Prevention and Treatment of Obstetric Venous Thrombosis (VTE)
This guideline has been reviewed and approved by the Maternal-Fetal Medicine Committee and the SOGC Committee
SOGC – Society of Obstetricians and Gynaecologists of Canada
Abstract
OBJECTIVE: To identify risk factors for perinatal venous thrombosis and to provide guidelines for risk assessment and preventive measures for thrombosis in women during pregnancy, as well as to provide diagnostic tests for venous thrombosis, and elements of acute and long-term treatment.
METHODS: To classify specific subgroups of women during pregnancy and to propose appropriate prevention programs. Xiao Jinchang, Department of Interventional Medicine, Affiliated Hospital of Xuzhou Medical College
RESULTS: Venous thrombosis is one of the important causes of mortality and morbidity in women during pregnancy and puerperium, and identifying the risk factors for its development and taking appropriate preventive measures can significantly reduce its incidence.
EVIDENCE COLLECTION: The Medline database was used to collect data, and relevant articles were screened while referring to the references of these articles.
RECOMMENDATION: Although there is a lack of evidence from Level I studies in women in pregnancy, there is ample evidence to support that prophylaxis significantly reduces the incidence of venous thrombosis in nonpregnant women. Many patients need to be considered for thromboprophylaxis based on risk assessment, including women with a prior history of VTE and a propensity for thrombosis on long-term anticoagulation, women with a prior history of VTE, women with a propensity for thrombosis who have never had a VTE, and women who have undergone cesarean delivery. Treatment with low-dose regular heparin is effective in reducing the incidence of VTE. Low-molecular heparin in pregnancy has been used to treat VTE, but experience is limited. Currently, low-dose plain heparin is the standard regimen for the treatment of VTE. After initial treatment with heparinization for VTE, maintenance anticoagulation, or continuous anticoagulation for a total of 3 months, is required throughout pregnancy and 6-12 weeks postpartum.
Brief description.
Venous thrombosis (VTE) is a major cause of maternal morbidity and mortality. The incidence of VTE in pregnancy ranges from 0.5 to 3 per 1000 pregnancies, with no significant difference in the incidence in early, mid- and late-term and postpartum periods. There are several high-risk factors for the development of VTE in pregnancy, and once VTE occurs, it is important to treat it as soon as possible so as to reduce the death rate from pulmonary embolism associated with it, as well as the incidence of DVT expansion and post-embolization leg syndrome.
In women with a prior history of VTE, the rate of recurrent VTE can be as high as 12%. Prophylactic treatment reduces the morbidity and mortality of the disease more than treatment after the onset of VTE.
High risk factors
There are a number of high-risk factors for the development of thromboembolic disease in pregnancy. The risk factors for the development of thromboembolic disease in women without pregnancy complications are detailed in Table 1
Table 1 High-risk factors associated with pregnancy
Hypercoagulable state
Blood stagnation
Endothelial damage
Increased coagulation factors II, VII, VII, VIII, IX, X, XII, and fibrinogen
Increased venous dilatation and decreased venous tone
Vascular endothelial damage during cesarean section or vaginal delivery
Increased platelet aggregation
50% reduction in venous blood flow to the extremities of the lower extremities in late pregnancy
Decreased plasma protein S, tissue-type fibrinogen, factor XII and XIII
Enlarged uterus affects venous return
Increased resistance to activated plasma protein C
Normal or decreased antithrombin
Risk factors for thromboembolism other than pregnancy itself are shown in Table 2
Table 2 Other risk factors
Previous history of VTE
Age >35
Obesity
Infection
Prolonged bed rest or braking
Shock/dehydration
Cesarean delivery
Vaginal surgery assisted delivery
Intrauterine device (IUD)
Peripartum pelvic surgery
Tendency to thrombosis
Congenital – plasma protein C and S deficiency
Resistance to activated protein C
(Leidendi factor V)
Antithrombin deficiency
Thrombocytopenia
Thrombospondin gene variants
Fibrinogen deficiency
Acquired-antiphospholipid syndrome
Nephrotic syndrome (reduced antithrombin activity)
Other risk factors for thrombotic predisposition to thrombosis to be further investigated
Thrombophilic tendency is a congenital or acquired coagulation abnormality that predisposes the body to venous thrombosis. The major risk factors for congenital thrombotic predisposition are detailed in Table 2, and just as congenital thrombotic predisposition itself is a polygenic disorder, there can be multiple factors that contribute to a woman’s congenital thrombotic predisposition. Increased thrombosis is also associated with an acquired thrombotic predisposition, such as antiphospholipid syndrome.
