Deep venous thrombosis (DVT) can occur in all parts of the deep veins, especially in the lower extremities, and has received increasing attention in recent years because of its acute thrombotic dislodgement that can lead to lethal or nonlethal pulmonary thromboembolism (PTE). In particular, women during pregnancy are more prone to lower extremity deep vein thrombosis due to the special physiological period they are in, with a six-fold higher incidence than in normal times [1]. It has been reported that thromboembolic disease has become one of the important causes of maternal death in developed countries such as Europe and the United States. Maternal deaths due to pulmonary embolism caused by combined DVT in women during pregnancy have also been increasingly reported in China in recent years. The questions of whether to terminate pregnancy immediately, whether to place inferior vena cava filter, and whether diagnostic radiotherapy and anticoagulant thrombolytic therapy will have adverse effects on the fetus in women with DVT are gradually attracting more attention from scholars. In this paper, the factors related to the vulnerability of women to DVT during pregnancy and the views of domestic and foreign scholars are reviewed as follows. Liu Ping, Department of Peripheral Vascular Medicine, The First Affiliated Hospital of Henan College of Traditional Chinese Medicine
1. High risk factors
1.1 Physiological and anatomical factors
Venous reflux disorder during pregnancy is due to the increase of gestational weeks, the enlarged uterus compresses the iliac vein and inferior vena cava, which causes obstruction of venous return and stagnation of blood flow, causing damage to the endothelial cells of blood vessels and changes in the vessel wall, which easily leads to thrombosis. Moreover, the left lower extremity veins have a long and circuitous route to the inferior vena cava, and the left common iliac vein is influenced by the compression of the right common iliac artery, therefore, thrombosis of the left lower extremity is more common than the right in women during pregnancy and childbirth.
1.2 Genetic risk factors
Congenital defects in both coagulation and anticoagulation systems can significantly increase venous thrombosis. Genetic predisposition to thrombosis is a major cause of increased occurrence of thromboembolism and adverse pregnancy outcomes in women. Adverse pregnancy outcomes include recurrent miscarriage, fetal death in mid- to late pregnancy, stillbirth, preterm delivery, severe fetal growth restriction (FGR), severe pre-eclampsia, placental abruptio, and placental infarction. Clinically apparent genetic predisposition to thrombosis has factor VLeiden mutations associated with FGR and severe preeclampsia.Kraaijenhagen et al. found elevated plasma factor VIII levels to be an important, prevalent, independent and dose-dependent risk factor for venous thromboembolism (VTE). Mutations in prothrombin G20210A are very rare in the Chinese population and are not an independent risk factor for VTE or pulmonary embolism [2]. Protein C is a key component of the anticoagulation system. Genetic defects that affect the function of the protein c system are a common risk factor for VTE [3]. Recent studies have found that the combined incidence of three genetic defects (protein c, protein s, and antithrombin deficiency) in patients with DVT formation in the Chinese population is 26.4% to 35.7%, which is significantly higher than that in the Western population. Protein C and protein S deficiencies are important risk factors for VTE in the Chinese population, whereas antithrombin deficiency is not significantly associated with the development of VTE [4]. Hyperhomocysteinemia is also an independent risk factor for VTE. Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the homocysteine metabolic pathway, and 15 mutations leading to MTHFR deficiency have been identified, while the most common is the C677T mutation in the MTHFR gene.
1.3 Acquired risk factors
Pregnancy is considered to be a hypercoagulable state. The increase of fibrinogen, the increase of coagulation factors II, VII, VIII and X, the decrease of fibrinolytic activity, the decrease of free protein S level and the increase of acquired anti-protein C activity make the blood of pregnant women in a hypercoagulable state. The myometrium and placental membranes are rich in thrombin, and the surgical trauma and birth injury during delivery can cause the release of these active substances in large quantities, which increase the tendency of blood coagulation and the risk of thrombosis The risk of thrombosis is further increased. Secondly, age over 35 years, obesity, smoking, multiple births, postpartum bleeding with hemostatic drugs and blood transfusion, hypertensive disorders of pregnancy, perinatal cardiomyopathy, overly enlarged uterus (excessive amniotic fluid, combined fibroids), cesarean section (especially emergency cesarean section), prolonged braking, cardiac insufficiency, varicose veins in the lower extremities and chronic hypertension are all risk factors.
