Venous Thromboembolism During Pregnancy and With Hormonal Contraceptives
Saskia Middeldorp
Mathilde Nijkeuter
Michiel Coppens
PART I: PREGNANCY-RELATED VENOUS THROMBOEMBOLISM
Epidemiology
Venous thromboembolism (VTE) complicates 1 to 2 per 1,000 pregnancies.1, 2, 3, 4 Furthermore, VTE is the leading cause of maternal death in Western countries, accounting for 1 to 2 deaths per 100,000 pregnancies and 20% to 30% of all maternal deaths.5, 6, 7 Compared to age-matched nonpregnant women, this implies a 4- to 16-fold risk increase during pregnancy.1 In the postpartum period, the relative risk of VTE has been found to be as high as 60.8
Deep vein thrombosis (DVT) accounts for 85% of pregnancy-related symptomatic VTE, and the majority, that is 65%, occur during pregnancy.9 Contrary to this, the majority (85%) of episodes of pulmonary embolism (PE) occur in the postpartum period.1 Approximately 22% of episodes of VTE during pregnancy occur in the first, 34% in the second, and 48% in the third trimester.10 Given the much longer duration of the antepartum period than the postpartum period, the daily absolute risk of VTE is highest postpartum.
Inherited thrombophilias also increase the risk, and absolute risk estimates are summarized in Table 116.1. The presence of a positive family history for VTE modifies the risk of a first pregnancy-related VTE and in this setting ranges between 1.7% and 14.0%, depending on the type of hereditary thrombophilia.11, 12 No data are available for the risk of a first pregnancy-related VTE in women with antiphospholipid syndrome. Outside of pregnancy, the persistent presence of lupus anticoagulants including anticardiolipin or b2-glycoprotein antibodies is associated with a 2- to 10-fold risk increase for a first VTE.13, 14 If all pregnancy-related VTE is considered, the presence of antiphospholipid syndrome is associated with a 15.8 (95% CI 10.9 to 22.8) times higher risk.6 It should be noted that in this study, antiphospholipid syndrome was classified by hospital admission code and that this risk increase, at least in part, is likely due to the coexistent history of VTE, which in itself was the strongest risk factor for pregnancy-related VTE (odds ratio [OR] 24.8, 95% CI 17.1 to 36.0).6 It is unclear what the risk of VTE is in women with antiphospholipid syndrome diagnosed on reproductive clinical criteria such as recurrent miscarriage. In a small study in women with recurrent miscarriage and antiphospholipid syndrome, the risk of subsequent thrombotic events was not increased compared to women with unexplained recurrent miscarriage.15 The risk of pregnancy-related VTE also increases with age, mode of delivery, and presence of comorbid conditions.1, 6, 16
Despite these strong risk increases, a strong evidence base for the management of pregnancy-related VTE is missing. It is striking that, contrary to nonpregnant patients, diagnostic strategies, therapeutic options, and preventive measures for VTE in pregnant and postpartum women have not been addressed adequately in well-sized observational or intervention studies. Therefore, management is not standardized between physicians, centers, and countries.
Pathophysiology
The elements of Virchow’s triad, that is, venous stasis, hypercoagulability, and vascular damage, are all more or less present during pregnancy and the postpartum period. This predisposition to develop VTE has probably evolved to protect women from hemorrhage during childbirth. Venous stasis already begins in the first trimester and is assumed to be caused by progesterone-induced venodilation.17 Compression of the pelvic veins by the gravid uterus becomes more important in the second and third trimester of pregnancy. A third component leading to increased venous stasis is the crossing of the right iliac artery over the left iliac vein that may lead to pulsatile compression of the iliac vein (FIGURE 116.1). Pregnancy is a hypercoagulable state caused by decreased anticoagulant activity, increased procoagulant activity, and decreased fibrinolysis. The decrease in anticoagulant activity is due to a decrease in protein S concentration and an increase in activated protein C (APC) resistance. The increase in procoagulant activity is a result of an increase in factor V, VII, VIII, IX, X, and fibrinogen concentrations.18 Fibrinolytic activity is decreased because of an increase in plasminogen activator inhibitor 1 and 2 activity and a decrease in tissue plasminogen activator (tPA). The third element of Virchow’s triad, that is, vascular damage, is induced by delivery. Forceps, vacuum extraction, and surgical delivery can aggravate this vascular injury.