Congenital and acquired thrombotic tendencies often coexist, and there are multiple factors that can lead to an increased risk of VTE.
It should be noted that women with both antiphospholipid syndrome and hyperhomocysteinemia have a significantly increased risk of venous thrombosis and should therefore be treated with daily oral low-dose aspirin.
Many women with a predisposition to thrombosis are asymptomatic, but screening tests for thrombotic predisposition should be performed in any pregnant woman with a personal or family history of VTE, especially if VTE occurs in the absence of other recognized risk factors, or if VTE has occurred during pregnancy at sites other than the pelvis or lower extremities. There is increasing evidence that women with the following pregnancy comorbidities also have a significantly increased propensity for thrombosis, such as late miscarriage, hypertensive disorders of pregnancy, and FGR, and women with a history of these pregnancy comorbidities should also be screened for a propensity for thrombosis.
Although there are many risk factors for the development of VTE during pregnancy, it should be noted that the majority of VTEs occur without the characteristic manifestations of those risk factors. A prudent physician should be on high alert for thromboembolic disease and should perform as thorough a workup as possible once signs and symptoms are identified, even if the patient is not at high risk for VTE.
Obstetrics-related thromboprophylaxis
The treatment of thrombosis is still controversial. The target, timing, and approach to prophylactic treatment of VTE are uniform, and the extent of anticoagulation therapy should depend on the specific risk factors for thrombotic tendencies in each individual.
a)
Women with a previous history of VTE with a known propensity for thrombosis who are on long-term anticoagulation therapy.
Regular anticoagulation therapy is recommended throughout pregnancy and for 6-12 weeks postpartum, after which previous anticoagulation therapy should be restarted. The specific treatment regimen is described in “Long-term Treatment of VTE in Pregnancy” and should be adjusted according to individual thrombotic tendencies.
b)
Women with a previous history of VTE.
The recurrence rate of VTE in this group of women is as high as 12%, but there is still controversy as to whether this group of women should be routinely treated for prophylactic thrombosis. There is a lack of prospective studies on whether prophylactic treatment of women during pregnancy reduces the recurrence of VTE. Based on the results of relevant studies in non-pregnant women, the following treatment regimens should be used in pregnant women with a previous history of VTE and anticoagulation should be maintained until at least 6 weeks postpartum.
Prophylactic regimen.
Normal heparin: 5000u subcutaneously every 12 hours, maintained throughout pregnancy.
Regular heparin: early pregnancy: 5000u subcutaneously every 12 hours; middle pregnancy: 7500u subcutaneously every 12 hours; late pregnancy: 10000u subcutaneously every 12 hours.
The rationale behind this protocol is that as the gestational weeks increase, the amount of heparin needs to be increased accordingly to achieve heparinization.
Low molecular heparin (LMWH)
Dalteparin sodium (Farnesamine): weight 71 Kg: 7500 IU subcutaneously once daily.
Enoxaparin: 40mg subcutaneously once daily.
The evidence for the routine application of the currently recommended LMWH regimen is not yet sufficient.
If the patient’s previous VTE is not related to pregnancy and exogenous hormone use, it is also possible to intensify clinical monitoring during pregnancy only, while using anticoagulation therapy for 6 weeks postpartum.
