Saskia Middeldorp, MD, PhD, and Wessel Ganzevoort, MD, PhD, discuss the diagnosis, treatment, and prevention of venous thromboembolism in pregnant women. This material is repurposed from “How I treat venous thromboembolism in pregnancy,” published in the November 5, 2020, edition of Blood.
- VTE occurs in 1-2 out of 1,000 pregnancies and is a leading cause of maternal mortality and morbidity, but high-quality evidence on the management of pregnancy-related VTE is scarce.
- LMWH in therapeutic doses is the treatment of choice during pregnancy; anticoagulation should be continued until 6 weeks after delivery, for a minimum total duration of 3 months.
- Postpartum, DOACs are an option if a woman does not breastfeed and long-term use is intended. LMWH and VKA use does not preclude breastfeeding.
- Management of delivery, including type of analgesia, requires a multidisciplinary approach and depends on local preferences and patient-specific conditions.
- Prophylaxis for recurrent VTE prevention in subsequent pregnancies is indicated in most women with a history of VTE.
Women who experience venous thromboembolism (VTE) during pregnancy or the postpartum period face a potentially life-threatening condition. VTE occurs in one to two of every 1,000 pregnancies, and the risk increases with age, mode of delivery, and presence of comorbid conditions.
However, the evidence base for managing VTE in pregnant and postpartum women remains weak and recommendations are extrapolated from nonpregnant populations. In the absence of evidence, it is impossible to identify optimal management, and there is wide variation among physicians, centers, and countries. In this review, we describe our approach to the diagnosis and treatment of women with VTE during pregnancy.
Diagnosis of Pregnancy-Related VTE
In pregnancy, the threshold of suspicion for deep vein thrombosis (DVT) and pulmonary embolism (PE) is low because VTE is a major cause of maternal morbidity and mortality.
D-dimer levels increase during pregnancy and are often higher than the regular threshold of 500 ng/mL, thus triggering further imaging for VTE diagnosis. The 2018 American Society of Hematology Clinical Practice Guidelines for the Management of VTE in the Context of Pregnancy recommend ventilation/perfusion (V/Q) scanning because it limits radiation exposure to the fetus and mother. However, V/Q scanning is not widely available, and it is likely that pregnancy-adapted computed tomography pulmonary angiography (CTPA) techniques are able to reduce the amount of maternal radiation without compromising sensitivity.
A pregnancy-adapted YEARS algorithm, described in the FIGURE, has been shown to be a safe and effective diagnostic strategy for pregnant women suspected of having PE.
Treatment of Pregnancy-Related VTE
Low-molecular-weight heparin (LMWH) is the drug of choice in pregnant women because it does not cross the placenta or have teratogenic effects.
Optimal use of therapeutic doses of LMWH in pregnant women is generally extrapolated from the nonpregnant population. For the initial treatment of acute VTE in pregnancy, there is no evidence base supporting a twice-daily regimen over a once-daily regimen of a therapeutic dose of LMWH. It is unclear whether the pre-pregnancy weight or the actual body weight should be used to determine the appropriate dose of LMWH, and we use the actual body weight at time of diagnosis.
LMWH leads to local bruising and skin reactions in up to 25% of pregnant patients, which are mainly type IV delayed hypersensitivity reactions at the injection site of subcutaneously administered LMWH. Type I allergy is rare and should always be considered, but if no symptoms or signs are present, we pragmatically switch to another LMWH. Danaparoid sodium or fondaparinux can be considered if all registered LMWHs lead to skin problems.
Unfractionated heparin (UFH) can be administered both intravenously (IV) and subcutaneously and has a similar fetal safety profile, but requires activated partial thromboplastin time monitoring and is associated with a higher risk of heparin-induced thrombocytopenia, the incidence of which is very low in pregnant patients (<0.1%). UFH is often considered for women in whom rapid reversal of the anticoagulant effect may be needed.
Vitamin K Antagonists
Because vitamin K antagonists (VKAs) cross the placenta and may cause warfarin embryopathy and long-term effects, we avoid the use of these agents throughout the entire pregnancy for the treatment and prevention of VTE.
