Review Article: Deep Vein Thrombosis in Pregnancy

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LITERATURE REVIEW

Trisha Alya Rahmi1, Fandy Winasis1, Lisa Elfira1, Ravenska Theodora1, Andy Kristyagita2 1. General Practitioner in RSUD Dr. M. Ashari Pemalang, Central Java, Indonesia

2. Departement of Cardiology ini RSUD Dr. M. Ashari Pemalang, Central Java, Indonesia Corespondence:

Abstract

Deep vein thrombosis (DVT) and pulmonary embolism are two examples of venous thromboembolism..The term DVT describes the development of a blood clot in the femoral and saphenous deep veins of the lower and upper extremities (more usually in the lower limbs). During pregnancy, DVT is more frequent than pulmonary embolism. Pulmonary embolism is the most severe complication of DVT in pregnant women and is still one of the top causes of maternal death in the industrialized world. Complete blood count, coagulation screen, urea, electrolytes, and liver function tests should be performed in the initial evaluation of the pregnant patient before starting therapeutic anticoagulation for VTE to rule out renal or hepatic dysfunction, which are risk factors for anticoagulant medication. However, because venous thromboembolism in pregnancy and deep vein thrombosis (DVT) are closely related in terms of prevalence, risk factors, and treatment choices, information about venous thromboembolism in pregnancy has also been presented when pertinent or when DVT data are not available. In order to manage and diagnose DVT in pregnant women, the current study intended to consolidate and present the most recent guidelines.

Keywords:

Fandy Winasis, email : [email protected]

Deep vein thrombosis, preganancy, anti-coagulant

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INTRODUCTION

Deep vein thrombosis (DVT) and pulmonary embolism are two examples of venous thromboembolism. The term DVT describes the development of a blood clot in the femoral and saphenous deep veins of the lower and upper extremities (more usually in the lower limbs). These clots have the potential to move to the right ventricle, the IVC, and ultimately the circulation. If they are inserted into the pulmonary artery, they can block the veins and result in Pulmonary Embolism (PE). DVT is therefore acknowledged as one of the fundamental causes of PE.

Compared to women who are not pregnant, pregnant women are more concerned about this issue. One risk factor for DVT is pregnancy, and some women are more likely than others to contract the condition. Pre-existing DVT, acquired thrombophilia, prior DVT from major surgery, ongoing medical conditions (such as cancer and heart disease), and high-risk inherited thrombophilia are the most significant risk factors for DVTduring pregnancy.

During pregnancy, DVT is more frequent than pulmonary embolism. However, because venous thromboembolism in pregnancy and deep vein thrombosis (DVT) are closely related in terms of prevalence, risk factors, and treatment choices, information about venous thromboembolism in pregnancy has also been presented when pertinent or when DVT data are not available. Pulmonary embolism is the most severe complication of DVT in pregnant women and is still one of the top causes of maternal death in the industrialized world. A increased risk of embolic consequences and the persistent post-thrombotic syndrome is linked to pregnancy-related DVT. In order to manage and diagnose DVT in pregnant women, the current study intended to consolidate and present the most recent guidelines

EPIDEMIOLOGY

About four times as likely to occur in pregnant women as in childbearing women who are not pregnant. It is at its peak in the third trimester and continues to rise for the first six weeks after delivery. The incidence of DVT among pregnant women is around 1.1 per 1000 deliveries. The risk of pregnancy related DVT is approximately three times higher than pregnancy related pulmonary embolism.

Endothelial damage in the pelvic vessel occurring durimg delivery might increase the relative risk of postpartum thromboembolic event at 6 – 12 weeks period after delivery. Most of the event-approximately 80% - occur in the first 3 weeks after delivery.