Women with a propensity for thrombosis but no previous VTE
The management of these patients is controversial and there are no adequate prospective studies showing the effectiveness of thromboprophylaxis in these patients. Because the risk factors for VTE vary among individuals, treatment management should also depend on the specific cause of thrombotic tendency. If the risk factor for VTE is antithrombin deficiency present throughout pregnancy, prophylactic anticoagulation therapy should be initiated once pregnancy is diagnosed and continued through the puerperium. Women with multiple risk factors for thrombotic tendencies are considered to be at higher risk for DVT and should also be treated as described above. In addition, VTEQ due to plasma protein C and S deficiency occurs in the puerperium, so anticoagulation therapy should be initiated at delivery or after delivery and maintained until 12 weeks postpartum.
For acquired thrombotic tendencies, such as antiphospholipid syndrome, the currently recommended prophylactic treatment regimen is low-dose aspirin combined with prophylactic heparin therapy.
This group of women should go to a specialized treatment and treatment regimen with an evidence level of III.
Propensity for puerperal thrombosis after cesarean section
There is no prospective research evidence regarding prophylactic thrombosis treatment after cesarean section to reduce the incidence of VTE. In a report, the Royal College of Obstetricians and Gynaecologists RCOG in the United Kingdom recommended postpartum prophylactic thrombosis treatment for women with an intermediate-high risk of VTE associated with cesarean delivery. Prophylactic treatment should be considered in the presence of high-risk factors such as previous VTE, known propensity for thrombosis, prolonged bed rest, or obese patients. Treatment should be started immediately after delivery of the newborn during cesarean section.
Regular heparin: 5000u subcutaneously every 12 hours until full bed mobility.
Low molecular heparin: for example: enoxaparin 20mg subcutaneously once daily.
Side effects of heparin therapy
Heparin-induced thrombocytopenia is due to heparin-dependent IgG antibodies. This complication is uncommon, with an incidence of about 3%, and occurs mostly 6-12 days after the start of heparin therapy. Thrombocytopenia may occur more rapidly if the patient has been previously treated with heparin. The risk of fatal hemorrhage is generally low, about 2-10%, but patients treated with plain heparin have a slightly increased risk of mild-to-moderate bleeding. Petechiae at the injection site are most common, but their occurrence can be reduced by proper training in injection technique. Osteoporosis is a dose-dependent complication related to the course of treatment. Allergy is a common complication during the use of common heparin. Regardless of the reason, anticoagulation in women who cannot use heparin should be performed by a hematologist.
Low molecular weight heparin (LMWH)
LMWH has limited experience in obstetric use. LMWH can be administered once or twice a day, depending on the weight of the pregnant woman, because of its anticoagulant effect, and does not require excessive monitoring during use. lMWH does not pass through the placenta and has been shown in animal studies to be non-teratogenic. bleeding does not tend to occur during LMWH use, but this still needs to be confirmed in large sample trials. platelets due to LMWH The incidence of platelet reduction and osteoporosis caused by LMWH is significantly lower than that of ordinary heparin, but its price is significantly higher than that of the latter. The use of LMWH in pregnancy remains to be studied in large clinical trials.
In North America, plain heparin is still the standard of care for anticoagulation during pregnancy. There is insufficient evidence that LMWH is superior to plain heparin in the prevention and treatment of obstetric VTE.
Warfarin (neo-dicoumarin)
Warfarin is contraindicated in pregnancy because of its adverse effects on the fetus. In early pregnancy, it can cause fetal warfarin syndrome (nasal bone hypoplasia, punctate epiphysis, abnormal eye development, and developmental delay). It can cause abnormalities in central nervous development throughout pregnancy. Neo-dicoumarin use during pregnancy also significantly increases the risk of fetal and neonatal hemorrhage.
Diagnosis of VTE
Diagnosis of deep vein thrombosis
Deep vein thrombosis (DVT) should be highly guarded during pregnancy and the puerperium. Deep vein thrombosis mostly occurs in the iliofemoral vein and the deep veins of the lower extremities, of which the left lower extremity accounts for 90%. The diagnosis is mostly clinical and objective and should be examined and diagnosed by possible non-invasive methods.