Direct Oral Anticoagulants
Direct oral anticoagulants (DOACs), including direct thrombin inhibitors and factor Xa inhibitors, are contraindicated in pregnancy and during breastfeeding. If a woman inadvertently becomes pregnant while using a DOAC, we advise switching to LMWH immediately.
Thrombolysis should not be withheld in pregnant women with life-threatening hemodynamic instability and PE. Whether catheter-directed thrombolysis for severe PE is associated with a lower risk of bleeding than systematic thrombolysis is unknown, even in the nonpregnant population.
We generally avoid placement of an inferior vena cava (IVC) filter in pregnant patients because experience during pregnancy is limited, and filter migration and inferior caval vein perforation have been described. This may be disregarded in exceptional circumstances, such as for a woman in whom the absolute contraindication for therapeutic anticoagulation would persist for weeks.
A 32-year-old woman 11 weeks into her pregnancy presented to the emergency department in a teaching hospital with left-sided chest pain that increased with inspiration and shortness of breath. Chest radiograph was normal and bilateral compression ultrasonography (CUS) of the legs showed normal compressibility of the femoral and popliteal veins and no signs of flow obstruction of the iliac veins on either side. Next, CTPA showed multiple central bilateral pulmonary emboli with a normal right/left ventricle ratio and a small infarction in the left lung.
She was treated with LMWH (tinzaparin 14,000 IU once daily, based on body weight at the time of diagnosis) and admitted to the obstetric ward for five days for pain relief. After hospital discharge, she continued with the same dose of LMWH, to which she adhered and tolerated well, apart from some mild bruising around the injection sites. She had adequate peak anti–factor Xa levels throughout pregnancy and normal platelet counts. Her chest pain subsided after a few weeks, but she remained somewhat short of breath throughout pregnancy.
A 27-year-old woman 32 weeks into her pregnancy was transported to our emergency department after a car accident. The present pregnancy had been uneventful except for some edema to just above the ankle on the right side for approximately two months, without swelling of her upper leg. The likelihood of VTE was considered low, and DVT was considered ruled out after a normal CUS.
After the accident, bilateral CUS found DVT of her left femoral vein and no signs of iliac vein obstruction; on the right side, no abnormalities were seen. CTPA confirmed the diagnosis of bilateral PE.
This patient had an absolute contraindication for both thrombolysis and therapeutic dose anticoagulation because of the neurotrauma. In the hours after admission, her cardiorespiratory status deteriorated, and after careful multidisciplinary consideration, it was decided to perform a combined procedure under general anesthesia. The interventional radiologist placed an IVC filter through the right femoral vein below the renal veins, and the obstetrician delivered the baby through a cesarean section.
Management of Delivery in Women With VTE
Several options for delivery in women using anticoagulants are possible and depend strongly on local preferences and experience, which result from the perception of risks and benefits of either the wait-for-spontaneous-delivery approach or the planned-delivery
Wait for Spontaneous Delivery
In our institution, the wait-for-spontaneous-delivery approach is the default choice with all dosages of LMWH. We pragmatically base this on the fact that advantages and disadvantages of both approaches are limited, and we primarily follow the golden rule of “when in doubt, abstain.”
The potential disadvantages of unplanned spontaneous delivery are the increased risk of bleeding and limiting accessibility to neuraxial analgesia, but data about this risk are very conflicting and of low quality.
Data on the potential disadvantages of planned delivery are conflicting. In women at very high risk for extension or recurrent VTE (arbitrarily within 1 month before expected delivery), we consider the risks of a prolonged period without anticoagulation to be higher, therefore scheduling a planned delivery so that the duration of time without anticoagulation can be minimized. Those at the highest risk of recurrence (proximal DVT or PE within two weeks before delivery) can be switched to therapeutic IV UFH, which is then discontinued four hours before the expected time of delivery or the use of neuraxial anesthesia.
Postpartum Duration of VTE
Anticoagulation should be restarted as soon as possible after delivery, depending on the estimated amount of vaginal blood loss and the type of delivery.
