolism during pregnancy: recent advancements and unresolved issues. Thromb Res. 2011;127(3):S13-S16.)

If clinical suspicion for DVT is high, and compression ultrasound and Doppler ultrasound of the iliac veins are negative or nonconclusive, magnetic resonance venography (MRV) is recommended as the next imaging modality in pregnant patients. There are limited data regarding the use of MRV during organogenesis, but magnetic resonance imaging (MRI) without contrast appears safe, especially after the first trimester.³⁰ This study should be done without contrast as gadolinium has potential harmful fetal risks.¹

Management

Medical Management

Low-molecular-weight heparins (LMWH) are the anticoagulant of choice for treating pregnant women with acute DVT.³¹ LMWH do not cross the placenta and do not appear in significant levels in breast milk.³¹ LMWH have less side effects in comparison with unfractionated heparin (UFH). Enoxaparin is the most commonly used LMWH at a dose of 1 mg/kg subcutaneous injection every 12 hours. The potential side effects of UFH include heparin-induced thrombocytopenia (HIT), hemorrhage, and osteoporosis.³²

The use of other heparin-like anticoagulants such as fondaparinux during pregnancy is limited and the American College of Chest Physicians (ACCP) recommends them only in patients with severe allergic reactions to heparin or HIT (grade 2C).³³ Vitamin K antagonists such as warfarin are contraindicated in pregnant women as they cross the placenta and may cause both teratogenicity and fetal bleeding.¹ Anticoagulants including the direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban and apixaban) cross the placental barrier, which can lead to anticoagulation within the fetus. These drugs are also secreted in breast milk. In animal studies, dabigatran and rivaroxaban cause teratogenic effects, placental abnormalities, fetal hemorrhage, and reduced fetal viability.³¹ The ACCP recommends avoiding the use of oral direct thrombin inhibitors and factor Xa inhibitors (Grade 1C) and that the treatment for acute VTE in pregnant women be continued for at least 6 weeks postpartum or for a minimum duration of 3 months of therapy.³³

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