VTE is currently considered to be a multi-causal disease, the result of hereditary risk factors and the interaction of hereditary and acquired risk factors.
2 Diagnostic basis and laboratory tests
The presentation of DVT in pregnant women is similar to that of the general patient, commonly in the left lower extremity, as swelling and pain in the limb, limitation of movement, dilatation of superficial veins, sometimes accompanied by fever and changes in limb color. It has been shown [5] that DVT occurs more often after 27 weeks in pregnancy, 1-2 weeks after delivery, and as late as 6 weeks. The clinical onset is usually unilateral, with the left side being more common. VTE is clinically suspected and diagnosed in less than 10% of pregnant women [6]. The reason for this is that clinical signs and symptoms of DVT and pulmonary embolism such as calf swelling, palpitations, shortness of breath, and dyspnea are also present in normal pregnant women. Therefore, laboratory tests should be performed as much as possible in high-risk patients.
2.1 D-dimer (D-dinner) test
D-dinner is a specific degradation product produced by cross-linking of fibrin monomers by activating factors and then hydrolysis by fibrinolytic enzymes, and is a molecular marker reflecting thrombin and fibrin activation [7], and many diseases that are associated with microthrombosis may lead to an increase in D-dinner [8]. When plasma D-dinner >0.500 mg/L, it has a high diagnostic value for deep vein thrombosis, pulmonary embolism and diffuse intravascular coagulation, while <0.500 mg/L can be used as an indicator to exclude the diagnosis [9].Chan et al [10] showed that a negative D-dinner test result in early and middle pregnancy has a high specificity with a negative prediction rate of 100%; a positive The sensitivity of the prediction rate was 100% and the specificity was 6O%. However, women's blood is in a physiologically hypercoagulable state during pregnancy, and most of the coagulation factors in plasma are increased to varying degrees. In order to maintain the dynamic balance of blood coagulation and fibrinolysis and to maintain the flow of blood, women in pregnancy experience a compensatory increase in fibrinolysis, resulting in a physiological increase in plasma D-dinner levels, which gradually increases with the progression of pregnancy. The diagnosis of deep vein thrombosis, pulmonary embolism and diffuse intravascular coagulation is inappropriate if only a 4-fold increase in plasma D-dinner levels compared to normal is used as a laboratory indicator of abnormality [11]. Some findings [12] suggest that the gradual increase in plasma D-dinner levels in pregnant women as pregnancy progresses is a physiological compensatory state, and that the D-dinner may gradually return to normal levels after the physiological hypercoagulable state is lifted after delivery. It has also been shown [13] that D-dinner levels increase gradually with gestational weeks, with the most significant changes from 2O to 31 weeks of gestation and stabilize after 32 weeks of gestation, suggesting that different reference value ranges should be used for serum D-dinner in pregnant women at different gestational weeks, which should not be influenced by age, but there are still few studies in this area. Therefore, based on the characteristics of the physiological changes of the blood system during pregnancy, the increase of plasma D-dinner during pregnancy cannot be used as the only diagnostic criteria for the diagnosis of deep vein thrombosis, pulmonary embolism and diffuse intravascular coagulation at present.
2.2 Ultrasonography
Venous compression ultrasound (CUS) is a non-invasive test with a sensitivity of 93.0% and specificity of 99.0% for the detection of proximal DVT, but with poor diagnostic accuracy for DVT in the distal end, especially in the calf segment [14]. Since it is noninvasive, it is a common method for the diagnosis of DVT in pregnant women. Currently, color Doppler flow imaging (CDFI) has largely replaced venography as the preferred method of examination in suspected cases of DVT and can detect thrombus in more than 95% of proximal lower limb veins.
