Venous thromboembolism in pregnancy: A silent threat

Venous thromboembolism (VTE) is a serious medical condition that affects thousands of pregnant women worldwide each year and has a reported incidence of 2 per 1000 deliveries [1]. It consists of deep venous thrombosis (DVT) and or pulmonary embolism (PE), both of which contribute significantly to maternal morbidity and mortality. Pregnancy, albeit a wondrous event, involves complex physiological processes that predispose pregnant women to the development of VTE; moreover, pre-existing medical conditions can increase this risk.

The signs and symptoms of VTE are often subtle and may be masked by general pregnancy profiles. The silent phenomenon of VTE is the leading cause of maternal mortality in the United Kingdom, ranks amongst the top 6 in the United States and is frequently reported in low- and middle-income countries (LMIC) as a cause of collapse and death, globally translating into 1.1 maternal deaths per 100 000 deliveries [[1], [2], [3], [4]]. Therefore, this editorial highlights the need for urgent steps to be taken in the effective prevention and management of VTE to avert the deleterious sequels.

The coagulation system begins to alter itself in the first trimester of pregnancy anticipating haemorrhage at delivery, rendering the duration of pregnancy and the postpartum period in a hypercoagulable state. Whilst this is a protective measure, pregnant women have a six-fold increased risk of developing VTE relative to their non-pregnant counterparts [5]. This is due to changes in the levels of clotting factors and anticoagulant compounds, dynamic increase in the circulatory volume of pregnancy, and the organic presence of the gravid uterus impeding venous return from the lower extremities. These contribute to the hypercoagulable environment, which exaggerates Virchow's Triad [5].

Considering the physiological and anatomical changes in pregnancy, risk stratification is crucial to mitigate against DVT and PE complications [5]. Risk assessment models (RAM) can identify those pregnant women at increased risk of VTE by examining clinical information (particularly the patient's history and examination findings) and trigger the administration of VTE prophylaxis to those in need [6,7]. There has been no consensus on the ideal VTE RAM; however, the key role of a RAM is to improve the ratio of benefit to risk, ensuring the safe administration of VTE prophylaxis. Events causing damage to the vascular endothelium, increasing viscosity of blood, and promoting venous stasis result in VTE. Therefore, risks factors for VTE are extensive and include medical and surgical conditions as well as complications of pregnancy and delivery. Such medical conditions include cardiac diseases (particularly those requiring prosthetic heart valves), admission to critical care units, hypertension, haematological diseases (thrombophilia and sickle cell disease), previous VTE, autoimmune disease (lupus and antiphospholipid diseases), endocrine disease (metabolic syndrome and diabetes), malignancy, obesity and smoking [1]. Additionally, the use of some drugs such as clozapine and olanzapine increase the risk of VTE, therefore the individual risk profile of each patient needs careful consideration prior to prescribing or administering any of the implicated medications. Surgical conditions include major pelvic and bone surgeries. Complications that occur in pregnancy and during delivery include hyperemesis gravidarum, multiple pregnancy, haemorrhage in the antenatal and postpartum periods, especially if blood transfusion is deemed lifesaving, caesarean delivery and postpartum infection [1].

Notably, pregnant women who had a thrombotic event in a previous pregnancy have a 3- to 4-fold increased risk of developing a recurrent VTE [1]. Preventing VTE in pregnancy therefore requires a multifaceted approach. Addressing modifiable risk factors and other specific interventions may also aid in mitigating against the development of VTE, for instance the use of lifestyle modification, including moderate exercise and regular movement, mindful eating plans and dietary intake, limiting substance use with the aim of ceasing use, and adequate hydration. Pregnancy considerations include the use of pressure stockings, intermittent pneumatic compression of the lower limbs during hospitalization, limiting immobilization by choice of good surgical technique, early ambulation post-surgical intervention, and avoiding unnecessary travel. Anticoagulation is another prophylactic measure but may result in bleeding complications in up to 2 % of pregnant women on heparin and low molecular weight heparin (LMWH) [1]. Therefore, the initiation of anticoagulation prophylaxis and treatment must be based on indication. Whilst VTE risk is high in pregnancy and the puerperium, not all pregnant women will require anticoagulation. Identification of the high-risk groups mentioned earlier remains pivotal to allow for timely and correct implementation of anticoagulation practices. In the authors' view, the use of reminders, including posters, apps and pocket guides, in practice settings is strongly recommended [8]. The suggested prophylactic doses of LMWH based on the presence of risk factors using evidence-based algorithms is a maximum of 1 mg/kg/day [9,10]. When LMWH is the anticoagulant of choice in women with a prosthetic heart valve, the practice of monitoring anti-Xa is recommended.