Venous angiography is the gold standard for the diagnosis of deep vein thrombosis. However, this invasive method of examination requires radiography, which is detrimental to the mother and fetus. Restrictive venography, which covers the abdomen and pelvis of the pregnant woman with a lead apron, can reduce the radiation exposure to the fetus to less than 0.05 rads, but the development of the iliac veins is somewhat compromised. If possible, restrictive venography should be used whenever possible.
Continuous impedance volume tracing (IPG) detects impedance changes caused by changes in blood flow to the limb. It allows for the exclusionary diagnosis of deep vein thrombosis, but its sensitivity and specificity are significantly reduced due to compression of the iliac veins in late pregnancy. In non-pregnant women, color Doppler ultrasound is 95% accurate for venography of N and femoral vein thrombosis. The thrombus can be seen at the embolic site of the vessel, and external compression can make it clearer. However, the internal compression from the pregnant uterus limits the sensitivity and specificity of detection during pregnancy.
There is a lack of research data regarding the application of color Doppler ultrasound for the detection of deep vein thrombosis during pregnancy and the evaluation of the safety of discontinuing anticoagulants in patients with multiple color Doppler negative pregnancies. However, in many medical centers, this simple, noninvasive test is used as the test of choice in women with suspected DVT pregnancies.
Both color Doppler ultrasound and IPG have low sensitivity for the diagnosis of lower extremity DVT. Repeat testing is required in patients with a high clinical suspicion but a negative screening test. If multiple tests are negative, treatment may be suspended. If noninvasive testing is not possible or its results are inconclusive, venous angiography should be performed.
The use of radioiodine-labeled fibrinogen scans in pregnancy remains controversial. Anticoagulation should be initiated if a venography photograph or a single noninvasive test suggests thrombosis.
Diagnosis of pulmonary embolism
As in nonpregnant women, the signs and symptoms of pulmonary embolism in pregnancy are nonspecific. Based on the atypical clinical presentation of pulmonary embolism and the importance of early anticoagulation, diagnostic testing should be performed whenever possible once suspected. Pulmonary angiography is the gold standard for the diagnosis of pulmonary embolism, but is invasive and has a high number of complications.
Chest X-rays and ventilation/perfusion scans (V/Q scans) are the first line of investigation and the effects of radiation on the fetus are very limited on V/Q scans. If the patient has no typical clinical presentation and the V/Q scan is normal, the diagnosis of pulmonary embolism can be ruled out. If there is a high clinical suspicion and the V/Q scan is highly probable, pulmonary embolism should be diagnosed. If pulmonary embolism is possible and the V/Q scan is moderately likely, further color Doppler or IPG should be performed to rule out pulmonary embolism. If these findings are normal but pulmonary embolism is still highly suspected clinically, further pulmonary angiography should be performed.
Because of the side effects of long-term anticoagulation therapy and hormonal therapy, further investigations should be performed to clarify the diagnosis in any patient with suspected VTE.
Treatment of VTE in pregnancy
The level of evidence-based medical evidence for the treatment of VTE in pregnancy is level II
Initial treatment.
A basic complete blood count, including platelet count, activated fractionless thromboplastin time APTT should be obtained prior to treatment.
Normal heparin: Initial dose is 5000 iu and subsequently maintained at 30,000 iu every 24 hours.
APTT was rechecked 6 hours after each dose.
Maintain APTT in the therapeutic range (1.5-2.5 times the normal control value).
Repeat every 24 hours.
Plasma heparin levels were measured and maintained at 0.2-0.42u/ml or APTT at 60-85 seconds.
Table 3 shows the specific procedure for the intravenous administration of plain heparin.
Table 3 Intravenous administration of plain heparin protocol (40 IU/ml heparin drip)
APTT (sec)
Dosage
Precautions
120
Discontinued 60 minutes 3840IU/24 hours IV
Repeat APTT every 6 hours
Achieving adequate anticoagulation in the first 24 hours is particularly important, and initial intravenous plain heparin therapy should be maintained for at least 5-7 days
Long-term maintenance therapy
1.