Clinical Presentation of VTE in Pregnancy
DVT in pregnant patients has a different distribution along the venous system as compared to nonpregnant patients. The predisposition for DVT to occur in the left leg, that is, almost 90% in pregnant patients, is much stronger than in nonpregnant patients (˜60%).10, 19, 20, 21 Isolated iliac vein thrombosis occurs in 17% of all DVT in pregnant women, whereas this is very uncommon in nonpregnant patients.20 Furthermore, in contrast to nonpregnant patients, more than 60% of DVT is restricted to the iliac and/or femoral vein, without calf vein involvement.20
Table 116.1 Risk of pregnancy-related VTE in thrombophilic women stratified by family history for VTE | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Diagnosis of VTE in Pregnant Women
Clinical Decision Rules and D-Dimer Testing
Studies on the diagnostic management strategies of DVT and PE have excluded pregnant women. Currently, no single study has adequately demonstrated the safety of ruling out VTE by clinical probability assessment combined with the use of D-dimers. In pregnancy, as in nonpregnant patients, d-dimer tests should not be used as a stand-alone test because of the small but important risk of a false-negative result. Objective imaging remains therefore the cornerstone of diagnosis and is crucial to avoid treating women who do not have VTE.22
Safety of Diagnostic Imaging in the Pregnant Patient
Imaging techniques to diagnose or exclude VTE in pregnancy should take into account the radiation exposure of the fetus (Table 116.2). These are much lower than the threshold dose for induction of malignancies (100 mSv) in the fetus and clearly justify the use of diagnostic testing involving radiation in pregnancy for the exclusion of potentially fatal VTE.23
Concerns have been raised that breast tissue of pregnant women, which receives particularly high doses of radiation, is supposedly especially susceptible to its carcinogenic effects, but evidence supporting this concern is not available.24
The iodinated contrast agents used in CT scanning and venography cross the placenta. Fetal exposure to iodinated contrast media is thought to be relatively short-lived. Although no effect on fetal thyroid function has ever been reported with clinical doses of iodinated contrast media, it is standard care that neonates of all mothers exposed to iodinated contrast media during pregnancy are screened for hypothyroidism.25, 26 Gadolinium contrast agents are used during MRI and do cross the placenta, but no neonatal adverse effects have been described and tests postpartum are not necessary.25 Only tiny amounts of iodinated or gadolinium contrast media are excreted in breast milk and only a minute proportion entering the baby’s gut is absorbed. This is considered insufficient to warrant stopping breast-feeding for 24 hours following either iodinated or gadolinium contrast agents.25
Diagnosing Deep Vein Thrombosis in Pregnancy
Compression ultrasonography (CUS) should be performed as a first test in a pregnant patient with a clinical suspicion of DVT (FIGURE 116.2). CUS has a sensitivity of 97% to 100% and a specificity of 98% to 99% outside of pregnancy, is noninvasive, and carries no radiation exposure.27, 28 Serial CUS testing after an initial normal test is of less value in pregnant patients, since DVT in pregnancy usually occurs in proximal veins without involvement of the calf veins. If doubt about the presence of DVT persists, limited venography with abdominal shielding should be considered. If iliac or pelvic vein thrombosis is suspected because of abdominal, groin, or back pain combined with swelling of the entire leg, CUS needs to be followed by duplex Doppler ultrasound or, alternatively, full venography can be performed. An absent waveform on modulation of respiration strongly suggests iliac vein thrombosis, but due to slow flow and external compression by the gravid uterus, false-positive ultrasound results may occur as well as false-negatives due to nonocclusive thrombi or collaterals. In centers with the availability of, and experience with, MRI, MR venography is a reasonable alternative test to venography in demonstrating iliac or pelvic vein thrombosis. However, the safety of excluding DVT when MR venography is normal has not been prospectively studied.