Clot or not, making the diagnosis of VTE in cases where there are no obvious clinical signs is difficult. The diagnosis of VTE involves a detailed history, physical examination, imaging, and ancillary tests. However, symptoms may be vague: cough, intermittent shortness of breath, and abrupt onset of chest pain and/or leg pain. Signs may include swelling, tenderness, redness and warmth of the lower extremities, tachycardia and possible abnormal breath sounds on lung examination. Bedside investigations include an electrocardiogram (ECG), portable chest x-ray (CXR), ultrasound duplex Doppler of the lower limbs and a point-of-care ultrasound of lung and cardiac windows. Further imaging may include cardiac echocardiography, CT pulmonary angiogram (CTPA) and ventilation perfusion scans (VQ scans) [4]. Notably, special considerations need to be made with regard to radiation exposure and breast cancer. Therefore, CTPA, which may increase the risk of breast cancer in these women, should be reserved when overt pathology is present on the CXR. Magnetic resonance imaging (MRI) can be useful in diagnosing the extent of deep pelvic vein thrombosis. Blood investigation may include a D-dimer test. Scoring systems used in the non-pregnant population, i.e. Wells score and revised Geneva criteria, seem not to be useful in the pregnant and postpartum population whilst the pregnancy adapted YEARS algorithm which includes D-dimer levels and the presence of three criteria (viz haemoptysis, clinical signs of DVT and PE) can exclude PE in suspected cases, reducing the exposure to CTPA in 32 % - 65 % of pregnant women [11]. It is best to involve a multidisciplinary team (MDT) early to assist with VTE diagnosis, management and the challenges (including any ethical dilemma) that may arise.

Systemic anticoagulation in the form of LMWH and unfractionated heparin are the preferred therapies of choice for most VTE cases as they reduce mortality and recurrence of VTE [12]. Anticoagulant therapy is initiated at diagnosis and is required for a minimum of 3 months and can continue for 6 months for optimal results. It is also crucial to emphasize that therapeutic anticoagulant should be commenced following strong clinical suspicion (intermediate or high clinical probability) of VTE, and discontinued if ancillary investigations exclude the pathology. LMWH has been shown to be superior during pregnancy, as it does not cross the placenta and can be administered on an outpatient basis. The usual therapeutic dose of LMWH is 1 mg/kg 12 hourly subcutaneously. Because of the short half-life properties of unfractionated heparin, it is advised that it is used in cases that need surgery or where delivery is imminent. Warfarin (vitamin K antagonist) crosses the placenta, is teratogenic and therefore should not be administered during the first trimester and within ten days (at least seven days) before childbirth. The latter allows the drug to be cleared from the fetal circulation and prevents intracranial bleeding, whose risk increases due to the mechanical effects of childbirth. To elaborate, Warfarin therapy is associated with embryopathy in the first trimester. It is also associated with fetal demise if used in high doses. Nonetheless, it can be used in the postpartum period and according to observational studies it is safe in breastfeeding mothers. Furthermore, safety evidence regarding the use of direct oral anticoagulants is limited to the postpartum period in women who are not breastfeeding [4]. In cases of sub-massive PE, and massive PE (i.e., those associated with cardiovascular collapse and obstructive shock), advanced treatment modalities are pertinent. These therapies include systemic thrombolysis, which carries a grave risk of haemorrhage to the mother and the fetus, and possible surgical thrombectomy. Acute limb ischaemia can be treated with catheter-related thrombolysis or thrombectomy. In severe cases where systemic thrombolysis is an absolute contraindication and systemic thrombectomy cannot be performed, urgent engagement must be made with specialized centres that offer intravenous filter placement and extra-corporeal membrane oxygenation [4]. Adequate psychological support must be readily available to assist both the patient and their families for the traumatic VTE experience. In subsequent pregnancies, the management should include shared decision making with the MDT because 15 % - 25 % of VTE in pregnancy is recurrent [1]. Pre-conception counselling must provide a safe and transparent platform to ensure that embarking on the next pregnancy is carefully considered and that all relevant safety measures have been established and are available.

In conclusion, to mitigate the effects of VTE, risk stratification of patients and the use of effective thromboprophylaxis to prevent the condition as well as prompt diagnosis and commencement of appropriate treatment are required.