Normal heparin
Dose adjustment after 6 hours of the first dose to maintain APTT at therapeutic levels (1.5-2.5 times normal control values or plasma heparin levels at 0.1-0.2iu).
2. Low molecular heparin
50-70Kg body weight female
Tinzaparin 175IU/Kg subcutaneously once daily.
Dalteparin: 200IU/Kg subcutaneously once a day.
Dose adjustment to maintain anti-Factor Xa activity level of 0.3-0.75 at 4 hours post-injection.
Routine monitoring is not required, but a separate anti-Factor Xa activity level checked during pregnancy provides assurance that the dose used is in the clinical range. Two daily applications seem to be more effective during pregnancy, especially in late pregnancy.
Treatment should be maintained throughout pregnancy and for 6-12 weeks postpartum, or anticoagulation should be maintained for 3 months.
Application of heparin during labor
If prophylactic antithrombotic therapy is administered, heparin should be discontinued as soon as there are regular contractions. In case of elective cesarean delivery, the last dose of heparin should be administered 6-8 hours prior to the cesarean section.
The half-life of LMWH is 4 hours. Therefore, each center should develop a protocol for the use of LMWH in labor, and if LMWH is used for prophylaxis, it should be discontinued 24 hours before induction of labor. If maintenance therapy is required, it should be changed to subcutaneous heparin maintenance several weeks before delivery according to the specific protocol of each center. The use of local anesthesia should be
be individualized, and the risk of subdural hematoma is not significantly higher if coagulation is normal or if heparin levels are below 0.4 IU/ml.
If heparin therapy is to be maintained throughout labor, heparin should be administered intravenously and the dose adjusted according to the APTT value. These patients have a slightly increased risk of hematoma after perineal scoliosis and vaginal tearing, but not an increased risk of postpartum hemorrhage. Local anesthesia is contraindicated in this group of patients.
If the patient’s APTT is significantly higher than therapeutic levels, fisetin should be given to counteract heparin. 1 mg of fisetin will neutralize 100 U of heparin. However, the intravenous dose of fisetin should not exceed 50 mg in 15 minutes.
Postpartum management
Heparin can be administered continuously for 4-12 hours after delivery. Treatment options depend on the patient’s clinical presentation, the presence of high-risk factors, and the mode of delivery.
If maintenance anticoagulation therapy is required after delivery, it can be maintained with an initial dose of intravenous heparin followed by oral warfarin, or it can be continued with subcutaneous heparin.
Whether heparin or oral warfarin is used for maintenance after delivery depends on the individual patient and the physician’s preference. Neither regimen interferes with breastfeeding.
Warfarin therapy should be started on the first day after delivery, with 7.5 mg/day orally on days 1-2, maintaining an International Normalized Ratio (INR) in the therapeutic range of 2-3 times. Warfarin oral therapy should be overlapped with IV heparin therapy for 4-5 days until the INR is greater than 2 for 2 consecutive days, then IV heparin should be discontinued.
The use of LMWH in lactating women has not been reported extensively.
All pregnant women without high-risk factors but who develop VTE should be screened for thrombotic tendency within 12 weeks postpartum. Molecular biology screening for thrombotic predisposition can be performed during pregnancy, but because pregnancy itself may lead to altered levels of antithrombin and plasma proteins C and S, the results of relevant laboratory tests are not always reliable and need to be reviewed postpartum.
Women with a confirmed thrombotic tendency requiring long-term treatment should be referred to a specialist at the relevant treatment center.
Non-pharmacological treatment
Compression stockings
Leg edema can be reduced by elevating the lower extremities and using graduated compression stockings. Compression stockings may reduce the incidence of post-thrombotic leg syndrome. However, there are no controlled studies on the use of compression stockings during pregnancy and postpartum.
Avoidance of sedentary activity There is insufficient evidence to support or oppose the use of this approach.