RISK FACTOR

Vein thromboembolism (VTE) has been found to occur more frequently in pregnant women 4 to 50 times more frequently than in nonpregnant ones. Pregnancy is a risk factor in and of itself for the development of VTE. The risk of DVT during pregnancy has been shown to be higher in certain situations. These include lupus, heart disease, sickle cell disease, genetic or acquired thrombophilia, prior thrombosis, the antiphospholipid syndrome, and thrombophilia. The

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requirement for preventive anticoagulation should be addressed when these are present. Age 35 and older, null parity, repeated gestations, obesity and inactivity, smoking, and null parity all raise risk by 1.5–2 fold. There is apparently an association between gestational diabetes and thrombosis, according to two studies by James et al. and Jacobsen et al. In the puerperium, post-partum infection increases the risk of thrombosis by 4-fold and cesarean delivery increases the risk 2-fold.

In all phases of pregnancy, the risk of VTE is higher compared to those in the general population who are not pregnant. Most studies indicate that VTE is distributed equally throughout the three trimesters of pregnancy. However, a third trimester prevalence (60%) and a first trimester predominance (50%) were reported in two large contradicting retrospective studies, respectively. Age 35 and older, null parity, repeated gestations, obesity, inactivity, and smoking all increase the risk of VTE antepartum by 1.5–2 fold. Varicose veins, inflammatory bowel disease, urinary tract infection, diabetes, and hospitalization for reasons other than childbirth (especially those lasting more than 3 days) are additional risk factors.

VTE is two to five times more prevalent postpartum than it was during the antepartum stage. The risk is greatest in the first six weeks postpartum, and even while it continues for another 12 weeks, the absolute risk after that seems to be modest. Data from a five-year retrospective crossover-cohort analysis of an insurance claims database with approximately 1.7 million women that looked at rates of thrombosis during the first year after delivery best illustrate this persisting (albeit reduced) postpartum thrombotic risk. The majority (68%) of reported thrombotic events were VTE, followed by stroke (28%) and myocardial infarction (4%). The risk of thrombosis peaked in the first six weeks postpartum (25 versus 2 per 100,000 deliveries; odds ratio [OR] 11, 95% CI 8-15) compared to rates at one year, and then decreased to lower but still high rates from weeks seven to twelve (6 versus 3 per 100,000 deliveries; OR 2, 95% CI 1.5-3.1). By 13 to 18 weeks, rates were comparable to the general population (3 versus 2 per 100,000 deliveries; OR 1.4, 95% CI 0.9- 2.1).

Patients with preeclampsia had a higher prevalence of venous thrombosis in the postnatal period, according to studies by Jacobsen et al. and Lindqvist et al. Emergency cesarean sections, stillbirths, varicose veins, pre-eclampsia/eclampsia, postpartum infections, increased maternal age >35 years, younger gestational age (36 weeks), obstetric hemorrhage, obesity, and medical comorbidities were among the many factors that went into the model and were associated with the highest risk.

Lower extremity DVTs in pregnancy are typically left-sided. Additionally, although DVT is still most frequently seen in the proximal veins, the prevalence of pelvic vein thrombosis is much higher during pregnancy and the puerperium (eg, femoral vein). There is no evidence to suggest that upper extremity DVT is more common during pregnancy or puerperium.

One study found 58 solitary left lower extremity DVTs, two bilateral DVTs, and no isolated right lower extremity DVTs among 60 pregnant women having a first episode of VTE. In a different retrospective study of 124 pregnant women with a diagnosis of DVT, 96

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patients reported involvement of the left leg in 88 percent of those for whom the affected side was known. This unusual pattern has been associated with greater venous stasis in the left leg caused by compression of the left iliac vein by the right iliac artery and inferior vena cava by the gravid uterus.

Compared to the general population, pelvic vein DVT is more frequently diagnosed during pregnancy. However, it is unknown how common it really is during pregnancy. This might be because pelvic vein thrombosis cannot be accurately diagnosed using compressive proximal vein ultrasonography. When compared to non-pregnant women, isolated pelvic vein DVT rates were greater in an analysis of the DVT-Free Registry that included 5451 consecutive patients with ultrasound-confirmed DVT (12 percent and 11 percent versus 1 percent, respectively). 64 percent of proximal DVTs were limited to the iliac and/or femoral vein, according to a retrospective analysis of 124 pregnant women.