 FIGURE 116.1 Venous stasis during pregnancy. The left leg represents the pregnant leg, while the right leg represents the nonpregnant leg. Venous stasis in pregnancy is caused by progesterone-induced venodilation and compression of the pelvic veins by the gravid uterus (here depicted posterior of the vessels for clarity, but in reality anterior of the blood vessels). These components of increased venous stasis during pregnancy add to the anatomic crossing of the right iliac artery over the left iliac vein that may lead to pulsatile compression of the iliac vein. VII, vena iliaca interna; VIE, vena iliaca externa; VFC, vena femoralis communis; VFS, vena femoralis superficialis; VFP, vena femoralis profunda; VP, vena poplitea; VTA, vena tibialis anterior; VTP, vena tibialis posterior; VPe, vena peronea. |
Diagnosing Pulmonary Embolism
FIGURE 116.3 depicts several algorithms that can be used in pregnant patients with a suspicion of PE, depending on local availability and expertise.22, 29 Although the diagnostic yield of CUS (algorithm a) of the legs is low in asymptomatic women, it is a reasonable approach to avoid radiation in women suspected of PE. When CUS demonstrates DVT, further testing is not necessary and the patient can be considered to have a VTE. In a recent study, CUS showed proximal DVT in 39 of 139 (31%) nonpregnant patients suspected of PE but without symptoms of DVT.30 In pregnant women, this percentage is probably much lower since the overall prevalence of VTE in suspected patients is lower, but there are no data available. Obviously, ultrasound testing should not lead to diagnostic delay and if negative must prompt objective diagnostic testing of the lungs. Furthermore, the possibility of a false-positive result should be taken into account, especially if the patient has had an ipsilateral DVT in the past.
Advantages of the algorithm starting with a CT scan (FIGURE 116.3, algorithm b) are the feasibility to reach a diagnostic conclusion and the possibility to detect an alternative diagnosis, combined with a low fetal radiation exposure. An ongoing prospective diagnostic management study in which CT as the single test was used to exclude PE during pregnancy in 85 women showed no symptomatic VTE during follow-up of 3 months (95% CI 0% to 3.5%; Nijkeuter et al., 2012). CT scan
results were inconclusive in 4 of 94 patients, that is, 4.2%. This percentage is much lower than the 19% and 35% reported in two retrospective studies but higher than in the nonpregnant population (0.9%).31, 32, 33
results were inconclusive in 4 of 94 patients, that is, 4.2%. This percentage is much lower than the 19% and 35% reported in two retrospective studies but higher than in the nonpregnant population (0.9%).31, 32, 33
Table 116.2 Radiation dose to the fetus by radiologic examination | ||||||||||||||||||||||||||||
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The algorithm containing perfusion scintigraphy (FIGURE 116.3, algorithm c) should bear in mind that a chest x-ray is advised to rule out other diagnoses and to increase the chance of a conclusive perfusion scan. Four studies evaluated the performance of lung scintigraphy in pregnancy; diagnostic scan results ranged from 75% to 94%.32, 34, 35, 36 Selection of patients by normal chest x-ray and no history of asthma or chronic obstructive pulmonary disease resulted in the higher percentage of diagnostic tests.32, 36 However, these were all retrospective studies that were subject to bias since no uniform diagnostic protocol was used. Hence, in up to a quarter of pregnant patients with suspected PE, perfusion scintigraphy needs to be followed by additional testing. This strategy obviously is associated with a higher amount of fetal radiation exposure.
Risks of Anticoagulant Drugs in Pregnant and Postpartum Women
In the next paragraphs, we discuss specific fetal and maternal safety issues for anticoagulant agents. Furthermore, as in the nonpregnant population, the most obvious maternal safety issue of any anticoagulant is the risk of bleeding, both antepartum as well as around delivery and in the postpartum period. These risks are described in the paragraphs of the specific agents if data are available in pregnant women.
 FIGURE 116.2 Algorithm of a clinical suspicion of DVT in pregnancy. CUS, compression ultrasonography; DVT, deep vein thrombosis; LMWH, low molecular weight heparin; MRI, magnetic resonance imaging. |
Vitamin K Antagonists
Vitamin K antagonists (VKAs) cross the placenta and the induced vitamin K deficiency in the fetus may cause fetal wastage, bleeding, and coumadin embryopathy, a disorder that is characterized by nasal hypoplasia and stippled epiphyses.37 This teratogenic effect is only present when VKAs are taken in the 6th to 12th weeks of gestation (defined as weeks after the 1st day of the last menstrual cycle). When VKAs are used throughout pregnancy, as is sometimes done in women with mechanical heart valves, the risk of congenital abnormalities is estimated between 3.7% and 6.4%.37, 38, 39 Although exposure during the second trimester of pregnancy does not lead to overt handicaps, careful examination of school-aged children who had been exposed to VKA in utero showed that 18 out of 274 exposed children (7%) had an increased risk for a “multiple adverse outcome,” that is, growth impairment, minor neurologic dysfunction, IQ < 80, and behavioral problems, in comparison to 2 children out of 231 nonexposed controls (risk difference 5.7%, RR 7.6, 95% CI 1.8 to 32.4).40, 41 The adverse outcomes were mainly found in boys, and of the affected children, 94% had been exposed during the second and third trimester only. From approximately 36 weeks gestation, the bleeding risk for the fetus during delivery is a reason to avoid VKA during this time.