Echocardiography and lower extremity DVT are the only diagnostic methods that provide direct evidence of PTE at the bedside. transesophageal echocardiography has a sensitivity and specificity of up to 8O% and 100%, respectively, for direct demonstration of larger pulmonary emboli [15]. color Doppler echocardiography with normal performance does not confirm or exclude the diagnosis of PTE. because 75% to 9O% of thrombi are from DVT in the pelvis and lower extremities. The current consensus is that pelvic and lower extremity venous color Doppler ultrasonography should be routinely performed when PTE is suspected.
2.3 Diagnostic imaging
If pulmonary embolism is suspected and ultrasonography is normal, additional diagnostic imaging is required. The purpose of chest x-ray is to exclude other causes of dyspnea and chest pain and to guide the next diagnostic tests. Nuclear lung ventilation/perfusion scan (v/Q) is an important diagnostic method for PTE. PTE can be excluded if the results are normal, but perfusion deficit is a non-specific presentation and only 1/3 is PTE. CT pulmonary arteriography (CTPA) is helpful to detect intracardiac thrombus and to assess the severity of PIE. A ratio of right ventricular diastolic short-axis maximum transverse diameter to left ventricular diastolic short-axis maximum transverse diameter greater than 1.4 and leftward septal shift are significantly associated with the clinical severity of PTE [16]. Recently, it has been proposed that it would be more scientific to apply spiral CT or V/Q imaging as the initial diagnostic tool in conjunction with the clinical morbidity of PTE[17] . It has been suggested that spiral CT examination is safe for the fetus and that attention to abdominal protection is necessary.
V/Q has a higher radiation dose to the fetus than CTPA examination, and pulmonary perfusion scanning alone will reduce radiation exposure to the fetus [18, 19]. However, CTPA has a higher radiation dose to the mother than scintigraphy [19]. Mothers with suspected venous embolism should be informed that V/Q screening gives a higher probability of developing tumors in the next generation in childhood than CTPA screening. However, the probability of causing breast cancer in the mother is lower than that of CTPA [18].
MRI has a sensitivity and specificity of 9O% to 100% for the diagnosis of symptomatic acute DVT, and is particularly advantageous for the diagnosis of pelvic and upper extremity DVT. However, its sensitivity for peroneal vein thrombosis is inferior to that of venography.MRI has no radiation exposure, is harmless to the fetus, and has high sensitivity and specificity for the diagnosis of iliac vein thrombosis [20].MRI has higher sensitivity and specificity for the diagnosis of intrapulmonary artery emboli, and compared with pulmonary angiography, it avoids the disadvantages of iodine contrast injection, is more acceptable to patients, and is suitable for patients who are allergic to iodine contrast [21].
2.4 Venography of the lower extremities
This is the gold standard for the diagnosis of deep venous embolism, showing the site, extent and degree of venous occlusion and the status of collateral circulation and venous function, and its diagnostic sensitivity and specificity are close to 100%. However, its use in pregnancy is severely limited due to the radiation that can be generated, and when it is necessary to use it, the examiner should take protective measures on the abdomen of the pregnant woman [21].
3 Treatment
3.1 Thrombolytic therapy
Pregnancy and the puerperium have been considered contraindications to thrombolytic therapy in the past, but it is now believed that thrombolysis or catheter thrombolysis can be applied to patients within 1 week of onset in the acute phase of DVT or in cases of concomitant PTE [22]. Thrombolytic drugs can still be applied within 2 weeks of thrombosis. There is no clear evidence that clinically used thrombolytic drugs such as streptokinase, urokinase, and rt-PA have teratogenic effects, among which streptokinase has been shown not to pass through the placenta, but thrombolysis can cause bleeding from the genital tract with an incidence of approximately 8.0% and is more severe.The 7th ACCP Evidence-Based Guidelines for Venous Thrombosis 2004 recommends that intravenous thrombolysis not be used routinely. Thrombolytic drugs should be contraindicated in patients before delivery unless massive PTE occurs.
