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Prevention and Treatment of Venous Thromboembolism in Pregnancy
Pregnant persons and those who are postpartum are at increased risk of venous thromboembolism (VTE). Although pregnancy-related VTE can affect any part of the venous circulation, as in the non-pregnant population, it most commonly manifests as deep vein thrombosis (DVT) or pulmonary embolism (PE). Management of pregnancy-related VTE is complicated as the diagnosis, prevention, and treatment of pregnancy-related VTE must consider fetal, as well as maternal, well-being. Moreover, there are limited high-quality data to help clinicians manage this patient population.
Epidemiology
VTE is a cause of significant maternal morbidity and mortality globally. The incidence of pregnancy-related VTE has been estimated at 1.2 per 1000 deliveries (95% confidence interval [CI], 0.6 to 1.8). Although this absolute risk is low, VTE is responsible for 3.2% of all maternal deaths. In higher-income countries, where death from obstetrical hemorrhage is less common, that figure is 13.8%.
In a meta-analysis of 20 studies, the pooled incidence of VTE was similar in each of the antepartum and postpartum periods at 0.6 per 1000 pregnant persons. Given the shorter length of the postpartum period, the daily risk is substantially higher after delivery (15- to 35-fold increase in relative risk) than during pregnancy (5- to 10-fold relative risk increase). The daily VTE risk is highest in the first three to six weeks after delivery, although a small absolute risk increase may be seen up to 12 weeks after delivery.
Risk Factors
The most important risk factor for pregnancy-associated VTE is a prior history of venous thrombosis, which increases the risk of VTE antepartum to 4.2% (95% CI, 0.3% to 6.0%) and postpartum to 6.5% (95% CI, 4.3% to 9.7%). The risk of antepartum recurrence has been reported to vary according to provoking factors present at the initial event, with estimated risks of 6.4% (95% CI, 3.9% to 10.4%), 3.6% (95% CI, 1.4% to 8.9%), and 1.1% (95% CI, 0.2% to 5.8%) in those with a history of hormonal-associated, unprovoked, and provoked (nonhormonal temporary risk factor) events, respectively.
Inherited thrombophilias are also important risk factors, especially when accompanied by a family history of VTE ( Table 141.1 ). While there have been many studies evaluating the association between hereditary thrombophilias and pregnancy-related VTE, the impact of acquired thrombophilias has been less well investigated in this setting. The most common acquired thrombophilia is antiphospholipid syndrome (see Chapter 139 ). There are few data on the risk of pregnancy-associated VTE in those with antiphospholipid antibody positivity and no prior thrombosis history; however, in those with obstetrical antiphospholipid syndrome, it has been estimated at 0% (95% CI, 0% to 1.2%) antepartum and 1.1% (95% CI, 0.2%% to 6.2%) postpartum.
Table 141.1
Asymptomatic Hereditary Thrombophilia and Risk of Pregnancy-Associated Venous Thromboembolism
Data from Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv . 2018;2(22):6–8.
| Thrombophilia | Antepartum Risk | Postpartum Risk |
|---|---|---|
| Positive Family VTE History [Absolute risk (95% CI) a ] | ||
| Antithrombin deficiency | 2.70% (95% CI, 0%–8.53%) | 4.83% (95% CI, 0%–15.65%) |
| Protein C deficiency | 1.63% (95% CI, 0%–5.02%) | 1.06 (95% CI, 0%–4.09%) |
| Protein S deficiency | 0% (95% CI, 0%–1.46%) | 1.76% (95% CI, 0%–5.99%) |
| Factor V Leiden, heterozygous | 0.50% (95% CI, 0.06%–1.21) | 0.62% (95% CI, 0%–1.90%) |
| Factor V Leiden, homozygous | 6.88% (95% CI, 1.04%–15.83%) | 5.87% (95% CI, 0.57%–14.44%) |
| Prothrombin mutation, heterozygous | 0 (95% CI, 0%–0.73%) | 0.95% (95% CI, 0%–3.26%) |
| Prothrombin mutation, homozygous | No data, likely at least as high as in those with no family history | No data, likely at least as high as in those with no family history |
| Combined thrombophilia | 0 (95% CI, 0%–2.35%), although risk likely at least as high as in those with no family history | 1.06% (95% CI, 0%–5.30%) |
| Negative Family VTE History [Risk Ratio (95% CI); Estimated absolute risk b ] | ||
| Antithrombin deficiency |
|
|
| Protein C deficiency |
|
|
| Protein S deficiency |
|
|
| Factor V Leiden, heterozygous |
|
|
| Factor V Leiden, homozygous |
|
|
| Prothrombin mutation, heterozygous |
|
|
| Prothrombin mutation, homozygous |
|
|
|
|
|
CI , Confidence interval; OR , odds ratio.
a Risks from family cohort studies, estimates of absolute risk (95% CI).
b Risks from case control studies, absolute risk estimated by OR × baseline VTE risk of 0.6/1000 pregnancies.
Many clinical risk factors have been shown to increase the risk of pregnancy-associated VTE ; however, most, including cesarean delivery, have only a small effect with absolute risks far less than 1% in each of the antepartum and postpartum periods. How combinations of independent risk factors might affect overall VTE risk has not been well studied, although one might reasonably expect that combinations of factors might result in more significant risks. Factors with estimated antepartum or postpartum VTE risks greater than 1% are listed in Table 141.2 .