The most significant risk factors for DVT during pregnancy are thrombophilia, either inherited or acquired, or a history of prior DVT. According to the data that is currently available, pregnant women who have experienced venous thrombosis in the past are more likely to have it occur again. The exact recurrence rates are unknown, despite the fact that the risk is thought to be between 2 and 10%.

Low levels of endogenous anticoagulants like protein C, protein S, and antithrombin III were associated to a moderate risk. Given the background incidence of VTE during pregnancy, which is roughly 1 per 1,000 deliveries, it is clear that the absolute risk of VTE in women without a prior event is still low for those who have the most prevalent hereditary thrombophilias. Less studies have been conducted on acquired thrombophilias, however chronic APLAs (lupus anticoagulants or anticardiolipin antibodies) are probably associated to an increased risk of VTE due to pregnancy. If there is a previous history of VTE, the American College of Obstetricians and Gynecologists (ACOG) recommends testing for antiphospholipid antibodies and inherited thrombophilias as well as scoring systems to aid with risk assessment.

The Lyon VTE risk score has been proposed by Dargaud et al. as a tool to provide a rational decision process for implementing safe and effective antepartum thromboprophylaxis in pregnant women at high risk of DVT. The Lyon score evaluates the risk of VTE during pregnancy based on three key parameters: previous history of VTE, known thrombophilia markers, and current risk factors associated with the current pregnancy. A point value is given to each item in each category in accordance with the level of risk that is believed to exist according to the literature. The idea of individualized medicine, which may be more successful and possibly more cost-effective than broad guidelines, is made possible by the use of instruments like this score system.

Pathophysiology DVT in Pregnancy

Pregnancy is defined as a prothrombotic condition due to hormonal changes, and the risk of VTE increases 5-50 times due to specific risk factors during pregnancy, compared to

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non-pregnant women. Virchow's triad: venous stasis, endothelial injury, and a hypercoagulable state, each feature might raise the risk of deep vein thrombosis during pregnancy.

1. Venous statis

Pregnancy-associated changes in venous capacitance and compression of large veins by the gravid uterus. The lower extremity veins of pregnant patients appear to be subject to increased stasis even before the uterus has significantly enlarged. Although blood volume and total venous return are supranormal in pregnancy, the linear flow velocity in the lower extremity veins is decreased due to hormonally induced dilation of capacitance veins, leading to venous pooling and valvular incompetence. These early modifications are enhanced by inferior vena caval and iliac vein compression by the gravid uterus. Assuming the left lateral decubitus position significantly increased the velocity in both lower extremities.

Venous stasis is caused by a hormonally driven drop in venous tone and uterine enlargement, which blocks venous flow. By weeks 25–29 of pregnancy, the venous flow velocity in the legs has decreased by around 50%. This lasts for around six weeks after delivery, after which normal venous velocities resume. The most typical location of DVT in women who are pregnant or recently gave birth is the left lower extremity (82%).^1,4 The left common iliac vein is compressed by the right common iliac artery, which is intensified by the growing uterus, for anatomical reasons.

2. Endothelial injury

Delivery is connected with vascular damage and alterations at the uteroplacental surface, which probably contribute to the increased risk of DVT in the immediate postpartum stage. Forceps, vacuum extraction, or surgical delivery can increase vascular intimal injury and amplify this phenomenon. During vaginal delivery, the risk of DVT increases by 6-11%

following pelvic vein endothelial damage due to Valsalva maneuver or venous hypertension.¹ It is possible for venous hypertension or the moment of birth to cause endothelial damage in the pelvic veins. In pregnancy and the puerperium, pelvic vein thrombosis, which is uncommon outside of pregnancy, causes 6–11% of DVT.

3. Hypercoagulability

Pregnancy is a hypercoagulable condition linked with progressive increases in several coagulation factors, including factors I, II, VII, VIII, IX, and X, along with a decrease in protein S.^1,2,4 A gradual rise in resistance to activated protein C is generally found in the second and third trimesters, and strong resistance to activated protein C. Activity of the fibrinolytic inhibitors PAI-1 and PAI-2 is increased during pregnancy, although total fibrinolytic activity may not be impaired.¹Following all the aforesaid modifications, it leads to a change in hemostatic condition, which in turn, raises the D-dimer and F1+2.