Generally, restarting therapeutic-dose anticoagulation 12 to 24 hours after delivery is feasible, but this period should be longer if hemostasis is not adequate. If the anticipated interval is longer than 24 hours because of bleeding, a prophylactic dose 24 hours after delivery should be considered.
In most women in whom the intention is to stop anticoagulation six weeks after delivery, continuation with therapeutic-dose LMWH is the most practical option.
In women who will continue anticoagulation indefinitely and who plan to breastfeed, we first restart LMWH and initiate the first loading dose of VKAs at least one day later. LMWH can be discontinued after at least three days of VKAs and as soon as the international normalized ratio is above 2.0. It is important to reassure women that they can breastfeed during use of either LMWH or VKAs. Alternatively, if women do not plan to breastfeed, LMWH can be replaced by a DOAC.
We treat women with therapeutic-dose LMWH until six weeks postpartum and for a minimum duration of three months. If the pregnancy-related VTE was the first episode, we advise discontinuation of anticoagulation after three months total duration or after six weeks postpartum.
Patient 1, continued
At a gestational age of 30 weeks, we performed CTPA because she felt increasingly breathless and was tachycardic, without another clear explanation such as anemia. CTPA showed complete resolution of PE and lung infarction. She went into spontaneous labor at a gestational age of 39 weeks plus two days and delivered a healthy girl 21 hours after the last injection of LMWH. Estimated blood loss was 200 mL, and LMWH was restarted 12 hours after delivery at full dose.
Two years later, the patient consulted us because she wanted to become pregnant again. Because she had a history of pregnancy-related VTE, we advised antepartum and postpartum prophylaxis with LMWH. She was enrolled in a randomized controlled trial comparing low-dose with intermediate-dose LWMH for the prevention of pregnancy-related recurrent VTE, and she was treated with the intermediate dose. There were no major issues during this pregnancy, and she delivered a healthy girl. She continued LMWH prophylaxis until six weeks after delivery.
Patient 2, continued
After delivery, the radiologist performed thrombosuction of the pulmonary arteries with a single bolus infusion of UFH 5,000 IU. She was then treated with a prophylactic dose of LMWH (nadroparin 2,850 IU) for six weeks, until the intracerebral blood was fully resorbed.
Attempts to retrieve the filter were unsuccessful. Next, therapeutic-dose LMWH was switched to full-dose DOAC. The presentation of the PE, together with the filter being present permanently as well as the patient’s preferences, led to the shared decision to continue some form of anticoagulation, and we switched to low-dose DOAC for secondary VTE prevention 4.5 months after the PE. She did not develop symptoms of post-thrombotic syndrome, nor did she have residual pulmonary symptoms. She gradually recovered from her neurologic trauma, and three years later, she had regained her previous functional level and was working.
Recurrent VTE Prevention
After pregnancy-related VTE, the risk of recurrence during subsequent pregnancies is 6 to 10% if no prophylaxis is administered. The risk of recurrence is influenced by the factors present during the first VTE, as is the case for nonpregnant patients.
Women who have had a single episode of VTE that was associated with a transient nonhormonal risk factor are at low risk of recurrence during pregnancy; the burden of subcutaneous injections, side effects, and risk of peripartum bleeding may not outweigh the high number needed to treat during pregnancy, and only postpartum thromboprophylaxis for six weeks is recommended.
In all other pregnant women with a history of VTE, both antepartum prophylaxis and postpartum prophylaxis are suggested. Given that the increased risk of VTE is similar across trimesters, we initiate LMWH prophylaxis as soon as a pregnancy test is positive, and to do so, we prescribe a starting dose of LMWH preconceptionally. The optimal dose of LMWH for prevention of pregnancy-related recurrent VTE is unknown.
Women who use anticoagulants outside of pregnancy should, if receiving DOACs, be switched to VKAs preconceptionally. As soon as the pregnancy test is positive, VKAs should be switched to therapeutic-dose LMWH, and the effect of VKAs can be reversed by oral vitamin K supplements.
Finally, it is very important that treating physicians counsel all young women with an episode of VTE about future pregnancies, as well as other related issues (e.g., the 5 Ps: period, pill, prognosis, pregnancy, and post-thrombotic syndrome).