Women can breast-feed during the use of VKAs; particularly nonlipophilic types such as acenocoumarol and warfarin.42, 43 Of the lipophilic phenprocoumon, only minute amounts are
excreted in the breast milk that are insufficient to prolong the prothrombin time in infants.44
excreted in the breast milk that are insufficient to prolong the prothrombin time in infants.44
 FIGURE 116.3 Algorithms of a clinical suspicion of PE in pregnancy. CT, computed tomography; CUS, compression ultrasonography; HP, high probability; ND, nondiagnostic; PE, pulmonary embolism; PA, pulmonary angiography. |
In a systematic review of VKA use in pregnant women with mechanical heart valves, major bleeding events occurred in 2.5% (95% CI 1.7% to 3.5%) of all pregnancies, most at the time of delivery.38
Low Molecular Weight Heparin
There is ample experience with low molecular weight heparin (LMWH) in pregnant women. These agents do not cross the placenta and are considered safe to use in pregnancy, based on numerous observational studies.12, 45 The need for, usually once daily, injections is a nuisance of LMWH, and the long-term use in pregnant women frequently leads to skin reactions, which are mainly type IV delayed hypersensitivity reactions at the injection site.46, 47, 48 Switching to another LMWH preparation is reported to be indicated in 25% of patients, and of these, about one-third also developed complaints with the use of another LMWH.46 The incidence of heparin-induced thrombocytopenia (HIT) in pregnant patients who are only treated with LMWH is considered very low (<0.1%),45 and therefore, the weak, grade 2C recommendation in the most recent American College of Chest Physicians (ACCP) guideline is to not routinely monitor platelet counts. The risk of HIT is assumed to be somewhat higher, between 0.1% and 1%, in women who have been exposed to unfractionated heparin prior to LMWH treatment and monitoring of platelet counts is advised.49 Small studies of bone density in pregnant women receiving prophylactic doses of LMWH suggest that the use of this medication does not induce more bone loss as compared to pregnant women who did not receive LMWH.50, 51
Although small amounts of LMWH are excreted into breast milk, LMWH is not absorbed after oral intake and this is unlikely to have any relevant effect in breast-fed infants.12, 52
The risk of significant bleeding with the use of LMWH in pregnant women is generally reported to be around 2% and as being mostly related to obstetric causes.45 These data are based on observational studies including a wide range of doses of LMWH with the majority of prophylactic and intermediate doses. Furthermore, these reports may be biased by selective publication of successful patient histories and underreporting of complications.53, 54, 55 When therapeutic doses are employed, the incidence of major bleeding was estimated to be 1.7% (95% CI 0.4% to 5.0%) in a systematic review of 15 studies (including 6 case reports) reporting 174 women who had been treated for acute VTE.45 In a prospective evaluation of 126 pregnant women with acute VTE, the risks for bleeding during pregnancy was 6%, with none of the episodes considered by the authors as major bleeding, although these included episodes of rectal bleeding from endometriosis and haemoptysis.56 The risk of postpartum hemorrhage (>500 mL of blood loss) was 5% in the first 24 hours after delivery, and secondary major postpartum
hemorrhage occurred in 2% of the women in the days thereafter. In our own study of 83 women who had been treated with therapeutic doses of LMWH, the incidence of postpartum hemorrhage was around 10%, which was not statistically different from a cohort of women who delivered in the same hospital and who were not treated with anticoagulants.57
hemorrhage occurred in 2% of the women in the days thereafter. In our own study of 83 women who had been treated with therapeutic doses of LMWH, the incidence of postpartum hemorrhage was around 10%, which was not statistically different from a cohort of women who delivered in the same hospital and who were not treated with anticoagulants.57
Unfractionated Heparin
Unfractionated heparin can be administered subcutaneously and dose adjustments can be made based on activated partial thromboplastin times (APTTs), but the short half-life leads to the need for a twice daily dosing regimen. Furthermore, unfractionated heparin is more frequently associated with osteoporosis, HIT, and type I allergic reactions than LMWH.12 Long-term unfractionated heparin use is known to cause symptomatic osteoporosis in up to 2% of patients.58 Thus, unfractionated heparin should be reserved for women with a contraindication to LMWH (mostly chronic renal failure with a creatinine clearance below 30 mL/min) or when LMWH is not available.12
Unfractionated heparin has a high molecular weight and a strong negative charge and does not pass into breast milk.