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A hypercoagulable state is gradually developed during pregnancy. Pregnancy is connected with hypercoagulability. Exists a procoagulant levels rising with anticoagulant levels falling, and fibrinolytic activity in preparation for delivery as well as venous stasis.

Around labor, the pelvic also experiences vascular injury. and transmission.

DVT diagnosed in Pregnancy History and Physiscal Examintaion

It is crucial to diagnose DVT in pregnant women as soon as possible since, if untreated, it can lead to Pulmonary Embolism. The most common symptoms like leg edema, tachycardia, tachypnea, and dyspnea that lead to suspicion of DVT in non-pregnant people frequently already exist as a result of physiological changes during pregnancy. The use of clinical prediction tools (Wells’

score and modified Geneva Score) for estimating the pre-test probability of DVT is not validated in pregnant women.

Swelling and pain in the extremities are the most frequent DVT presentation signs.

Erythema and difficulty of walking are further symptoms. Pregnancy increases the risk of isolated DVT in the iliac veins. The symptoms of isolated iliac vein thrombosis can include back pain, leg edema, and stomach pain. Until the thrombus advances distally into the femoral veins, which causes pain and edema throughout the entire affected leg, these vague symptoms are frequently neglected.

Chan et al. suggested a clinical prediction tool for first-trimester pregnant women to help in DVT diagnosis. It includes three clinical criteria: (i) left lower extremity symptoms, (ii) difference in calf circumference of more than 2 cm and (iii) presentation in the first trimester, collectively called the LEFt rule. When compressive ultrasound (CUS) is utilized as the initial diagnostic method and the results are unclear, the LEFt rule might be applied.

Laboratory Testing D-dimer

D-dimer levels rise during pregnancy, which causes a high rate of false-positive tests. As a result of the pregnancy-related hypercoagulable condition, this shows enhanced thrombin activity and increased fibrinolysis after fibrin formation throughout the pregnancy. This test is therefore non-

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specific and unreliable, but if combined with clinical probability ratings, the use of D-dimer normal ranges unique to pregnancy might increase the test's clinical value.

Supporting Investigation

The use of non-ivasive and non-ionizing imaging is preferred when diagnosing pregnant individuals.

Currently, ultrasound and magnetic resonance imaging are two such non-invasive techniques (MRI).

When MRI is not an option, contrast-enhanced computed tomography (CT) may be used to identify pelvic DVT. However, this method is not optimal and is rarely advised because it exposes both the mother and the fetus to radiation.

Compression ultrasonography (CUS), the first-line diagnostic method for the evaluation of DVT in pregnancy, combines real-time imaging of the deep veins with venous compression. It is advised that the iliofemoral veins be subjected to a Doppler evaluation as part of the compression ultrasonography.

In cases of symptomatic femoropopliteal DVT in the general population, CUS diagnostic accuracy is excellent. However, the anatomical position of the iliofemoral veins and the size of the gravid uterus make CUS difficult in cases of pelvic vein thrombosis, which is most frequently seen in pregnant women. The sensitivity for the diagnosis of iliac vein DVT in pregnancy is increased when CUS combined with the Valsalva maneuver, as well as with the evaluation of venous flow changes with respiration. The iliac veins should be included in lower limb CUS for investigation of suspected DVT, according to recent American Society of Hematology guidelines on the management of venous thromboembolism in pregnant women. Women with clinical symptoms strongly suggestive of DVT who have no thrombus identified on standard CUS may require further imaging.

Management

One of the most significant and difficult challenges in healthcare is pregnancy. Making decisions on patient care can be extremely difficult because any complications could endanger both the mother and the fetus. Inappropriate pharmaceutical use is linked to very serious adverse effects such fetal hemorrhage, embryopathy, or bleeding during vaginal birth. Therefore, when employing treatment regimens for pregnancy-related VTE, a few fundamental ideas should be kept in mind.