3.2 Anticoagulation therapy
The commonly used anticoagulants include heparin (UFH), low molecular heparin (LMWH), heparinoids, pentasaccharide, and oral coumarins such as warfarin, etc. UFH and LMWH have been shown not to cross the placenta and are not found in breast milk and are safe for the fetus and infant. Coumarins cross the placental barrier and have teratogenic effects [23] and are contraindicated during pregnancy. A small amount of warfarin is secreted in the milk of puerperal women taking warfarin and does not have anticoagulant effects on the nursing infant; therefore, the drug can be applied to postpartum women if necessary. Currently UFH and LMWH are still the drugs of choice for the treatment of DVT in pregnant women.
3.3 Inferior vena cava filter
The inferior vena eava filter (IVCF) itself has no role in the treatment of thrombosis; it is meant to prevent the occurrence of PTE, especially lethal PTE [24]. And anticoagulation after IVCF placement is mandatory [25]. It is important to emphasize that strict anticoagulation therapy is effective in reducing the incidence of PTE, so IVCF is not necessary for every patient with lower extremity DVT [26]. There are no large number of case reports on the placement of IVCF in patients with DVT during pregnancy, and its long-term effects and safety need to be further studied with a large number of case data statistics. However, the effect of fetal volume growth on IVCF with increasing gestation should be considered, so placement of permanent IVCF in women of pregnancy and childbearing age is not recommended to prevent possible deformation and displacement of the filter and the risk of fetal teratogenicity in pregnant women who need to take long-term anticoagulant drugs such as warfarin sodium tablets.
3.4 Topical Chinese medicine treatment
Clinical application of Chinese herbs such as mannitol and ice chips, which are beneficial to water and swelling, can relieve the swelling of the limb and improve the symptoms. There are no reports of teratogenicity, but further clinical studies should be conducted to determine their safety and effectiveness.
4 Prevention
Strengthening the management of pregnancy and early application of medical compression stockings can reduce the incidence of post-thrombotic sequelae. Pregnant women with a history of DVT due to a non-inherited hypercoagulable state can be closely monitored without prophylactic pharmacological anticoagulation if they are not at risk of recurrence prenatally. Prophylactic anticoagulation is recommended throughout pregnancy and the puerperium for pregnant women with an inherited hypercoagulable state, regardless of the history of onset [21]. In pregnant women with high-risk factors, the cause is removed. According to the body mass index of pregnant women to regulate the growth of body mass during pregnancy, timely correction of poor dietary habits such as high sugar and high fat, appropriate activities to avoid excessive increase in body mass; timely treatment of gestational hypertensive diseases to reduce the slow flow of blood due to blood viscosity; for severe pregnancy vomiting or other diseases, timely rehydration to avoid dehydration caused by fasting, resulting in blood concentration. Strictly grasp the indications for cesarean delivery, reduce the chance of injury and bed rest, and get down to the ground as soon as possible after delivery to promote venous return of lower limbs. For those who are not suitable to move on the ground due to some diseases, they should turn over regularly and massage the lower limbs to promote venous blood circulation.
5 Conclusion
In women with lower extremity deep vein thrombosis during pregnancy, termination of pregnancy should be based on the principle of informed consent. The conditions of application of inferior vena cava filter placement (if anticoagulation is contraindicated) should be strictly controlled in the context of the patient’s gestational week, and should not be abused, and permanent filters are generally not recommended unless necessary; thrombolytic drugs are not routinely recommended and should be contraindicated before delivery; oral warfarin anticoagulation is generally considered contraindicated in pregnancy and may be used during lactation on an elective basis. Obstetricians and vascular physicians should fully understand the etiology and diagnosis of DVT, focus on prevention during pregnancy, strengthen the work of education, and provide timely examination, early diagnosis, and active and sound treatment for those with symptoms in order to maximize the protection of maternal and fetal safety and reduce the occurrence of complications and long-term sequelae.
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