In a retrospective cohort study of 100 pregnancies in 77 women, the rate of major antepartum bleeding in pregnant women treated with unfractionated heparin was 1% (95% CI 0.2% to 5.4%), which is consistent with reported rates of bleeding associated with heparin therapy in nonpregnant patients.59
Other Heparin-Like Anticoagulants
Danaparoid and fondaparinux have been and are increasingly being used in pregnancy, although the experience in human pregnancies is limited.12, 60 Furthermore, minor anticoagulant activity could be detected in fetal cord blood in five neonates of mothers who were treated with fondaparinux, indicating some placental transfer of the pentasaccharide.61 Thus, in the absence of extensive safety data, danaparoid and fondaparinux should be reserved for women who do not tolerate heparin, most often when all registered heparins lead to type I allergy, skin problems, or HIT.62
Very little is known about the passage of fondaparinux or danaparoid into human breast milk. Since both agents are not absorbed after oral intake, it is unlikely to have any anticoagulant effect in breast-fed infants.63
Thrombin and Factor Xa Inhibitors
A few case reports have described the use of parenteral thrombin inhibitors in pregnancy, but these data are insufficient to conclude on their safety in pregnant women.12 There is no place for new oral anticoagulants, since the human reproductive risks of these medications, that is, dabigatran, rivaroxaban, and apixaban, are unknown. The summaries of product characteristics for dabigatran and rivaroxaban describe animal reproductive toxicity.
It is recommended by the manufacturers that breast-feeding women do not use these medications.12
Thrombolytics
Although thrombolysis is contraindicated in pregnancy, a recent literature review identified 13 case reports that described its use in pregnant patients with massive PE.64, 65 Recombinant tPA and streptokinase are large molecules that do not cross the placenta, whereas urokinase does.64 In these severely ill women, fetal death occurred in 15% and preterm delivery in approximately 30% of cases.
The risk of maternal major bleeding complications was 30.8%; 95% CI (9.1 to 61.4).64
Treatment of Acute VTE in Pregnant Women
Pregnant women have been excluded from all clinical trials investigating various treatment regimens in acute VTE. In pregnancy, the volume of distribution of LMWH changes and glomerular filtration rate increases in the second trimester. Dosing therapeutic LMWH in pregnant women is associated with uncertainties about whether a prepregnancy weight or actual body weight needs to be used to determine the appropriate dose, whether dose adjustments are required as the pregnancy progresses, and whether a twice daily regimen should be preferred over a once daily regimen. Data from pharmacokinetic studies of various LMWHs in pregnant women have shown conflicting results with regard to the need for dose escalation to maintain levels within the therapeutic range.66, 67, 68, 69, 70, 71 The ACCP guidelines do not provide specific advice about anti-Xa level monitoring, in the absence of large studies using clinical endpoints demonstrating that there is an optimal therapeutic anti-Xa LMWH range or that dose adjustments increase the safety or efficacy of therapy.12 Nevertheless, in our practice, we prescribe therapeutic doses of LMWH throughout pregnancy and monitor anti-Xa levels to achieve a 4-hour postinjection peak level of 0.8 to 1.6 U/mL with a once daily regimen of LMWH (0.6 to 1.0 if a twice daily regimen is used).72 Prospective observational studies have not demonstrated an increase in the risk of recurrence with the once daily regimen over the twice daily regimen,56, 73 and a once daily regimen likely enhances adherence. Women should be treated at least until 6 weeks postpartum, since the daily risk in any woman to develop VTE is highest during this period.8 Extrapolating the optimal duration of anticoagulation of nonpregnant patients with a VTE provoked by a major temporary risk factor, the minimum duration should be 3 months, so this postpartum treatment may be longer if VTE occurred in late pregnancy.74
For women in whom the need for rapid counteraction of the anticoagulant effect is anticipated, intravenous unfractionated heparin to achieve a therapeutic APTT is a reasonable short-term option. Unfractionated heparin has a short half-life (3 hours) and can be completely counteracted by protamine sulfate, although there are no solid safety data of the latter agent in pregnancy. In our experience, these presumed benefits are often counterbalanced by difficulty in achieving APTTs in the desired range, with the obvious risk of extending thrombosis as a result of undertreatment in a woman with acute VTE and overanticoagulation in a woman in whom this option is chosen because of an increased risk of bleeding.
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