These principles include the capacity to utilize a drug regimen for both primary and secondary treatment of thrombosis throughout pregnancy and postpartum, as well as 1) the right efficacy of the regimen and 2) the regimen's safety for mother and fetus. The treatments utilized when pregnant are briefly explained in the section below.

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Initial Assesment

Complete blood count, coagulation screen, urea, electrolytes, and liver function tests should be performed in the initial evaluation of the pregnant patient before starting therapeutic anticoagulation for VTE to rule out renal or hepatic dysfunction, which are risk factors for anticoagulant medication. Because pregnancy and the presence of thrombus affect several aspects, a thromophilia screen should not be done, and the results will not change how VTE is managed acutely.

Anticoagulan in Pregnancy

All patients with VTE, with the exception of high-risk patients, such as those who have a history of recent major surgery, are treated with anticoagulants as the first line of treatment. In general, heparin and heparin-like medications (such as unfractionated heparin (UFH), low molecular weight heparins (LMWH), danaparoid sodium, and pentasaccharide) are used as anticoagulants in the prevention and treatment of VTE (in all patients). Anticoagulants are among the most effective treatments used to stop the consequences of DVT in pregnant patients. However, each medication has particular benefits and risks during pregnancy that must be considered while selecting a medication.

Table 1 Differences between LMWH and Unfractionated Heparin

Low Molecular Weight Heparin Unfractionated Heparin Fetus/Newborn  Does not cross placenta

 No evidence of

teratogenicity or increased risk of fetal bleeding

 Safe while breastfeeding

 Does not cross the placenta

 No evidence of

teratogenicity

Monitoring  Consider baseline platelet count, serum creatinine

 Routine monitoring of anti- Xa levels not recommended

 Consider periodic platelet count as indicated

 Consider baseline platelet count and monitor for HIT

Recomendation  LMWH is safe and effective for prevention of VTE in

 Not routinely recommended

as first line

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pregnancy

 Agent of choice for antenatal and postnatal thromboprophylaxis

 Reduce dose if renal impairment or consider UFH

 Consider increased dose if antithrombin deficiency

thromboprophylaxis in pregnancy

 Consider switching from LMWH to UFH prior to onset of labour/planned birth

Table 2 Agent Anti Coagulant Consideration

Agent Consideration

Warfarin  Vitamin K antagonist that is

teratogenic especially in the first trimester

 Crosses placenta and may cause fetal haemorrhage

 Seek specialist advice before use during pregnancy

 For women with mechanical heart valves

May be indicated based on individual assessment of risk and benefit

Recommendation incorporates the woman’s values and preferences Seek specialist advice

 Consider postnatal only if prolonged

thromboprophylaxis/treatment indicated

Fondavarinux  Discuss with a team experienced in

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their use before commencement

 Limit fondaparinux to women with severe allergic reactions to heparin who cannot receive danaparoid

 Withhold for 5 days prior to birth (due to long half-life)

Aspirin  No controlled trials on the use of

aspirin for thromboprophylaxis in pregnancy

 The American College of Physicians recommend against the use of aspirin as sole agent for VTE prophylaxis in any pregnancy

 No adverse fetal or maternal outcomes were reported in a meta- analysis of large randomised controlled trials of low-dose aspirin for the prevention of pre-eclampsia in pregnancy

 Insufficient evidence to recommend routine use of aspirin for thromboprophylaxis in the antenatal or postnatal period

CONCLUSION

The term DVT describes the development of a blood clot in the femoral and saphenous deep veins of the lower and upper extremities (more usually in the lower limbs). Compared to women who are not pregnant, pregnant women are more concerned about this issue. deep vein thrombosis (DVT) are closely related in terms of prevalence, risk factors, and treatment choices, information about venous thromboembolism in pregnancy has also been presented when pertinent or when DVT data are not available. Pulmonary embolism is the most severe complication of DVT in pregnant women and is still one of the top causes of maternal death in the industrialized world. Complete

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blood count, coagulation screen, urea, electrolytes, and liver function tests should be performed in the initial evaluation of the pregnant patient before starting therapeutic anticoagulation for VTE to rule out renal or hepatic dysfunction, which are risk factors for anticoagulant medication.

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