Table 141.2
Clinical Risk Factors for Pregnancy-Associated Venous Thromboembolism With Estimated Risks of Greater Than 1%
Data from Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv . 2018;2(22):6–8; and Bates SM, Middeldorp S, Rodger M, et al. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J Thromb Thrombolysis . 2016;41(1):92–128.
| Clinical Risk Factor | Adjusted Odds Ratio (95% CI) from Case Control Studies and Estimated Absolute Risk (%) a | Absolute Risk % (95% CI) |
|---|---|---|
| Antepartum | ||
| Prior venous thromboembolism | 4.2% (95% CI, 0.3%–6.0%) | |
|
6.4% (95% CI, 3.9%–10.4%) | |
|
3.6% (95% CI, 1.4%–8.9%) | |
|
1.1% (95% CI, 0.2%–5.8%) | |
| Immobility b with prepregnancy BMI ≥25 kg/m 2 | OR: 62.3 (95% CI: 11.5–337.0) Estimated absolute risk: 3.8% | |
| Dermatomyositis |
|
|
| Severe ovarian hyperstimulation syndrome or ovarian hyperstimulation syndrome requiring hospitalization | 1.6%–6.6% | |
| Myeloid leukemia |
|
|
| Postpartum | ||
| Prior venous thromboembolism | 6.5% (95% CI, 4.3–9.7%) | |
| Immobility b with prepregnancy BMI ≥25 kg/m 2 | OR: 40.1 (95% CI: 8.0–201.5) Estimated absolute risk: 2.4% | |
| Infection c following vaginal delivery |
|
|
BMI, Body mass index; CI , confidence interval; OR , odds ratio.
a Absolute risk estimated by OR × baseline VTE risk of 0.6/1000 pregnancies.
b Immobility classified as strict bedrest for ≥1 week in the antepartum period.
c Infection defined as clinical signs/symptoms with fever and elevated white blood cell count.
Pathophysiology
The pathophysiology of pregnancy-associated VTE can be related to Virchow’s triad. Changes in hemostasis include alterations in levels of coagulation factors and natural inhibitors of coagulation that favor thrombosis (increased levels of factor VIII and factor X, von Willebrand factor, and fibrinogen, as well as decreased protein S levels) and a reduction in fibrinolytic activity (increased activity of plasminogen activator inhibitors-1 and -2 and decreased tissue plasminogen activator activity). VTE risk is also heightened by decreased lower extremity venous flow resulting from hormonally mediated increases in lower limb venous distensibility and capacity, as well as by compression of the pelvic veins by the gravid uterus and of the left iliac vein by the right iliac artery. Damage to the endothelium may occur from venous distension and at the time of delivery.
Clinical Manifestations
The clinical manifestations of pregnancy-associated VTE can be similar to those in the non-pregnant population and include lower extremity pain, tenderness, and swelling for DVT and chest pain, dyspnea, tachypnea, tachycardia, palpitations, hemoptysis, pre-syncope/syncope, and apprehension for PE. Symptoms or signs of lower extremity DVT occur in less than 25% of pregnant persons with proven PE.
Differences in VTE presentation during pregnancy include a predilection for left leg DVT (greater than 80% of cases during pregnancy) and for isolated iliac and/or femoral vein thrombosis. These latter events usually present with back, flank, or buttock pain and swelling and discoloration of the entire leg.
Differential Diagnosis
The differential diagnosis for DVT includes venous insufficiency, superficial vein thrombosis, cellulitis, hematoma, ruptured Baker’s cyst, congestive heart failure, and tumor. The differential diagnosis for PE is extensive and includes pneumonia, pleurisy, congestive heart failure, pneumothorax, musculoskeletal pain, and myocardial infarction. Of course, symptoms like those of VTE are common even in uncomplicated pregnancies and are not usually due to DVT or PE. It is, therefore, important to ask about sudden changes or worsening in symptoms and to be vigilant for associated features of VTE out of keeping with normal pregnancy.
Studies in which pregnant women with symptoms suggestive of DVT or PE underwent appropriate testing report a prevalence of VTE of less than 10%. However, healthcare providers must have a high index of suspicion for VTE when a pregnant woman presents with these symptoms since missing a diagnosis exposes the patient to the risk of fatal PE.
Laboratory Manifestations
While D-dimer levels are instrumental in guiding the investigation of suspected VTE in the nonpregnant population, there is less of a role for D-dimer measurements in the pregnant population. The majority of pregnant patients have an elevated D-dimer, especially as pregnancy progresses. However, D-dimer values are significantly higher in pregnant patients who have confirmed DVT, compared with pregnant patients without DVT. While higher D-dimer cut-points or trimester specific D-dimer levels have been proposed to improve the utility of D-dimer values during pregnancy, these strategies have not been validated. D-dimer levels should not be used in isolation to evaluate a pregnant woman with suspected DVT or PE. A systematic meta-analysis that investigated the safety of D-dimer to rule out VTE in pregnant persons reported a high sensitivity and negative predictive value for the assay ; the authors suggested that their results suggest that D-dimer can safely rule out VTE during pregnancy when the disease prevalence is consistent with a low/intermediate or unlikely pre-test probability. However, the number of studies (three prospective, one retrospective) and subjects with VTE ( n = 69) were small and only two of the included studies were prospective management studies. Recent advances in the use of D-dimer in combination with clinical prediction rules in pregnant patients are described below.
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